Wednesday, November 19, 2008
statins medscape cardiology 14-11-2008
Summary
Introduction: Statins have diverse anti-inflammatory effects in addition to their lipid-lowering ability. This study assesses the rate of chronic obstructive pulmonary disease (COPD) exacerbation and intubations in patients taking statins.
Methods: This is a retrospective cohort study of 185 patients with COPD exacerbation, with a 1-year follow-up. Outcomes examined were repeat hospitalisation and intubations for COPD exacerbation. Baseline characteristics for which the p-value was ≤ 0.10 were considered as covariates for inclusion in a multivariate model.
Results: The statin group had fewer episodes of exacerbation and required intubation fewer times than the subjects not receiving statins (p <>2 agonists as a covariate were 3.01 (CI: 1.46-6.10) for exacerbation and 8.89 (CI: 3.67-21.32) for intubation. Time to outcome during the observation period was reduced by statins with the hazard ratio (HR) for exacerbation of 0.19 (CI: 0.06-0.14); HR for statins reducing intubation was 0.14 (95% CI: 0.10-0.30).
Conclusions: These data suggest that the use of statins may be associated with lower incidence of both exacerbations and intubations in patients with COPD.
statins
medscape cardiology medscape
14-11-2008
statins
Abstract and Introduction
Abstract
Background: Few data are available on the use of statins after publication of the National Cholesterol Education Program Third Adult Treatment Panel (ATP-III) guidelines in 2001.
Objective: To determine changes in statin use and its impact on low-density lipoprotein cholesterol (LDL-C) control among US adults from 1999 to 2004.
Methods: High LDL-C levels and statin use among 1911 participants of the National Health and Nutrition Examination Survey (NHANES) 2003-2004 were determined and compared with 1770 and 2094 participants of NHANES 1999-2000 and NHANES 2001-2002, respectively. Statin use was obtained from review of participants' drug containers. High LDL-C levels and LDL-C control were defined, using risk-specific cut-points from the ATP-III guidelines.
Results: Statins were taken by 24 million Americans in 2003-2004, an increase from 12.5 million in 1999-2000. In 1999-2000, 2001-2002, and 2003-2004, statins were being used by 19.6%, 27.3%, and 35.9% of US adults with high LDL-C levels, respectively (p trend <0.001). Age-standardized mean LDL-C declined from 119.9 to 112.0 to 100.7 mg/dL among statin users between 1999-2000, 2001-2002, and 2003-2004. LDL-C control to ATP-III recommended targets was achieved by 49.7%, 67.4%, and 77.6% of statin users in 1999-2000, 2001-2002, and 2003-2004, respectively (p trend <0.001). Among US adults with high LDL-C, after multivariate adjustment, non-Hispanic blacks were 39% less likely (prevalence ratio = 0.61; 95 CI 0.39 to 0.97) than non-Hispanic whites to be taking statins.
Conclusions: Statin use continues to increase among US adults and this has led to substantial improvements in LDL-C control. Nevertheless, suboptimal statin use, especially among racial/ethnic minorities, continues to prevent the maximal public health benefit from this effective drug class.
anticoagulans warfarin
Anticogulant medications are high-risk, complex agents, used in settings where the continuum of care is often fragmented. The implementation expectations of NPSG 3E will set a new safe practice standard for anticoagulation therapy in our hospitals nationwide.
The eighth edition of the ACCP Antithrombotic and Thrombolytic Evidenced-Based Clinical Practice Guidelines provides an up-to-date guide for clinical decision making in the treatment of thromboembolic disease. Finally, the promising phase III clinical trials for 2 new drugs, dabigatran and rivaroxapan, may simplify the treatment of thromboembolism. These new drugs are surely a welcome development for patients who have had no alternative to warfarin in more than 60 years.
Medscape gasteroenterology 14 11 2008
Anticogulant medications are high-risk, complex agents, used in settings where the continuum of care is often fragmented. The implementation expectations of NPSG 3E will set a new safe practice standard for anticoagulation therapy in our hospitals nationwide.
The eighth edition of the ACCP Antithrombotic and Thrombolytic Evidenced-Based Clinical Practice Guidelines provides an up-to-date guide for clinical decision making in the treatment of thromboembolic disease. Finally, the promising phase III clinical trials for 2 new drugs, dabigatran and rivaroxapan, may simplify the treatment of thromboembolism. These new drugs are surely a welcome development for patients who have had no alternative to warfarin in more than 60 years.
Medscape gasteroenterology 14 11 2008
bètablokkers
Medscape cardiology 14-11 2008
homoseksualiteit gay lesbien
Medscape gasteroenterology 11-10=2008
Abstract
Background: Lesbian, gay and bisexual (LGB) people may be at higher risk of mental disorders than heterosexual people.
Method: We conducted a systematic review and meta-analysis of the prevalence of mental disorder, substance misuse, suicide, suicidal ideation and deliberate self harm in LGB people. We searched Medline, Embase, PsycInfo, Cinahl, the Cochrane Library Database, the Web of Knowledge, the Applied Social Sciences Index and Abstracts, the International Bibliography of the Social Sciences, Sociological Abstracts, the Campbell Collaboration and grey literature databases for articles published January 1966 to April 2005. We also used Google and Google Scholar and contacted authors where necessary. We searched all terms related to homosexual, lesbian and bisexual people and all terms related to mental disorders, suicide, and deliberate self harm. We included papers on population based studies which contained concurrent heterosexual comparison groups and valid definition of sexual orientation and mental health outcomes.
