Archief Roodbont

colonoscopy

2012-02-11T01:54:00.000-08:00

Summary and Comment

Same-Day vs. Split-Dose Bowel Preparation for Afternoon Colonoscopy

Same-day preparation produced better cleansing, with fewer adverse events and less disruption of daily activities.

Several studies have clearly shown that split-dosing bowel preparations (giving half the preparation the evening before colonoscopy and half on the morning of the procedure) is superior to day-before dosing with regard to both cleansing efficacy and tolerability (JW Gastroenterol Jun 24 2011). In other studies, same-day dosing has provided better cleansing compared with evening-before dosing for afternoon colonoscopy (JW Gastroenterol Dec 3 2010) and equivalent cleansing and better tolerability compared with split-dosing (JW Gastroenterol Oct 1 2010). To further explore the merits of this strategy, researchers in the U.K. conducted a nonrandomized, single-blind study of same-day versus split-dose bowel-cleansing regimens in 227 patients who underwent afternoon screening colonoscopy.

In the split-dose group, 95 consecutive patients, recruited during a 6-month period, were given three sachets of sodium picosulphate at noon and 5:00 PM the day before the procedure and at 8:00 AM the morning of the procedure. In the same-day group, 132 consecutive patients, recruited during the succeeding 6-month period, were given sodium picosulphate at 7:00 AM and 10:00 AM the morning of the procedure.

The same-day group achieved better-quality bowel preparation than the split-dose group (P=0.005) and experienced fewer adverse events (P=0.002) and less disruption of daily activities (P<0.001). In addition, patients strongly preferred the same-day regimen.

Comment: This trial is the second to demonstrate a preference for same-day dosing for bowel preparation when patients are scheduled for afternoon colonoscopy. The study has certain weaknesses, in that it was not randomized and the split-dose regimen involved one dose being given at noon the day before colonoscopy (in most split-dose regimens, the first dose is taken the evening before the procedure). Nevertheless, the case continues to build for same-day bowel preparation when patients are scheduled for afternoon colonoscopy.

— Douglas K. Rex, MD

Published in Journal Watch Gastroenterology February 10, 2012

dementia

2012-02-10T01:27:00.001-08:00

Summary and Comment

Cognitive Decline Begins in Middle Age

The decline accelerated as years advanced.

Cognitive performance declines with advancing age. When this decline begins, however, is unclear. In this prospective cohort study, investigators estimated the 10-year decline in cognitive function in London civil servants (age, 45).

At baseline, the 5200 men and 2200 women were divided into five age groups (45–49, 50–54, 55–59, 60–64, and 65–70) and underwent cognitive testing. Cognitive outcomes were tests of memory, reasoning, vocabulary, and phonemic and semantic fluency. Participants were assessed three times during the next 10 years. All cognitive outcomes, except vocabulary, declined significantly in all baseline age groups with evidence for faster decline in older participants. For example, in men who were 45 to 49 at baseline, the 10-year decline in reasoning scores was 3.6%, whereas in men who were 65 to 70, it was 9.6%. (Similar results were obtained for women.)

Comment: In this prospective study, cognitive decline occurred in all age quintiles between 45 and 70 and was faster among older participants. Whether these results can be generalized is unknown, but the results have important public health implications. As the authors note, "research needs to identify the determinants of cognitive decline and assess the extent to which the cognitive trajectories of individuals are modifiable." One issue not addressed by the authors is the distinction between "normal aging" and the cognitive decline that heralds dementia syndromes.

— Paul S. Mueller, MD, MPH, FACP

Published in Journal Watch General Medicine February 9, 2012

dementia stroke

2012-02-09T04:30:00.001-08:00

Summary and Comment

Stroke Survivors Face a High Burden of Vascular Dementia

Delayed dementia after stroke is common and appears to reflect mostly vascular pathology.

Nearly one tenth of previously cognitively intact patients develop dementia in the year after stroke. The relative contributions of vascular injury and neurodegeneration to this cognitive decline remain unclear. Therefore, investigators conducted a longitudinal study of 355 older patients (aged 75) who were free of dementia 3 months after stroke. Participants underwent neuropsychological testing annually; the investigators identified incident cases of dementia according to standard DSM-IV criteria. The researchers performed brain autopsies in 50 of the 176 participants who died.

Over time, 142 patients (40%) withdrew from neuropsychological follow-up, but their baseline characteristics were similar to those of patients who continued follow-up. During an average follow-up period of nearly 4 years, dementia occurred in 85 patients (24%). The risk for dementia correlated with vascular risk factors but not APOE allele status. Of the 50 patients who came to brain autopsy, 23 had incident dementia, and vascular dementia was the neuropathological diagnosis in 18 (78%) of these cases.

Comment: Although this study was limited by a high rate of loss to follow-up, the reporting of autopsy results provides novel and important information about the causes of poststroke dementia. The findings suggest that poststroke dementia more often results from vascular than from neurodegenerative pathology. Whether treatment of vascular risk factors reduces the risk for poststroke dementia remains unknown, but the possibility of such a benefit adds to the value of secondary stroke prevention strategies — such as antihypertensive, antithrombotic, and statin drugs — that have already been proven to reduce morbidity and mortality from other forms of vascular disease.

— Hooman Kamel, MD

Published in Journal Watch Neurology February 7, 2012

potassium kalium

2012-02-09T04:17:00.000-08:00

Summary and Comment

U-Shaped Association Between Potassium Level and Acute-MI Mortality

Hypokalemia was associated with increased mortality, but so were serum potassium levels 4.5 mEq/L, suggesting that repletion measures should be moderated.

On the basis of small studies with surrogate outcomes, current practice guidelines for managing ST-elevation myocardial infarction (STEMI) recommend maintaining a potassium level greater than 4.0 mEq/L. To explore the association of potassium levels with mortality, investigators used the Cerner Health Facts database to conduct a retrospective cohort study involving 38,689 patients with biomarker-confirmed acute MI and one or more serum potassium level measurements during hospitalization (mean number of measurements, 5.9). Mean admission potassium level was 4.2 mEq/L, and levels remained fairly constant during hospitalization.

In-hospital mortality was 6.9%. Mortality was lowest (4.8%) in patients with postadmission potassium levels of 3.5 to <4.0 mEq/L and similar (5.0%) in patients with postadmission potassium levels of 4.0 to <4.5 mEq/L. However, in-hospital mortality was twice that rate (10%) in patients with postadmission potassium levels of 4.5 to <5.0 mEq/L and continued to rise with higher potassium levels. In-hospital mortality was also significantly increased (13%) at potassium levels less than 3.5 mEq/L. The U-shaped association persisted after multivariable adjustment and did not differ between patients who received potassium supplementation during hospitalization and those who did not. In-hospital ventricular fibrillation or cardiac arrest occurred in 1707 patients (4.4%); rates of these events were relatively flat across a wide range of potassium levels and were substantively increased only in patients with the lowest or highest mean potassium levels (<3 or 5.0 mEq/L).

Comment: These findings confirm that hypokalemia is associated with worse outcome in patients with acute myocardial infarction; moreover, they reveal a similar adverse effect of hyperkalemia. As editorialists note, the fact that mortality was not affected by potassium supplementation suggests that potassium level may be a marker of severity of illness or of other underlying conditions. Nonetheless, a serum potassium target somewhat lower and narrower than that currently recommended for these patients seems reasonable.

— Joel M. Gore, MD

Published in Journal Watch Cardiology February 8, 2012

K Kalium potasium hypokalemia

2012-02-09T04:16:00.001-08:00

SUMMARY AND COMMENT

U-Shaped Association Between Potassium Level and Acute-MI Mortality

February 8, 2012 | Joel M. Gore, MD

Hypokalemia was associated with increased mortality, but so were serum potassium levels 4.5 mEq/L, suggesting that repletion measures should be moderated.

Reviewing: Goyal A et al. JAMA 2012 Jan 11; 307:157

Scirica BM and Morrow DA. JAMA 2012 Jan 11; 307:195

statins

2012-02-03T15:18:00.000-08:00

January 30, 2012 (Boston, Massachusetts)— A large meta-analysis has shown that statins are as effective in women as in men for the reduction of cardiovascular outcomes and all-cause mortality, leaving investigators to conclude that statins should be used in all appropriate patients regardless of sex [1].

"There have been a large number of clinical trials looking at the benefits of statin use, but the ability for us to prove that the benefits extend to both men and women has been limited, in part because of numbers," lead investigator Dr William Kostis (Massachusetts General Hospital, Boston) told heartwire . "There have been studies that have shown benefits in men, and where they have shown a trend toward benefit in women they were unable to show a statistically significant difference. Because of this, we undertook the meta-analysis, and what we found was what we had hoped to find, and that was that the benefits of reducing cardiovascular outcomes and all-cause mortality extend to both men and women."

The meta-analysis, published in the February 7, 2012 issue of the Journal of the American College of Cardiology, included 18 clinical trials of statin therapy with clinical outcomes for men and women. The analysis included 141 235 subjects, including 40 275 women, from studies such as JUPITER, ALLHAT-LLT, ASCOT-LLA, Heart Protection Study, MEGA, PROVE-IT, and TNT, among others. Ten of the studies were secondary-prevention studies, and eight studies were designed as primary-prevention trials, although five of the primary-prevention studies did include a proportion of patients with cardiovascular disease.

In an editorial accompanying the study [2], Dr Lori Mosca (Columbia University Medical Center, New York) states that the finding of "no interaction by sex in this contemporary meta-analysis is concordant with prior meta-analyses that were limited by smaller numbers of women and suggests statin therapy has similar proportional benefits for men and women, regardless of the type of end point studied or the level of population risk."

Primary- and Secondary-Prevention Studies

In the meta-analysis, statin therapy significantly reduced the risk of cardiovascular events 19% in women and 23% in men. The treatment effect in women was more pronounced in the secondary-prevention studies, where a 22% reduction in the risk of cardiovascular events was observed, compared with the 15% reduction in outcomes found in the primary-prevention studies. The reduction in events was similar in studies that used placebo/usual care and low-dose statin therapy as the control arm.

Regarding all-cause mortality, the researchers report that treatment with statin therapy significantly reduced the risk of death in women by 10% in the primary- and secondary-prevention studies and by 13% when the primary-prevention studies were analyzed separately. The effect of statin therapy on all-cause mortality in women enrolled in the secondary-prevention studies was not statistically significant, and there was only a trend toward a reduction in all-cause mortality in men enrolled in the primary-prevention studies.

When investigators stratified patients by expected mortality, they found that statin therapy resulted in a significant reduction in cardiovascular outcomes in patients at low, medium, and high risk.

"This is a very large meta-analysis and it gives us good evidence to show that the benefit of statin use extends to both men and women," said Kostis. "It even extends to people considered low risk. I think going forward, as there will continue to be other statin trials and new agents, we want to make sure that women and people from all demographics are represented in the population studies, because it will allow us to show that benefits extend to all subpopulations, and if there are differences to see what they are with regard to safety and efficacy."

The Institute of Medicine has recently called for more sex-specific reporting of data for safety and efficacy outcomes. In the meta-analysis by Kostis and colleagues, there were not enough data to evaluate the adverse side effects of statin therapy in women, as just two studies reported sex-specific adverse-outcomes data. Future sex-specific results in cardiovascular medicine trials are needed to assess absolute and relative benefits, adverse outcomes, and cost-effectiveness.

Good for the Goose . . .

In her editorial, Mosca points out that "only a handful" of primary-prevention studies were available for analysis, and four of these trials enrolled patients at low risk for cardiovascular events, making it difficult to provide much clarity surrounding the controversy of statin use in women. In addition, the meta-analysis focused on the relative reduction in risk and does not provide data on the absolute benefit of treatment.

If treatment decisions regarding statins are driven by the annual mortality risk of the patient in primary prevention, the absolute risk of cardiovascular disease and corresponding proportional reduction in risk from statin therapy are needed to make "informed clinical choices."

"Only then we will know with less uncertainty whether what is good for the gander is also good for the goose," writes Mosca.

vitamine D

2012-02-02T08:37:00.001-08:00

From Journal of the American Geriatrics Society

Effect of Vitamin D Supplementation on Muscle Strength, Gait and Balance in Older Adults

A Systematic Review and Meta-analysis

Susan W. Muir, PhD; Manuel Montero-Odasso, MD, PhD, AGSF

Authors and Disclosures

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Abstract and Introduction

Abstract

Objectives: To systematically review and quantitatively synthesize the effect of vitamin D supplementation on muscle strength, gait, and balance in older adults.
Design: Systematic review and meta-analysis.
Setting: MEDLINE, EMBASE, Cochrane Library, bibliographies of selected articles, and previous systematic reviews were searched between January 1980 and November 2010 for eligible articles.
Participants: Older adults (≥60) participating in randomized controlled trials of the effect of supplemental vitamin D without an exercise intervention on muscle strength, gait, and balance.
Measurements: Data were independently extracted, and study quality was evaluated. Meta-analysis using a fixed-effects model was performed and the I ² statistic was used to assess heterogeneity.
Results: Of 714 potentially relevant articles, 13 met the inclusion criteria. In the pooled analysis, vitamin D supplementation yielded a standardized mean difference of −0.20 (95% confidence interval (CI) = −0.39 to −0.01, P = .04, I ² = 0%) for reduced postural sway, −0.19 (95% CI = −0.35 to −0.02, P = .03, I ² = 0%) for decreased time to complete the Timed Up and Go Test, and 0.05 (95% CI = −0.11 to 0.20, P = .04, I ² = 0%) for lower extremity strength gain. Regarding dosing frequency regimen, only one study demonstrated a beneficial effect on balance with a single large dose. All studies with daily doses of 800 IU or more demonstrated beneficial effects on balance and muscle strength.
Conclusion: Supplemental vitamin D with daily doses of 800 to 1,000 IU consistently demonstrated beneficial effects on strength and balance. An effect on gait was not demonstrated, although further evaluation is recommended.

Introduction

Vitamin D deficiency has recently gained much attention because of its association with cardiovascular disease, cancer, falls, fractures, and mortality.^[1–3] Older adults are especially at risk of developing vitamin D deficiency because of low sunshine exposure, less skin capacity to synthesize vitamin D, poorer absorption of vitamin D with less activation in the kidneys and peripheral tissues, and fewer or lower expression of vitamin D receptors in peripheral tissues.^[4–7]

In older adults, vitamin D deficiency has been associated with important determinants of disability, including poor physical performance, low muscular strength, cognitive impairment, falls, and fractures.^[8–15] Falls and fractures are also strongly associated with muscle weakness and gait and balance deficits.^[16] Because muscle weakness is a feature of the clinical syndrome of vitamin D deficiency, it has been postulated that vitamin D deficiency may precipitate and potentiate muscle weakness and functional decline in older people.^[17]

During the last decade, it has been demonstrated that vitamin D supplementation reduces fall risk in older adults when doses of 700 to 1,000 IU per day are used.^[18,19] This beneficial effect on fall reduction in isolation from exercise prescription seems to occur through action on neuromuscular function.^[17,18] Vitamin D receptors (VDRs) are present in several tissues throughout the body, including bone, muscle, and brain,^[20,21] and their expression and activity decline with aging.^[20] Serum levels of vitamin D decline significantly with aging, and this has been associated with reduced VDR activation and reduced muscle cell function.^[21] This low expression and activity has been well documented in muscle, which affects the response of myocytes to vitamin D.^[21]

Additionally, VDRs have been located in the human cortex and hippocampus and at a cellular level are present in neurons and glial cells.^[20] Vitamin D deficiency in older people has been associated with impairments in the central nervous system, including cognitive decline and balance problems,^[22] and in the peripheral nervous system, including reduction of nerve conduction velocity.^[23] It has been suggested that vitamin D affects neuromuscular control and coordination^[24] and may act as a neurosteroid hormone.^[25]

Based on these age-associated changes, there is a compelling rationale to believe that there is a beneficial effect of vitamin D supplementation on neuromuscular function in older adults, particularly when high doses are used.^[17] A recent review of vitamin D in adult health and disease supported fall risk reduction but did not comment on physical function effects.^[26]

Previous systematic reviews on the effect of vitamin D supplementation on muscle function reported insufficient evidence to support the therapeutic use of vitamin D alone.^[8,27] The use of vitamin D in combination with calcium supplementation was noted to have some supporting evidence, although more-definitive work was recommended.^[27] A potential explanation for these inconclusive findings could be related to variation in important research elements, such as heterogeneity in study quality, and variability in assessment methods of physical performance. Most importantly, and in light of the recent meta-analysis findings on fall risk, an important factor to consider is the dose and treatment regimen of vitamin D evaluated in each study.^[18]

As was hypothesized in a previous review in 2005,^[17] higher doses of vitamin D, at least 800 IU daily, may be necessary to improve muscle strength- and physical performance-related outcomes in older adults. Therefore, the objective of this systematic review was to assess the efficacy of vitamin D supplementation, including variations in dose and treatment regimen, on muscle strength, balance, and gait in older adults.

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gout jicht diuretics diuretica

2012-02-02T08:17:00.000-08:00

From British Medical Journal

Antihypertensive Drugs and Risk of Incident Gout Among Patients With Hypertension

Population Based Case-Control Study

Hyon K Choi; Lucia Cea Soriano; Yuqing Zhang; Luis A García Rodríguez

Authors and Disclosures

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Abstract and Introduction

Abstract and Introduction

Abstract

Objective To determine the independent associations of antihypertensive drugs with the risk of incident gout among people with hypertension.
Design Nested case-control study.
Setting UK general practice database, 2000-7.
Participants All incident cases of gout (n=24,768) among adults aged 20-79 and a random sample of 50,000 matched controls.
Main outcome measure Relative risk of incident gout associated with use of antihypertensive drugs.
Results After adjusting for age, sex, body mass index, visits to the general practitioner, alcohol intake, and pertinent drugs and comorbidities, the multivariate relative risks of incident gout associated with current use of antihypertensive drugs among those with hypertension (n=29,138) were 0.87 (95% confidence interval 0.82 to 0.93) for calcium channel blockers, 0.81 (0.70 to 0.94) for losartan, 2.36 (2.21 to 2.52) for diuretics, 1.48 (1.40 to 1.57) for β blockers, 1.24 (1.17 to 1.32) for angiotensin converting enzyme inhibitors, and 1.29 (1.16 to 1.43) for non-losartan angiotensin II receptor blockers. Similar results were obtained among those without hypertension. The multivariate relative risks for the duration of use of calcium channel blockers among those with hypertension were 1.02 for less than one year, 0.88 for 1-1.9 years, and 0.75 for two or more years and for use of losartan they were 0.98, 0.87, and 0.71, respectively (both P<0.05 for trend).
Conclusions Compatible with their urate lowering properties, calcium channel blockers and losartan are associated with a lower risk of incident gout among people with hypertension. By contrast, diuretics, β blockers, angiotensin converting enzyme inhibitors, and non-losartan angiotensin II receptor blockers are associated with an increased risk of gout.

Introduction

Hypertension is one of the most common comorbidities of gout. According to the latest estimates from the US National Health and Nutrition Examination Survey (2007-8), 74% of patients with gout have hypertension,^[1] which corresponds to 6.1 million adults in the United States alone. This substantial burden of comorbidity possibly stems from copathogenesis of the two conditions or renal changes in hypertension leading to decreased urate excretion. Studies have shown that the presence of hypertension is independently associated with the risk of incident gout^[2] through reduced renal blood flow with increased renal and systemic vascular resistance and decreased renal excretion of urate.^[3-6]

Certain antihypertensive drugs also increase the levels of serum uric acid and thus may contribute to the risk of gout. For example, in addition to the well known entities of diuretic induced hyperuricaemia and gout,^[3,7,8] the use of β blockers has been shown to increase levels of serum uric acid in short-term trials.^[8,9] However, calcium channel blockers and losartan have been found to lower serum uric acid levels,^[10-16] carrying the potential to lower the risk of gout. To date, however, no study has investigated the relation between various antihypertensive agents and the risk of gout. To address these issues, we analysed a cohort of 24,768 people with newly diagnosed gout and 50,000 matched controls from the health improvement network database.

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gout jicht diuretics diuretica

2012-02-02T01:06:00.000-08:00

Gout and Diuretics in Hypertensive Patients

Diuretic use raised risk for gout by several percentage points.

Observational data have suggested that gout is associated independently with both hypertension and diuretic use. In a prospective study, researchers determined incidence of diuretic-associated gout in nearly 6000 hypertensive patients with no histories of gout at baseline.

During 9 years of follow-up, 37% of patients received diuretics. Incidence of gout was 5.5% among diuretic users (5.0% among thiazide users and 7.0% among loop-diuretic users) and 2.9% among patients who did not use diuretics. After adjustment for potentially confounding variables (except serum uric acid), use of thiazides and loop diuretics were both significantly associated with incident gout (hazard ratios, 1.4 and 2.3, respectively). Compared with serum uric acid levels in nonusers of diuretics, levels rose by a mean of 0.65 mg/dL among those who began taking thiazides and 0.96 mg/dL among those who began taking loop diuretics. The association between diuretics and gout was no longer significant after additional adjustment for serum uric acid; this finding is consistent with the assumption that diuretic-induced increases in serum uric acid mediate the association between diuretic use and gout.

Comment: According to these results, diuretic use raises risk for gout by several percentage points in hypertensive patients. Increased risk for gout is among the potential adverse effects of thiazides that clinicians should consider when choosing first-line antihypertensive drugs.

— Allan S. Brett, MD

Published in Journal Watch General Medicine January 26, 2012

jicht gout diuretics chlorthalidon

2012-01-27T03:44:00.000-08:00

Gout and Diuretics in Hypertensive Patients

Diuretic use raised risk for gout by several percentage points.

— Allan S. Brett, MD

Published in Journal Watch General Medicine January 26, 2012

PPI

2012-01-20T00:31:00.001-08:00

Summary and Comment

PPIs and CAP, Revisited

In a retrospective, nested case-control study, the risk for community-acquired pneumonia was 29% higher with current use of a proton-pump inhibitor than with past use.

Some researchers have postulated that, by facilitating bacterial colonization of the stomach and upper intestine, suppression of gastric acid increases the risk for community-acquired pneumonia (CAP). Proton-pump inhibitors (PPIs) are among the most potent suppressors of gastric-acid secretion and are commonly prescribed — often without clear indications. Attempts to prove an association between PPI exposure and CAP have yielded inconsistent results. Now, researchers have conducted a retrospective, nested case-control study to explore this issue further.

Analysis of linked pharmacy and administrative databases from the New England Veterans Healthcare System yielded 71,985 patients who were newly prescribed PPIs between October 1997 and September 2007. Within this group, 1544 patients developed CAP after PPI initiation. These case patients were matched by age and follow-up duration with 15,440 controls who received new PPI prescriptions during the same period but did not develop CAP. PPI use was categorized as current if the prescription end date was after the index CAP date and past if it preceded this date.

Cases were significantly more likely than controls to have one or more medical comorbidities (in addition to gastroesophageal reflux), to have been hospitalized 90 days before the diagnosis of CAP, and to have been prescribed other medications possibly linked to CAP. The risk for developing CAP was higher in patients with current PPI use than in those with past use (adjusted odds ratio, 1.29; 95% confidence interval, 1.15–1.45). PPI prescription at a dose exceeding the standard daily dose (significantly more common in case patients than in controls) was also associated with CAP (P=0.012).

Comment: Because the study was retrospective and did not involve review of medical records, the results must be interpreted cautiously. However, the findings do suggest a modest effect of PPIs on the risk for CAP.

— Neil M. Ampel, MD

Published in Journal Watch Infectious Diseases January 18, 2012

stroke beroerte AF

2012-01-19T07:48:00.001-08:00

Summary and Comment

Even Subclinical AF Is Associated with Stroke

In patients with pacemakers, asymptomatic AF is common and warrants increased vigilance.

Trials of anticoagulants for stroke prevention generally involve patients with frequent and symptomatic atrial fibrillation (AF); however, the growing population of patients with implanted cardiac devices has enabled the detection of subclinical AF. The manufacturer-sponsored ASSERT trial in patients with a dual-chamber pacemaker or implantable cardioverter-defibrillator was designed to evaluate whether a special pacing algorithm would prevent AF and whether subclinical AF is associated with clinical events. All 2580 participants had hypertension and no history of AF.

Three months after enrollment, device detection algorithms had recorded subclinical atrial tachycardia (defined as an atrial rate >190 beats/minute for >6 minutes) in 10% of patients. At this point, participants with pacemakers were randomized to receive or not to receive continuous overdrive atrial suppression.

During a mean of 2.5 years of follow-up, use of the special pacing algorithm did not significantly reduce AF. Clinically documented AF occurred in only 16% of patients with device-documented atrial tachycardia in the first 3 months. Subclinical atrial tachycardia in the first 3 months was significantly associated with both clinically documented AF and stroke or systemic embolism. However, the association with stroke or systemic embolism was no longer significant when patients with atrial tachycardia detected after the first 3 months (an additional 24.5%) were included in the analysis.

Comment: Clinical atrial fibrillation is not only associated with stroke but is almost certainly causative; moreover, no evidence suggests that symptomatic AF is more prothrombotic than asymptomatic AF. Although the current findings are by no means definitive for guiding anticoagulation decisions, they do support taking device-documented subclinical AF seriously. If an asymptomatic patient's CHADS₂ score is high and subclinical episodes are frequent or prolonged, I would consider anticoagulation. These findings also support aggressively screening patients with cryptogenic stroke for occult AF and initiating anticoagulation if any AF is detected.

— Mark S. Link, MD

Published in Journal Watch Cardiology January 18, 2012

DEPRESSION DEPRESSIE

2012-01-17T06:23:00.000-08:00

Reviewing: Launay JM et al. Translat Psychiatry 2011 Nov 22;

SUMMARY AND COMMENT

How Well Are We Treating Depression?

January 13, 2012 | Steven Dubovsky, MD

Despite a broader range of antidepressants and psychotherapies and more generic medications, this analysis of Medicaid data shows that the treatment of depression has not become cheaper and better.

Reviewing: Fullerton CA et al. Arch Gen Psychiatry 2011 Dec 68:1218

SUMMARY AND COMMENT

Match Prototype to Patients to Identify Personality Disorders

January 13, 2012 | Joel Yager, MD

Empirically validated narrative prototypes help clinicians accurately diagnose personality disorders.

Reviewing: Westen D et al. Am J Psychiatry 2011 Dec 15;

SUMMARY AND COMMENT

Arsenic-Laden Rice: Another Contaminant to Worry About?

January 13, 2012 | Jonathan Silver, MD

Arsenic levels were elevated in pregnant women who ate moderate amounts of rice, but the implications of this finding remain unknown.