Results: Of 13706 papers identified, 476 were initially selected and 28 (25 studies) met inclusion criteria. Only one study met all our four quality criteria and seven met three of these criteria. Data was extracted on 214,344 heterosexual and 11,971 non heterosexual people. Meta-analyses revealed a two fold excess in suicide attempts in lesbian, gay and bisexual people [pooled risk ratio for lifetime risk 2.47 (CI 1.87, 3.28)]. The risk for depression and anxiety disorders (over a period of 12 months or a lifetime) on meta-analyses were at least 1.5 times higher in lesbian, gay and bisexual people (RR range 1.54–2.58) and alcohol and other substance dependence over 12 months was also 1.5 times higher (RR range 1.51–4.00). Results were similar in both sexes but meta analyses revealed that lesbian and bisexual women were particularly at risk of substance dependence (alcohol 12 months: RR 4.00, CI 2.85, 5.61; drug dependence: RR 3.50, CI 1.87, 6.53; any substance use disorder RR 3.42, CI 1.97–5.92), while lifetime prevalence of suicide attempt was especially high in gay and bisexual men (RR 4.28, CI 2.32, 7.88).
Conclusion: LGB people are at higher risk of mental disorder, suicidal ideation, substance misuse, and deliberate self harm than heterosexual people.
statins
Summary and Comment
More Data on Statins in Primary Prevention — The JUPITER Study
Among otherwise healthy patients with high hsCRP levels, rosuvastatin lowered the incidence of adverse cardiovascular events during 2 years of therapy.
The role of statin therapy in primary prevention is uncertain for patients whose cholesterol levels are not markedly elevated. Among such patients, elevated levels of high-sensitivity C-reactive protein (hsCRP) are associated with excess cardiovascular risk. In this international industry-sponsored study, 17,802 people (men’s age, 
50; women’s age, 60) without known cardiovascular disease and with LDL cholesterol levels <130 src="http://general-medicine.jwatch.org/math/ge.gif" alt="≥" _base_href="http://general-medicine.jwatch.org" border="0">2 mg/L were randomized to receive daily rosuvastatin (Crestor; 20 mg) or placebo. Exclusion criteria were numerous and included diabetes, uncontrolled hypertension, and various other chronic diseases.
The trial was stopped early, after a median follow-up of 1.9 years. Rosuvastatin lowered mean LDL cholesterol level by 50% and hsCRP level by 37%. The incidence of the primary endpoint (first major adverse cardiovascular event, including unstable angina, myocardial infarction, stroke, arterial revascularization, or death from cardiovascular causes) was significantly lower in the rosuvastatin group than in the placebo group (0.77 vs. 1.36 per 100 person-years; hazard ratio, 0.56); occurrence of all components of the composite endpoint was lower in the rosuvastatin group, as was the overall mortality rate (HR, 0.8). Physician-reported new-onset diabetes was significantly more common in the rosuvastatin group; median glycosylated hemoglobin (HbA1c) level at 24 months also was higher with rosuvastatin.
Comment: In this study of apparently healthy subjects with elevated hsCRP levels, statins lowered the incidence of adverse cardiovascular events; this result supports expanded use of statins in primary prevention. An editorialist sounds several cautionary notes, however, mentioning the high proportion of patients who were excluded from enrollment, the relatively modest absolute effect size (about 100 people need to be treated for almost 2 years to prevent 1 event), the higher incidence of diabetes, and the lack of long-term data on hazards of statin therapy. He also reminds us that this is a randomized trial of statin therapy, not of hsCRP testing, and he advocates selective, rather than routine, use of hsCRP testing.
— Kirsten E. Fleischmann, MD, MPH
Published in Journal Watch General Medicine November 18, 2008
Citation(s):
Ridker PM et al. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med 2008 Nov 20; 359:2195. (http://dx.doi.org/10.1056/NEJMoa0807646)
Original article (Subscription may be required)
Medline abstract (Free)
Hlatky MA. Expanding the orbit of primary prevention — Moving beyond JUPITER. N Engl J Med 2008 Nov 20; 359:2280. (http://dx.doi.org/10.1056/NEJMe0808320)
Original article (Subscription may be required)
Medline abstract (Free)
Saturday, November 15, 2008
statins CRP
Medscape Nov-10-2008
From the American Heart Association (AHA) 2008 Scientific Sessions
From Heartwire — a professional news service of WebMD
November 10, 2008 (New Orleans, Louisiana) — The Justification for the Use of Statins in Primary Prevention: An Intervention Trial Evaluating Rosuvastatin (JUPITER) started the American Heart Association (AHA) 2008 Scientific Sessions here with a bang, shaking up the field of primary prevention with new data showing that the treatment of apparently healthy patients with a statin cuts their risk of cardiovascular disease morbidity and mortality by almost half [1].
In a study of individuals with low low-density lipoprotein (LDL) cholesterol but elevated C-reactive-protein (CRP) levels, investigators showed that rosuvastatin (Crestor, AstraZeneca) 20 mg significantly reduced the primary end point—a composite of nonfatal myocardial infarction (MI), nonfatal stroke, hospitalization for unstable angina, revascularization, and confirmed death from cardiovascular causes—by 44% compared with individuals treated with placebo.
Presented by Dr Paul Ridker (Brigham and Women's Hospital, Boston, MA) during the late-breaking clinical-trials session and published online in the New England Journal of Medicine to coincide with the AHA presentation, investigators showed that the benefits extended to all subgroups, including "robust reductions in cardiovascular events with statin therapy in women and black and Hispanic populations, for which data on primary prevention are limited," write the JUPITER investigators.
Calling JUPITER "one of the most important clinical trials in the long history of statin studies," Dr Steven Nissen (Cleveland Clinic, OH) told heartwire that such large reductions in clinical events in less than two years among patients considered healthy by conventional definitions is likely to change the guidelines.
"Ideally, if a patient comes to me with normal LDL-cholesterol levels—in JUPITER, the median LDL-cholesterol level was 108 mg/dL—I tell him to keep doing what he's doing and to go about his business," said Nissen. "Now, what happens when that same patient arrives in my office and I know his CRP is elevated? I know that treating him with intensive statin therapy, despite what the guidelines state, is going to cut his risk of cardiovascular morbidity and mortality in half."
Dr James Stein (University of Wisconsin Medical School, Madison) echoed the sentiments of others when he said that the findings are going to pose challenges, particularly as clinicians grapple with changing how they think about and treat seemingly low-risk patients.
"It is a true landmark in preventive cardiology, not only for its findings, but even more so for the challenges it raises to our current strategies for use of cholesterol-lowering medications and to our risk-assessment paradigms," said Stein.
Stopped after 1.9 years of study JUPITER was designed as a four-year study but was stopped by AstraZeneca after just 1.9 years based on recommendations from an independent data monitoring board and the JUPITER steering committee. When the study was stopped on March 29, 2008, as reported by heartwire at that time, the company reported unequivocal evidence of a reduction in cardiovascular morbidity and mortality among patients treated with rosuvastatin compared with those treated with placebo. Despite the benefits, Dr Sanjay Kaul (Cedars Sinai Medical Center, Los Angeles, CA) questioned why it was stopped so early, "especially when we have no idea about the long-term safety of very low LDL levels as achieved in this trial." |
Reductions in cardiovascular events line up in JUPITER
JUPITER is a large, multinational, long-term, double-blind, placebo-controlled, randomized clinical trial that included 17,802 healthy men and women assigned to rosuvastatin 20 mg or placebo. The study was designed to assess whether statin therapy should be given to apparently healthy individuals with normal LDL cholesterols but elevated C-reactive protein levels (CRP >2.0 mg/L).
Among patients treated with rosuvastatin, LDL-cholesterol levels were cut in half, decreasing from a median 108 mg/dL at baseline to 55 mg/dL at 12 months. CRP levels were also significantly reduced, declining from 4.2 mg/L at baseline to 2.2 mg/L at 12 months. Triglyceride levels were reduced 17% from baseline among those treated with statin therapy. These effects persisted over the course of the study.
Baseline and change in LDL cholesterol and CRP levels during study period
| Measure | Baseline | 12 mo | 24 mo | 36 mo | 48 mo |
| LDL cholesterol (mg/dL) | |||||
| Rosuvastatin 20 mg | 108 | 55 | 54 | 53 | 55 |
| Placebo | 108 | 110 | 108 | 106 | 109 |
| High-sensitivity CRP (mg/L) | |||||
| Rosuvastatin 20 mg | 4.2 | 2.2 | 2.2 | 2.0 | 1.8 |
| Placebo | 4.3 | 3.5 | 3.5 | 3.5 | 3.3 |
After 1.9 years of follow-up, treatment with rosuvastatin significantly reduced the primary composite end point 44% compared with placebo. This reduction was observed among nearly all of the individual end points, including a 55% reduction in nonfatal MI, a 48% reduction in the risk of nonfatal stroke, and a 47% reduction in the risk of hard cardiac events (a composite of MI, stroke, and death from cardiovascular causes).
In terms of absolute benefits, the proportion of patients who had an MI, stroke, revascularization, or hospitalization for unstable angina or died from cardiovascular causes was 1.6% in the rosuvastatin arm and 2.8% in the placebo arm, an absolute risk reduction of 1.2%. Similarly, the proportion of patients with hard cardiac events—cardiovascular death, MI, and stroke—was reduced from 1.8% in the placebo arm to 0.9% in the rosuvastatin arm, an absolute reduction of 0.9%.
JUPITER: Outcomes according to study group
| End point | Patients with event, rosuvastatin (n=8901), n | Patients with event, placebo (n=8901), n | Hazard ratio (95% CI) |
| Primary end point* | 142 | 251 | 0.56 (0.46-0.69) |
| Nonfatal MI | 22 | 62 | 0.35 (0.22-0.58) |
| Any MI | 31 | 68 | 0.46 (0.30-0.70) |
| Nonfatal stroke | 30 | 58 | 0.52 (0.33-0.80) |
| Any stroke | 33 | 64 | 0.52 (0.34-0.79) |
| Revascularization | 71 | 131 | 0.54 (0.41-0.72) |
| Hospitalization for unstable angina | 16 | 27 | 0.59 (0.32-1.10) |
| Revascularization or hospitalization for unstable angina | 76 | 143 | 0.53 (0.40-0.70) |
| MI, stroke, or death from cardiovascular causes | 83 | 157 | 0.53 (0.40-0.69) |
| Death on any known date | 190 | 235 | 0.81 (0.67-0.98) |
| Any death | 198 | 247 | 0.80 (0.67-0.97) |
A subgroup analysis revealed no heterogeneity in any of the results, including an analysis of subgroups based on age, race, or ethnic group, as well as baseline LDL-cholesterol and CRP levels. The investigators report that even patients considered to be at very low risk—those who did not smoke, were not overweight, did not have metabolic syndrome, or had a Framingham risk score of 10% or less—benefited from statin therapy.