Reviewing: Gilbert-Diamond D et al. Proc Natl Acad Sci U S A 2011 Dec 20; 108:20656

Free Full-Text Article

Summary and Comment

How Serotonin Reuptake Inhibitors Work: Understanding More Fundamental Mechanisms of Action

By stimulating microRNA miR-16 in the midline serotonergic raphe, fluoxetine initiates signaling cascades that lead to hippocampal neurogenesis.

Several lines of evidence suggest that in adults, antidepressant therapies enhance neurogenesis in the hippocampus, but how this process occurs has been unclear. These researchers studied the effects of fluoxetine in mice and in humans. They worked out several pathways that begin with the stimulation by fluoxetine of the microRNA miR-16 in serotonergic neurons in raphe and ultimately result in hippocampal neurogenesis.

In a series of experiments in mice, fluoxetine activated raphe miR-16, which decreased raphe levels of the serotonin reuptake transporter (SERT). In turn, these events directly caused brain-derived neurotropic factor (BDNF) and two other signaling molecules to act on the hippocampus. Indirectly, the same events resulted in release of another protein from the raphe nuclei, S100β, which in turn stimulated the locus coeruleus to induce SERT and secrete serotonin. Both the direct and indirect pathways caused decreases in hippocampal miR-16, which sequentially led to increases in both hippocampal SERT and the bcl-2 protein (which promotes neurotrophic function), which in turn stimulated neurogenesis. In nine patients with major depression, 12-week fluoxetine treatment increased levels of the three signaling molecules in cerebrospinal fluid. The interventions were accompanied by improvements in several mouse models of depression, as well as in the patients. See accompanying figure.

Comment: These findings draw together several seemingly unconnected lines of research. The authors identify miR-16 as a "missing link" between serotonin reuptake inhibitor treatment and hippocampal neurogenesis and as a "micromanager" of the intervening changes in the raphe nucleus, locus coeruleus, serotonin receptor transporter, serotonin secretion, and hippocampal neurogenesis. The processes appear to work through the cooperative and integrated activities of several signaling molecules. Further clarification of these pathways may help refine therapeutic strategies for depressive disorders.

— Joel Yager, MD

Published in Journal Watch Psychiatry January 13, 2012

Citation(s):

Launay JM et al. Raphe-mediated signals control the hippocampal response to SRI antidepressants via miR-16. Translat Psychiatry 2011 Nov 22; 1:e56. (http://dx.doi.org/10.1038/tp.2011.54)

depression depressie

2012-01-05T07:53:00.001-08:00

Antidepressants and risks of suicide and suicide attempts: a 27-year observational study.

J Clin Psychiatry. 2011; 72(5):580-6 (ISSN: 1555-2101)

Leon AC; Solomon DA; Li C; Fiedorowicz JG; Coryell WH; Endicott J; Keller MB
Department of Psychiatry, Weill Cornell Medical College, New York, NY 10065, USA. acleon@med.cornell.edu

OBJECTIVE: The 2007 revision of the black box warning for suicidality with antidepressants states that patients of all ages who initiate antidepressants should be monitored for clinical worsening or suicidality. The objective of this study was to examine the association of antidepressants with suicide attempts and with suicide deaths.

METHOD: A longitudinal, observational study of mood disorders with prospective assessments for up to 27 years was conducted at 5 US academic medical centers. The study sample included 757 participants who enrolled from 1979 to 1981 during an episode of mania, depression, or schizoaffective disorder, each based on Research Diagnostic Criteria. Unlike randomized controlled clinical trials of antidepressants, the analyses included participants with psychiatric and other medical comorbidity and those receiving acute or maintenance therapy, polypharmacy, or no psychopharmacologic treatment at all. Over follow-up, these participants had 6,716 time periods that were classified as either exposed to an antidepressant or not exposed. Propensity score-adjusted mixed-effects survival analyses were used to examine risk of suicide attempt or suicide, the primary outcome.

RESULTS: The propensity model showed that antidepressant therapy was significantly more likely when participants' symptom severity was greater (odds ratio [OR] = 1.16; 95% CI, 1.12-1.21; z = 8.22; P < .001) or when it was worsening (OR = 1.69; 95% CI, 1.50-1.89; z = 9.02; P < .001). Quintile-stratified, propensity-adjusted safety analyses using mixed-effects grouped-time survival models indicate that the risk of suicide attempts or suicides was reduced by 20% among participants taking antidepressants (hazard ratio, 0.80; 95% CI, 0.68-0.95; z = -2.54; P = .011).

CONCLUSIONS: This longitudinal study of a broadly generalizable cohort found that, although those with more severe affective syndromes were more likely to initiate treatment, antidepressants were associated with a significant reduction in the risk of suicidal behavior. Nonetheless, we believe that clinicians must closely monitor patients when an antidepressant is initiated.

fosamax biphosfanate

2012-01-04T01:40:00.000-08:00

Summary and Comment

Bisphosphonate Use Extends Implant Survival After Primary Hip and Knee Arthroplasty

In a U.K. study, bisphosphonate users had significantly lower rates of revision.

The most common indication for revision hip or knee arthroplasty is implant loosening caused by resorption of bone that supports the implant. In this population-based retrospective cohort study, investigators assessed whether use of bisphosphonates, which have antiresorptive properties, can lengthen implant survival.

Using the U.K.'s General Practice Research Database, researchers identified 42,000 patients who underwent primary total knee or hip arthroplasty from 1986 through 2006. At 5 years, bisphosphonate users (essentially defined as those who took bisphosphonates for at least 6 months) had a significantly lower revision rate than nonusers (0.93% vs. 1.96%). In analyses adjusted for confounding factors, bisphosphonate use was associated with a significant twofold increase in implant survival. Assuming an arthroplasty failure rate of 2% during 5 years, the authors estimated that 107 patients who underwent primary hip or knee arthroplasty would need to be treated with bisphosphonates to prevent one revision arthroplasty.

Comment: As the authors note, revision hip or knee arthroplasty has "a poorer clinical outcome than primary joint surgery and is more costly." Needless to say, patients (and their physicians) would like to avoid this outcome. These results suggest that bisphosphonate use is associated with a lower rate of hip and knee revision arthroplasty and longer implant survival.

— Paul S. Mueller, MD, MPH, FACP

Published in Journal Watch General Medicine January 3, 2012

2011-12-24T02:31:00.001-08:00

Dabigatran etexilate versus warfarin in management of non-valvular atrial fibrillation in UK context: quantitative benefit-harm and economic analyses

BMJ 2011; 343 doi: 10.1136/bmj.d6333 (Published 31 October 2011)

Cite this as: BMJ 2011;343:d6333

Correspondence to: D A Hughes d.a.hughes@bangor.ac.uk

Accepted 8 September 2011

Abstract

Objectives To determine the incremental net health benefits of dabigatran etexilate 110 mg and 150 mg twice daily and warfarin in patients with non-valvular atrial fibrillation and to estimate the cost effectiveness of dabigatran in the United Kingdom.

Design Quantitative benefit-harm and economic analyses using a discrete event simulation model to extrapolate the findings of the RE-LY (Randomized Evaluation of Long-Term Anticoagulation Therapy) study to a lifetime horizon.

Setting UK National Health Service.

Population Cohorts of 50 000 simulated patients at moderate to high risk of stroke with a mean baseline CHADS₂ (Congestive heart failure, Hypertension, Age≥75 years, Diabetes mellitus, previous Stroke/transient ischaemic attack) score of 2.1.

Main outcome measures Quality adjusted life years (QALYs) gained and incremental cost per QALY of dabigatran compared with warfarin.

Results Compared with warfarin, low dose and high dose dabigatran were associated with positive incremental net benefits of 0.094 (95% central range −0.083 to 0.267) and 0.146 (−0.029 to 0.322) QALYs. Positive incremental net benefits resulted for high dose dabigatran in 94% of simulations versus warfarin and in 76% of those versus low dose dabigatran. In the economic analysis, high dose dabigatran dominated the low dose, had an incremental cost effectiveness ratio of £23 082 (€26 700; $35 800) per QALY gained versus warfarin, and was more cost effective in patients with a baseline CHADS₂ score of 3 or above. However, at centres that achieved good control of international normalised ratio, such as those in the UK, dabigatran 150 mg was not cost effective, at £42 386 per QALY gained.

Conclusions This analysis supports regulatory decisions that dabigatran offers a positive benefit to harm ratio when compared with warfarin. However, no subgroup for which dabigatran 110 mg offered any clinical or economic advantage over 150 mg was identified. High dose dabigatran will be cost effective only forpatients at increased risk of stroke or for whom international normalised ratio is likely to be less well controlled.

Introduction

Atrial fibrillation is the most common sustained cardiac arrhythmia, with an estimated prevalence in the United Kingdom of 10% in patients aged 75 or over and an associated fivefold increase in the risk of ischaemic stroke.1 2 Bed days for patients with a primary or secondary diagnosis of atrial fibrillation cost the National Health Service (NHS) £1.9bn (€2.2bn; $2.9bn) in 2008, with outpatient and other inpatient costs totalling £329m.3

Warfarin is the mainstay of oral thromboprophylactic anticoagulation treatment.4 However, patients show considerable variability in their response to warfarin, which, coupled with a narrow therapeutic range, necessitates frequent monitoring and adjustment of dosage to ensure optimal anticoagulation. Deviations outside the therapeutic range (international normalised ratio (INR) 2.0-3.0) increase the risk of both strokes and haemorrhagic events.5

Dabigatran etexilate is a new oral direct thrombin inhibitor that may provide an alternative to warfarin; it has the advantage of not requiring regular monitoring. In the multinational, Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) study, 18 113 patients with non-valvular atrial fibrillation and at least one risk factor for stroke were randomised to one of two doses of dabigatran (110 mg or 150 mg, twice daily) or dose adjusted warfarin.6 After a median follow-up of two years, the rates of the primary outcome (stroke or systemic embolism) were similar to those for warfarin among patients assigned the lower dose but were lower among patients assigned the higher dose (1.11% v 1.71% per year; relative risk 0.66, 95% confidence interval 0.53 to 0.82; P=0.0001). Compared with warfarin, the annual rate of major bleeding was lower among patients assigned dabigatran 110 mg (2.71% v 3.36%; relative risk 0.80, 0.69 to 0.93; P=0.003) but similar among those assigned 150 mg. Dabigatran was associated with higher rates of myocardial infarction, but these were not statistically significant.7

The US Food and Drug Administration (FDA) was satisfied of the positive benefit to harm balance of dabigatran but failed to identify a subgroup of patients in which the benefit-harm profile was superior for the 110 mg dose compared with the 150 mg dose and consequently approved only the higher dose.8 However, both doses have been approved by other regulatory authorities, including the European Medicines Agency, which specifies 150 mg twice daily for patients under 80 years of age and 110 mg twice daily for those aged 80 and over or as an option when the thromboembolic risk is considered to be low and the risk of bleeding is high.9

Against this background, we describe a quantitative analysis of the trade-off between thrombotic and bleeding risks—events that have differential effects on life expectancy and quality of life—as a basis to guide clinicians’ prescribing. We also develop a health economic evaluation to estimate the cost effectiveness of dabigatran in patients with non-valvular atrial fibrillation, given the considerable uncertainty about its cost effectiveness in the UK healthcare setting.

dabigatran warfarin

2011-12-23T01:29:00.000-08:00

Risks for Stroke, Bleeding, and Death in Patients With Atrial Fibrillation Receiving Dabigatran or Warfarin in Relation to the CHADS₂ Score: A Subgroup Analysis of the RE-LY Trial

Jonas Oldgren, MD, PhD;
Marco Alings, MD, PhD;
Harald Darius, MD, PhD;
Hans-Christoph Diener, MD, PhD;
John Eikelboom, MD;
Michael D. Ezekowitz, MD, PhD;
Gabriel Kamensky, MD, PhD;
Paul A. Reilly, PhD;
Sean Yang, MSc;
Salim Yusuf, MBBS, DPhil;
Lars Wallentin, MD, PhD; and
Stuart J. Connolly, MD,
on behalf of the RE-LY Investigators

+ Author Affiliations

From Uppsala Clinical Research Centre and Department of Medical Sciences, Uppsala University, Uppsala, Sweden; Working Group on Cardiovascular Research, Utrecht, the Netherlands; Vivantes Klinikum Neukölln, Berlin, Germany; University Duisburg-Essen, Duisburg and Essen, Germany; Population Health Research Institute and McMaster University, Hamilton, Ontario, Canada; Lankenau Institute for Medical Research and the Heart Center, Wynnewood, Pennsylvania; University Hospital Bratislava, Bratislava, Slovakia; and Boehringer Ingelheim Pharmaceuticals, Ridgefield, Connecticut.

Abstract

Background: CHADS₂ is a simple, validated risk score for predicting the risk for stroke in patients with atrial fibrillation not treated with anticoagulants. There are sparse data on the risk for thrombotic and bleeding complications according to the CHADS₂ score in patients receiving anticoagulant therapy.

Objective: To evaluate the prognostic importance of CHADS₂ risk score in patients with atrial fibrillation receiving oral anticoagulants, including the vitamin K antagonist warfarin and the direct thrombin inhibitor dabigatran.

Design: Subgroup analysis of a randomized, controlled trial. (ClinicalTrials.gov registration number: NCT00262600)

Setting: Multinational study setting.

Patients: 18 112 patients with atrial fibrillation who were receiving oral anticoagulants.

Measurements: Baseline CHADS₂ score, which assigns 1 point each for congestive heart failure, hypertension, age 75 years or older, and diabetes mellitus and 2 points for stroke.

Results: Distribution of CHADS₂ scores were as follows: 0 to 1—5775 patients; 2—6455 patients; and 3 to 6—5882 patients. Annual rates of the primary outcome of stroke or systemic embolism among all participants were 0.93% in patients with a CHADS₂ score of 0 to 1, 1.22% in those with a score of 2, and 2.24% in those with a score of 3 to 6. Annual rates of other outcomes among all participants with CHADS₂ scores of 0 to 1, 2, and 3 to 6, respectively, were the following: major bleeding, 2.26%, 3.11%, and 4.42%; intracranial bleeding, 0.31%, 0.40%, and 0.61%; and vascular mortality, 1.35%, 2.39%, and 3.68% (P < 0.001 for all comparisons). Rates of stroke or systemic embolism, major and intracranial bleeding, and vascular and total mortality each increased in the warfarin and dabigatran groups as CHADS₂ score increased. The rates of stroke or systemic embolism with dabigatran, 150 mg twice daily, and of intracranial bleeding with dabigatran, 150 mg or 110 mg twice daily, were lower than those with warfarin; there was no significant heterogeneity in subgroups defined by CHADS₂ scores.

Limitation: These analyses were not prespecified and should be deemed exploratory.

Conclusion: Higher CHADS₂ scores were associated with increased risks for stroke or systemic embolism, bleeding, and death in patients with atrial fibrillation receiving oral anticoagulants.

STROKE BEROERTE

2011-12-21T07:19:00.001-08:00

Summary and Comment

Poststroke Blood Pressure Affects Risk for Recurrent Stroke

Risk was elevated with low and high systolic BP.

Risk for a first ischemic stroke is generally proportional to the level of systolic blood pressure (BP), but optimal poststroke BP for prevention of recurrent stroke is less clear. To examine this issue, researchers conducted a post hoc analysis of data from a previously published secondary prevention study that involved about 20,000 patients (mean age, 66; two thirds men) with recent noncardioembolic ischemic stroke (JW Cardiol Aug 27 2008).

The original study addressed the role of various antiplatelet regimens, and BP was managed by investigators at their discretion. Patients were assessed several times during a mean follow-up of 2.5 years, during which the risk for recurrent stroke was about 8%. Compared with patients who had low-normal systolic BP (120–129 mm Hg), risk for recurrent stroke was elevated in patients whose mean systolic BP during the study was very low (<120 mm Hg; 29% relative increase), high (140–149 mm Hg; 23% increase), or very high (150 mm Hg; 108% increase); risk with high-normal systolic BP (130–139 mm Hg) was similar to that with low-normal BP. These analyses were adjusted for clinical and demographic factors.

Comment: These post hoc analyses are sufficiently strong to support a recommendation to maintain systolic BP in the normal range (120–139 mm Hg) –– but not lower — in stroke patients. However, rigorous prospective studies to confirm this conclusion are warranted.

— Thomas L. Schwenk, MD

Dr. Ovbiagele is an Associate Editor for Journal Watch Neurology but was not involved in the selection or summarization of this article.

Published in Journal Watch General Medicine December 20, 2011

rivaroxaban Xarelto Warfarin

2011-12-20T06:59:00.000-08:00

Het grote voordeel voor de trombosepatiënten is dat er niet meer routinematig gemonitord hoeft te worden, de regelmatige injecties onnodig zijn en er niet meer noodzakelijk een dieet gevolgd moet worden. In plaats daarvan hoeven de patiënten slechts eenmaal per dag een tabletje te nemen.

Xarelto is in 27 lidstaten toegelaten voor trombosebeen en hartritmestoornissen, maakt farmaceut Bayer bekend. Volgens specialisten vervalt daarmee niet alleen voor trombosepatiënten een enorme belasting, maar ook is deze eenmaal daagse pil ‘single drug’ voor het gezondheidszorgsysteem een lastenverlichting.

In ons land worden ongeveer 41.000 Nederlanders jaarlijks getroffen door een beroerte, ook wel herseninfarct genoemd. Meer dan 216.000 mensen leven met de gevolgen van een beroerte. Patiënten met de hartritmestoornis boezemfibrilleren hebben een vier tot vijfvoudig verhoogd risico op het krijgen van een herseninfarct. In ons land lijden 300.000 mensen aan boezemfibrilleren, wat kan leiden tot gevaarlijke bloedstolsels.

Het middel Xarelto kwam bij wereldwijd onderzoek naar voren als een medicijn dat voordelen biedt ten opzichte van het vaak voorgeschreven middel Warfarine aan patiënten met boezemfibrileren. Aan deze studie deden ruim 14.000 patiënten in 45 landen mee. Vanuit Nederland waren twintig ziekenhuizen betrokken.

zout hoge bloeddruk sodium intake

2011-12-17T14:18:00.001-08:00

Hypertension for December 15, 2011

SUMMARY AND COMMENT

Sodium Excretion of >7 g or <3 g Daily Is Associated with Elevated Cardiovascular Morbidity

December 13, 2011 | Thomas L. Schwenk, MD | General Medicine

By comparison, higher potassium excretion was associated with lower stroke risk.

Reviewing: O'Donnell MJ et al. JAMA 2011 Nov 23/30; 306:2229

Whelton PK. JAMA 2011 Nov 23/30; 306:2262

Free Full-Text Article

Summary and Comment

Sodium Excretion of >7 g or <3 g Daily Is Associated with Elevated Cardiovascular Morbidity

By comparison, higher potassium excretion was associated with lower stroke risk.

The WHO recommends daily sodium intake of less than 2 g, based on relatively short trials in which the effect of sodium intake on blood pressure was assessed. In this study, researchers analyzed data for 28,880 patients in two international clinical trials of an angiotensin-receptor blocker; most patients (mean age, 67; 70% men) had histories of myocardial infarction, stroke, hypertension, or diabetes. People with congestive heart failure (CHF), decreased renal function, or uncontrolled hypertension were excluded. Mean daily sodium excretion (a surrogate for sodium intake) was 4.77 g, and daily potassium excretion was 2.19 g.

At 5 years, a composite outcome of cardiovascular mortality, myocardial infarction, stroke, and hospitalization for CHF occurred in 4729 patients. Patients with urinary sodium excretion of 4 to 6 g daily had the lowest risk for the composite outcome. Risk was higher by 21%, 16%, 15%, and 49% for patients with daily excretion of <2 g, 2–3 g, 7–8 g, and >8 g, respectively. Compared with patients who had daily potassium excretion of <1.5 g, risk for stroke was 32% lower in those with excretion of >3 g. These analyses were adjusted for numerous clinical and demographic factors.

Comment: This J-shaped relation between sodium intake and cardiovascular outcomes conflicts with current recommendations to limit daily sodium intake to 2 g. However, an editorialist is unconvinced and believes that randomized trials are needed to account for confounding caused by preexisting disease and risk factors. The small number of patients with low sodium intake — 3% of the total sample had urinary excretion <2 g daily — also tempers the results. Consuming a diet high in natural foods and low in processed foods would result in a lower sodium–potassium ratio –– which could be more important than the actual intake levels.

— Thomas L. Schwenk, MD

Published in Journal Watch General Medicine December 13, 2011

dabigatran aspirine warfarin

2011-12-17T14:06:00.000-08:00

December 12, 2011 (San Diego, California) — The use of aspirin reduces the risk of recurrent venous thromboembolism (VTE) by more than half when compared with placebo, according to the results of a new study [1]. Investigators say the reduction in VTE risk, which was achieved without an increased risk of bleeding, makes aspirin an attractive treatment option for the extended prevention of recurrent VTE once oral anticoagulation has been stopped.

"Patients with a first episode of VTE usually receive initial therapy with heparin, which is given for five to seven days, and then they are switched over to oral anticoagulants," lead investigator Dr Cecilia Becattini (University of Perugia, Italy) told heartwire . "Oral anticoagulant therapy [with vitamin-K antagonists] is not very practical, as it requires laboratory monitoring and medical visits for adjustments. More important, there is the potential for harmful bleeding complications with warfarin, which can occur in about 3% of patients."

The past couple of years have seen the emergence of more anticoagulants for VTE, including the US Food and Drug Administration approval of rivaroxaban (Xarelto, Bayer/Johnson & Johnson) for prevention of deep venous thrombosis (DVT) in the setting of knee- or hip-replacement surgery. Apixaban (Eliquis, Bristol-Myers Squibb/Pfizer) has been approved in Europe for the prevention of VTE events in adult patients who have undergone elective hip- or knee-replacement surgery, while edoxaban (Lixiana, Daiichi Sankyo), another direct factor Xa inhibitor, is approved in Japan. Data from the RECOVER trial also showed that the new anticoagulant dabigatran (Pradaxa, Boehringer Ingelheim) was effective when used in the VTE setting, and it is currently approved for use in Europe.

"There are a lot of new agents out there that don't require laboratory monitoring, and some of these new oral anticoagulants have already been approved for use in patients with venous thromboembolism," said Becattini. "But again, they are anticoagulants, and while they are effective, the risk of bleeding complications is not zero."

In this study, known as WARFASA, which was presented at the American Society of Hematology 2011 Annual Meeting, the researchers tested whether the use of aspirin therapy was more effective than placebo in reducing the risk of recurrent VTE in patients treated with warfarin for six to 18 months following the first idiopathic VTE. After the initial treatment with warfarin, the drug was stopped, and 205 patients were randomized to 100 mg aspirin once daily and 197 patients to placebo.

During the two-year study period, recurrent symptomatic VTE occurred in 28 patients in the aspirin arm and 43 patients in the placebo group (6.6% per patient-year vs 11.2% per patient-year, respectively). In multivariate analysis, aspirin reduced the risk of recurrent VTE 42% (hazard ratio 0.58; 95% CI 0.36–0.93) compared with placebo. The risk of major bleeding and clinically relevant nonmajor bleeding was identical in the aspirin- and placebo-treated patients, with one major bleed and three clinically relevant bleeds reported in both groups. There was no significant difference in mortality.

Not as Efficacious, But Not as Risky

To heartwire , Becattini said that the bleeding risk with aspirin is 10-fold lower than that of other oral anticoagulants, and this study shows that putting a patient on aspirin extended therapy lowers the risk of recurrence without any significant increase in bleeding. It is a practical, low-cost option for clinicians and patients, even though it is not as efficacious for the reduction of recurrent VTE as other agents.

"You have to consider that in clinical trials, dabigatran and rivaroxaban showed an 80% to 90% reduction in the risk of venous thromboembolism, which is about double what we found with aspirin," she said. "These are the newer agents, but we don't yet know everything about their potential side effects. As well, there is the issue of cost."

After a three- or six-month treatment course with oral anticoagulants, Becattini said her center typically evaluates the risk for recurrent VTE by assessing conditions that were present at the time of the first event, such as trauma or surgery. Recurrent VTE can occur in as many as one in five patients in the two-year period following the withdrawal of oral anticoagulants.

"In cases that were associated with transient risk factors, we know the risk of a second venous thromboembolism is very low," she said. "So after three or six months, oral anticoagulants are usually discontinued. After the first episode, we'll stop the drugs and advise the patient about symptoms, telling them to come back to the hospital at the first sign something might be wrong.

gewichtsverlies, pancreatitis

2011-12-15T03:15:00.000-08:00

Question

An 86-year old patient in a senior living center has lost 34 pounds in the past 6 months. She claims her appetite is good, and no medical problems are apparent. How should I approach the evaluation of weight loss in this elderly patient?

Response from Barbara Resnick, PhD
Professor, University of Maryland; Nurse Practitioner, a Continuing Care Retirement Community, Baltimore, Maryland

Unexplained weight loss or losing weight without trying is often, but not always, associated with an underlying medical disorder. Loss of a few pounds is rarely a cause for concern in an older individual. A provider should be concerned, however, about unexplained weight loss over a 6-month period of 10 pounds (4.5 kg), weight loss of more than 5% of the patient's body weight, or weight loss that is persistent despite interventions.

The first thing to check when evaluating weight loss is whether the patient is eating a sufficient number of calories to maintain body weight. A dietician can be of value if help is needed in making such a determination. If intake is inadequate, it is helpful to look for psychosocial factors or normal changes of aging that might be contributing to reduced dietary intake. Changes in smell and taste, nausea, constipation, poor oral health, functional changes that make shopping and cooking challenging, eating alone, and being unable to afford food are all factors associated with reduced intake. If the underlying problem is found to be poor intake, interventions should focus on increasing oral intake and calories. High calorie snacks and small frequent meals are reasonable options. Nutritional supplements (eg, Ensure®), if accessible and affordable, are another option. Dietary restrictions (eg, low sodium diets) should be eliminated.

When dietary intake seems to be adequate, the weight loss is more likely to be a consequence of disease. Numerous medical problems can cause or contribute to unexplained weight loss (Table).

Table. Diseases Associated With Weight Loss

Addison disease

Cancer

Celiac disease

Chronic obstructive pulmonary disease

Crohn disease

Dementia

Depression

Diabetes

Heart failure

HIV/AIDS

Hypercalcemia

Thyroid disease

Parkinson disease

Peptic ulcer

Tuberculosis

Ulcerative colitis

Irritable bowel disease

Clostridium difficile

Causes include undiagnosed celiac disease, thyroid disorders, malignancies, dementia, depression, and diabetes. A comprehensive history and physical will guide the search for an underlying cause of the weight loss. History taking should particularly explore possible signs and symptoms that may indicate an underlying clinical problem such as cough, nausea, constipation, or pain. The physical exam should look for lymphadenopathy, breast changes, or thyroid changes. Laboratory tests should be ordered to evaluate for infection, anemia, electrolyte imbalances, and renal disease.

Treatment involves addressing the underlying cause for the unintentional weight loss (improving management of blood glucose in diabetes, treating depression, etc) and work to increase oral intake. If no improvement in weight occurs, then the patient should be re-evaluated with respect to the level of energy that is being expended (eg, is in the patient acutely ill or wandering excessively?) If no additional cause can be identified, consideration of pharmacologic management with appropriate medications to increase weight can be considered.

vitamine D

2011-12-15T03:09:00.001-08:00

Question

How should vitamin D supplementation be managed in these specific populations?

Response from Darrell Hulisz, PharmD
Associate Professor, Case Western Reserve University School of Medicine; Clinical Specialist in Family Medicine, University Hospitals, Case Medical Center, Cleveland, Ohio

A previous Ask the Experts column written by Dr. Darrell Hulisz, "Which Is Better: Vitamin D2 or D3?", generated many readers' questions. Dr. Hulisz answers these questions below in a follow-up column.

Vitamin D is essential for adequate intestinal absorption of calcium. Chronic vitamin D deficiency can decrease serum calcium and can trigger a compensatory release of parathyroid hormone (PTH).^[1,2] This may produce secondary hyperparathyroidism, resulting in the mobilization of calcium from bone and a reduction in bone mineral density (BMD).^[2,3] Chronic vitamin D deficiency can lead to muscle weakness and increase the risk for osteoporotic fractures, falls, rickets, and osteomalacia.^[2,4,5] In light of the recent attention given to vitamin D deficiency, several questions arise regarding supplementation in special populations.

What form of vitamin D is recommended in chronic kidney disease?

Vitamin D is produced endogenously in the skin and converted to active metabolites in the liver and kidney. Upon exposure to ultraviolet irradiation, provitamin D3 (7-dehydrocholesterol) in the skin is converted to previtamin D3, which is then isomerized to vitamin D3 (cholecalciferol). Vitamin D3, whether cutaneously formed or obtained in the diet as cholecalciferol, is subsequently hydroxylated in the liver to 25-hydroxyvitamin D (25-OH VD). This is the major circulating form of vitamin D that is assayed to detect deficiency.^[1]

A subsequent hydroxylation of 25-OH VD occurs in the kidney to form 1,25-dihydroxyvitamin D, the major biologically active form of vitamin D, also known as calcitriol.^[1,2] Thus, in the setting of severe chronic kidney disease (CKD), formulations of calcitriol may be preferred over vitamin D2 and D3 to treat deficiency because the terminal hydroxylation occurs in the kidney.

In the setting of CKD it is important to estimate glomerular filtration rate (GFR) and to determine serum 25-OH VD, calcium, phosphorous, and intact PTH levels when choosing the most optimal regimen. Supplementation of vitamin D plays a major role in the prevention of secondary hyperparathyroidism in patients with CKD.^[6-8] According to clinical practice guidelines from the National Kidney Foundation, the preferred form of supplementation is guided by serum 25-OH VD levels, stage of kidney failure, and presence or absence of secondary hyperparathyroidism.^[9] Before and during supplementation, both serum calcium and phosphorous levels should be drawn every 3 months. If levels of these minerals rise, vitamin D supplementation may need to be withheld or the dosage modified.^[9]

In the presence of secondary hyperparathyroidism, which usually begins in stage 3 or 4 of CKD (GFR 30-59 mL/min and 15-29 mL/min, respectively), the preferred agent for supplementation is an activated vitamin D sterol (eg, calcitriol or paricalcitol). Supplementation should begin when serum levels of 25-OH VD fall below 30 ng/mL. The vitamin D sterol dose depends on the serum levels of 25-OH VD, PTH, calcium, and phosphorus. Likewise, in stage 5 of CKD (GFR < 15 mL/min and patients treated with hemodialysis or peritoneal dialysis), an activated vitamin D sterol is also preferred in lieu of vitamin D2 or D3.^[9]

However, in the absence of secondary hyperparathyroidism, as is often the case in patients with GFR > 60 mL/min or only mild renal impairment, either oral vitamin D2 or D3 can be used. Studies indicate that vitamin D2 (ergocalciferol) is much less potent and has a shorter duration of action than D3 (cholecalciferol) and that vitamin D3 more effectively raises 25-OH VD levels.^[10-13] Thus, cholecalciferol is preferred in patients with normal or mild renal impairment (GFR > 60 mL/min) with a normal intact PTH level.

What dose of cholecalciferol is suggested for preventing deficiency?

Several guidelines have been issued by national organizations that recommend varying amounts of vitamin D intake. A recent consensus report has been issued by the Institute of Medicine.^[13] This guideline states that for most patients the recommended daily allowance of vitamin D should be 600-800 IU. However, increased amounts are necessary for treating known deficiency, such as 25-OH VD levels below 20 ng/mL. Supplemental vitamin D may become necessary in conditions in which risk factors for deficiency exist, such as living in extreme northern latitudes or lack of solar exposure, malabsorptive states, corticosteroid use, chronic dietary deficiency, and pregnancy. However, in these situations the dose of vitamin D is best guided by 25-OH VD levels.

What is the upper limit of vitamin D intake?

As a dietary supplement, patients should not exceed a daily amount of 4000 IU of vitamin D,^[13] though higher doses may be needed temporarily to treat documented deficiency. Most cases of vitamin D toxicity have been associated with 25-hydroxyvitamin D levels greater than 88 ng/mL, a level that would necessitate a daily intake of 40,000 IU or more of vitamin D.^[14] No significant changes from baseline in serum calcium levels or urinary calcium excretion were noted in patients given 4000 IU/day of vitamin D3 for up to 5 months.^[15] In addition, cholecalciferol 100,000 IU administered to patients every 4 months for 5 years was found to be safe.^[16]

Which vitamin D preparations are available in an oral liquid?

Vitamin D3 (cholecalciferol) is available as a concentration solution, ranging from 400 IU to 4000 IU per drop. Vitamin D2 (ergocalciferol) is also available in various liquid formulations, but it is commercially available in limited supply due to the superiority of cholecalciferol. Calcitriol, the activated vitamin D sterol, is available in a 1-µg/mL solution for oral administration.

pancreatitis chronic

2011-12-15T03:04:00.000-08:00

From Current Opinion in Gastroenterology

Chronic Pancreatitis

Matthew J. DiMagno; Eugene P. DiMagno

Authors and Disclosures

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Abstract and Introduction

Abstract

Purpose of review: We review important new clinical observations in chronic pancreatitis made in the past year.
Recent findings: Tropical pancreatitis associates with SPINK1 and/or CFTR gene mutations in approximately 50% of patients, similar to the frequency in idiopathic chronic pancreatitis. Corticosteroids increase secretin-stimulated pancreatic bicarbonate concentrations in autoimmune pancreatitis (AIP) by restoring mislocalized CFTR protein to the apical ductal membrane. Most patients with asymptomatic hyperenzymemia have pancreatic lesions of unclear significance or no pancreatic lesions. Common pitfalls in the use of diagnostic tests for exocrine pancreatic insufficiency (EPI) confound interpretation of findings in irritable bowel syndrome and severe renal insufficiency. Further study is needed to improve the accuracy of endoscopic ultrasonography (EUS) to diagnose chronic pancreatitis. Celiac plexus block provides short-term pain relief in a subset of patients.
Summary: Results of this year's investigations further elucidated the genetic associations of tropical pancreatitis, a reversible mislocalization of ductal CFTR in AIP, the association of asymptomatic pancreatic hyperenzymemia with pancreatic disorders, limitations of diagnostic tests for EPI, diagnosis of chronic pancreatitis by EUS and endoscopic pancreatic function testing and treatment of pain.

Introduction

Chronic pancreatitis is a progressive inflammatory and fibrotic disease of the pancreas with hallmark features of abdominal pain, malabsorption, malnutrition, diabetes mellitus and pancreatic calcifications. Currently, there is no definitive medical treatment for pancreatic inflammation, fibrosis or pain. In this review we focus on genetic associations of tropical pancreatitis, reversible mislocalization of ductal cystic fibrosis transmembrane conductance regulator (CFTR) in autoimmune pancreatitis (AIP), asymptomatic pancreatic hyperenzymemia, testing for exocrine pancreatic insufficiency (EPI), diagnosis of chronic pancreatitis by endoscopic ultrasound (EUS) and endoscopic pancreatic function testing (ePFT) and neuropathic pain of chronic pancreatitis.

Section 1 of 9

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islam

2011-12-12T10:20:00.000-08:00

Canadian security intelligence service

ARCHIVED: Commentary No. 30: The Rising Tide of Islamic Fundamentalism (I)

Commentary No. 30 has been archived.

Archived Content

Information identified as archived on the Web is for reference, research or recordkeeping purposes. It has not been altered or updated after the date of archiving. Web pages that are archived on the Web are not subject to the Government of Canada Web Standards. As per the Communications Policy of the Government of Canada, you can request alternate formats on the "Contact Us" page.

Dr. Wm. Millward

April 1993
Unclassified

Abstract: The first of this two-part series examines the roots and goals of the Islamic revival that has been taking place in the Middle East and North Africa, and the differences between mainstream and militant Islamism. April 1993. Author: Dr. Wm. Millward.

Editors Note: This issue of Commentary, and the next, comprise a two-part series on Islamic Fundamentalism by Dr. Wm. Millward, a Strategic Analyst in the Analysis and Production Branch of CSIS. Dr. Millward is a frequent contributor to these pages, having written on Egypt and Iran, the Middle East Peace Process and the Gulf War.

In Part I of this series, Dr. Millward examines the genesis and objectives of the Islamic revival, and traces its two basic patterns-mainstream and militant Islamism-in the major countries of the Middle East and North Africa. Deliberately excluded from this discussion, and left to Part II, is the question of support for Islamism in what the author terms "A Growing Iranian Islamist Network". In the next issue of Commentary, Part II focuses on the nature of the threat.

Disclaimer: Publication of an article in the Commentary series does not imply CSIS authentication of the information nor CSIS endorsement of the author's views.

Introduction

Periodic resurgence is an integral part of several major religious traditions around the world. The spiritual and cultural renewal of many parts of the Islamic world in the second half of the 20th century is neither unique nor aberrant; it has not happened in a vacuum or under static conditions. It coincided with the demise of the colonial era, the retreat from empire, the liberation and independence of a host of former colonial states, the emergence of a world system centred on the United Nations, and more recently, the end of the cold war and the disappearance of the bipolar world of East and West.

In this broad context it is hardly surprising that many Muslims in the Middle East and elsewhere have felt the need to renew their commitment to the faith of their ancestors, and use it as a badge of identity in forging their own unique place in the modern world. In the process, the belief system called Islam has shown itself once again to be both a durable source of religious inspiration and spiritual guidance, as well as an ideological frame of reference capable of motivating its adherents towards self-assertion in political and social affairs.

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A Question of Terminology

By an informal consensus, religious activism in the Muslim lands of the Middle East and North Africa has been labelled Islamic Fundamentalism, although most Muslims regard the term as a misnomer. Islam they say, unlike some other traditions, has always been characterized by its observance of fundamental principles. According to one Western academic, "The basic problem with the concept of fundamentalism is that it is an ethnocentric, militantly secularist categorization based on specious cross-cultural analogies." [Gregory Rose, Religious Resurgence and Politics in the Contemporary World, ed. Emile Sahliyeh, Albany: SUNY Press 1990. p. 219].

Responding to these objections, many writers have preferred to use the term "the Islamic movement" or simply "Islamism" and "Islamist" when referring to the revivalist and activist tendency among modern Muslims. Other commonly used terms are "intégrisme" and "radical political Islam". Whatever this phenomenon may be called, it is important to distinguish its several varieties and their chief characteristics as these are manifested in the major countries and principal centres of Muslim activism in the Middle East today. The Islamic movement is not a homogenous, unified and monolithic social phenomenon wherever it appears.

It can also seem inaccurate to speak of Islamic revival as if Islam had lost a good deal of its popularity and was, if not moribund, at least much weakened. On the contrary, it has continued through the ages to be popular, vibrantly alive, and expanding in numbers of adherents and territories represented. The Muslim community has continued to draw on Islam's deep reserves of spiritual nourishment to expand the frontiers of its presence through migration and missionary activity in Africa, Asia, Europe and the Americas. By most estimates, one billion people today consider themselves Muslim. Until recently it was the politicalface of Islam that was largely missing from the stage of public affairs. To speak of Islamic revival in recent years is to emphasize the growing desire of more Muslims to assert themselves on the plane of social and political action.

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The Genesis of Islamic Revival

Broadly speaking, the Islamist trend among Muslims refers to those groups and movements in several countries which are seeking to establish, overtly or covertly, an Islamic government or state. The rationale for such an objective is that an Islamic government could be expected to enforce some if not most of the laws and rules of Islam (the Shari'a), including those relating to dress code, relations between the sexes, prohibition of alcohol and gambling, punishments for specified crimes, and restrictions on banking and interest. This would allow those who were citizens of such a state to live their lives more fully in accordance with the requirements of faith. It would facilitate the earning of spiritual credit and smooth the path to salvation. It would also give the Muslims concerned a larger say in determining their own affairs and make it easier to protect their interests in relations with outsiders.

Muslims calling for the revival of their religion and community have stressed the need for individual spiritual renewal by rededication to the moral and ethical prescriptions of their faith, and the need to revitalize the community at large, the collectivity of the Muslims in its physical and political context. Some prominent Islamist thinkers and activists during the last century have emphasized the internal and spiritual axis of renewal, while others have urged specific steps or courses of action to improve the social and political condition of Muslims at large.

In the heyday of modern imperialism, one of the most outspoken activists was Jamal al-Din al- Afghani (Asadabadi), a thinker and orator who preached a gospel of pan-Islam and anti-imperialism-primarily in the Sunni Muslim territories of India, Egypt and Turkey-as the most efficient means of renewing the condition of Middle East Muslims in his time (d.1897). Other successful exponents of the Islamist movement and message have urged reform in both the internal and external dimensions of the lives of Muslims. It is not widely known beyond the frontiers of Iran that one of the most popular tracts by the Ayatollah Ruhollah Khomaini was a booklet dealing with individual moral and spiritual renewal, with the imposing title The Greater Crusade: The Struggle with the Carnal Self.

If adherents to Islam are urged to focus their attention on their relationship to Allah as well as their relationships to one another and outsiders, Islamists argue that the Muslims generally have neglected the second half of their responsibility as believers, particularly in the sphere of politics and relations with non-Muslims. The prototype of Islamic government was the system put in place in 7th century Arabia by the prophet Muhammad before he died in 632 A.D., and perhaps some of its successor structures, usually referred to as the Caliphate.

Since the abolition of the Ottoman Caliphate in 1924-the last of these indigenous multinational Islamic governments-most Middle Eastern Muslims have been governed either by traditional tribal, feudal and monarchical rulers, or by modernized and at least partly secularized élites. The latter and most of the former, so the Islamists say, are more responsive to the interests of outside powers and forces, mostly non-Muslim, and not sufficiently attentive to the real needs of their subjects as Muslims. They must therefore be replaced by individuals who are more cognizant of the Islamic method in government and more likely to enable the majority population to live their lives in stricter conformity with the rules of Islam.

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Objectives of Islamism

Most Islamist groups in the Middle East share the common objective of creating a truly Islamic society in which they can live under a régime governed by the rules of their faith as codified in Islamic law. For the extremists, the first condition for the achievement of this objective is the forcible overthrow of the current ruling élites in the Middle East, including such diverse régimes as the monarchies of Morocco and Saudi Arabia, the Emirates of Kuwait and the United Arab Emirates, and the secular governments of Algeria, Egypt and Tunisia. For Islamists in Israel and the Occupied Territories, it is the destruction of the state of Israel. The imported ideologies of communism, socialism, liberalism and nationalism are regarded, not completely without justification, as failures where they have been tried, and undesirable where they have not because they are either non-Islamic in their policies, or appear otherwise incompatible with Islamic norms.

The longer-term objective of the Islamist movement is the formation of a bloc of states whose governments apply Islamic law and practices. It hopes that such a bloc would be able, by itself or in alliance with other Third World nations, to change the rules of the international system, especially in relation to trade, and thus alter the current balance of economic and political power world-wide. In this sense, some consider their worldview threatening to the West. The Islamists believe that Islam can create, or help to create, a just political order at the international as well as at the state level. As for most Third World régimes, for them the current rules and regulations were laid down by the great powers to protect their own interests and to perpetuate their political and economic dominance.

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Two Basic Patterns: Mainstream and Militant

Those Muslims who strive to establish an Islamic government or state can be divided in two groups according to the methods they employ to achieve their aims. The mainstream Islamist trend seeks to accomplish its aims by working within the existing rules and regulations of its members' respective societies. They are generally not opposed to a degree of political pluralism, to working within the system, to democratic participation, and acknowledge the interests and rights of minorities. These Islamists are generally pragmatic, and do not rule out the existence of a market economy. Mainstream Islamists include the Muslim Brothers of Egypt and Jordan, and some sections of Front islamique du salut-the Islamic Salvation Front (FIS) in Algeria, before it was deprived of its electoral victory, declared illegal and driven underground.

The second category of those who espouse the concept of an Islamic state are the militant, radical and revolutionary Islamists who are prepared to use violence in their efforts to unseat existing governments. This trend is best illustrated in Egypt by some elements of the Islamic Organizations (Jama'at Islamiyya) and by Islamic Jihad (Jihad Islami). The threat of Islamic fundamentalism which is widely publicized in the West these days comes exclusively from this group of Islamists. They generally reject the idea of pluralism, political or otherwise, decry democracy as non-Islamic, and repress ethnic, linguistic and religious minorities. Terrorist tactics are normally considered a legitimate tool in the arsenal available to such groups.

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Social Support for Islamism

As general economic and social conditions remain static or decline in many parts of the Islamic Middle East, and governments remain incapable of dealing with these problems, the popularity of the Islamist outlook rises. Social and economic distress today-poverty and unemployment among the youth-feed the growing sense of disenchantment with the social and political status quo. The general economic malaise is exacerbated by the growing disparity between rich and poor. Régimes which count on imported social and economic programs-some dictated by the International Monetary Fund-to solve domestic problems are regarded as failures and un-Islamic.

In Algeria there is a substantial base of broad support for the Islamist current. Roughly 25 percent of the electorate, some three million people, voted for the Front islamique du salut (FIS) candidates in the federal election in the fall of 1991. Estimates of the number of committed, hard-core activists identified with FIS have varied from a handful to several hundred. Since the organization was declared illegal and severely repressed, the number of those who are now prepared to use violence to achieve their goals has substantially increased. The Algerian military is considered a bastion of opposition to the Islamists; while this assumption may be quite safe with regard to the higher ranks, many observers worry about the junior officers and lower ranks, which are thought to contain Islamist sympathizers whose loyalty to the current régime may be soft. Severe state repression is believed to have increased sympathy for the Islamists, even in intellectual circles.

In Lebanon, Hizballah is a religious, military and, since its participation in elections in the summer of 1992, a political force. Its primary constituency is the Shi'a population of the northern Biqa' valley, along with several villages in the Jabal 'Amil region in south Lebanon. The Shi'ites in Lebanon number 1.2 million, the largest religious group-41 percent-in a population of less than three million. Hizballah does not represent all the Shi'i Muslims of Lebanon but competes with the much more moderate, and numerically stronger, AMAL organization which it tries to radicalize, albeit with only limited success. The two groups were involved in a bitter three-year struggle that terminated in a peace accord in 1990 sponsored by their patrons in Tehran and Damascus. Hizballah candidates elected to the Lebanese parliament are believed to have drawn support from some Christian voters as well.

As for the membership of Hamas and Palestine Islamic Jihad, they represent a cross-section of all classes in the Occupied Territories of the West Bank and Gaza Strip. The 417 men from these two groups deported in December 1992 by Israel into south Lebanon give some indication of the people who support the Islamic movement in the territories. They are described as "ardent Islamists". Among them were several imams or spiritual guides. The militants included young students, labourers, shopkeepers and small traders, mechanics and a few professionals, mostly physicians and engineers. Some observers estimate that support for these militant Islamic groups in the Occupied Territories is running as high as 40 percent of the adult population.

In Egypt, the government has gone on the offensive against the Islamic militants, whose activities have long since spread from Upper Egypt to the capital. The Minister of the Interior, Abdel Halim Musa, in a press release in early February, claimed that in the preceding year religious extremists had killed 34 members of the police and security forces, military and civilian. [al-Hayat, February 6, 1993. p.7] Estimates of the number of militants active in Egypt vary between 10,000 and 30,000. Whatever the real number, it is in fact quite small as a percentage of total population. The mainstream Islamists of the Muslim Brotherhood are far more numerous than their extremist counterparts with perhaps as many as two million members and hundreds of thousands-if not millions-of sympathizers. A high percentage of Brotherhood members belong to the professional classes.

There is little prospect that economic and political conditions are going to improve in Algeria or Egypt or the Occupied Territories. An Islamist-oriented régime may well come to power in Algeria in the medium term. Another possible scenario is that growing Islamic extremism coupled with an increasingly harsh government response will lead to social fragmentation and anarchy in Algeria. In Egypt, although the government is under increasing pressure from Islamic militants, and is responding in kind, it is unlikely that an Islamic government will come to power in the next three to five years. As the level of tension between the authorities and their Islamist opponents rises, the possibility that a new round of conflict could spark a crisis increases proportionately. In the interim Egyptian officials will expend greater effort to step up the dialog with the Islamists and try to ensure that domestic and foreign policies continue along the path of gradual Islamization. As in Algeria, so in Egypt, the military is concerned with preserving its relative position in the social hierarchy and would therefore not approve the establishment of an Islamist-based government at this stage.

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Saudi Arabia: Fundamentalist-Yes; Islamist-Yes and No

In a special sense the Kingdom of Saudi Arabia is the quintessential fundamentalist Islamic state. In addition to its role as the custodian of Islam's two sacred sanctuaries at Mecca and Medina, the kingdom is said to represent the religious tradition in its most pristine or puritanical version, Wahhabism. This is not to be confused with "orthodoxy". Defenders of the current political system in the kingdom argue that it still reflects today the ideals of the first Islamic revolution begun two and a half centuries ago with the formation of an alliance between the fundamentalist preacher Muhammad b. Abd al-Wahhab and the tribal chieftain, Muhammad b. Sa'ud, and completed with the conquest of Hijaz and the holy cities by their descendants Abd al-Aziz b. Saud and his supporters in 1924.

Critics on the other hand ridicule such claims and point out that since the discovery of oil and the acquisition of vast wealth, the monarchy has ceased to defend the interests of the Muslims at large and become dependent on non-Muslim power for its survival. Proof of this is the role played by Saudi Arabia in the Gulf crisis. The mere presence on the sacred soil of Arabia of nearly half a million non-Muslim combatants, albeit far removed from the two holy sanctuaries, for the purpose of defending the kingdom from Saddam and ultimately driving him from Kuwait, was a highly symbolic illustration of this dependence.

An Islamic, if not an Islamist, opposition in Saudi Arabia operates on three fronts. One is the Sunni populist and radical fundamentalist sentiment which was expressed in the takeover of the Grand Mosque in Mecca in December of 1979. This trend appears to have been eliminated since the incident was put down. The second source of opposition comes from that sector of the population, roughly 7 percent and located almost entirely in the Eastern province, who are Shi'a by rite, and have been subject to incessant propaganda from their fellow sectarians in Iran ever since the Islamic revolution. They seek full rights for Shi'a citizens, not state power. A third focus of opposition comes from many professional religious scholars who oppose the existing political system in the kingdom chiefly because of its dependence on the West. The institution of the ulama and the power it exercises in Saudi Arabia is tightly controlled by the government. It is unlikely that the dissident ulama will become a source of threat to the Saudi regime in the foreseeable future, but their presence behind the scenes will be a reminder to the government that some institutionalized forum for the expression of dissent is an urgent desideratum.

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Increasing Organization: A Fundamentalist International?

The concept of organization and structure has been implicit in the Islamic faith and community from its inception. As a universal creed designed to accommodate humanity at large, even the earliest Muslims had to give their attention to the needs of new converts and the requirements of an expanding community. With the annual gathering of the believers in performance of the ritual obligation of pilgrimage, there is a sense in which the idea of the congress or annual general meeting was built into the system. But the universal caliphate was never coterminous with all the territory occupied by Muslims after the death of the Prophet. Power and control was frequently disputed from the periphery to the centre, and once the last Islamic empire of the Ottomans began to decline and fragment, the concept of structure and organization in the Islamic community became a more local and particular concern.

From the point of view of the Islamists, the transnational structures and organizations of the Muslim world have been dominated too long by those states which are subservient to foreign interests. The network of organizations and bodies with representatives in other Muslim states in the region has been controlled from the outset by the wealthy states of the peninsula, particularly Saudi Arabia. Through such groups as WAMY (World Assembly of Muslim Youth) and WML (World Muslim League) the peninsula states distribute funds for Muslim causes elsewhere, promote regular conferences and study groups, and attempt to defend Muslim interests and set the agenda for the Muslim world in its domestic and international settings.

The Jidda-based OIC (Organization of the Islamic Conference) is the most important Islamic body for discussing matters of foreign relations between Muslim states and international problems affecting Muslim interests. The Satanic Verses/Salman Rushdie issue was debated in the OIC. The same body is currently the forum for discussion of the Islamic dimension to the conflicts in the former Yugoslavia, Somalia, the West Bank and Gaza, and others. The OIC has not yet, however, been able to galvanize its members into taking joint action on issues.

Nonetheless, the concept of a "fundamentalist international" has occasioned widespread attention and an appreciable degree of discomfort and fear in the West. In this post cold-war era, some would even see it as having replaced communism as a major threat to world peace and security. We will turn the discussion toward the nature of this perceived threat in the subsequent issue (#31) of Commentary.