Of note, among the 6801 women included in JUPITER, rosuvastatin significantly reduced the primary composite end point by 46%. "These are our most impressive data in women in the primary-prevention setting," Dr Roger Blumenthal (Johns Hopkins Medical Institute, Baltimore, MD) told heartwire.
In terms of side effects, significantly more patients in the rosuvastatin arm developed new diabetes, and they also had significantly higher glycated hemoglobin levels, report investigators. Any reported serious adverse events were similar between the placebo and statin-therapy arms.
Lulled into a false sense of security with "normal" LDL cholesterol levels
To heartwire, Stein said the results, despite the significant risk reduction in apparently healthy individuals, are not surprising. He praised the JUPITER investigators and the study sponsor for exposing the current LDL-cholesterol thresholds for lipid-lowering therapy as arbitrary, but more important, as a poor indicator of cardiovascular risk.
"Many patients with heart attacks have normal LDL-cholesterol values," said Stein. "Thus, doctors and patients are lulled into a false sense of security when their LDL cholesterol is 'normal' and then are surprised when they have a heart attack. JUPITER illustrates this point perfectly. If you look at the median values—age 66 years, body-mass index 28.3 kg/m2, systolic blood pressure 134 mm Hg, and 41% with metabolic syndrome—you know these people are going to have heart attacks and strokes and die. Indeed, in the placebo arm, the event rate was 1.36% per year. But current guidelines say not to treat them."
Nissen pointed out that there has been a lot of recent pushback against the cholesterol hypothesis, with many speculating that lowering LDL-cholesterol levels had no impact on the reduction of cardiovascular risk. Patients in the JUPITER study, he pointed out to heartwire, had a significant 50% reduction in LDL-cholesterol levels, coupled with the significant 37% reduction in CRP levels, and this suggests that LDL cholesterol remains an important end point clinicians should treat.
"Reducing LDL cholesterol while at the same time treating inflammation is one of the reasons why this treatment was so successful," said Nissen. Two other studies, analyses of the PROVE-IT and REVERSAL trials, by Ridker and Nissen, respectively, previously showed that lower CRP levels are associated with fewer cardiovascular events independent of LDL-cholesterol levels [2,3]. Stein said he thinks LDL-cholesterol levels of 100 mg/dL are still too high if the patient has other markers of risk, such as increased age, obesity, and hypertension.
Should every patient undergo CRP testing?
In an editorial accompanying the published study, Dr Mark Hlatky (Stanford University School of Medicine, CA) agreed that guidelines are likely to be revisited, although he is cautious on just how big an impact the findings will have on clinical practice [4].
"JUPITER provides yet more evidence about the effectiveness of statin therapy in reducing cardiovascular risk, even among persons who would not currently be considered for pharmacotherapy," writes Hlatky. "Guidelines for primary prevention will surely be reassessed on the basis of the JUPITER results, but the appropriate size of the orbit of statin therapy depends on the balance between the benefits of treatment and its long-term safety and cost."
To heartwire, Kaul said he is not quite as bullish on the findings as others, noting that nearly one out of every five patients screened was enrolled, which has implications about the generalizability for clinical practice, as very few patients have elevated CRP without traditional risk factors. Moreover, clinicians and health-policy experts should focus on the absolute risk reductions, he said.
"The absolute risk differences are less impressive than the relative differences and, together with cost and long-term safety considerations, will serve to temper the conclusions of the study," said Kaul.
In his editorial, Hlatky calculated that 120 patients need to be treated for 1.9 years to prevent one death from cardiovascular causes, MI, or stroke, and this benefit needs to be balanced against concerns about significantly higher glycated hemoglobin levels and increased diabetes incidence observed in the rosuvastatin arm. The JUPITER investigators, on the other hand, calculated the number needed to treat (NNT) based on the primary-end-point event and report that the NNT with rosuvastatin for two years to prevent one primary end point is 95 and just 31 need to be treated for four years to prevent one primary-end-point event.
In his editorial, Hlatky said the design of JUPITER provides only limited information about the role of CRP testing in clinical practice, since investigators did not compare subjects with and without CRP measurements and did not compare the use of CRP with the use of other markers of cardiovascular risk.
"At this point, the current guidelines for measurement of high-sensitivity CRP remain reasonable," writes Hlatky. Measurements of CRP may be obtained in asymptomatic individuals who have an intermediate level of risk, based on standard clinical risk markers, and in whom treatment might change depending on the high-sensitivity CRP level. Blumenthal said most doctors use CRP as a "tie-breaker" to make a decision about which men >50 years and women >60 years would benefit from statins.
Stein told heartwire that the use of more widespread screening of CRP values needs more investigation. The test has high variability and is elevated with infections and injuries, so abnormally high CRP levels do not always reflect arterial injury or cardiovascular-disease risk.