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Commentary is a regular publication of the Analysis and Production Branch of CSIS. Inquires regarding submissions may be made to the Chairman of the Editorial Board at the following address:

The views expressed herein are those of the author, who may be contacted by writing to:

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statins

2011-12-10T07:48:00.000-08:00

From Journal of the American Geriatrics Society

The Cholesterol Conundrum

John E. Morley, MB, BCh

Authors and Disclosures

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Abstract and Introduction
When Should Statins be Used in Older Persons?
Conclusion

References

Abstract and Introduction

Introduction

Twenty-one years ago, Fran Kaiser and I published an editorial in this journal entitled "Cholesterol can be lowered in older persons. Should we care?"^[1] This editorial was written in response to a series of epidemiological articles suggesting that, in old persons, low cholesterol was associated with greater total mortality. In this issue of the Journal, Newson and colleagues^[2] found that higher total cholesterol and non-high-density lipoprotein cholesterol (HDL-C) in older persons was associated with a lower risk of noncardiovascular and total mortality. In part, this was attributable to a lower risk of cancer deaths.

One reason for the association between low cholesterol and mortality is that low cholesterol is associated with weight loss. Epidemiological studies have found that intentional or unintentional weight loss is associated with greater mortality.^[3] Although the authors adjusted their analysis for body mass index (BMI), many overweight persons lose weight while their BMI remains high. Many reasons have been suggested for why weight loss may increase mortality, including occult or mild disease, loss of bone and muscle mass, loss of adipose stem cells, inappropriate medication dosing, and release of fat-soluble toxins into the circulation.

Another possibility is that some components of non-HDL-C may be protective against disease and that persons who survive into old age are more likely to be enriched for these protective elements. Low-density lipoprotein cholesterol LDL-C consists of a triglyceride-enriched, small, dense LDL that the arteries preferentially take up and is readily oxidized and a large, buoyant LDL.^[4] This large LDL is nonatherogenic and is one of the factors associated with exceptional longevity.[5, 6] Increases in large LDL are associated with lower levels of the cholestryl ester transfer protein (CETP) and greater frequency in the homozygosity of the 1405 valine allele of CETP (VV genotype).

The correlation between low cholesterol and frailty may further explain the relationship with cholesterol reverse epidemiology in older persons.^[7] Frailty is strongly associated with subsequent mortality^[8] and with high cytokine levels and weight loss, both of which would lower cholesterol.

Section 1 of 3

Next: When Should Statins be Used in Older Persons? »

dabigatran warfarin

2011-12-10T01:15:00.001-08:00

From News Alerts > Heartwire

FDA Investigating Serious Bleeding Events With Dabigatran

Michael O'Riordan

December 7, 2011 (Rockville, Maryland) — The US Food and Drug Administration (FDA) announced today that it is now investigating postmarketing reports of serious bleeding events in patients taking dabigatran etexilate (Pradaxa, Boehringer Ingelheim) [1].

"FDA is working to determine whether the reports of bleeding in patients taking Pradaxa are occurring more commonly than would be expected, based on observations in the large clinical trial that supported the approval of Pradaxa," according to the drug safety communication issued by the agency.

That large clinical trial is RE-LY. As reported previously by heartwire , rates of fatal bleeding were numerically lower with the higher dose tested in the trial--150 mg twice daily--at 0.23% per year (230 per 100 000 patient-years) compared with warfarin at 0.33% per year (330 per 100 000 patient-years). Life-threatening bleeds were more common, numerically, in the 150-mg group than in the 110-mg group tested in the trial. The 110-mg dose was not approved by the FDA, although it is on other worldwide markets.

Bleeding events with dabigatran have already prompted safety advisories in Japan and Australia and have led to labeling updates in Europe and the US focusing on the need for monitoring renal function. In November, Boehringer Ingelheim confirmed that between March 2008 and October 31, 2011 there were 260 fatal bleeding events worldwide.

The FDA said it will inform the public and clinicians about any new information about bleeding risks when it becomes available. In the meantime, the agency said it believes the anticoagulant provides an important health benefit when used as directed and that patients taking dabigatran should not stop taking the drug without talking to their doctor.

The FDA also noted that physicians should report adverse events or side effects related to dabigatran use to the FDA's MedWatch Safety Information and Adverse Event Reporting Program.

Af aspirine

2011-12-08T10:19:00.000-08:00

Original Research

Net Clinical Benefit of Adding Clopidogrel to Aspirin Therapy in Patients With Atrial Fibrillation for Whom Vitamin K Antagonists Are Unsuitable

Stuart J. Connolly, MD;
John W. Eikelboom, MBBS;
Jennifer Ng, MSc;
Jack Hirsh, MD;
Salim Yusuf, MD;
Janice Pogue, MSc, MA;
Raffaele de Caterina, MD, PhD;
Stefan Hohnloser, MD; and
Robert G. Hart, MD,
on behalf of the ACTIVE (Atrial Fibrillation Clopidogrel Trial with Irbesartan for Prevention of Vascular Events) Steering Committee and Investigators

+ Author Affiliations

From McMaster University, Hamilton, Ontario, Canada; Gabriele d'Annunzio University, Chieti, Italy; and Goethe University, Frankfurt, Germany.

Abstract

Background: Adding clopidogrel to aspirin therapy reduces stroke in patients with atrial fibrillation (AF) but increases hemorrhage.

Objective: To quantify the net benefit of adding clopidogrel to aspirin therapy, accounting for differences in clinical significance between ischemic and hemorrhagic events.

Design: Observational cohort study to assign the relative weighting of events and post hoc analysis of randomized trial data to assess net benefit of dual antiplatelet therapy in the ACTIVE (Atrial Fibrillation Clopidogrel Trial with Irbesartan for Prevention of Vascular Events) clinical trials.

Setting: Global randomized clinical trial.

Patients: 10 041 patients with AF, 7554 of whom were not candidates for warfarin therapy.

Measurements: Ischemic events (ischemic stroke or myocardial infarction) and hemorrhagic events (hemorrhagic stroke or subdural or extracranial bleeding), weighted by the hazard ratio for death (or death or disability) after an event relative to death (or death or disability) after ischemic stroke. The net clinical benefit of dual antiplatelet therapy in the ACTIVE A trial participants was defined as the sum of weighted event incidence with dual antiplatelet therapy subtracted from the sum of weighted event incidence on control treatment, expressed as ischemic stroke equivalents prevented per 100 patients years.

Results: Adding clopidogrel to aspirin therapy prevented 0.57 ischemic stroke equivalent (95% CI, −0.12 to 1.24) per 100 patient-years of treatment when weighted by hazard for death after ischemia or hemorrhage and 0.67 ischemic stroke equivalent (CI, −0.03 to 1.18) when weighted by death or disability after ischemia or hemorrhage.

Limitation: No attempt was made to relate deaths used for weighting to events; disability data were missing for more than one half of patients.

Conclusion: Adding clopidogrel to aspirin therapy resulted in a modest net benefit among patients with AF for whom warfarin was unsuitable. The benefit would probably be clinically relevant for some patients, but estimates could not exclude the possibility of either no benefit or very small harm in this population

IgG4 pancreatitis

2011-12-06T09:35:00.001-08:00

Autoimmun Rev. 2010 Jul;9(9):591-4. Epub 2010 May 10.

The birthday of a new syndrome: IgG4-related diseases constitute a clinical entity.

Takahashi H, Yamamoto M, Suzuki C, Naishiro Y, Shinomura Y, Imai K.

Source

First Department of Internal Medicine, Sapporo Medical University School of Medicine, Japan. htakahas@sapmed.ac.jp

Abstract

IgG4-related disease is a distinct clinical entity, whose characteristic features are the following; Serum IgG4 is prominently elevated, IgG4-positive plasma cells infiltrate in involved tissues, various mass-forming lesions with fibrosis develop in a timely and spatial manner and the response to corticosteroids is prompt and good. IgG4-related diseases mainly target two organs. One is the pancreas (autoimmune pancreatitis; AIP), and the other comprises the lacrimal and salivary glands, the clinical phenotype is Mikulicz's disease (MD). MD has long been considered a manifestation of Sjögren's syndrome (SS). However, we noticed several clinical differences in case of MD from SS; no deflection of female sex differences, mild sicca syndrome, good response to corticosteroids, no positivity of anti-SS-A/SS-B antibodies. In addition, elevated level of serum IgG4 and abundant infiltration of plasma cells expressing IgG4 were reported in MD patients. Those are common features of IgG4-related diseases. MD often coexisted with IgG4-related diseases such as AIP, retroperitoneal fibrosis, and IgG4-associated nephropathy. Based on those findings, it has been considered to recognize IgG4-related diseases including MD as a new clinical entity. The etiology of IgG4-related systemic diseases remains to be elucidated. It is necessary to accumulate and analyze larger data from patients worldwide.

statin lipitor

2011-12-02T15:02:00.001-08:00

From FDA Approvals > Heartwire

Generic Atorvastatin Now Available in US

Sue Hughes

Authors and Disclosures

Posted: 12/01/2011

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December 1, 2011 (Princeton, New Jersey) — The US FDA has approved the first generic version of atorvastatin--from Ranbaxy Laboratories. The generic is now available as 10-mg, 20-mg, 40-mg, and 80-mg tablets, manufactured by Ohm Laboratories [1].

Ranbaxy has exclusivity to market generic atorvastatin until May 2012, after which time many more generic versions will become available.

Atorvastatin has until now been available only as the branded Lipitor (Pfizer), which has been the world's top-selling drug for several years. Last year, it had worldwide sales of $10.7 billion, of which $7.9 billion were in the US.

In an effort to keep some of its market share, Pfizer is producing an "authorized generic" product that is being marketed by Watson Pharmaceuticals. Pfizer has also agreed to deals with pharmacy-benefit managers to keep dispensing Lipitor for a time at generic prices. It has also launched a "Lipitor for you" program, which includes a card limiting a patient's copayment to $4, valid until the end of 2012, with the company reimbursing the pharmacy the remaining copayment value.

Patients will benefit enormously from the availability of the lower-cost generics, with many more now being able to afford to take atorvastatin, which is a more potent statin than others that have been available generically. Insured patients will also be better off, as the insurance copay for generic drugs is much cheaper than that for branded drugs.

Dr William Boden (University at Buffalo Schools of Medicine, NY), recently told heartwire that the availability of generic atorvastatin should bring public-health benefits. "At the moment the most widely prescribed generic statin is simvastatin. This will now change to atorvastatin, as all those patients who can't afford the large copays on the branded product will be able to get it much cheaper. That means more people will be on a more powerful statin, and cholesterol levels in general should be lower."

warfarin AF

2011-11-30T01:05:00.001-08:00

Adverse Drug Events Cause Many Hospitalizations in Elders

A few medications cause most of the problems that lead to emergency hospitalization in older patients.

Adverse drug events (ADEs) leading to emergency department (ED) visits or emergency hospitalizations are particularly common in older patients. The recent national focus on preventable rehospitalizations brings identifying and addressing high-risk medications to the healthcare forefront.

Investigators used 2007–2009 data from a nationally representative sample of 58 hospitals to estimate that nearly 100,000 emergency hospitalizations (1.5% of all emergency hospitalizations among elders) occurred annually due to medication injury in older patients (age, 65); they excluded cases of intentional self-harm, drug abuse, therapeutic failures, or drug withdrawal. Almost half (48%) of ADE-related hospitalizations among elders were in patients older than 80. Four medications accounted for more than two thirds of these ADE-related emergency hospitalizations: warfarin (33%), insulins (14%), oral antiplatelet agents (13%), and oral hypoglycemic agents (11%). Warfarin-related hemorrhages accounted for an estimated 21,000 emergency hospitalizations annually. Interestingly, medications designated as high risk by national quality measures (i.e., Healthcare Effectiveness Data and Information Set [HEDIS] high-risk medications or Beers-criteria potentially inappropriate medications) rarely caused emergency hospitalizations (1.2% and 6.6%, respectively) among older patients.

Comment: The nearly 100,000 annual emergency hospitalizations caused by ADEs in older patients represent an opportunity to prevent patient harm and lower healthcare use. Augmenting efforts to reconcile medications accurately at care transitions, as well as more aggressive drug monitoring for medications that commonly cause hospitalizations (including drug management programs), would help improve patient safety and prevent ADE-related hospitalizations. Policies to promote patient safety should target these identified medication classes for which evidence of patient harm exists.

— Daniel D. Dressler, MD, MSc, SFHM

Published in Journal Watch Hospital Medicine November 23, 2011

statins

2011-11-24T09:21:00.000-08:00

November 23, 2011 — Results from the long-term follow-up of the Heart Protection Study (HPS) may offer reassurance that statins are safe and effective in patients at high risk for vascular disease, according to new research published online November 23 in The Lancet.

The average decline in low-density lipoprotein cholesterol with statins in the initial 5-year period that patients received them was 1.0 mmol/L, with a 23% proportional drop in major vascular events (95% confidence interval [CI], 19 - 28; P < .0001). The benefit persisted largely unchanged during the 11-year follow-up period, with no further improvements in either major vascular events (risk ratio [RR], 0.95; 95% CI, 0.89 - 1.02) or vascular mortality (RR, 0.98; 95% CI, 0.90 - 1.07). There was also no evidence of added harm during the combined in-trial and follow-up period for cancer at all sites (RR, 0.98; 95% CI, 0.92 - 1.05), or any particular site, or in mortality attributed to cancer (RR, 1.01; 95% CI, 0.92 - 1.11), or for nonvascular causes (RR, 0.96; 95% CI, 0.89 - 1.03).

The authors, from the HPS Collaborative Group, Clinical Trial Service Unit, Oxford, United Kingdom, write: "These findings provide further support for the prompt initiation and long-term continuation of statin treatment in people at increased risk of vascular events."

The study is based on extended follow-up data from the randomized HPS, conducted in the United Kingdom. Between July 1994 and May 1997, investigators randomly assigned 20,536 high-risk men and women between the ages of 40 and 80 years to receive 40 mg simvastatin daily or placebo for approximately 5 years. At final follow-up in 2001, investigators instructed the patients to continue taking the statins unless there were any contraindications. The absolute benefits of treatment continued during the 5-year in-trial period and rose year after year, but they plateaued in the years after the trial.

Patients were followed for an average of 5.3 years (standard deviation, 1.2), with posttrial follow-up lasting an average of 11 years (standard deviation, 0.6). Other important findings include that a first diagnosis of any cancer (other than nonmelanoma skin cancers) was the same throughout the in-trial and extended follow-up periods, at 1749 (17.0%) in the simvastatin group vs 1744 (17.0%) in the placebo group (RR, 0.98; 95% CI, 0.92 - 1.05; P = .60). For patients aged 70 years or more at baseline, there was also no increase in genitourinary, gastrointestinal, respiratory, hematological, or any other malignant disease.

The study was blinded for the most part, unless physicians felt it important to know whether their patients were receiving the drug or not. As a result, 18% of the simvastatin-treated patients and 13% of the patients receiving the placebo were unblinded. Some observational studies found that statins were linked to excess cancers, particularly in the elderly, making posttrial follow-up a priority.

In an accompanying commentary, Payal Kohli, MD, and Christopher P. Cannon, MD, from the TIMI Study Group, and Cardiovascular Division of Brigham and Women's Hospital, Boston, Massachusetts, point to several randomized studies that have demonstrated the safety of statins on extended follow-up. They write: "The original concerns about statin safety...were probably heavily confounded. We now have strong evidence from HPS and several other randomized controlled trials that prolonged treatment with statins is indeed efficacious, safe, and has long-lasting beneficial effects, even after discontinuation of therapy."

The study was funded by the UK Medical Research Council, the British Heart Foundation, Merck & Co, and Roche Vitamins. The authors of the HPS Collaborative Group and Dr. Kohli have disclosed no relevant financial relationships. Dr. Cannon states that he has received research funding from Accumetrix, AstraZeneca, Glaxo SmithKline, Merck, and Takeda. He also has received honoraria from Pfizer and AstraZeneca, has participated in advisory boards for Bristol-Myers Squibb/sanofi-aventis, Novartis, and Alnylam, and has equity in Automedics Medical Systems.

Lancet. Published online November 23, 2011. Abstract

cholesterol kaas boter

2011-11-20T05:29:00.000-08:00

From Reuters Health Information

Is Cheese Better Than Butter for Heart Health?

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By Andrew M. Seaman

NEW YORK (Reuters Health) Nov 15 - Doctors and nutritionists have long recommended avoiding all animal fats to trim cholesterol, but Danish researchers report that cheese may not be so bad, and probably shouldn't be lumped in the same category as butter.

Their study, published online October 26 in the American Journal of Clinical Nutrition, found that people who ate daily servings of cheese for six-week intervals had lower LDL cholesterol than when they ate a comparable amount of butter. The cheese-eaters also did not have higher LDL during the experiment than when the same subjects ate a normal diet.

Dr. Elizabeth Jackson, assistant professor of medicine at the University of Michigan Health Systems, told Reuters Health that the study was well done, but does not really change what cardiologists currently recommend.

"We want people to have a diet focused on whole grains and vegetables and moderate fats," said Dr. Jackson, who was not involved in the work.

The researchers, from the University of Copenhagen in Denmark, set out to learn what effects cheese and butter had on heart disease risk factors, such as HDL, LDL and total cholesterol levels.

They followed about 50 people who answered ads in local newspapers. Each person was put on a controlled diet and added a measured amount of cheese or butter daily.

Throughout, each participant was compared against his or herself, to follow the changes in the body caused by the foods.

Researchers gave each person cheese or butter, both made from cows milk, equal to 13% of their daily energy consumption from fat.

During six-week intervals, each person ate the set amount of cheese or butter, separated by a 14-day cleansing period in which they returned to their normal diet. Then they switched, and for six weeks those who had eaten the cheese before, ate butter, while the butter eaters in the first phase changed over to cheese.

Despite eating more fat than had been in their normal diet, the cheese eaters showed no increase in LDL or total cholesterol. While eating butter, however, the same subjects had LDL levels about 7% higher on average.

While eating cheese, subjects' HDL cholesterol dropped slightly compared to when they ate butter, but not compared to their normal eating period.

The authors speculate there could be several reasons why cheese behaved differently than butter, but nothing conclusive.

For one, cheese has a lot of calcium, which has been shown to increase the amount of fat excreted by the digestive tract. (See Reuters Health story of October 21, 2011).

The researchers did detect a little more fecal fat during the time the group ate cheese, but the amounts were not statistically significant.

Other possible explanations involve the large amount of protein in cheeses and its fermentation process, both of which could affect the way it's digested compared with butter.

The study was supported by the Danish Dairy Board and the National Dairy Research Institute.

SOURCE: http://bit.ly/vDIMx7

Am J Clin Nutr 2011.

NEW YORK (Reuters Health) Nov 15 -

dementia ACE inhibitors

2011-11-15T03:59:00.000-08:00

From Medscape Education Clinical Briefs

ARBs May Reduce Risk for Alzheimer's and Other Dementia

*Clinical Context

Clinicians can face a difficult choice in deciding what class of antihypertensive medication to prescribe for their patients. However, all medications used to treat hypertension are not equal in their effects on important cardiovascular outcomes. A review by De Caterina and Leone, which appeared in the May 15, 2010, issue of The American Journal of Cardiology, concluded that beta-blockers are associated with worse results in the prevention of stroke compared with the use of other antihypertensive medications. Moreover, beta-blockers may not prevent coronary artery disease when used to treat patients with hypertension. They fail to lower central blood pressure to the degree of other antihypertensive drugs, and they have negative metabolic effects, which might contribute to higher rates of cardiovascular disease.

Beta-blockers have also been associated with worsened cognitive outcomes compared with angiotensin II receptor blockers (ARBs). It is possible that both angiotensin-converting enzyme (ACE) inhibitors and ARBs can reduce the risk for incident dementia. The current study by Kehoe and colleagues examines this possibility in a large cohort of patients.

Study Synopsis and Perspective

Controlling blood pressure with an ARB rather than other antihypertensive agents may significantly reduce the risk for Alzheimer's disease (AD) and vascular dementia (VaD), suggest results of a large observational study from the United Kingdom.

In the study, the risk for AD was 53% lower in older adults prescribed an ARB compared with those prescribed other antihypertensive agents. The risk was 24% lower in those prescribed an ACE inhibitor.

Patrick G. Kehoe, PhD, coleader of the Dementia Research Group at Frenchay Hospital, Bristol, and colleagues report their study in the October issue of the Journal of Alzheimer's Disease.

Dr. Kehoe and colleagues say their findings support those of a recent study in a predominantly male population from the United States. In that study, reported previously by Medscape Medical News, men prescribed ARBs had a lower incidence and rate of progression of AD than those prescribed ACE inhibitors or other cardiovascular drugs.

The accumulating observational and biological evidence in favor of ARBs protecting against dementia "strengthens the need for them to be studied more rigorously in the future," Dr. Kehoe and colleagues conclude.

Although "interesting, these are not conclusive findings," coauthor Richard M. Martin, PhD, from the University of Bristol, notes in a statement. "We now need to do the clinical trials to properly test our observations."

Accumulating Evidence

The study was a nested case-control study within the UK general practice research database. It was designed to see whether ARBs and ACE inhibitors are more strongly associated with AD, VaD, and other dementias relative to other antihypertensive drugs such as calcium channel blockers, beta-blockers, or thiazide diuretics.

Although both ARBs and ACE inhibitors reduce angiotensin II signaling, "now believed to be involved in the pathobiology of AD, ARBs are unlikely to interrupt ACE-mediated [amyloid-beta] degradation," unlike ACE inhibitors, the researchers note in their article. "These mechanisms of action suggest that ARBs may have benefits over [ACE inhibitors] in the etiology of AD," they write.

Included in the analysis were 9197 patients, aged 60 years and older, who were diagnosed between 1997 and 2008 with probable or possible AD (n = 5797), VaD (n = 2186), or unspecified/other dementia (n = 1214). Each case patient was matched by age, general practice, and sex to up to 4 control patients (n = 39,166).

The researchers observed that patients ever prescribed either ARBs or ACE inhibitors were less likely to develop AD, VaD, or other dementia than patients ever prescribed other antihypertensive medications. The associations were stronger for ARBs than for ACE inhibitors.

Table. Dementia Outcomes With ARBs and ACE Inhibitors vs Other Agents

Outcome	ARBs, OR (95% CI)	ACE inhibitors, OR (95% CI)
Probable AD	0.47 (0.37 - 0.58)	0.76 (0.69 - 0.84)
Probable VaD	0.70 (0.57 - 0.85)	0.82 (0.75 - 0.91)
Unspecified/other dementia	0.62 (0.47 - 0.81)	0.85 (0.75 - 0.96)

OR, odds ratio; CI, confidence interval

These associations did not differ by age, comorbidities, or blood pressure, suggesting little confounding by observed comorbidities, the researchers say. There was also evidence of a dose–response relationship between ARBs and AD (P = .009).

In analyses restricted to patients exposed either to ARBs or ACE inhibitors as their only therapy, there was an inverse association of ARB sole therapy (OR, 0.63; 95% CI, 0.45 - 0.88), but not ACE inhibitor sole therapy (OR, 1.01; 95% CI, 0.91 - 1.12).

"Preaching to the People"

Reached for comment, Gustavo C. Román, MD, medical director of the Nantz National Alzheimer Center at the Methodist Neurological Institute in Houston, Texas, who was not involved in the study, said it "reaffirms the need to control blood pressure, and the sooner, the better."

Dr. Román said he has been "preaching to the people that you need to keep your blood pressure under good control because it really seems that vascular disease, and especially hypertension, opens the gate to the amyloid-beta changes, although the mechanism is not very clear.

"Whatever the mechanism, it has been demonstrated over and over that vascular disease, in particular hypertension, is a risk factor for the development of [AD]," he added.

The study was supported by the North Bristol National Health Service Trust. The authors and Dr. Román have disclosed no relevant financial relationships.

J Alzheimers Dis. 2011;26:699-708. Abstract

pancreas

2011-11-09T01:10:00.001-08:00

Howell MD, Novack V, Grgurich P, et al
Arch Intern Med. 2010;170:784-790

Study Summaries

The incidence and severity of Clostridium difficile infections (CDI) are increasing at an alarming rate. Because the gastric acid barrier is one of the defense mechanisms for protecting the integrity of the normal gut microflora environment, acid-suppression therapy has beensuggested as treatment for a number of intestinal pathogenic infections -- including C difficile -- but this remains controversial.

These 2 reports suggest that the increased risk for CDI with proton pump inhibitors (PPIs) is not at all modest, and that gastric acid is potentially important in protecting against infection from this pathogen.

The study by Linsky and colleagues is a pharmacoepidemiologic cohort trial in which a secondary analysis was performed with data collected prospectively on 101,796 patients discharged from a tertiary care medical center during a 5-year period. As use of acid-suppression therapy increased, the reported risk for nosocomial CDI also increased, from 0.3% (95% confidence interval [CI], 0.21%-0.31%) in patients who did not receive acid-suppression therapy, to 0.6% (95% CI, 0.49%-0.79%) in those who did receive histamine2-receptor antagonist (H₂RA) therapy, to 0.9% (95% CI, 0.80%-0.98%) in patients who received daily PPI treatment, and to 1.4% (1.15%-1.71%) in those who received more frequent PPI therapy.

folium zuur

2011-11-09T00:39:00.000-08:00

Lancet 2011 Aug 13; 378:584.
Diet, Genes, and Stroke Risk: Another Look at Homocysteine and Folate
A genetic analysis and a meta-analysis suggest that lowering homocysteine levels reduces stroke risk more in low-folate regions than in areas with folate fortification, and that folate status modifies the effect of MTHFR alleles on stroke risk.
The MTHFR 677CT polymorphism is associated with elevated homocysteine levels and with increased stroke risk. Vitamin therapy with folic acid, vitamin B6, and vitamin B12 lowers homocysteine levels; however, randomized controlled trials (RCTs) of vitamin therapy for elevated homocysteine levels have not shown reductions in stroke risk (Arch Intern Med 2010; 170:1622). Folate consumption affects serum homocysteine levels and varies by geographic region. The RCTs evaluating the effect of homocysteine lowering on stroke risk were predominantly performed in areas with folic acid supplementation, which could explain the lack of benefit.
To investigate the potential modifying effect of folate status on the association between the MTHFR 677CT variant and stroke risk, researchers reassessed genetic studies that included data for homocysteine concentration and stroke. The investigators compared their genetic-analysis findings with a meta-analysis of 13 RCTs of homocysteine-lowering treatments to reduce stroke risk and found the following:

The effect of the MTHFR 677CT polymorphism on homocysteine concentration was modified substantially by folate consumption: The effect was larger in low-folate areas (e.g., Asia) than in areas with folate fortification (e.g., the U.S.).
The effect of the MTHFR 677CT polymorphism on stroke risk was also larger in low-folate regions than in areas with folate fortification.
In an analysis limited to only large studies, the authors predicted that lowering homocysteine levels would reduce stroke risk more in low-folate regions than in areas with folate fortification.

Comment: These findings suggest that homocysteine-lowering therapy would have the greatest effect in geographic areas with low dietary folate consumption. Because RCTs have failed to show benefit of folate therapy (Arch Intern Med 2010; 170:1622) and have suggested that there may even be harm (N Engl J Med 2006; 354:1578), I would not currently recommend folate supplementation. However, folate supplementation may have a role in those with the MTHFR 677CT variant, particularly in low-folate regions. To date, no trial has been conducted exclusively in a low-folate region to evaluate the effect of homocysteine reduction on stroke risk. The ongoing China Stroke Primary Prevention Trial — which is comparing stroke risk with enalapril alone to enalapril plus folic acid in hypertensive individuals without established cardiovascular disease — may show whether homocysteine lowering can reduce stroke risk in low-folate regions.
— Amytis Towfighi, MD Dr. Towfighi is Assistant Professor, Department of Neurology, University of Southern California, Los Angeles; and Chair, Department of Neurology, Rancho Los Amigos National Rehabilitation Center, Downey, CA.
Published in Journal Watch Neurology October 25, 2011
Citation(s): Holmes MV et al. Effect modification by population dietary folate on the association between MTHFR genotype, homocysteine, and stroke risk: A meta-analysis of genetic studies and randomised trials. Lancet 2011 Aug 13; 378:584.
http://www.ncbi.nlm.nih.gov/pubmed/21803414?dopt=Abstract

MRI panceas

2011-11-03T05:01:00.000-07:00

ScienceDaily (Oct. 3, 2011) — Magnetic Resonance Imaging (MRI), an important diagnostic test, has traditionally been off limits to more than 2 million people in the United States who have an implanted pacemaker to regulate heart rhythms or an implanted defibrillator to prevent sudden cardiac death. Now, in a study published in the October 4 issue of Annals of Internal Medicine, cardiologists at Johns Hopkins report that a protocol they developed has proved effective in enabling patients with implanted cardiac devices to safely undergo an MRI scan.

"We believe this is the largest prospective study of MRI in patients with implanted devices," says lead author Saman Nazarian, a Johns Hopkins cardiac electrophysiologist and an assistant professor of medicine at the Johns Hopkins University School of Medicine.

"The guidelines we have published can be used to make MRI more available to people who could benefit from early detection of cancer and other diseases and for guiding surgeons during procedures. MRI is considered superior to CT scans in many clinical scenarios, especially for brain and spinal cord imaging," adds Nazarian. To date, more than 700 patients with implanted cardiac devices have safely undergone MRI exams at Johns Hopkins.

vitamine B12 foliumzuur

2011-11-02T14:39:00.000-07:00

From AccessMedicine from McGraw-Hill

Vitamin B₁₂ Status Linked to Cognitive Decline and MRI Changes

S. Andrew Josephson, MD

Authors and Disclosures

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Guidelines suggest serum B₁₂ measurement in patients with suspected dementia in order to screen for severe B₁₂ deficiency as a potentially treatable cause of cognitive decline. There remains a concern that some individuals with more modestly low levels of B₁₂ may also experience cognitive decline that may be made clinically worse by high levels of serum folate, a more common occurrence in the United States since the introduction of mandatory folic acid grain supplementation. A recent study (Tangney et al., 2011) aimed to examine the relationship between cognitive decline, MRI changes, and levels of B₁₂ and other biochemical markers of B₁₂ deficiency, namely serum homocysteine and methylmalonic acid (MMA).

Participants in the study were part of the Chicago Health and Aging Project, a longitudinal cohort study of 6158 persons. At baseline, all patients received in-home interviews that included cognitive testing repeated in 3-year cycles. Stratified random sampling of patients at each cycle triggered both a clinical neurologic evaluation and phlebotomy. The present study includes 121 of these randomly selected patients who underwent cognitive testing followed by brain MRI on average 4.6 years later. The average age of the patients included was 79 years, and 51% were women. Of the group, 17.5% demonstrated elevated serum homocysteine values (>14 µmol/L) and 15.2% had elevated MMA (>271 nmol/L).

The authors found that both homocysteine and MMA were significantly associated with poorer cognitive testing across multiple domains; B₁₂ levels demonstrated no such association. For each 1-µmol/L increase in homocysteine, for example, the global cognitive score decreased by 0.03 standardized units (p = .04). Examination of MRI measures demonstrated that serum homocysteine concentration was significantly associated with an increased volume of white matter hyperintensities even after adjustment for age, sex, race, education, dementia, and APOE4 status. Higher levels of homocysteine and MMA were each significantly associated with decreased total brain volume (a measure of atrophy) even after adjustment. Interestingly, the association of homocysteine with cognitive function was no longer significant after adjustment for white matter volume or cerebral infarcts, and the association of MMA with cognitive function was no longer significant after adjustment for total brain volume.

This study is not the first to examine these relationships, but it does paint a tantalizing picture that modest amounts of B₁₂deficiency, as noted by elevation of MMA and homocysteine, may either lead to or speed the rate of cognitive decline in elderly patient populations. The model that emerges is that elevated MMA (a more specific marker for B₁₂ deficiency) may affect cognition through reduction in total brain volume, and homocysteine (which can also be elevated in folate deficiency and other conditions) may mediate effects on cognition through increased white matter hyperintensities and cerebral infarcts. For the clinician, it is reasonable to encourage adequate B₁₂ intake among the elderly, but future studies are needed to determine whether B₁₂ levels should be measured routinely (perhaps via serum MMA or homocysteine levels) in patients without cognitive decline and then supplementation initiated in hopes of preventing decline.

folium zuur

2011-10-21T12:06:00.000-07:00

October 17, 2011 — Folic acid supplements taken from 4 weeks before to 8 weeks after conception have been linked to a significantly lower prevalence of severe language delay in children, according to a study published in the October 12 issue of JAMA.

Dr. Christine Roth

"Severe language delay is associated with a range of childhood neuropsychiatric disorders, such as autism, and is also associated with difficulties in achieving literacy," lead author Christine Roth, ClinPsyD, from the Norwegian Institute of Public Health in Oslo, told Medscape Medical News.

Even though half of the children who are rated as having language delay at age 3 years, especially if it is in the moderate range, grow out of it by the time they reach school age, many continue to struggle with language difficulties, said Dr. Roth, who is also a visiting researcher at the Mailman School of Public Health at Columbia University in New York City.

Studies have shown that periconceptional folic acid supplements reduce the risk for neural tube defects, but none of the trials have followed-up to investigate whether the supplements have effects on neurodevelopment that only show after birth, she said.

"Unlike the United States, Norway does not fortify foods with folic acid, increasing the contrast in relative folate status between women who do and do not take folic acid supplements," she noted.

With this in mind, Dr. Roth set out to specifically study periconceptional folic acid use and language delay.

The analysis included 19,956 boys and 18,998 girls born to mothers participating in the Norwegian Mother and Child Cohort Study between 1999 and 2008. The researchers used data on children born before 2008 whose mothers returned the 3-year follow-up questionnaire by June 2010.

The investigators found that 204 children (0.5%) had severe language delay, defined as minimal expressive language (only 1-word or unintelligible utterances). Of the 9052 children whose mothers took no folic acid supplements, severe language delay was reported in 81 children (0.9%), but among the 7127 children whose mothers did take folic acid supplements, severe language delay was reported in 28 children (0.4%).

"If in future research this relationship were shown to be causal, it would have important implications for understanding the biological processes underlying disrupted neurodevelopment, for the prevention of neurodevelopmental disorders, and for policies of folic acid supplementation for women of reproductive age," senior author Ezra Susser, MD, DrPh, from the Mailman School of Public Health and the New York State Psychiatric Institute, New York City, said in a statement.

Dr. Roth added that Norwegian women should follow the current recommendations of starting to take a folic acid supplement of 0.4 mg daily 1 month before becoming pregnant and continuing through the second to third month of pregnancy.

"This means, of course, that women who might become pregnant should take supplements, so that they will be taking supplements if pregnancy does occur."

However, she stops short of saying that the findings should be used in creating formal policy recommendations.

"Our study does offer some further evidence in favor of the current recommendations, but we caution that it is premature to use it as a basis for formulating policy recommendations," she said.

The study was supported by the Norwegian Ministry of Health and the Ministry of Education and Research, the National Institutes of Health/National Institute of Environmental Health Sciences, and the Norwegian Research Council. Dr. Roth and Dr. Susser have disclosed no relevant financial relationships.

JAMA. 2011; 306:1566-1573. Abstract

depression

2011-10-13T12:51:00.001-07:00

Commentary

Contemporary psychiatry has been surprised and chagrined by recent meta-analyses demonstrating that antidepressant drugs have statistically weak benefits among those with mild or moderate depressions, or perhaps total lack of benefit. The benefits of antidepressant drugs have only been consistently demonstrable for the most severe depressions, leaving clinicians without a mainstay for treating mild–moderate depression.

The study of Lieverse and colleagues is therefore extremely welcome, for it demonstrates that bright light can benefit outpatients aged above 60 years with mild major depressions. The bright light benefits were confirmed by a range of rating scales. Moreover, there were no adverse effects significantly more common in the bright light treated group.

Although bright light showed some superiority of response during 3 weeks of treatment, it was peculiar that greater relative benefit was observed in the bright light intervention group at 6 weeks, 3 weeks after the bright light was withdrawn. This was unexpected based on previous light treatment studies. One would like to know more about the results that would likely be obtained with longer intervals of treatment, as well as longer intervals of post-treatment follow-up.

A number of previous studies of bright light treatment (BLT) have suggested promising antidepressant benefits, particularly the inpatient studies of Martiny¹ which combined bright light with antidepressants. The current study provides the strongest evidence for bright light benefits in outpatients, particularly in the older age group. More trials and longer term trials are needed.

As the costs and adverse effects of BLT seem minimal, and bright light has proven its worth in treating seasonal depressions, clinicians are beginning to offer BLT now to patients with non-seasonal depression. This study will encourage treatment with bright light for patients aged above 60 years.

Daniel F Kripke
Professor of Psychiatry Emeritus, University of California San Diego, La Jolla, California, USA

dementia AF

2011-10-13T12:45:00.001-07:00

Discussion

In this population-based study of older adults, AF was associated with a 40% to 50% higher risk of AD and all-cause dementia, independent of stroke. This higher risk persisted after adjustment for many cardiovascular risk factors and diseases and in numerous sensitivity analyses. Because participants were followed prospectively and screened routinely for cognitive impairment, and dementia was ascertained using sensitive and valid methods, the findings provide more-rigorous information than many prior studies of this question. Considerable efforts were made to identify and account for clinically recognized stroke, so the estimates reflect the associations between AF and dementia beyond its known association with clinical stroke.

Several biological mechanisms may underlie the association between AF and dementia and AD. First, AF leads to incomplete atrial emptying, which may lead to thrombus formation in the left atrial appendage. This can result in systemic embolization, including to the brain. In addition to clinically recognized stroke, people with AF experience silent cerebral emboli.^[15] It has previously been reported that cerebral microinfarcts are an important neuropathological predictor of clinical dementia.^[32] It is not known whether AF increases the risk of cerebral microinfarcts. Second, AF is associated with greater beat-to-beat heart rate variability, which may lead to cerebral hypoperfusion.^[13] Either or both of these mechanisms may be associated with other neuropathological entities associated with dementia, such as neurofibrillary tangles, Lewy bodies, and hippocampal sclerosis. These findings are consistent with Fortuhi's "dynamic polygon" hypothesis,^[33] which posits that multiple processes and risk factors act together to produce late-life dementia. People with late-life dementia and AD commonly have multiple neuropathological findings (e.g., vascular pathology or Lewy bodies in addition to AD lesions).^[34] It may be that, in people with levels of AD pathology insufficient to produce dementia on their own, additional insults from AF decrease cognitive reserves and hasten the onset of dementia or AD.

In addition to the mechanisms described above, there are other possible explanations for the association observed between AF and dementia. First, AF and dementia may share underlying risk factors or pathophysiological processes, such as inflammation. It may be that despite efforts to control for cardiovascular risk factors and clinical cardiovascular disease, AF serves as a marker for the overall burden of cardiovascular disease. Second, subtle changes in the brain may affect autonomic input to the heart, changing cardiac conduction and leading to AF. However, the outcome of incident dementia was studied, so autonomic changes should have been minimal in these cases with early AD.

These findings are consistent with those of prior cross-sectional studies^[4,35] and with some^[6–8] but not all^[16–20] longitudinal studies. (For more information, please see summary table provided as Appendix S1.) Three of eight longitudinal studies reported that participants with AF were at higher risk of dementia than those without,^[6–8] although one study found this association only in participants with mild cognitive impairment,^[7] and another found an association at 5 years of follow-up but not 1 or 10 years.^[8] Five longitudinal studies found no association.^[16–20] In general, the studies that found an association examined a younger population than those that found no association, but there were other important differences. The methods used to detect AF and dementia varied widely. Only one prior study^[6] presented data about AF diagnosed during follow-up; other studies ascertained AF only at baseline. Because the current study identified AF diagnosed during follow-up, it is likely that it had more-complete ascertainment than most prior studies, improving its accuracy and power. Some studies used measures of dementia that have poor sensitivity or specificity, such as ICD-9 codes from administrative data^[6] or Mini-Mental State Examination scores less than 24.^[16] The current study included the largest number of dementia cases identified using sensitive and rigorous methods of any study to date. Only one prior study included more dementia cases,^[6] but it relied purely on administrative data to identify dementia, which likely led to substantial misclassification. This probably led to bias, the direction of which cannot be predicted.

This study has limitations. Diagnoses of dementia and AD were based on clinical criteria, and although neuroimaging studies were available for many dementia cases, research-quality neuroimaging was not performed. Cases of vascular or mixed dementia may have been misclassified as AD. It is not likely that this detracts from the findings, because prior work has established that in late-life dementia, people who meet neuropathological criteria for AD commonly have additional coexisting neuropathological findings, often vascular lesions.^[34] The association between AF and AD remained present when the outcome was limited to participants with probable AD, a group that is likely to meet neuropathological criteria for AD.^[34]

It is likely that some cases of AF that did not come to clinical attention were missed, particularly those that were transitory or asymptomatic. It is difficult to predict how this misclassification would have affected the results. If this misclassification was nondifferential, the true association between AF and dementia may be stronger than was observed. Information about AF duration and persistence was lacking, so these aspects of AF could not be examined in relation to dementia. The timing of dementia onset and the onset of self-reported CHD, stroke, and CHF were subject to error because the exact date of onset was not known, so it was estimated as occurring halfway between ACT visits. Covariates including CHD and CHF were measured from self-report, which may be inaccurate. Information about valvular heart disease or echocardiographic findings such as left atrial dilation and impaired systolic function, which are associated with development of AF, was not available.^[10] All of these limitations could have led to residual confounding. The study population was predominantly white and well educated, which may limit generalizability. Participants who died or withdrew from ACT may have differed from those who remained in the study in terms of their likelihood of having AF and of developing dementia, which may have led to bias.

The findings have important clinical implications. AF is common, and its prevalence is increasing.^[36] It is not known whether specific treatments for AF could modify the greater risk of dementia observed. If such treatment could delay the onset of dementia by even a few years, this could have a substantial effect on the burden of dementia in the population. Although one recent observational study reported that participants with AF who underwent catheter ablation had a lower risk of dementia than those who did not,^[37] these results may have been biased because treatment was not randomly assigned. Additional research is needed to examine the relationship between various treatments for AF and cognitive outcomes. Clinical trials and comparative effectiveness studies examining AF treatments will surely continue to study stroke and mortality but should also use sensitive and rigorous measures to ascertain cognitive decline and incident dementia so that these important outcomes can be evaluated. Future research seeking ways to avert the increasing burden of dementia should aim to determine the extent to which AF might be a modifiable risk factor.

AF atrium fibrillation

2011-10-13T01:00:00.000-07:00

Can Atrial Fibrillation Cause MR?

In patients with AF and normal-leaflet-motion MR, those who were in sinus rhythm after AF ablation had less MR than those with recurrent AF.

Functional mitral regurgitation (MR) with normal leaflet motion is typically caused by annular dilation associated with left ventricular (LV) enlargement. In the present study, investigators postulated that normal-leaflet-motion MR can also result from annular dilation associated with atrial fibrillation (AF), a condition they termed "atrial functional MR." They retrospectively screened 828 patients undergoing first AF ablation to identify 53 (6.4%) with moderate or greater MR and normal leaflet motion. All patients had LV ejection fractions 50%.

Compared with a randomly selected reference cohort with mild or no MR, subjects were older and more likely to have persistent AF and hypertension. Of the patient characteristics included in multivariate analysis, large mitral annular dimension was associated with the largest odds ratio for MR (8.39). Thirty-two subjects underwent 1-year echocardiographic follow-up. Compared with patients with recurrent AF, those in sinus rhythm had significantly less MR (mean MR jet-to-left-atrial [LA] ratio, 0.16 vs. 0.28) and a significantly smaller mean LA volume index (24 cc³/m² vs. 31 cc³/m²), as well as a smaller mean annular dimension (3.2 cm vs. 3.5 cm; P=0.06).

Comment: This is the largest study to date to demonstrate an association between atrial fibrillation and secondary, normal-leaflet-motion mitral regurgitation and the first to demonstrate early resolution of MR with restoration of sinus rhythm by ablation, suggesting a causal relationship. If these findings are confirmed in a prospective study, a strategy of rhythm control may be preferable to one of rate control in these patients.

— Howard C. Herrmann, MD

Published in Journal Watch Cardiology October 12, 2011

polio

2011-10-12T03:27:00.001-07:00

In 2000, the inactivated poliovirus vaccine (IPV) replaced the oral poliovirus vaccine (OPV) for routine immunization in the United States to prevent vaccine-associated paralytic polio, as reported by the American Academy of Pediatrics (AAP) in the December 1999 issue of Pediatrics. In the January 24, 1997, issue of MMWR. Recommendations and Reports, the US Centers for Disease Control and Prevention found that approximately 8 cases of OPV-associated paralytic polio occurred per year. Three combination vaccines that include IPV are licensed for use in the United States, according to the Centers for Disease Control and Prevention in the August 7, 2009, issue of MMWR. Morbidity and Mortality Weekly Report.

This policy statement from the AAP addresses the recommendations for poliovirus vaccination.

Study Synopsis and Perspective

The AAP has updated its recommendation for the administration of poliovirus vaccines, clarifying the standard schedule for immunization, as well as the minimal ages and minimal intervals between doses, according to a policy statement published online September 26 in Pediatrics.

Although the use of the OPV beginning in the early 1960s led to the elimination of polio in the United States, with the last reported outbreak seen in 1979, wild polioviruses still occur naturally in 4 countries: Afghanistan, India, Nigeria, and Pakistan. The fact that these 4 countries exported the virus to other countries that reported polio cases in 2009 points to the potential for the virus to be brought into the United States, the AAP policy statement says.

Twenty countries reported 1349 cases of polio in 2010, and 14 countries have reported 333 polio cases through August 23 of this year.

The IPV replaced the OPV as the vaccine of choice in the United States in 2000 in an effort to prevent rare but serious vaccine-associated paralytic polio. The current vaccination schedule, designed to produce immunity early in life, calls for 3 doses of IPV at 2, 4, and 6 through 18 months of age, and a fourth dose at 4 through 6 years of age. The AAP recommends that if risk for exposure is imminent, such as when a person travels to 1 of the 4 countries with wild polioviruses, then the doses should be administered at the minimum ages and intervals.

Within the United States, pockets of underimmunized children could lead to an outbreak if the wild viruses migrate to where those children are living, the AAP says.

The AAP statement says that after an individual receives the IPV series of doses, immunity is "long-term, possibly lifelong." However, another recommendation in its statement is that even adults who completed immunization with OPV or IPV early in life get a single dose of IPV if they are at increased risk for exposure to wild poliovirus in 1 of the countries.

Three combination vaccines and 1 stand-alone vaccine are licensed in the United States. Diphtheria and tetanus toxoids and acellular pertussis adsorbed, hepatitis B (DTaP-HepB-IPV; Pediarix, GlaxoSmithKline), is licensed for the first 3 doses and through 6 years of age. DTaP, IPV, and Haemophilus influenza type b (DTaP-IPV/Hib; Pentacel, Sanofi Pasteur) is licensed for all 4 doses through 4 years of age. DTaP-IPV (Kinrix, GlaxoSmithKline) is licensed for the last dose at ages 4 through 6. IPV (Poliovax, Sanofi Pasteur), the stand-alone vaccine, is licensed for all doses in infants, children, and adults.

The World Health Assembly set a goal in 1988 of eradicating polio worldwide. At that time, an estimated 350,000 cases of polio existed in 125 countries. That number decreased to 1604 cases in 2009.

Pediatrics. Published online September 26, 2011. Full text

Related Link
The Centers for Disease Control and Prevention provides extensive information on Polio Vaccination for healthcare professionals and patients, including downloadable patient teaching tools available in English and Spanish.

Study Highlights

The last reported poliovirus outbreak in the United States occurred in 1979.
Worldwide, poliovirus cases decreased from 1604 cases in 2009 to 1349 cases in 2010.
The US population is at risk for poliovirus because of imported cases and because of underimmunized children.
The estimated cost of medical care is $520,000 per case of poliovirus.
The seroconversion rate is more than 95% after administration of the 3-dose primary vaccine series.
Seroconversion rates and geometric mean titers are affected by maternal antibody, the age of the child, and the interval between doses.
Seroconversion rates for serotypes 1, 2, and 3 are higher when the vaccine is given at ages 2, 4, and 6 months vs ages 6, 10, and 14 weeks.
Seroconversion rates and geometric mean titers are lower in children with higher maternal antibody levels; the number of maternal antibodies usually decreases as the children get older.
Antibody levels are lower in children who received the vaccine in 1-month vs 2-month intervals.
The duration of immunity after the IPV series might be life-long.
Countries that provide an IPV booster dose at age 4 years or older show sustained elimination of polio.
4 IPV preparations are available in the United States:
- IPV for ages 2, 4, 6 to 18 months, and 4 to 6 years
- DTaP-HepB-IPV for ages 2, 4, and 6 months
- DTaP-IPV-Hib for ages 2, 4, 6, and 15 to 18 months
- DTaP-IPV for ages 4 to 6 years
The standard immunization schedule is IPV doses at ages 2 months, 4 months, 6 to 18 months, and 4 to 6 years.
For those at risk for imminent exposure to poliovirus from travel or outbreak, the following minimal ages and intervals for IPV doses should be used:
- The minimal age for dose 1 is 6 weeks.
- The minimal interval is 4 weeks between doses 1 and 2 and between doses 2 and 3.
- The minimal interval is 6 months between doses 3 and 4.
The final IPV dose should be given at ages 4 to 6 years and at least 6 months after the previous dose, regardless of the number of previous doses.
Immunocompromised and immunodeficient children should follow the same IPV schedule as children with normal immune systems, although the vaccine might not be as effective.
Adults at increased risk for exposure to polio can receive a single IPV dose, even if the primary IPV or OPV immunization series was completed.

Clinical Implications

The standard schedule for IPV in children is a total of 4 doses at ages 2 months, 4 months, 6 to 18 months, and 4 to 6 years, with at least a 4-week interval between doses 1 and 2 and doses 2 and 3, and at least a 6-month interval between doses 3 and 4. The final dose should be given at ages 4 to 6 years regardless of the number of prior doses.
For children at risk for imminent exposure to polio, the recommended inactivated poliovirus vaccine schedule can begin at the minimal age of 6 weeks. Adults can receive a single IPV dose even if primary immunization with OPV or IPV is complete.

warfarin dabigatran rivaroxaban

2011-10-06T00:36:00.000-07:00

On September 8, 2011, the Cardiovascular and Renal Drugs Advisory Committee of the Food and Drug Administration (FDA) discussed data submitted in support of the new drug application for rivaroxaban for preventing stroke and non–central nervous system systemic embolic events in patients with nonvalvular atrial fibrillation. Supportive evidence came primarily from ROCKET-AF (Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation; ClinicalTrials.gov number, NCT00403767),1 in which more than 14,000 patients were randomly assigned in a double-blind fashion to either 20 mg of rivaroxaban once daily or warfarin therapy targeting an international normalized ratio (INR) of 2 to 3. The primary aim was to assess whether rivaroxaban was noninferior to warfarin, with a secondary aim of assessing superiority.

In ROCKET-AF, a noninferiority margin of 1.38 for the relative risk of stroke or systemic embolism was based on an approval criterion that rivaroxaban be superior to placebo by at least 50% of the margin by which warfarin is superior to placebo, as estimated from a meta-analysis of six placebo-controlled reference studies. Per-protocol “on-treatment” analyses were prespecified because of concerns in noninferiority trials that events occurring with equal probabilities after patients discontinue randomized treatments might dilute the trials' sensitivity to true treatment differences and thus increase the risk of falsely declaring a treatment noninferior.2 In the primary analysis, the relative risk of stroke or systemic embolism with rivaroxaban as compared with warfarin was 0.79, with a 95% confidence interval that excluded the prespecified noninferiority margin. The risk of major bleeding events was somewhat higher with rivaroxaban, especially when double counting is avoided by excluding hemorrhagic strokes that were included in the efficacy end point of stroke or systemic embolism.

ROCKET-AF had important strengths, including its double-blind design and the favorable efficacy results noted above. However, thorough analyses provided by the FDA identified important issues affecting interpretation of these results.

In noninferiority trials, the “constancy assumption” must be satisfied: the control treatment, as administered in the new trial, must have the same magnitude of benefit relative to placebo as it had in the reference trials used to estimate its effect. The noninferiority margin might need to be modified if the results in the control group are for a different patient population, intensity of treatment, or measure of outcome than was used in the reference trials. Concerns about nonconstancy in ROCKET-AF were related to the higher-risk patients enrolled in the study, the more than 5% of patients who discontinued follow-up due to “withdrawal of consent,” and the fact that the INR for patients in the warfarin group was in the therapeutic range (between 2 and 3) only 55% of the time — considerably less than the 62 to 73% seen in other recent clinical trials. When the FDA analyzed data only from ROCKET-AF sites whose patients' average time in the therapeutic range was above specified thresholds, they found that the relative risk of stroke or systemic embolism with rivaroxaban was considerably higher (near unity) if the threshold was 67%, whereas with a threshold near 55% (corresponding to sites with an average time in the therapeutic range of about 65%), the relative risk was closer to that observed in the study as a whole.