"However, I suspect we should start using it more often," he said. "For starters, it makes communication easier. It summarizes a myriad of metabolic problems that individually are not bad enough to treat but collectively indicate increased risk. Increased CRP tells you that. It is one number, and explaining and implementing it may be easier for physicians and patients than trying to explain why 'borderline' high blood pressure and being 'a little overweight' are bad. They damage and inflame blood vessels, and high CRP shows it."
AstraZeneca sponsored the JUPITER study.
American Heart Association (AHA) 2008 Scientific Sessions. Presented November 9, 2008.
Sources
schizophrenia schizofrenie psychosis
Medscape Medical News 2008. © 2008 Medscape
"All [other] ethnic groups, whether they are immigrants or not, are at greater risk of psychosis than British-born whites," lead author Jeremy W. Coid, MD, from St. Bartholomew's Hospital, in London, told Medscape Psychiatry.
"This work identifies populations with higher rates of psychoses who have a need for more mental health resources," he added.
These findings, from the East London First Episode Psychosis Study, are published in the November issue of the Archives of General Psychiatry.
Schizophrenia Higher Among Blacks in the United Kingdom
In addition to stress caused by the life-altering event of immigration itself, immigrants and their children are likely to face discrimination and social exclusion, said Dr. Coid.
These socioeconomic factors may combine with genetic factors to push an individual over the threshold for a psychotic illness. On the other hand, individuals in certain ethnic groups may be protected from some of these stresses by having strong religious, cultural, and family support networks.
"For instance, among second-generation United Kingdom–born individuals, the risk of psychosis is elevated for men and women of African and Caribbean origin, but not for South Asian men, perhaps because of the buffering effects of family and cultural lifestyles in this subgroup," said Dr. Coid
Previous studies reported that blacks of Caribbean origin living in the United Kingdom and their United Kingdom–born children had higher rates of schizophrenia compared with blacks living in the Caribbean. On the other hand, this increased prevalence of psychosis has not been consistently found in Asian immigrants from the Indian subcontinent, the largest immigrant group to the United Kingdom.
To investigate the incidence and types of psychoses across different immigrant groups and generations, the researchers examined individuals living in East London, an area with the highest numbers of socioeconomically deprived individuals in the United Kingdom.
Deprived Inner-City Dwellers
The eligible study population included over 800,000 individuals aged 18 to 64 years living in 3 neighboring inner-city London boroughs over a 24-month period during the late 1990s.
The researchers identified 484 individuals who presented to psychiatric services for a first episode of psychosis.
More than 55% of the individuals had schizophrenia, one-quarter had affective psychoses (with prominent mood symptoms), and close to 20% had a nonaffective psychosis other than schizophrenia.
Participants were categorized according to 1 of 6 ethnic groups: white British, white other (primarily Irish or European), black Caribbean, black African, Asian (Indian, Pakistani, and Bangladeshi groups), or other (Chinese, other Asian, or other groups).
More than 95% of the white British individuals were born in the United Kingdom.
First-generation black Caribbean immigrants were older than other first-generation immigrants, since most had emigrated from the Caribbean in the 1950s and 1960s, whereas other ethnic groups were more recent immigrants.
Research Agenda Shift
Both first- and second-generation immigrants were at increased risk for both nonaffective and affective psychoses.
Blacks from the Caribbean, followed by blacks from Africa and to a lesser extent non-British whites and Asians, but not "other" minorities, all had a significantly higher risk for psychoses than native white British individuals.
Children of blacks who emigrated from the Caribbean had a significantly higher risk for nonaffective psychosis than their parents, whereas there was no significant generational difference in incidence of nonaffective psychosis among other minority groups. This was mainly because first-generation blacks from the Caribbean, unlike the other newer immigrant groups, have now largely passed beyond the age range with greatest risk for first psychosis, said Dr. Coid.
Both first- and second-generation Asian women had higher incidence rates of nonaffective psychosis compared with their white British counterparts, but Asian men did not, possibly due to protective factors in social or family structures.
"Our results suggest that given the same age structure, the risk of psychoses in first and second generations of the same ethnicity will be roughly equal," the researchers write.
"We suggest that socioenvironmental factors operate differentially by ethnicity but not by generation status, even if the exact specification of these stressors differs across generations," they add.
"These findings shift the research agenda in a different direction," said Dr. Coid. Rather than look at generational differences, research into the incidence of psychosis among immigrants should focus on ethnicity and different protective factors among different minority groups.
The study was funded by grants from St. Bartholomew’s Hospital and the Royal London Hospital Special Trustees and East London and the City Mental Health NHS Trust R&D. The study authors report no relevant disclosures.
Arch Gen Psychiatry. 2008;65:1250-1258. Abstract
dementia
Medscape Medical News 2008. © 2008 Medscape
In 1 of the first and largest studies of its kind, researchers used a novel amyloid-tracking agent called Pittsburgh Compound B (PiB) and positron-emission tomography (PET) to pick up areas of amyloid deposits in healthy living volunteers. In the past, it was only through autopsies that such plaque deposits could be detected.
"It's very revolutionary that we can reliably detect the pathology of AD in living people," said one of the investigators, Dr. William E. Klunk, MD, PhD, professor of psychiatry and neurology at the University of Pittsburgh School of Medicine, in Pennsylvania.
"Profound Implications"
These findings have "profound implications" for future preventive strategies and might lay the groundwork to possibly predict "fairly accurately" who will develop AD 5 to 10 years before the onset of symptoms, said the study authors.