Even in noninferiority trials, per-randomization analyses should be conducted. These analyses avoid the bias that occurs with per-protocol on-treatment analyses when patients discontinue their randomized treatment for reasons related to the treatment itself and the patients who do so have a different risk profile from those who don't. The importance of per-randomization analyses is very apparent in ROCKET-AF. The on-treatment analysis was based on observations that were truncated at 2 days after discontinuation of randomized treatment — a time frame likely to miss events related to inadequate coagulation during the transition to alternative treatment. There was greater risk of such events in the group receiving rivaroxaban, with its 5-to-9-hour half-life, than in the group receiving warfarin, with its 40-hour half-life. There was a much higher rate of stroke or systemic embolism in the rivaroxaban group than in the warfarin group (31 vs. 12 detected events) between day 2 and day 7 after discontinuation of randomized treatment. In the per-randomization analysis that captured these events, the relative risk of stroke or systemic embolism with rivaroxaban was 0.88, with a 95% confidence interval of 0.78 to 1.03, so superiority was not established. A positive trend seen in the per-protocol analysis of myocardial infarctions was similarly attenuated. A striking increase in death rates after the discontinuation of randomized treatment further complicates the noninferiority assessment in ROCKET-AF.

The Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) (NCT00262600), which provided the pivotal data in support of dabigatran's approval, compared open-label use of dabigatran with warfarin in more than 18,000 patients. The estimated relative risk of stroke or systemic embolism in a per-randomization analysis was 0.66 (95% confidence interval, 0.53 to 0.82) in a setting in which the average time in therapeutic range with warfarin was 64%.3 Although the trial was not blinded and dabigatran's effect on the risk of myocardial infarction was slightly unfavorable, the results robustly support the superiority of dabigatran over warfarin. RE-LY is also relevant to deliberations regarding rivaroxaban's approval. According to FDA policy, “It is essential that a new therapy must be as effective as alternatives that are already approved for marketing when the disease to be treated is life-threatening or capable of causing irreversible morbidity (e.g., stroke or heart attack).”2,4 Does rivaroxaban satisfy this criterion? In particular, are additional data needed to evaluate whether rivaroxaban is noninferior to dabigatran?

The RE-LY results and uncertainty about the validity of the constancy assumption in ROCKET-AF raise concerns that rivaroxaban could be inferior to either dabigatran or warfarin, particularly when the latter is “used skillfully.” The apparent nonconstancy of warfarin treatment between the two trials is problematic, although it's unclear whether the lower average time in therapeutic range in ROCKET-AF reflects greater difficulty in caring for higher-risk patients or is an artifact of the protocol design and trial conduct, including the mandated blinding of INR monitoring. Further concerns relate to a trend toward higher event rates in the rivaroxaban group than in the warfarin group as patients were transitioned to usual care — excess events that weren't captured in the primary efficacy analyses. The FDA also noted that ROCKET-AF's once-daily dosing of rivaroxaban wasn't really supported by the available pharmacokinetic and pharmacodynamic data. If the apparent noninferiority of once-daily rivaroxaban to warfarin was due primarily to a low time in therapeutic range in the warfarin group and the exclusion of excess events after randomized treatment was discontinued, then that dosing strategy might be unacceptably inferior to dabigatran. These circumstances could lead to an unproven treatment displacing an effective treatment on the basis of overzealous promotion of more convenient once-daily dosing.

The majority of the advisory committee judged that ROCKET-AF's results supported approval of rivaroxaban for stroke prevention in patients with atrial fibrillation. Justifications included the strength of evidence for noninferiority relative to warfarin in a high-risk population, the expectation that evidence can be obtained to establish that risk will be reduced by short-term continuation of rivaroxaban when transitioning to other anticoagulant therapy, the belief that postmarketing studies can address FDA concerns that a twice-daily dosing regimen is more appropriate, and the interest in having an additional option that (some are convinced) adequately preserves the efficacy of existing treatments. It was suggested that rivaroxaban might be used in patients who have an inadequate response to or cannot take dabigatran or warfarin, although data are not available to directly address rivaroxaban's efficacy and risks in such settings. The FDA will take the advisory committee's discussion and other insights under consideration; the target date for FDA action, according to the agency's Web site, is November 5, 2011.

Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.

This article (10.1056/NEJMp1110639) was published on October 5, 2011, at NEJM.org.

simvastatine

2011-10-05T10:06:00.001-07:00

From Medscape Internal Medicine > Medicine Matters

Clarifying Simvastatin Warnings -- It's Not Just 80 mg

Sandra A. Fryhofer, MD

Authors and Disclosures

Posted: 09/28/2011

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Hello. I'm Dr. Sandra Fryhofer. Welcome to Medicine Matters. The topic is the simvastatin saga, our review of the FDA's latest warnings about this popular statin. Here's why it matters.

When my patients needed statins, I always started with simvastatin. It was generic. It was on all the pharmacy plans. The price point was right. Prescribing was hassle free. There were no complex forms to fill out and explain to my patients. But on June 8, 2011, the FDA released new warnings about the dangers of high-dose simvastatin, which affects many people. In 2010, an estimated 2.1 million US patients were prescribed a product containing 80 mg simvastatin. The FDA also issued new warnings about dosing and drug interactions. Here are the highlights:

Restrictions for 80-mg simvastatin

Avoid prescribing 80-mg simvastatin because of the high risk for myopathy.
80-mg simvastatin is satisfactory if the patient has been on it for a year with no evidence of myopathy.

Restrictions for intermediate- and low-dose simvastatin

No more than 20 mg for patients taking amlodipine and ranolazine
No more than 10 mg for patients on amiodarone, verapamil, and diltiazem

Restrictions for simvastatin at any dose

The FDA has mandated drug-labeling changes warning that simvastatin is contraindicated in patients on gemfibrozil, certain antifungal medications (itraconazole, ketoconazole, posaconazole), certain antibiotics (erythromycin, clarithromycin, telithromycin) as well as HIV protease inhibitors, nefazodone, cyclosporine, and danazol.

The information on adverse effects with simvastatin are not new. In 2004, when the A to Z trial was published in JAMA,^[1] an editorial expressed concerns about increased rates of myopathy in patients on simvastatin. The most recent study to cast dispersions on simvastatin was SEARCH, published in The Lancet in 2010.^[2] It linked simvastatin 80-mg doses to increased risk for myopathy.

So why didn't the FDA act sooner? That's not clear, but the word is out now. Simvastatin problems are public property. Patients know about them and depend on us to clear up their medication regimens. Not all statins are created equal and the least expensive drug may not necessarily be the best for your patient. Please also check "Switching From Simvastatin 80 mg: How to Shop for Statins" from my column Staying Well. For Medicine Matters, I'm Dr. Sandra Fryhofer.

PTSD Dr. Brunner post traumatische stress disorder

2011-10-04T01:56:00.000-07:00

Why Don't All Traumatized People Develop PTSD?

Two genetic studies raise the possibility of identifying specific aspects of the stress response system that could be treated in trauma-exposed patients.

Only a minority of people exposed to severe trauma develop post-traumatic stress disorder (PTSD), which suggests that certain factors (some of them possibly genetic) may be involved in vulnerability to PTSD. Two studies look at this question.

Mehta and colleagues studied 209 people recruited from an inner-city hospital (90% black; mostly low-income) who had experienced at least one adult trauma; 70% had developed PTSD. The researchers focused on links among PTSD, sensitivity of the glucocorticoid receptor (GR), and a single nucleotide polymorphism (SNP) of FKBP5, a GR co-chaperone involved in negative feedback regulation of the hypothalamic–pituitary–adrenal (HPA) axis. Among PTSD patients, after adjustment for childhood and adult traumas and depression, greater GR receptor sensitivity (measured by dexamethasone suppression) was associated with being an A allele carrier than with GG homozygosity, which was associated with lower baseline serum cortisol levels. Neither PTSD nor genotype alone predicted dexamethasone suppression. However, researchers identified another 41 genes (32 previously unreported) that participate in GR regulation; 19 appeared to form a network related to FKBP5 regulation of HPA axis activation in PTSD.

In Mercer and colleagues' study, 204 undergraduate women (mean age, 20), who had participated in a study of traumatic experiences, social supports, and sexual victimization, were reassessed twice after a lone shooter killed or wounded 26 people on campus (mean follow-ups, 3.2 weeks and 8.4 months). Genotyping of three loci in the serotonin transporter genetic region was performed. Severity of postshooting PTSD symptoms was predicted by the number of exposure events (e.g., hearing gunfire or being hurt), but not by previous traumas or social support. After statistical corrections and adjustment for the shooting exposure, higher PTSD symptom scores (especially avoidance) and acute stress disorder after the shooting were associated with a multimarker genotype that decreases expression of the serotonin transporter.

Comment: Studies of gene interactions are subject to false positive results (see JW Psychiatry Sep 12 2011) even after traditional corrections for multiple statistical tests. Still, these studies show that vulnerability to an abnormal stress response is genetically heterogeneous. People with a specific allele in a gene network that regulates the HPA axis may be vulnerable to suppression of cortisol production resulting from burnout of the stress response. Genetic interactions that reduce resilience of serotonergic systems that moderate arousal may increase susceptibility to excessive stress responses. As genotyping becomes cheaper and more reliably tied to clinical phenotypes, clinicians may be able to identify trauma-exposed people who would respond to interventions aimed at a specific dimension of stress response systems.

— Steven Dubovsky, MD

Published in Journal Watch Psychiatry October 3, 2011

stroke

2011-10-02T00:21:00.000-07:00

Medical Management Is Superior to Stenting for Intracranial Arterial Stenosis

The rate of postprocedural strokes was unacceptably high in patients who received stents.

Stenting is now available for patients with intracranial arterial stenosis, an important cause of stroke. This procedure finally has been examined in a randomized trial, funded by the NIH and a device manufacturer. Patients with recent transient ischemic attacks or nondisabling strokes — attributed to intracranial arterial stenoses of 70% to 99% — received either "aggressive medical management" alone or the same management plus angioplasty and stenting. The qualifying artery was the middle cerebral in 44% of patients, internal carotid in 21%, basilar in 22%, and vertebral in 13%.

After 451 patients were randomized, the trial was stopped because of adverse outcomes in the stent group: At 30 days after enrollment, the primary endpoint (stroke or death) had occurred in 14.7% of stented patients and in 5.8% of medical-management patients — a highly significant difference; most strokes in stented patients occurred immediately after their procedures. Beyond 30 days, the ipsilateral stroke rate was 6% in both groups during average follow-up of 1 year.

Comment: In this study of patients with recently symptomatic intracranial arterial stenosis, medical management — consisting of aspirin, blood pressure treatment, lipid treatment, lifestyle modification, and a 3-month course of clopidogrel — clearly was superior to angioplasty plus stenting. Even discounting periprocedural strokes, stenting conferred no advantage during 1 year of follow-up.

— Allan S. Brett, MD

Published in Journal Watch General Medicine September 29, 2011

Citation(s):

Chimowitz MI et al. Stenting versus aggressive medical therapy for intracranial arterial stenosis. N Engl J Med 2011 Sep 15; 365:993. (http://dx.doi.org/10.1056/NEJMoa1105335)

Medline abstract (Free)

warfarin dabigatran rivaroxaban

2011-09-17T02:17:00.000-07:00

September 15, 2011 (Amsterdam, the Netherlands) — Results of a small study published online September 6, 2011 in Circulation show that prothrombin complex concentrate (PCC) appears to be an effective antidote for rivaroxaban that could be used to stop or prevent serious bleeding in patients taking this new anticoagulant. However, the same study showed that PCC has no influence on dabigatran [1].

Dabigatran, a direct thrombin inhibitor, and rivaroxaban, a direct factor Xa inhibitor, have shown promise as anticoagulants that can be prescribed in fixed doses and do not require frequent monitoring. But so far, no human studies have assessed whether prohemostatic agents can stop the anticoagulant effect of either drug in the patient suffering a major bleed or undergoing emergency surgery, according to study authors, Dr Elise Eerenberg (Academic Medical Center, Amsterdam, the Netherlands) and colleagues. PCC is a good candidate for an antidote because it contains the coagulation factors II, VII, IX, and X in a high concentration and enhances thrombin generation, Eerenberg et al explain.

The researchers randomized 12 healthy male volunteers to either 20 mg of rivaroxaban twice a day or 150 mg of dabigatran twice a day for two and a half days, followed by either a single 50-IU/kg dose of PCC or a similar dose of saline. After 11 days, the patients repeated this procedure with the other anticoagulant treatment.

Rivaroxaban induced a significant prolongation of the prothrombin time (15.8 vs 12.3 seconds at baseline; p<0.001) that was immediately and completely reversed by the PCC to an average of 12.8 seconds (p<0.001). The endogenous thrombin potential, a measure of blood coagulability, was inhibited by rivaroxaban (51% vs 92% at baseline, p<0.002) and normalized with PCC (114%, p<0.001), while the saline had no effect.

Dabigatran also increased the activated partial thromboplastin time, ecarin clotting time, and thrombin time, but PCC did not restore coagulability of the blood to the baseline levels in any of these coagulation tests. "The question of how the effect of dabigatran can be antagonized remains unanswered," the authors explain. They suggest that other strategies for reversing dabigatran could include repeated doses of PCC, recombinant factor VIIa, or a combination of PCC and recombinant factor VIIa, but these strategies have yet to be investigated in trials.

This was the first study to investigate the effect of PCC for reversal of these new anticoagulant agents in humans, according to the authors, and it "may have important clinical implications," but the effects of PCC in patients with bleeding events while treated with anticoagulants will have to be studied in further trials.

This study was supported by an unrestricted research grant from Sanquin, the Netherlands, which also supplied PCC.

warfarin

2011-09-14T01:42:00.001-07:00

SUMMARY AND COMMENT

ARISTOTLE: Another Competitor Beats Warfarin Free!

August 29, 2011 | Mark S. Link, MD

Apixaban, a factor Xa inhibitor, outperforms warfarin at stroke and systolic embolism prevention in AF patients.

Reviewing: Granger CB et al. N Engl J Med 2011 Aug 28;

Mega JL. N Engl J Med 2011 Aug 28;

stroke vascular dementia

2011-09-12T15:08:00.000-07:00

Learning Objectives

Upon completion of this activity, participants will be able to:

Report whether overall calcification in the coronary arteries, aortic arch, extracranial carotid arteries, and intracranial carotid arteries identified on computed tomography scan is associated with cerebral infarcts, microbleeds, and white matter lesions on brain magnetic resonance imaging scan.
Describe whether separate calcification in the coronary arteries, aortic arch, extracranial carotid arteries, or intracranial carotid arteries identified on computed tomography scan is associated with cerebral infarcts, microbleeds, and white matter lesions on brain magnetic resonance imaging scan.

Calcification of the carotid artery noted on computed tomography (CT) scan might predict the risk for stroke, as reported by Nandalur and colleagues in the February 2006 issue of AJR. American Journal of Roentgenology. In the July 2010 issue of Lancet Neurology, Pantoni reported that white matter lesions (WMLs), cerebral infarcts, and cerebral microbleeds on magnetic resonance imaging (MRI) scan are important markers of cerebrovascular disease.

This study by Bos and colleagues, based on the prospective population-based cohort Rotterdam Study described by Hofman and colleagues in the 2009 issue of the European Journal of Epidemiology, assesses the relationship between calcification in major vessel beds identified by CT and MRI markers of vascular brain disease.

Study Synopsis and Perspective

Arterial calcification in major vessel beds outside the brain, as shown with MRI, is associated with vascular brain disease and may be linked to future risk for dementia and stroke, a new study shows.

"Most notably, larger intracranial carotid calcification load relates to larger WML volumes, and larger extracranial carotid calcification load relates to the presence of cerebral infarcts, independently of ultrasound carotid plaque score," the authors, led by Daniel Bos, MD, from Erasmus Medical Center, Rotterdam, the Netherlands, write. Such calcification "provides novel insights into the etiology of vascular brain disease," the authors note.

"The relationship between calcium in atherosclerotic plaque and brain changes exists on top of the effect of classic cardiovascular risk factors such as high blood pressure, smoking and diabetes," senior author Meike W. Vernooij, MD, PhD, also from Erasmus Medical Center, said in a statement.

The amount of calcified plaque outside the brain provided more information about the extent of brain changes than traditional ultrasound measures of plaque in the carotid artery, the authors add.

The findings were published online August 25 in Arteriosclerosis, Thrombosis and Vascular Biology.

The Rotterdam Study

The researchers studied 885 community-dwelling people (50.8% women), mean age 66.7 years, who were participants in the Rotterdam Study, a prospective, population-based cohort study on causes of disease in the elderly.

The authors used CT scans to measure calcification in the coronary arteries, aortic arch, and extracranial and intracranial carotid arteries. They also used brain MRI scans to assess cerebral infarcts, microbleeds, and WMLs, which are considered important markers of vascular brain disease.

The study found that higher CT calcification was associated with larger WML volume and the presence of cerebral infarcts, but not with presence of cerebral microbleeds.

The strongest associations were between intracranial carotid calcification and WML volume, and between extracranial carotid calcification and infarcts. Adjusting for cardiovascular risk factors or ultrasound carotid plaque scores did not change these results.

"The distinction between the impact of calcification in the extracranial and intracranial carotids adds to the current belief that [WMLs] mainly result from disease in smaller intracranial vessels, while brain infarctions are thought to be mainly caused by larger vessel disease," Dr. Vernooij said in a statement.

The authors note that using CT-calcification measurement on a large scale means exposing people to radiation and requires further research.

They add that they can speculate about the possibilities for using CT for such a purpose in the future and point out that at this time, CT is being used more frequently for both diagnostic and screening purposes.

"It is a long way from these results towards making meaningful inferences on what this means for screening individual subjects with CT. Primarily, this study provides novel insight into the link between atherosclerosis and vascular brain disease, which we will use for further studies on how atherosclerosis may affect brain function, and ultimately the risk to develop dementia," Dr. Vernooij told Medscape Medical News.

Dr. Vernooij added that this does not imply that screening for vessel calcification will be cost-effective.

"In the short term, a practical use of our findings in clinical practice could be found in the fact that cardiac CT scans are increasingly performed to assess the risk for coronary heart disease. For a clinician, it may be useful to understand that calcification in coronary arteries, though far away from the brain, may indicate presence of subclinical brain disease as well. However, at present this does not have, yet, implications for therapeutic management," Dr. Vernooij said.

Interesting, but no Clinical Effect at Present

In general, calcification is a marker for chronic and more extensive vascular disease, Joseph Broderick, MD, Albert Barnes Voorheis Chair of Neurology at University of Cincinnati, Ohio, told Medscape Medical News.

"This study of arterial calcification in 4 vascular beds by CT, and correlating this with brain parenchymal changes on MRI, has not been done before," Dr. Broderick, a spokesperson for the American Academy of Neurology, said. "However, it is not surprising that [intracranial carotid artery] calcification correlates better with MRI tissue changes than coronary or aortic arch calcification."

He added that he found it "interesting" that large-vessel calcification load was not associated with microbleeds. "However, these microbleeds have generally been associated with small-vessel, rather than large-vessel, disease. For instance, amyloid vascular disease in brain is small-vessel disease of the cortical vessels."

What Is Old Is New Again

The findings from this study are consistent with a growing body of knowledge, Patrick Lyden, MD, chairman of the Department of Neurology at Cedars-Sinai Medical Center, Los Angeles, California, told Medscape Medical News.

"These patients all had atherosclerosis; they had hardening of the arteries. That's all that calcium is telling you, that there's hardening of the arteries, so you see hardening of the arteries outside the brain, and that tells you there is something wrong in the brain."

Dr. Lyden noted that originally, Alzheimer's disease was thought to be caused by atherosclerosis in the brain.

"When Alzheimer published his very first paper in Germany, he said that Alzheimer's disease was really due to hardening of the arteries in the brain. Then, about 30 years ago, a very clever biochemist showed that no, it has nothing to do with hardening of the arteries. It's all about amyloid, it's all about plaques and tangles in the brain, and so the vascular part of the story was forgotten. But in the last 5 years, the vascular part of the story has been rediscovered, and doctors are paying attention to it again," he said.

Dr. Bos and Dr. Lyden have disclosed no relevant financial relationships. Dr. Vernooij was supported by an Alzheimer's Association Grant.

Arteriscler Thromb Vasc Biol. Published online August 25, 2011. Abstract

pancratitis

2011-09-10T04:27:00.001-07:00

Pregabalin Reduced Pain from Chronic Pancreatitis

A 3-week treatment with the gabapentoid pregabalin was superior to placebo and might be a useful adjunct agent for this difficult-to-treat condition.

Patients with chronic pancreatitis often have abdominal pain, which can be intractable and difficult to control. Therapeutic options are limited, and many patients become dependent on, and even addicted to, narcotic analgesics for pain control. Nonopioid agents have been suggested as adjuncts to narcotics but have not been tested in randomized studies. These include gabapentoids (gabapentin and pregabalin), which have shown efficacy in treating a wide variety of neuropathic conditions that seem to share neuropathic mechanisms and central pain processing patterns found in painful chronic pancreatitis.

To investigate the efficacy and safety of the gabapentoid pregabalin in reducing pain from chronic pancreatitis, researchers in Denmark and the Netherlands randomized 64 patients (out of 236 screened) with chronic pancreatitis and chronic abdominal pain to receive either pregabalin (escalating doses to a maximum of 300 mg twice a day) or placebo for 3 weeks in a double-blind trial. Pain relief (the primary endpoint) was measured using a visual analog scale of 0 (no pain) to 10 (worst pain imaginable). Opioid use was allowed, as long as the dose was stable. Study groups were well matched in baseline demographics and clinical characteristics.

Pain relief was better in the pregabalin group than the placebo group (decrease in average pain score, 36% vs. 24%; P=0.02). This difference of 12% translated to a number needed to treat (NNT) of 8. More pregabalin recipients than placebo recipients reported "much" or "very much" improvement in treatment response (44% vs. 21%; P=0.048). Pregabalin recipients also achieved a much larger reduction in opioid use. Adverse effects of the central nervous system were more common in the pregabalin group (feeling drunk, light-headedness), but these seemed to decrease during the course of the trial.

Comment: This is the first placebo-controlled study to assess the efficacy of gabapentoids in treating the pain of chronic pancreatitis. Pregabalin was superior to placebo, with a reasonable NNT of 8. Treatment of pain in these patients is challenging, and even small additions to our armamentariums are valuable. Although pregabalin did not eliminate pain, the effect of reducing both pain and the need for narcotic analgesics is clinically valuable. Also, a slight uptick in quality of life was seen but did not achieve statistical significance. Even though gabapentin has not yet been studied, we hope that it will also be effective. Long-term studies of these agents and others will be useful in gauging their effects in these difficult-to-treat patients. Meanwhile, use of gabapentoids as an adjunctive agent should be strongly considered in patients with painful chronic pancreatitis.

— Chris E. Forsmark, MD

Published in Journal Watch Gastroenterology September 9, 2011

rivaroxaban warfarin

2011-09-08T06:29:00.000-07:00

Rivaroxaban versus Warfarin in Nonvalvular Atrial Fibrillation

Manesh R. Patel, M.D., Kenneth W. Mahaffey, M.D., Jyotsna Garg, M.S., Guohua Pan, Ph.D., Daniel E. Singer, M.D., Werner Hacke, M.D., Ph.D., Günter Breithardt, M.D., Jonathan L. Halperin, M.D., Graeme J. Hankey, M.D., Jonathan P. Piccini, M.D., Richard C. Becker, M.D., Christopher C. Nessel, M.D., John F. Paolini, M.D., Ph.D., Scott D. Berkowitz, M.D., Keith A.A. Fox, M.B., Ch.B., Robert M. Califf, M.D., and the ROCKET AF Steering Committee for the ROCKET AF Investigators

N Engl J Med 2011; 365:883-891September 8, 2011

Background

The use of warfarin reduces the rate of ischemic stroke in patients with atrial fibrillation but requires frequent monitoring and dose adjustment. Rivaroxaban, an oral factor Xa inhibitor, may provide more consistent and predictable anticoagulation than warfarin.

Methods

In a double-blind trial, we randomly assigned 14,264 patients with nonvalvular atrial fibrillation who were at increased risk for stroke to receive either rivaroxaban (at a daily dose of 20 mg) or dose-adjusted warfarin. The per-protocol, as-treated primary analysis was designed to determine whether rivaroxaban was noninferior to warfarin for the primary end point of stroke or systemic embolism.

Results

In the primary analysis, the primary end point occurred in 188 patients in the rivaroxaban group (1.7% per year) and in 241 in the warfarin group (2.2% per year) (hazard ratio in the rivaroxaban group, 0.79; 95% confidence interval [CI], 0.66 to 0.96; P<0.001 for noninferiority). In the intention-to-treat analysis, the primary end point occurred in 269 patients in the rivaroxaban group (2.1% per year) and in 306 patients in the warfarin group (2.4% per year) (hazard ratio, 0.88; 95% CI, 0.74 to 1.03; P<0.001 for noninferiority; P=0.12 for superiority). Major and nonmajor clinically relevant bleeding occurred in 1475 patients in the rivaroxaban group (14.9% per year) and in 1449 in the warfarin group (14.5% per year) (hazard ratio, 1.03; 95% CI, 0.96 to 1.11; P=0.44), with significant reductions in intracranial hemorrhage (0.5% vs. 0.7%, P=0.02) and fatal bleeding (0.2% vs. 0.5%, P=0.003) in the rivaroxaban group.

Conclusions

In patients with atrial fibrillation, rivaroxaban was noninferior to warfarin for the prevention of stroke or systemic embolism. There was no significant between-group difference in the risk of major bleeding, although intracranial and fatal bleeding occurred less frequently in the rivaroxaban group. (Funded by Johnson & Johnson and Bayer; ROCKET AF ClinicalTrials.gov number, NCT00403767.)

Supported by Johnson & Johnson Pharmaceutical Research and Development and Bayer HealthCare.

statines

2011-09-05T05:47:00.001-07:00

Clinical Context

Hyperlipidemia is a common clinical problem, and all patients with hyperlipidemia should receive dietary advice to reduce lipid levels. However, can dietary changes match statins in improving the lipid profile? Some of the authors of the current study performed a trial comparing a dietary portfolio featuring plant sterols, soy protein, viscous fiber, and almonds vs a low-fat diet, with or without lovastatin. Their results, which were published in the July 23, 2003, issue of the Journal of the American Medical Association, demonstrated that the diet portfolio group experienced similar decreases in low-density lipoprotein (LDL) cholesterol and C-reactive protein (CRP) levels at 4 weeks vs the lovastatin plus low-fat diet group.