"I see this as good news, bad news," Dr. Klunk told Medscape Neurology. The good news is that scientists are at a point where they can now screen people and detect amyloid in time to intervene with therapy. The bad news is that there isn't yet a proven therapy. "And as we sit here today, if we treat only people who have symptomatic Alzheimer's disease, we're already 10 years behind the pathology," he said.
For the study, investigators included 43 healthy cognitively normal subjects between the ages of 65 and 88 years. "It's important to note that this is a community-derived sample," said Dr. Klunk. "They're as representative of the typical elderly population as we could get."
These subjects underwent a battery of neurological and cognitive assessments as well as the PET PiB scanning. PiB is a derivative of an older dye that detects amyloid but only in autopsy tissue, as it can't enter the living brain. In a long and painstaking process, Dr. Klunk and his colleague Chester A. Mathis, PhD, professor of radiology at the University of Pittsburgh School of Medicine, modified that original compound to come up with an agent that not only can be used in a living brain but also is better at binding to amyloid.
Like Craft Glitter
Dr. Klunk likens the upgraded agent to craft glitter sprinkled over a paper dotted with glue. After turning the paper upside down, some of the glitter scatters but some sticks to the glue to create a pattern. "The paper is like the nonamyloid brain, the glue is like the amyloid in the brain, and the glitter is like PiB."
To help define amyloid positivity, an additional 19 cognitively normal subjects underwent the same diagnostic neuropsychological screening and PiB PET scanning. Using a complicated system of eliminating outliers, investigators came up with a cutoff for amyloid-positive status.
The PET scans used in the study concentrated on particular regions of the brain, including: frontal lobe, anterior cingulate gyrus (ACG), lateral temporal, mesial temporal, occipital, parietal, precuneus cortex (PRC)/posterior cingulate gyrus (PCG), sensorimotor cortices, and anterior-ventral stratum.
Equal Cognitive Performance
Of the 43 cognitively normal subjects, 9 (21%) showed early amyloid deposits in at least 1 area of the brain — about the same percentage as is found in postmortem studies. Investigators found no differences in cognitive performance or in demographics between the amyloid-positive and amyloid-negative groups.
Significantly, the investigators also noted that the amyloid deposition was primary in regions that ultimately develop heavy amyloid loads in AD patients, especially the ACG and the PRC/PCG cortex
"These folks can tolerate the pathology, so there's time to do something about it," said Dr. Klunk. "They have amyloid, but the brain isn't malfunctioning yet."
Unexpectedly, the amyloid-positive group performed better on 1 of the cognitive tests — the delayed word-recall test — perhaps because they have particularly high cognitive reserves in areas such as the medial temporal lobe that are relatively unaffected by amyloid deposition. But Dr. Klunk does not want to place too much emphasis on this finding. "We did a lot of tests, so I don't think the fact that 1 of them was a little better in the people who had amyloid than those who didn't is the message," he said. "What's more important is that in all these tests, there's really nothing to shake a stick at as far as picking the amyloid-positive people out from the amyloid-negative people."
Will the 9 seniors with amyloid go on to develop AD, and are the other 34 subjects protected from developing this disease? "That's what the research will tell us as we follow these people," said Dr. Klunk. "But the working hypothesis for now is that the Alzheimer's patients will come from this cohort who already has the pathology. We'll find out if this is correct."
"We're Not There Yet"
Meanwhile, it would be ideal if these 9 patients could be treated to decrease the risk of developing AD. "We're not there yet, although that's obviously what we would love to do," said Dr. Klunk, adding that he and his colleagues have some ideas of potential preventive approaches. One such approach could be to use 1 of the promising immunotherapies now being tested. "But we first need to show that the latest iteration of these immunotherapies is safe in AD patients and that they effectively remove amyloid from these patients," he said.
Although he recognizes the value of autopsy studies, Dr. Klunk pointed out the advantages of PiB in detecting amyloid in the brain of cognitively normal people. For one thing, in the case of postmortem examinations in people with normal cognitive test results, the assessment may have taken place months or even years before death, raising the possibility that such individuals were not cognitively normal when they died.
"Also, if they were tested very close to death [and did not test normal], you can't be sure if something related to their death affected their cognitive function, and, most important, you can't follow them to then find out if this really was a precursor to AD or whether it was just an irrelevant finding in their brain."
This research adds another element to the ongoing discussion of the relationship between amyloid and cognition. While some studies have found that the amyloid burden is related to the degree of cognitive impairment in AD, others have failed to uncover a correlation. This current study points to the complicated nature of this relationship, said Dr. Klunk. "It's not a one-to-one thing," he said. "Just as a certain mass of cholesterol in our arteries does not equal a certain number of heart attacks, a given mass of amyloid does not equal a given deficit on a cognitive test."
GE Healthcare holds a license agreement with the University of Pittsburgh based on the technology described in this paper. Drs. Klunk and Mathis are coinventors of PiB and, as such, have a financial interest in this license agreement. GE Healthcare provided no grant support for this study and had no role in the design or interpretation of results or preparation of the manuscript. All other authors have no conflict of interest.
Arch Neurol. 2008;65:1509-1517. Abstract
Friday, November 14, 2008
vtamine B12 dementia
Vitamin B12 key to aging brain
Neurology sept-8- 2008
MONDAY, Sept. 8 (HealthDay News) -- Older individuals with low levels of vitamin B12 seem to be at increased risk of having brain atrophy or shrinkage, new research suggests.