The best means to implement a dietary portfolio to reduce serum lipids are largely unknown. The current study by Jenkins and colleagues examines the effect of intensity of dietary advice on serum lipid outcomes among adults with hyperlipidemia.

Study Synopsis and Perspective

A diet rich in foods with proven heart-healthy benefits is significantly better than a diet low in saturated fat for reducing LDL-cholesterol levels in patients with hyperlipidemia, according to the results of a new study [1]. The "dietary portfolio" of cholesterol-lowering foods reduced LDL-cholesterol levels by 26 mg/dL, nearly as large a reduction as was observed in some of the earliest statin trials, according to researchers.

"The four major components of the dietary portfolio are foods that the Food and Drug Administration has recognized as being able to carry a heart-healthy claim for their ability to lower serum cholesterol levels," said lead investigator Dr David Jenkins (University of Toronto, ON). "These include soy proteins, sticky types of fibers like oats, barley, and psyllium, vegetables, viscous fibers, nuts, and plant sterols. We basically looked for ways in which these components were enriched in foods obtainable from the supermarket and encouraged people with support and help to look after themselves."

Speaking with heartwire, Jenkins said the foods included in the diet have been shown to reduce serum LDL-cholesterol levels by as much as 28% to 35%. Unknown, however, was how effective the dietary portfolio would be in real-world conditions or how effective the diet would be compared with a standard diet low in saturated fat.

Portfolio Diet vs Diet Low in Saturated Fat

Published in the August 24, 2011 issue of the Journal of the American Medical Association, the 24-week, parallel-design study included 351 patients with hyperlipidemia from four academic medical centers in Canada. Patients were randomized to one of two dietary interventions: a standard diet low in saturated fat; and the portfolio diet consisting of plant sterols, soy protein, viscous fibers, and nuts. In addition to the portfolio diet, the patients eating the heart-healthy foods received dietary advice for six months, with intensive-treatment patients receiving seven 40-minute counseling sessions and the routine-treatment portfolio patients receiving two counseling sessions.

The purpose of the different intensities of dietary counseling was to determine whether the routine dietary portfolio, which would be considered manageable by physicians in that it required just two counseling sessions, would be as effective as a more intensive treatment arm requiring multiple office visits.

Intensive therapy with the portfolio diet reduced LDL-cholesterol levels 13.8% from baseline, a reduction of 26 mg/dL (p<0.001). Similarly, patients treated with the portfolio diet who received just two counseling sessions also had significant reductions in LDL cholesterol, which was reduced 13.1% from baseline, or down 24 mg/dL. The reductions in LDL cholesterol were not statistically different in the two dietary-portfolio treatment arms.

Overall, individuals who followed more of a plant-based diet within the dietary portfolio had the lowest reduction in LDL-cholesterol levels, noted Jenkins.

Comparatively, patients in the control arm eating a standard low-saturated-fat diet reduced their LDL cholesterol levels 3%, down 8 mg/dL from baseline. The percentage reduction in LDL cholesterol was significantly greater in both portfolio diets compared with the low-saturated-fat diet (p<0.001).

To Treat or Not to Treat With a Statin

To heartwire , Jenkins noted that patients in the study had an average LDL-cholesterol level of 171 mg/dL at baseline, so they were considered hyperlipidemic but were not taking any medication to lower their cholesterol levels. The next step for the researchers is to test the effectiveness of the heart-healthy portfolio diet in patients with increased cardiovascular risk or those taking medications to lower their LDL-cholesterol levels. The hope is that eating a diet rich in soy proteins, viscous fibers, nuts, and vegetables can incrementally add to the benefit offered by LDL-lowering medications.

"We don't regard this as the end of the line by any means in terms of where we have to go with this diet," said Jenkins. "We have to see what this diet does in combination with statins, how much of an advance we can get, and whether we can actually lower the dose of statin therapy. More important, we need to know if the diet is applied over a long period of time, do we actually see a cardiovascular-outcome benefit, initially in ultrasound and magnetic-resonance imaging of the arteries, and in the longer term, in improvements in cardiovascular events."

Jenkins added that patients in the present analysis are typically patients that cause some problems for doctors, mainly in the sense that "they can be scratching their heads" about whether or not they should be treated with a statin. These results showed that the diet can help pull patients out of a middle-risk category to one that is lower risk. For example, the diet resulted in a 10% reduction in the Framingham risk score, which is sufficient to take a patient from moderate risk to low risk, he said.

bewegen, warfarin

2011-09-05T05:40:00.000-07:00

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Assess trends in physical activity levels among adults in Taiwan.
Distinguish a low threshold of physical activity required to reduce the risk for mortality.

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Clinical Context

Although many adults worldwide fail to meet stated recommendations for physical activity, the approach to physical activity can vary from culture to culture. The authors of the current study note that East Asians tend to be less physically active vs adults in Western countries. A previous study by Ku and colleagues, which appeared in the December 2006 issue of Preventive Medicine, found that only 14% of Taiwanese adults met national recommendations for physical activity levels. In contrast to Western countries, adults 45 years and older were more likely to be active vs young people. Limited formal education and a paying job were risk factors for physical inactivity.

Given this background, can at least a modest amount of physical activity promote significant reductions in mortality risk? A minimal amount of exercise necessary to improve life expectancy has not yet been identified. The current study by Wu and colleagues, which was also based in Taiwan, examines the effects of different levels of physical activity on the risk for mortality.

Study Synopsis and Perspective

The minimal amount of physical activity to reduce mortality risk is 15 minutes a day of moderate-intensity exercise, according to the results of a prospective cohort study reported online August 16 in The Lancet.

"Exercising at very light levels reduced deaths from any cause by 14 percent," said senior author Xifeng Wu, MD, PhD, professor and chair of the University of Texas MD Anderson Cancer Center Department of Epidemiology, in a news release. "The benefits of exercise appear to be significant even without reaching the recommended 150 minutes per week based on results of previous research."

The study cohort consisted of 416,175 persons in Taiwan (199,265 men and 216,910 women) who were evaluated between 1996 and 2008 in a standard medical screening program. Average duration of follow-up was 8.05 ± 4.21 years. Participants were categorized according to the amount of weekly exercise self-reported on a questionnaire as inactive, low, medium, high, or very high activity. For each group, life expectancy and hazard ratios (HRs) were calculated for mortality risk, with use of the inactive group as the standard.

The average amount of exercise in the low-volume activity group was 92 minutes per week (95% confidence interval [CI], 71 - 112) or 15 ± 18 minutes per day. Risk for all-cause mortality was 14% lower (HR, 0.86; 95% CI, 0.81 - 0.91), and life expectancy was 3 years longer in the low-volume activity group vs the inactive group.

Beyond the minimal amount of 15 minutes of daily exercise, each additional 15 minutes was associated with a further reduction in all-cause mortality risk by 4% (95% CI, 2.5 - 7.0) and in all-cancer mortality risk by 1% (95% CI, 0.3 - 4.5). These benefits of exercise were seen in all age groups, in both sexes, and in persons at risk for cardiovascular disease. Compared with individuals in the low-volume group, inactive persons had a 17% increased risk for mortality (HR, 1.17; 95% CI, 1.10 - 1.24).

"15 min a day or 90 min a week of moderate-intensity exercise might be of benefit, even for individuals at risk of cardiovascular disease," the study authors write.

Limitations of this study include observational design with possible confounding, reliance on self-report to determine exercise amount, lack of generalizability to other populations, and possible loss to follow-up.

In an accompanying editorial, Anil Nigam and Martin Juneau, from Montreal Heart Institute and Université de Montréal in Quebec, Canada, note that "this is the first observational study of this size to report important and global health benefits at such a low volume of leisure-time physical activity [LTPA] with this degree of precision."

"The knowledge that as little as 15 min per day of exercise on most days of the week can substantially reduce an individual's risk of dying could encourage many more individuals to incorporate a small amount of physical activity into their busy lives," Drs. Nigam and Juneau write. "Governments and health professionals both have major roles to play to spread this good news story and convince people of the importance of being at least minimally active."

The exercise project was funded by the Taiwan Department of Health Clinical Trial and Research Center of Excellence, and the Taiwan National Health Research Institutes supported this study. The study authors and editorialists have disclosed no relevant financial relationships.

Lancet. Published online August 16, 2011.

warfarin hersen bloedinkjes

2011-09-05T05:36:00.001-07:00

Abstract

In the last decade or so, cerebral microbleeds (CMBs) – tiny perivascular hemorrhages seen as small, well-demarcated, hypointense, rounded lesions on MRI sequences that are sensitive to magnetic susceptibility – have generated increasing interest among neurologists and clinical stroke researchers. As MRI techniques become more sophisticated, CMBs are increasingly detected in various patient populations (including all types of stroke, Alzheimer’s disease and vascular cognitive impairment) and healthy community-dwelling older people. Their presence raises many clinical dilemmas and intriguing pathophysiological questions. CMBs are emerging as an important new manifestation and diagnostic marker of cerebral small-vessel disease. They are a potential predictor of future intracerebral hemorrhage risk, a possible contributor to cognitive impairment and dementia and a potential key link between vascular and degenerative pathologies. In this article, we discuss the available pathological, neuroimaging and clinical studies in the field, and we provide a modern overview of the clinical and pathophysiological implications of CMBs in different disease settings.

Introduction

The past decade has witnessed increasing interest in cerebral microbleeds (CMBs), reflected by the proliferation of publications about them.^[1] CMBs are defined radiologically as small, rounded, homogeneous, hypointense lesions on T2*-weighed gradient-recalled echo (T2*-GRE) and related MRI sequences that are sensitive to magnetic susceptibility (Figure 1).^[2] Scharf et al. were the first to report on small, intracerebral black dots of signal loss on T2-weighted spin-echo MRI in patients with hypertensive cerebrovascular disease and intracerebral hemorrhage (ICH) associated with ischemic white matter disease and lacunar infarcts.^[3] They called these lesions ‘hemorrhagic lacunes’, and their further characterization using T2*-GRE MRI sequences led to the current radiologic definition of ‘microbleeds’, a term coined by Offenbacher and colleagues in 1996.^[4] A key feature of CMBs is that they are not seen well on conventional computed tomography or MRI scans (Figure 1). Available histopathological studies suggest that CMB radiological lesions are due to tiny bleeds adjacent to abnormal small vessels, being mainly affected by hypertensive angiopathy (arteriolosclerosis – usually lipohyaline degeneration related to hypertension) or cerebral amyloid angiopathy (CAA).^[5]

statines

2011-09-02T15:24:00.001-07:00

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August 28, 2011 (Paris, France) — Long-term results of the Anglo-Scandinavian Cardiac Outcomes--Lipid-Lowering Arm (ASCOT-LLA) study, eight years after the trial officially stopped, showed that treatment with 10 mg of atorvastatin (Lipitor, Pfizer) reduced all-cause mortality compared with placebo, mainly through a reduction in noncardiovascular deaths [1].

Presenting the results at a hot-line session today at the European Society of Cardiology (ESC) 2011 Congress, investigators observed that reductions in the risk of death from respiratory illness and infection contributed to the overall reduction in all-cause mortality. "The numbers are large, the data are convincing, but we have no definitive explanation to date for the hypothesized legacy effect of atorvastatin on noncardiovascular-death risk reduction," said lead investigator Dr Peter Sever (Imperial College, London, UK).

The study was published online August 28, 2011 in the European Heart Journal to coincide with the ESC presentation.

Chair of the hot-line session, Dr George Parcharidis (Aristotle University of Thessaloniki, Greece), asked, somewhat tongue-in-cheek, whether the data were sufficiently strong to support prescribing all young adults a statin for long-term treatment in the hope of reducing all-cause mortality. "They say that one swallow does not make a summer, and I would never advocate atorvastatin to young people on the basis of these findings," responded Sever. "But what these findings do demand is a prospective study in patients at high risk for infection to determine whether the presence of a statin could reduce serious sepsis or death from serious infectious illness."

ASCOT-LLA and the Long-Term Effects of Atorvastatin

The results of ASCOT-LLA were first presented and simultaneously published online in the Lancet in 2003 [2]. As reported by heartwire , lipid lowering with atorvastatin resulted in a significant 36% reduction in the primary end point of fatal coronary heart disease and nonfatal MI after a median follow-up of 3.3 years. At the time the study was stopped, there was a nonsignificant trend toward reduction in all-cause mortality. Upon completion of ASCOT-LLA, investigators continued to collect mortality data and evaluated the mortality outcomes in participants originally randomized to atorvastatin or placebo in the ASCOT-LLA arm for a median of 11 years.

At the end of the extended follow-up, all-cause mortality was significantly reduced by 14% (hazard ratio [HR] 0.86; 95% CI 0.76–0.98), and noncardiovascular mortality was significantly reduced by 15% (HR 0.85; 95% CI 0.73–0.99). There was no difference in death from cardiovascular causes.

Looking more closely at deaths from noncardiovascular causes, investigators found that deaths due to cancer were not statistically significant between those treated with atorvastatin vs placebo. There was, however, a significant 36% reduction in deaths due to infection and respiratory illness (HR 0.64; 95% CI 0.42–0.97), driven primarily by deaths due to infection.

During the session, Sever noted there are emerging data on the effects of statins on infection, with preclinical studies showing statins modulate neutrophil function, reduce proinflammatory cytokine release, improve vascular function, have antithrombotic properties, and improve outcomes from pneumonia and sepsis. Results of other observational studies have suggested that prior statin use reduces mortality from sepsis. Despite these observations, Sever said that there is still the possibility of confounding bias in some of the observational studies that have shown a benefit of statins in pneumonia and sepsis and that caution should be used when interpreting such results until a randomized clinical trial is performed.

Serious Decision for Primary Prevention Patients

Dr Guy De Backer (University Hospital, Ghent, Belgium), the discussant who also wrote an editorial that accompanies the published study [3], said that the introduction of statins into primary prevention is a serious decision considering that asymptomatic patients would be advised to take a drug for the rest of their lives and the only treatment benefit would be that "nothing happens." Moreover, there is little long-term safety data. For these primary-prevention trials, the mean patient age is 55 to 66 years old and the median length of statin use is just under five years, and yet primary-prevention patients would likely be treated with a statin for 15 to 20 years.

For this reason, the long-term ASCOT-LLA study is welcome, said De Backer. In primary-prevention studies, the most important clinical outcome is total mortality and quality of life, he added. One of the reassuring results of ASCOT-LLA is that the results confirm the benefits observed in the Scandinavian Simvastatin Survival Study (4S) and West of Scotland Prevention Study (WOSCOPS). In 4S, WOSCOPS, and ASCOT-LLA, there were significant 15%, 12%, and 14% reductions in all-cause mortality, respectively--all achieving statistical significance. He added that data suggesting a therapeutic role for statins in the management of pneumonia and sepsis are supported by observational studies.

Still, De Backer, like Sever, urges caution in interpreting the findings, especially because there is no explanation for the long-term carryover effect of statins on all-cause mortality but not on cardiovascular mortality. The data are essentially a subgroup analysis, and the reduction in all-cause mortality might be the result of chance, De Backer added. Quoting Dr Peter Sleight (Oxford University, UK), De Backer said, "Subgroup analyses are fun to look at, but don't believe them."

warfarin

2011-09-01T03:47:00.001-07:00

SUMMARY AND COMMENT

ARISTOTLE: Another Competitor Beats Warfarin Free!

August 29, 2011 | Mark S. Link, MD

Apixaban, a factor Xa inhibitor, outperforms warfarin at stroke and systolic embolism prevention in AF patients.

Reviewing: Granger CB et al. N Engl J Med 2011 Aug 28;

Mega JL. N Engl J Med 2011 Aug 28;

poly pill statines

2011-09-01T03:45:00.001-07:00

BMJ 2011; 343:d4044 doi: 10.1136/bmj.d4044 (Published 28 July 2011)

Cite this as: BMJ 2011; 343:d4044

Research

Effectiveness and cost effectiveness of cardiovascular disease prevention in whole populations: modelling study

OPEN ACCESS

Pelham Barton, reader in mathematical modelling1,
Lazaros Andronis, research fellow1,
Andrew Briggs, W R Lindsay chair in health policy and economic evaluation2,
Klim McPherson, visiting professor of public health epidemiology3,
Simon Capewell, professor of clinical epidemiology4

+ Author Affiliations

¹Health Economics Unit, Public Health Building, University of Birmingham, Birmingham B15 2TT, UK
²Health Economics and Health Technology Assessment, University of Glasgow, Glasgow, UK
³New College, University of Oxford, Oxford OX1 2JD, UK
⁴Public Health Department, University of Liverpool, Liverpool L69 3GB, UK

Correspondence to: P Barton p.m.barton@bham.ac.uk

Accepted 13 May 2011

Abstract

Objective To estimate the potential cost effectiveness of a population-wide risk factor reduction programme aimed at preventing cardiovascular disease.

Design Economic modelling analysis.

Setting England and Wales.

Population Entire population.

Model Spreadsheet model to quantify the reduction in cardiovascular disease over a decade, assuming the benefits apply consistently for men and women across age and risk groups.

Main outcome measures Cardiovascular events avoided, quality adjusted life years gained, and savings in healthcare costs for a given effectiveness; estimates of how much it would be worth spending to achieve a specific outcome.

Results A programme across the entire population of England and Wales (about 50 million people) that reduced cardiovascular events by just 1% would result in savings to the health service worth at least £30m (€34m; $48m) a year compared with no additional intervention. Reducing mean cholesterol concentrations or blood pressure levels in the population by 5% (as already achieved by similar interventions in some other countries) would result in annual savings worth at least £80m to £100m. Legislation or other measures to reduce dietary salt intake by 3 g/day (current mean intake approximately 8.5 g/day) would prevent approximately 30 000 cardiovascular events, with savings worth at least £40m a year. Legislation to reduce intake of industrial trans fatty acid by approximately 0.5% of total energy content might gain around 570 000 life years and generate NHS savings worth at least £230m a year.

Conclusions Any intervention that achieved even a modest population-wide reduction in any major cardiovascular risk factor would produce a net cost saving to the NHS, as well as improving health. Given the conservative assumptions used in this model, the true benefits would probably be greater.

atrial fibrillation warfarin

2011-08-29T10:16:00.000-07:00

A New Era for Anticoagulation in Atrial Fibrillation

Jessica L. Mega, M.D., M.P.H.

August 28, 2011 (10.1056/NEJMe1109748)

Article

References

For more than 50 years, warfarin has been the primary medication used to reduce the risk of thromboembolic events in patients with atrial fibrillation. Despite its clinical efficacy, warfarin has multiple, well-known limitations, including numerous interactions with other drugs and the need for regular blood monitoring and dose adjustments. Thus, clinicians and patients have been eager to embrace alternative oral anticoagulants that are equally efficacious but easier to administer.

In this issue of the Journal, Granger and colleagues report the impressive primary results of the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation trial (ARISTOTLE; ClinicalTrials.gov number, NCT00412984).1 A total of 18,201 subjects with atrial fibrillation and at least one additional risk factor for stroke were enrolled in the trial and were randomly assigned to receive the direct factor Xa inhibitor apixaban (at a dose of 5 mg twice daily) or warfarin (target international normalized ratio [INR], 2.0 to 3.0). The trial was designed to test whether apixaban was noninferior to warfarin with respect to efficacy. The investigators found that apixaban was not only noninferior to warfarin, but actually superior, reducing the risk of stroke or systemic embolism by 21% and the risk of major bleeding by 31%. In predefined hierarchical testing, apixaban, as compared with warfarin, also reduced the risk of death from any cause by 11%.

These results come on the heels of two other, large, phase 3 trials in which novel anticoagulants were compared with warfarin in patients with atrial fibrillation: the Randomized Evaluation of Long-Term Anticoagulation Therapy trial (RE-LY, NCT00262600)2 and Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF, NCT00403767).3 The RE-LY trial evaluated the direct thrombin inhibitor dabigatran in two different doses, 110 mg and 150 mg, both administered twice daily. ROCKET AF evaluated the direct factor Xa inhibitor rivaroxaban at a dose of 20 mg once daily.

The trials have a number of similar conclusions. Apixaban, dabigatran, and rivaroxaban, as compared with warfarin, all significantly reduce the risk of hemorrhagic stroke. In fact, in all the studies, the reductions in the primary efficacy end point — which included hemorrhagic as well as ischemic stroke — were greatly influenced by this dramatic reduction in the risk of hemorrhagic stroke. Of the three drugs, only dabigatran at a dose of 150 mg holds the distinction of also having significantly reduced the risk of ischemic stroke as compared with warfarin; nonetheless, even in this case, there was a greater influence on hemorrhagic stroke than on ischemic cerebrovascular events. Similarly, the risk of particularly serious bleeding was reduced with each of the three drugs, as compared with warfarin, and apixaban therapy also resulted in lower rates of all major bleeding. Thus, the newer anticoagulants boast favorable bleeding profiles as compared with warfarin in patients with atrial fibrillation.

There is also a shared theme with respect to mortality. Apixaban is the first of the newer anticoagulants to show a significant reduction in the risk of death from any cause as compared with warfarin (hazard ratio, 0.89; 95% confidence interval [CI], 0.80 to 0.99; P=0.047). Although the current findings are notable, both dabigatran and rivaroxaban, as compared with warfarin, showed similar directional trends. In the RE-LY trial, there was a borderline reduction in the risk of death from any cause with dabigatran at a dose of 150 mg, as compared with warfarin (hazard ratio, 0.88; 95% CI, 0.77 to 1.00; P=0.051). Similar trends in the risk of death from any cause were observed with rivaroxaban in the intention-to-treat analysis in ROCKET AF (hazard ratio, 0.92; 95% CI, 0.82 to 1.03; P=0.15). Thus, there is approximately a 10% reduction in the risk of death from any cause across these three trials in which the newer anticoagulants were compared with warfarin in patients with atrial fibrillation.

Despite these similarities, there are important differences in the design of the studies and in the administration of the drugs. In the RE-LY trial, the assignments to dabigatran or warfarin were not concealed. In contrast, the ROCKET AF and ARISTOTLE trials successfully achieved a double-blind design. In the RE-LY and ARISTOTLE trials, dabigatran and apixaban were administered twice daily; in ROCKET AF, rivaroxaban was administered once daily. Subjects in the RE-LY and ARISTOTLE trials could have only one additional risk factor for stroke, whereas ROCKET AF enrolled a higher-risk population. The mean percentage of time in which the INR was in the therapeutic range of 2.0 to 3.0 — a metric that assesses the quality of warfarin dosing — was 64% in the RE-LY trial, 55% in the ROCKET AF trial, and 62% in the ARISTOTLE trial. There were additional differences among the studies with respect to their statistical analysis plans and power. These factors highlight the challenges with cross-trial comparisons. Head-to-head studies, which are not currently available, would allow for direct assessments among these novel compounds.

Will these newer anticoagulants be better than warfarin for the treatment of all patients with atrial fibrillation? The direct thrombin and factor Xa inhibitors overcome the need for routine blood monitoring, and the trial results have been encouraging overall and across important subgroups. For example, in the ARISTOTLE trial, the efficacy of apixaban was consistent in subgroups according to baseline stroke risk and according to whether patients had or had not been taking warfarin before entering the study. However, switching to a newer agent may not be necessary for the individual patient in whom the INR has been well controlled with warfarin for years. In addition, although the newer anticoagulants have a more rapid onset and termination of anticoagulant action than does warfarin, agents to reverse the effect of the drugs are still under development and are not routinely available.

In addition, generic warfarin is expected to be markedly less expensive than the newer agents even after the costs associated with regular INR monitoring are considered. One analysis has suggested that dabigatran, as compared with warfarin, could be cost-effective in patients with atrial fibrillation.4 Additional data on cost-effectiveness are likely to further influence clinical decision making. Thus, although the oral direct thrombin and factor Xa inhibitors are attractive alternatives, it is likely that warfarin will continue to be used worldwide in many patients with atrial fibrillation.

The original mission to replace warfarin began with a search for drugs that were simply noninferior to warfarin. The ARISTOTLE trial, in conjunction with the RE-LY and ROCKET AF trials, suggests that apixaban, dabigatran, and rivaroxaban have gone even further. Across three large studies with different populations of patients with atrial fibrillation, the direct thrombin and factor Xa inhibitors have been shown to have a more favorable bleeding profile than warfarin and are at least as efficacious. Information about another direct factor Xa inhibitor, edoxaban, in patients with atrial fibrillation, will be available at the conclusion of the Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation–Thrombolysis in Myocardial Infarction Study 48 (ENGAGE AF-TIMI 48, NCT00781391).5 After all this time, a new era of anticoagulation appears to be emerging for patients with atrial fibrillation.

Disclosure forms provided by the author are available with the full text of this article at NEJM.org.

This article (10.1056/NEJMe1109748) was published on August 28, 2011, at NEJM.org.

Source Information

From the Thrombolysis in Myocardial Infarction Study Group, Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston.

PPI

2011-08-27T04:07:00.001-07:00

August 24, 2011 — The nonprofit consumer advocacy group Public Citizen is petitioning the US Food and Drug Administration (FDA) to add black box warnings to the product labels of all proton pump inhibitors (PPIs) on the market.

The black box warnings should alert clinicians and patients that these drugs can cause long-term dependence and other serious adverse effects, Public Citizen says in a statement released yesterday.

The group is also calling for patient medication guides to be distributed with all PPIs and for the makers of the drugs to notify clinicians of these adverse effects and of the need to try safer alternatives first for conditions such as gastroesophageal reflux disease (GERD).

"These drugs are being prescribed far too commonly to people who shouldn't be taking them," Sidney Wolfe, MD, director of Public Citizen's Health Research Group, said in a prepared statement. "As a result, millions of people are needlessly setting themselves up to become dependent on PPIs while exposing themselves to the serious risks associated with long-term therapy.

"The FDA should act immediately to ensure that patients and physicians are adequately warned of these effects, and reminded of the many safer alternatives for common conditions such as acid reflux," he added.

More Education, Not Warnings, Needed

Reached for independent comment, Kenneth DeVault, MD, professor and chair, Department of Medicine, Mayo Clinic, Jacksonville, Florida, told Medscape Medical News that he does not think that greater warnings are needed on PPIs, "but that education of providers and consumers is important."

"Honestly," he said, "the risks of these medications, even when over the counter, are less than some other common drugs, such as nonsteroidal anti-inflammatories and even aspirin."

Still, Dr. DeVault said he is "becoming more likely to try to find the 'lowest effective dose' " for his patients. "That might be a once-daily PPI, a lower-dose PPI, an H2 receptor blocker, or in some patients, simply leading a less 'refluxogenic lifestyle.'