Brain atrophy is associated with Alzheimer's disease and impaired cognitive function.
Although the study, published in the Sept. 8 issue of Neurology, can't confirm that lower levels of B12 actually cause brain atrophy, they do suggest that "we ought to be more aware of our B12 status, especially people who are vulnerable to B12 deficiency [elderly, vegetarians, pregnant and lactating women, infants], and take steps to maintain it by eating a balanced and varied diet," said study co-author Anna Vogiatzoglou, a registered dietician and doctoral candidate in the department of physiology, anatomy and genetics at the University of Oxford, in England.
"It's worth looking at B12 levels. It's a simple blood test," affirmed Dr. Shari Midoneck, an internist at the Iris Cantor Women's Health Center in New York City. "It doesn't hurt to take B12."
Good sources of the vitamin include meat, fish, milk and fortified cereals.
According to the study authors, vitamin B12 deficiency is a public health problem, especially among older people.
This study involved 107 volunteers aged 61 to 87 who were cognitively normal at the beginning of the study. All participants underwent annual clinical exams, MRI scans and cognitive tests and had blood samples taken.
Individuals with lower vitamin B12 levels at the start of the study had a greater decrease in brain volume. Those with the lowest B12 levels had a sixfold greater rate of brain volume loss compared with those who had the highest levels of the vitamin.
Interestingly, none of the participants were deficient in vitamin B12, they just had low levels within a normal range.
"They all had normal B12 levels, yet there was a difference between the higher levels and the lower levels in terms of brain shrinkage, which is new information which could potentially change what we recommend to people in terms of diet," said Dr. Jonathan Friedman, an associate professor of surgery and neuroscience and experimental therapeutics at Texas A&M Health Science Center College of Medicine and associate dean of the College of Medicine, Bryan-College Station campus.
Other risk factors for brain atrophy include high blood pressure, diabetes and high cholesterol.
Not only might B12 levels be a modifiable risk factor for cognitive decline, it might also be a clue to help clinicians assess cognitive problems earlier on.
Right now, it's not clear what the biological mechanisms behind the link might be, nor is it clear whether added B12 would avert brain atrophy.
"We are doing a clinical trial in Oxford in which we are giving B vitamins [including B12] to elderly people with memory impairment," Vogiatzoglou said. "In this trial, we are doing MRI scans at the start and the end, and so, we will be able to find out if taking B vitamins really does slow down the shrinking of the brain. The trial will be completed in 2009."
HealthDay Copyright (c) 2008 ScoutNews, LLC. All rights reserved.
Wednesday, November 12, 2008
AF (atrial fibrilation)
Een score van 0 dan 1,9 % kans op hersen infarct en een score vanb 6 dan 18,2 % kans
zie ook nieuwe middelen onder in dit stuk
(New Orleans, LA, USA), November 10, 2008: Many advances in the medical management of atrial fibrillation (AF) have debuted in the past few years. In this session, presenters discussed strategies for improving outcomes related to warfarin use and described investigational approaches to the management of AF.
Approximately 15% of strokes occur in patients with atrial fibrillation (AF). The risk of stroke in AF patients increases with age, from a 1.5% annual risk in patients aged 50-59 years to 23.5% in those aged 80-89 years. Indeed, elderly patients with AF are at the highest risk for stroke and the highest risk for hemorrhage. After adjusting for comorbid cardiovascular conditions, AF is associated with a 50% to 90% increase in mortality risk. Furthermore, stroke is a leading cause of serious long-term disability.
Five landmark clinical trials - AFASAK, SPAF, BAATAF, CAFA, and SPINAF - have demonstrated the unequivocal benefits of warfarin in preventing stroke among patients with AF. Additional trials have shown that the optimal international normalized ratio (INR) for patients with AF is 2.0 to 3.0. Below 2.0, patients have an increased risk for ischemic stroke, and above 3.0, the risk for intracranial bleeding begins to rise.
Dr. Hylek emphasized the importance of the CHADS2 score in identifying patients for whom the burdens and risks of warfarin therapy are justified. The CHADS2 scoring system assigns 1 point to each of four risk factors for stroke: Congestive heart failure, Hypertension, Age ≥75 years, and Diabetes. In addition, 2 points are assigned for prior Stroke, TIA, or systemic embolus. The annual risk for stroke is directly related to CHADS2 score, ranging from 1.9% for a CHADS2 score of 0 to 18.2% for a CHADS2 score of 6.
“There’s no excuse for not being able to calculate a CHADS2 score when discussing the importance of warfarin use with your patients,” Dr. Hylek said. The 2006 American College of Cardiology/American Heart Association/European Society of Cardiology (ACC/AHA/ESC) guidelines for the management of patients with AF recommend therapy based on CHADS2 risk category. [1] For patients with no risk factors, aspirin 81 to 325 mg daily is recommended. For patients with a CHADS2 score of 1, the guidelines suggest aspirin 81 to 325 mg daily or warfarin (INR 2.0-3.0). For patients with a CHADS2 score >1, the guidelines recommend warfarin therapy (INR 2.0-3.0) for long-term risk management.