"We need to make sure we understand that for a significant proportion of patients with acid reflux, this is a lifestyle condition where a better diet and weight loss may result in the patient not needing any acid blocker at all," Dr. DeVault explained.

PPIs Widely Prescribed

PPIs, which effectively suppress the production of stomach acid, are among the most widely used classes of drugs in the world. In the United States alone, an estimated 119 million PPI prescriptions were dispensed in 2009, at a price tag of $13.6 billion.

PPIs are approved to treat GERD, as well as gastric ulcers, erosive esophagitis, and stomach bleeding associated with using nonsteroidal anti-inflammatory drugs, although they are often prescribed for other reasons and for longer than indicated, some studies have suggested.

PPIs have been shown to be generally well tolerated with relatively few short-term adverse effects. Common adverse effects include headache, nausea, diarrhea, abdominal pain, fatigue, and dizziness.

Adverse effects related to long-term use of PPIs have been less well studied, but may include an increased risk for fractures of the hip, spine, and wrist; hypomagnesemia, possibly leading to cardiac arrhythmia; infections such as pneumonia and Clostridium difficile diarrhea; and reduced effectiveness of the antiplatelet clopidogrel, although the clinical significance of this is debated. Many of these possible adverse effects are already contained in PPI labeling.

Rebound Hyperacidity

A key concern of Public Citizen is the possibility of long-term dependence on PPI therapy resulting from rebound acid hypersecretion when the medication is stopped, which is not currently noted on the label.

For example, in a study published in 2009 in Gastroenterology, researchers reported that acid inhibition with a PPI for 8 weeks induces acid-related symptoms in "a significant proportion" of asymptomatic patients when therapy is withdrawn.

"We find it highly likely," the authors write, "that the symptoms observed in this trial are caused by [rebound acid hypersecretion,] and that this phenomenon is equally relevant in patients treated long term with PPIs. These results justify the speculation that PPI dependency could be 1 of the explanations for the rapidly and continuously increasing use of PPIs."

The authors of a related commentary in the journal concluded: "The current finding that these drugs induce symptoms means that such liberal prescribing is likely to be creating the disease the drugs are designed to treat and causing patients with no previous need for such therapy to require intermittent or long-term treatment."

PPIs Beneficial in Appropriate Patients

Colin W. Howden, MD, FACG, and Peter J. Kahrilas, MD, FACG, address this issue of PPI withdrawal and rebound hyperacidity in a 2010 commentary published in the American Journal of Gastroenterology.

The authors conclude: "PPI treatment continues to be the optimal management strategy for most patients with [GERD] and is indicated for chronic use as ulcer prophylaxis in nonsteroidal anti-inflammatory drug takers at high risk for bleeding.

"However, as with all drugs, PPIs should be dosed appropriately, and should be reserved for patients with conditions for which there is clear evidence of benefit from therapy," they write.

Dr. DeVault told Medscape Medical News, "There is probably a short-lived (2 weeks or so) theoretical increase in acid capacity after stopping PPI therapy, which might make it more difficult to stop the drugs in selected patients, and might even lead to acid symptoms in some normal individuals."

In contrast, he said he thinks that "a good bit of that 'rebound' is actually related to the symptoms, in that the patient simply feels better on the PPI and therefore wants to continue, but the converse remains a possibility."

"At this point," Dr. DeVault noted, "PPIs are still my first choice for acid suppression, but it is critical to evaluate the patient and not blindly continue these medications when they are not helping.

"A common mistake is for a provider to become convinced the patient has an acid-related problem and gradually escalate the degree of acid suppression, when taking a step back and doing some diagnostic evaluation may reveal that the problem is not acid-related at all," he added.

statins

2011-08-25T08:20:00.001-07:00

From Medscape Internal Medicine > Staying Well With Sandra Fryhofer, MD

Switching From Simvastatin 80 mg: How to Shop for Statins

Sandra A. Fryhofer, MD

Authors and Disclosures

Posted: 08/12/2011

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Savvy Statin Shopping
The Simvastatin Saga: Review of the FDA Drug Safety Warnings
Mechanisms of Statin-Related Muscle Injury
Final Thoughts From the Statin Savvy Shopper

References

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Sandra A. Fryhofer, MD
Clinical Associate Professor of Medicine, Emory University School of Medicine, Atlanta, Georgia; Past President, American College of Physicians, Philadelphia, Pennsylvania

Savvy Statin Shopping

Let's go shopping. This edition of Staying Well focuses on how to be a savvy shopper in choosing a statin for your patients, a timely issue in light of the US Food and Drug Administration's (FDA's) new simvastatin warnings. Seasoned shoppers always check the sale racks first, but don't buy something -- even if on sale -- if the "size and style" aren't right. Apply this analogy to picking a statin. Although the first thing to look for is price, it should not be the only deciding factor. Simvastatin is certainly one of the cheapest statins, but is it the best choice for your patients?

My Personal Disclaimer

I admit that I have been a little lazy. For the last several years, when my patients needed statins I always started with simvastatin. It was generic. It was on all the pharmacy plans, so the price point for patients was right. Prescribing was hassle free: no cumbersome forms to fill out and explain. However, the recent FDA warnings about the dangers of high-dose simvastatin and additional warnings about dosing and drug interactions have led me to rethink this strategy and take a closer look at the different statins available. It is now time to find out the facts and make necessary changes in prescribing patterns. Maybe it's time for a new "style" of treatment. Here is some information to help you decide.

Statin Characteristics

This statin dose equivalency guide gives equivalent doses of available statins along with generic and brand names and selected characteristics (Table 1).^[1-5]

Table 1. Statin Dose Equivalency Guide

Medication	Dose Equivalent	Pharmacotherapeutic Factor	Metabolism	Metabolites
Rosuvastatin (Crestor®)	2.5 mg	Hydrophilic	CYP2C9	Active (minor) metabolite
Atorvastatin (Lipitor®)	5 mg	Lipophilic	P450 3A4 (CYP3A4)	Active metabolite
Simvastatin (Zocor®)^a	10 mg	Lipophilic	P450 3A4 (CYP3A4)	Active metabolite
Lovastatin (Altoprev®, Mevacor®)	20 mg	Lipophilic	P450 3A4 (CYP3A4)	Active metabolite
Pravastatin (Pravachol®)	20 mg	Hydrophilic	Renal metabolism	No active metabolites
Fluvastatin (Lescol®, Lescol® XL)	40 mg	Lipophilic	CYP2C9	No active metabolites
Pitavastatin (Livalo®)	1 mg	Lipophilic	Little metabolism by CYP3A4	No active metabolites

^aAlso in combination medications: ezetimibe/simvastatin (Vytorin®) and niacin extended release/simvastatin (Simcor®)

Table 2 is from the FDA Drug Safety Communication and gives relative low-density lipoprotein (LDL) efficacy for the different statins. Note that pitavastatin (Livalo®) is a newer statin and was FDA approved in 2009.

Table 2. Relative LDL-Lowering Efficacy of Statin and Statin-Based Therapies

Atorva	Fluva	Pitava	Lova	Prava	Rosuva	Vytorin®^a	Simva	%↓ LDL-C
--	40 mg	1 mg	20 mg	20 mg	--	--	10 mg	30%
10 mg	80 mg	2 mg	40/80 mg	40 mg	--	--	20 mg	38%
20 mg	--	4 mg	80 mg	80 mg	5 mg	10/10 mg	40 mg	41%
40 mg	--		--	--	10 mg	10/20 mg	80 mg	47%
80 mg	--		--	--	20 mg	10/40 mg	--	55%
	--		--	--	40 mg	10/80 mg	--	63%

Atorva = atorvastatin; Fluva = fluvastatin; LDL-C = low-density lipoprotein cholesterol; Pitava = pitavastatin; Lova = lovastatin; Prava = pravastatin; Rosuva = rosuvastatin; Simva = simvastatin
^aNo incremental benefit of Vytorin on cardiovascular morbidity and mortality over and above that demonstrated for simvastatin has been established.
Data from US Food and Drug Administration. June 8, 2011. Available at: http://www.fda.gov/Drugs/DrugSafety/ucm256581.htm ^[4]

Association of Pharmacologic Factors With Adverse Effects

Statins that are hydrophilic (pravastatin and rosuvastatin) are less likely to cross skeletal muscle membranes and are less likely to cause adverse effects.^[3]

Statins that don't have active metabolites (fluvastatin, pravastatin, and pitavastatin) are less likely to cause adverse effects. Rosuvastatin has only a minor active metabolite.^[3,5]

Drug metabolism pathway plays a role in drug-drug interactions and subsequent safety. This is especially important for patients on multiple medications:

For statins metabolized by P450 3A4 (CYP3A4) (simvastatin, lovastatin, atorvastatin), concomitant administration of medications that inhibit the CYP3A4 pathways (protease inhibitors, cyclosporine, amiodarone, fibrates) is problematic. The result is increased statin levels and increased risk for muscle tissue injury.
On the other hand, fluvastatin and rosuvastatin (metabolized by CYP2C9) and pravastatin (metabolized by the kidneys) are considered to be safer statin choices for patients on multiple medications.^[3]

Section 1 of 4

Next: The Simvastatin Saga: Review of the FDA Drug Safety Warnings »

folium zuur

2011-08-13T00:39:00.001-07:00

SUMMARY AND COMMENT

Is Folic Acid a Risk Factor for CRC?

August 12, 2011 | Douglas K. Rex, MD

No type of folate, including folic acid, increased the risk for colorectal cancer.

Reviewing: Stevens VL et al. Gastroenterology 2011 Jul 141:98

Lee JE et al. Gastroenterology 2011 Jul 141:16

dementia bloedvaten

2011-08-08T13:17:00.000-07:00

According to the current study by Gorelick and colleagues, by 2025 there will be 1.2 billion persons worldwide who will be 60 years and older. Also, in persons 80 years and older — a fast-growing population in developed countries — approximately 20% experience difficulties in activities of daily living, with cognitive impairment increasing in prevalence with age. In addition, risk markers for stroke are now understood to be risk markers for Alzheimer's disease and other cognitive impairments. Vascular cognitive impairment (VCI) is a cause of microvascular brain damage, and arterial stiffness and atherosclerotic changes may be common risk factors for VCI.

This statement from the American Heart Association (AHA) and the American Stroke Association (ASA) describes vascular contributions to cognitive impairment and provides recommendations for prevention, treatment, and future research.

Study Synopsis and Perspective

Vascular changes are "important" contributors to cognitive impairment and dementia and should be routinely addressed in clinical practice, according to a new scientific statement from the AHA and ASA.

The 42-page statement, "Vascular Contributions to Cognitive Impairment and Dementia," was published online July 21 in Stroke and will appear in the September print issue of the journal. The American Academy of Neurology and the Alzheimer's Association have endorsed the statement. The Alzheimer's Association participated in its development.

In comments to Medscape Medical News, Philip B. Gorelick, MD, MPH, cochair of the writing group for the statement and director of the Center for Stroke Research at the University of Illinois College of Medicine at Chicago, said vascular factors "have long been thought to be an important contributor to cognitive decline and dementia in later life."

Still, they have not received as much attention as Alzheimer's disease, "which has been on the center stage of scientific inquiry," he added.

Introducing 'Vascular Cognitive Impairment'

Dr. Gorelick and the writing group systematically reviewed published studies, guidelines, personal files, and expert opinion to summarize existing evidence, indicate gaps in current knowledge, and, when appropriate, offer recommendations for care.

"Over time and with careful study, vascular factors have been found to play a role in both vascular and so-called neurodegenerative forms of cognitive impairment such as Alzheimer disease," Dr. Gorelick said.

On the basis of the evidence, the writing group formally introduces the construct of "vascular cognitive impairment" (VCI). This, they say, captures "the entire spectrum of cognitive disorders associated with all forms of cerebral vascular brain injury — solely stroke — ranging from mild cognitive impairment through fully developed dementia.

"The neuropathology of cognitive impairment in later life is often a mixture of Alzheimer disease and microvascular brain damage," the study authors note, "which may overlap and synergize to heighten the risk of cognitive impairment."

In this regard, magnetic resonance imaging and other neuroimaging techniques "play an important role" in detecting and defining VCI, they advise.

What's Good for the Heart Is Good for the Brain

It is now "accepted," the team writes, that many of the traditional risk markers for heart disease and stroke are also risk markers for VCI and Alzheimer's disease.

"Stroke and heart disease are linked by a number of cardiovascular risk factors, such as hypertension, hypercholesterolemia, diet, tobacco exposure, and other factors," Dr. Gorelick explained. "These vascular factors and others may play a causal role in the development of cognitive impairment and dementia in later life."

Carotid intimal-medial thickness and arterial stiffness are "emerging as markers of arterial aging and may serve as risk markers for VCI," the writing group points out.

Detection and control of the traditional risk factors for stroke and cardiovascular disease may help guard against VCI. "We encourage clinicians to use screening tools to detect cognitive impairment in their older patients and continue to treat vascular risks according to nationally- and regionally-accepted guidelines," the study authors write.

"At the very least," Dr. Gorelick said, screening for and treatment of vascular risk factors, including hypertension, hyperglycemia, and hypercholesterolemia, may reduce the occurrence of stroke and heart disease. "There may be an added benefit of prevention and treatment of vascular risk factors — the prevention of cognitive impairment and dementia in later life," he added.

Specifically, in persons at risk for VCI, the writing group concludes that

Smoking cessation is reasonable (Class IIa; Level of Evidence A);
Moderation of alcohol intake, weight control, and physical activity may be reasonable (all Class IIb; Level of Evidence B); and
Use of antioxidants and B vitamins is not useful, based on current evidence (Class III; Level of Evidence A).

For individuals with vascular dementia, they conclude that

Donepezil can be useful for cognitive enhancement (Class IIa; Level of Evidence A);
Galantamine can be beneficial for individuals with mixed Alzheimer disease/vascular dementia (Class IIa; Level of Evidence A); and
The benefits of rivastigmine and memantine are not well established in vascular dementia (Class IIb; Level of Evidence A).

The study authors also note that a Mediterranean-type dietary pattern has been associated with less cognitive decline in several studies and may be reasonable (Class IIb; Level of Evidence B).

Vitamin supplementation is not proven to improve cognitive function, even if homocysteine levels have been positively influenced, and its usefulness is not well established (Class IIb; Level of Evidence B). The effectiveness of antiaggregant therapy for VCI is not well established (Class IIb; Level of Evidence B).

Reached for comment, Thomas Russ, MD, PhD, from the University of Edinburgh, Scotland, said, "This is a clear outline of the difficulties surrounding the rather complicated overlap and interaction between vascular changes and the neuropathological changes of Alzheimer disease both resulting in cognitive impairment and dementia.

"The recommendations for prevention are a useful restatement of the current state of knowledge and a helpful reminder that we need to intervene sufficiently early in a condition which develops over the course of years and decades — ie, middle age," added Dr. Russ, who was not involved in the writing group.

Dr. Gorelick has disclosed no relevant financial relationships. A complete list of disclosures for writing group members is available with the original article. Dr. Russ has disclosed no relevant financial relationships.

Stroke. Published online July 21, 2011.

gout jicht

2011-08-04T07:50:00.000-07:00

NSAIDs

NSAIDs are the usual first-line treatment for gout, and no specific agent is significantly more or less effective than any other.^[2] Improvement may be seen within 4 hours, and treatment is recommended for 1–2 weeks.^[2]^[6] They are not recommended, however in those with certain other health problems, such as gastrointestinal bleeding, renal failure, or heart failure.^[33] While indomethacin has historically been the most commonly used NSAID, an alternative, such as ibuprofen, may be preferred due to its better side effect profile in the absence of superior effectiveness.^[16] For those at risk of gastric side effects from NSAIDs, an additional proton pump inhibitor may be given.^[34]

atrium fibrillatie NSAID's

2011-08-04T07:24:00.000-07:00

From British Medical Journal

Non-Steroidal Anti-Inflammatory Drug Use and Risk of Atrial Fibrillation or Flutter

Population Based Case-Control Study

Morten Schmidt; Christian F Christiansen; Frank Mehnert; Kenneth J Rothman; Henrik Toft Sørensen

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Abstract and Introduction
Methods
Results
Discussion

Abstract

Objectives To examine the risk of atrial fibrillation or flutter associated with use of non-selective non-steroidal anti-inflammatory drugs (NSAIDs) or selective cyclo-oxygenase (COX) 2 inhibitors.
Design Population based case-control study using data from medical databases.
Setting Northern Denmark (population 1.7 million).
Participants 32 602 patients with a first inpatient or outpatient hospital diagnosis of atrial fibrillation or flutter between 1999 and 2008; 325 918 age matched and sex matched controls based on risk-set sampling.
Main outcome measures Exposure to NSAID use at the time of admission (current use) or before (recent use). Current use was further classified as new use (first ever prescription redemption within 60 days before diagnosis date) or long term use. We used conditional logistic regression to compute odds ratios as unbiased estimates of the incidence rate ratios.
Results 2925 cases (9%) and 21 871 controls (7%) were current users of either non-selective NSAIDs or COX 2 inhibitors. Compared with no use, the incidence rate ratio associating current drug use with atrial fibrillation or flutter was 1.33 (95% confidence interval 1.26 to 1.41) for non-selective NSAIDs and 1.50 (1.42 to 1.59) for COX 2 inhibitors. Adjustments for age, sex, and risk factors for atrial fibrillation or flutter reduced the incidence rate ratio to 1.17 (1.10 to 1.24) for non-selective NSAIDs and 1.27 (1.20 to 1.34) for COX 2 inhibitors. Among new users, the adjusted incidence rate ratio was 1.46 (1.33 to 1.62) for non-selective NSAIDs and 1.71 (1.56 to 1.88) for COX 2 inhibitors. Results for individual NSAIDs were similar.
Conclusions Use of non-aspirin NSAIDs was associated with an increased risk of atrial fibrillation or flutter. Compared with non-users, the association was strongest for new users, with a 40-70% increase in relative risk (lowest for non-selective NSAIDs and highest for COX 2 inhibitors). Our study thus adds evidence that atrial fibrillation or flutter needs to be added to the cardiovascular risks to be considered when prescribing NSAIDs.

Introduction

Non-steroidal anti-inflammatory drugs (NSAIDs) are widely used to treat inflammatory conditions and pain.^[1] By inhibiting cyclo-oxygenase (COX)-1 mediated production of prostaglandins,^[1] non-selective NSAIDs are known to cause gastrointestinal toxicity^[1] and a variety of nephrotoxic syndromes.^[2] An alternative is selective COX 2 inhibitors, available in the form of older or newer agents.^[3] The newer COX 2 inhibitors, introduced into clinical practice in 1998, were developed as NSAIDs with an improved gastrointestinal side effect profile.^[1] The cardiovascular safety of all marketed newer COX 2 inhibitors requires thorough evaluation in view of the increased cardiovascular^[4-6] and renal risk^[2] reported for several of these drugs.

Atrial fibrillation is the most common rhythm disorder observed in clinical practice. It more than doubles in prevalence during each advancing decade of life, from 0.5% at age 50-59 years to above 10% at age 80-89 years.^[7] It is associated with increased mortality and morbidity, mainly due to haemodynamic impairments that exacerbate or even cause heart failure,^[8] and a threefold to fourfold increased risk of thromboembolic stroke.^[9]

Use of NSAIDs may increase the risk of atrial fibrillation through its adverse renal effects—for example, fluid retention, electrolyte disturbances, and blood pressure destabilisation ^[2,6]—but the evidence for such effects is limited.^[10,11] Although no original research has been published on COX 2 inhibitors and atrial fibrillation, a meta-analysis summarised data from 114 clinical trials and found that rofecoxib was associated with an increased risk of cardiac arrhythmias (relative risk 2.90, 95% confidence interval 1.07 to 7.88).^[10] Because the meta-analysis included only 286 incident arrhythmias, precision was low and risk of arrhythmia subtypes such as atrial fibrillation could not be examined.^[10] Recently, traditional NSAIDs (that is, non-selective NSAIDs and older COX 2 inhibitors) have been associated with increased risk of chronic atrial fibrillation (incidence rate ratio 1.44, 1.08 to 1.91).^[11]

Any confirmed association between use of NSAIDs and atrial fibrillation would have major clinical and public health implications. Older people are of special concern because the prevalence of use of NSAIDs and the incidence of atrial fibrillation increase with age. To address the limitations of the existing literature, we conducted a large population based case-control study examining whether and to what extent use of NSAIDs increases the risk of atrial fibrillation or flutter.

Section 1 of 4

Next: Methods »

warfarin stroke

2011-08-03T03:24:00.001-07:00

Summary and Comment

Stroke Risk-Stratification Scores Have Limited Prognostic Value in Elders with AF

The authors suggest anticoagulation for all elders with atrial fibrillation.

Several stroke risk-stratification scores are available to determine which patients with atrial fibrillation (AF) will benefit from long-term warfarin anticoagulation. However, these scores were based on populations in which elders — the group most likely to have AF — were underrepresented. In this study, U.K. investigators compared the predictive power of eight stroke risk-stratification scores (CHADS₂ original, CHADS₂ revised, Framingham, NICE, ACC/AHA/ESC, ACCP, CHA₂DS₂-VASchttp://general-medicine.jwatch.org/articles/JO2011030301.jpg, and Rietbrock modified CHADS₂) among 665 participants (age, 75; mean age, 81; 55% men) with AF who did not take warfarin throughout or for part of the Birmingham Atrial Fibrillation Treatment of the Aged (BAFTA) trial.

After median follow-up of 2.2 years, 54 participants (8.0%) experienced ischemic stroke, 13 (2.0%) had transient ischemic attacks, and 4 (0.6%) suffered systemic embolism. All scores performed poorly (C-statistic range, 0.55–0.62, indicating that prediction of stroke for any given person wasn't much better than chance).

Comment: In this study, various stroke risk-stratification scores had limited ability to predict ischemic stroke in elders with AF. The authors conclude that "until better scores are available," clinicians should consider all older patients (age, 75) with AF to be at high risk for stroke and should offer long-term anticoagulation to those who are appropriate candidates for this treatment (rather than prescribing aspirin, which is less effective in preventing stroke and is associated with an incidence of major bleeding events that is similar to warfarin's in this population).

— Paul S. Mueller, MD, MPH, FACP

Published in Journal Watch General Medicine August 2, 2011

vascular dementia Alzheimer stroke

2011-07-23T04:58:00.000-07:00

July 21, 2011 — Vascular changes are "important" contributors to cognitive impairment and dementia and should be routinely addressed in clinical practice, according to a new scientific statement from the American Heart Association (AHA) and the American Stroke Association (ASA).

The 42-page statement, Vascular Contributions to Cognitive Impairment and Dementia, was published online July 21 in Stroke and will appear in the September print issue of the journal. The American Academy of Neurology and the Alzheimer's Association have endorsed the statement. The Alzheimer's Association participated in its development.

Still, they have not received as much attention as Alzheimer's disease, "which has been on the center stage of scientific inquiry," he added.

Introducing 'Vascular Cognitive Impairment'

In this regard, magnetic resonance imaging (MRI) and other neuroimaging techniques "play an important role" in detecting and defining VCI, they advise.

What's Good for the Heart is Good for the Brain

It is now "accepted," the team writes, that many of the traditional risk markers for heart disease and stroke are also risk markers for VCI and Alzheimer's disease.

"Stroke and heart disease are linked by a number of cardiovascular risk factors, such as hypertension, hypercholesterolemia, diet, tobacco exposure, and other factors,” Dr. Gorelick explained. "These vascular factors and others may play a causal role in the development of cognitive impairment and dementia in later life."

Carotid intimal-medial thickness and arterial stiffness are "emerging as markers of arterial aging and may serve as risk markers for VCI," the writing group points out.

Specifically, in persons at risk for VCI, the writing group concludes that

Smoking cessation is reasonable (Class IIa; Level of Evidence A);
Moderation of alcohol intake, weight control, and physical activity may be reasonable (all Class IIb; Level of Evidence B); and
Use of antioxidants and B vitamins is not useful, based on current evidence (Class III; Level of Evidence A).

For individuals with vascular dementia, they conclude that

Donepezil can be useful for cognitive enhancement (Class IIa; Level of Evidence A);
Galantamine can be beneficial for individuals with mixed Alzheimer disease/vascular dementia (Class IIa; Level of Evidence A); and
The benefits of rivastigmine and memantine are not well established in vascular dementia (Class IIb; Level of Evidence A).

The study authors also note that a Mediterranean-type dietary pattern has been associated with less cognitive decline in several studies and may be reasonable (Class IIb; Level of Evidence B).

Stroke. Published online July 21, 2011.

NSAID's omeprazol

2011-07-23T04:46:00.000-07:00

Summary and Comment

Nonadherence to Gastroprotective Therapy Among NSAID Users

Low adherence increased risk for upper gastrointestinal bleeding.

The risk for upper gastrointestinal (UGI) bleeding in patients taking nonselective nonsteroidal anti-inflammatory drugs (NSAIDs) can be reduced by concomitant gastroprotective therapy. However, many patients do not comply with this approach.

To evaluate adherence to gastroprotective therapy and its effect on UGI events, investigators conducted a nested case-control study using three large national databases from the UK, the Netherlands, and Italy. Among a cohort of NSAID users aged 50 years who took gastroprotective agents, patients with UGI events were identified. Adherence to gastroprotective therapy was determined using pharmacy data and compared between patients with and without UGI events.

Investigators documented 117,307 episodes of NSAID use with gastroprotective cotherapy. Patient adherence was rated as low (<20%) among 4.9% of the group and high (>80%) among 68.1%. A total of 339 UGI events occurred. The risk for such events was greater in those with low versus high adherence (odds ratio, 2.39 for all events; and OR, 1.89 for bleeding).

Comment: The authors conclude that nonadherence to gastroprotective therapy is associated with an increased risk for upper gastrointestinal events and bleeding and that strategies to improve adherence should be developed. Despite the limitations of retrospective database studies, this study's notable strengths were inclusion of patient databases from three European countries (each of which showed the same result) and use of a cohort taking both NSAIDs and gastroprotective agents, which eliminated the possibility of confounding through channeling of patients with higher risk of incident symptoms. However, the results compare only the patients with lowest (<20%) and highest (>80%) adherent, whereas many patients are occasionally adherent. We cannot conclude from this study if a threshold adherence rate lower than 80% exists that should be targeted clinically.

— David J. Bjorkman, MD, MSPH (HSA), SM (Epid.)

Published in Journal Watch Gastroenterology July 22, 2011

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What form of vitamin D is recommended in chronic kidney disease?

What dose of cholecalciferol is suggested for preventing deficiency?

What is the upper limit of vitamin D intake?

Which vitamin D preparations are available in an oral liquid?

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