Despite considerable evidence supporting the use of anticoagulation therapy in the management of AF, warfarin is under-utilized across treatment settings. In a survey of community and academic hospitals in the US, nearly half of high-risk AF patients (47%) were not being treated with warfarin therapy. [2] In a European survey, only 54% of high-risk AF patients were receiving warfarin therapy. [3]
Long-term adherence to warfarin therapy is also low among patients with AF. Up to 25% of patients aged 80 years or older discontinued therapy within 90 days for reasons excluding death or return to normal sinus rhythm. [4] Factors associated with decreased use of oral anticoagulation include perceived bleeding risk, lack of proximity to an INR monitoring site, patient preference, and the innate difficulties of warfarin use.
Many strategies are available for improving adherence to anticoagulant therapy. For example, gastrointestinal (GI) complications are an important cause of early treatment withdrawal, particularly among elderly patients who are more sensitive to the mucosal effects of antiplatelet therapy. In 2008, the ACC and AHA published an expert consensus document on reducing the GI risks of antiplatelet therapy and NSAID use. [5]
New research will allow physicians to improve risk stratification for patients requiring anticoagulant therapy. Emerging tools that may be incorporated in risk-stratification models include genetic information and a range of biomarkers, including d-dimer and markers of anti-oxidant and anti-inflammatory activity.
“For the first time in years, there is some promise for medical therapy in AF,” said Dr. Page. In this presentation, he described recent trials that have demonstrated the benefits of pharmacologic cardioversion as a method for restoring sinus rhythm in patients with AF.
Vernakalant hydrochloride, a novel mixed ion channel antagonist, is under investigation for acute conversion in patients with AF. In the ACT I trial, 336 patients were randomly assigned to treatment with vernakalant or placebo and stratified by AF duration: 3 hours to 7 days (short duration) or 8 to 45 days (long duration). Among vernakalant-treated patients, 52% in the short-duration group converted to sinus rhythm compared with 4% of patients in the placebo group
The AF-CHF trial compared pharmacological rate control with drug- and defibrillation-based sinus rhythm maintenance in 1376 patients with systolic heart failure and AF. [7] Researchers found that a routine strategy of rhythm control did not reduce the rate of cardiovascular death compared with a rate-control strategy. After a mean of 37 months, 27% of patients in the rhythm-control group died from cardiovascular causes, compared with 25% in the rate-control group (HR 1.06; p=0.59). Findings from AF-CHF suggest that clinicians can safely use the rate-control approach, which is far less invasive and usually less costly than rhythm control, in high-risk AF patients.
The ATHENA trial, the largest AF trial to date, compared dronedarone and placebo in 4628 patients (mean age: 72 years) with paroxysmal/persistent AF. [8] After a mean follow-up of 21 months, dronedarone reduced the risk of first cardiovascular hospitalization or death by 24% compared with placebo (p<0.001).>p=0.176), it did reduce the risk of cardiovascular death by 29% (HR: 0.71; p=0.034) and cardiovascular hospitalization by 25% (HR: 0.75; p<0.001).
Additional data from the ATHENA trial will be published in upcoming months, Prof. Page said. Together, findings from ACT I, AF-CHF, and ATHENA may provide physicians with a range of new options for the medical management of AF.
statines
JUPITER trial: Rosuvastatin cuts CV events in ‘healthy’ people with low LDL, raised CRP
The lipid-lowering drug rosuvastatin nearly halves the risk of major cardiovascular events in apparently healthy people who have normal lipid levels but raised levels of high-sensitivity C-reactive protein, the JUPITER study has found.
Saturday, November 08, 2008
CRP en bloedvaten
Link between CRP and vascular risk ‘may not be causal’
4 November 2008
MedWire News: Genetically determined elevations in C-reactive protein (CRP) are not associated with the risk for ischemic vascular disease, suggesting that the association between CRP levels and vascular risk is not causal.
The conclusion, by a Danish team, comes from a retrospective analysis of data from four independent cohort studies: The Copenhagen City Heart Study, the Copenhagen General Population Study, the Copenhagen Ischemic Heart Disease Study, and the Copenhagen Carotid Stroke Study.
Participants in each study were genotyped for four single-nucleotide polymorphisms (rs3091244, rs1130864, rs1205, and rs3093077) in the gene encoding CRP.
As expected, the CRP genotypes were significantly associated with plasma CRP levels; the most common genotype combinations resulted in a difference of up to 64% in CRP levels between the lowest and highest levels.
Using statistical modeling, and assuming a causal relationship between CRP and vascular disease, the researchers predicted that a 64% increment in plasma CRP levels due to CRP genotype would increase ischemic heart disease risk by up to 32% and ischemic cerebrovascular disease risk by up to 25%.
However, a pooled analysis of actual trial data indicated that the odds ratios for heart and cerebrovascular disease were not significantly affected by CRP genotype.
“In conclusion, we show that genetic variants that are associated with lifelong increases in plasma CRP levels are not associated with an increased risk of ischemic heart disease or ischemic cerebrovascular disease,” write Jeppe Zacho (University of Copenhagen) and co-authors in the New England Journal of Medicine.
“This finding suggests that the increase in the risk of ischemic vascular disease associated with higher plasma CRP levels observed in epidemiologic studies may not be causal, but rather that increased CRP levels are simply a marker for atherosclerosis and ischemic vascular disease.”
N Engl J Med 2008; 359: 1897–1908
warfarin en PPI
SUMMARY AND COMMENT
Risk Factors for Recurrent GI Bleeding
November 7, 2008 | David J. Bjorkman, MD, MSPH (HSA), SM (Epid.)
Risk increased with use of oral warfarin and was reduced by use of a PPI, but not by use of a histamine-2–receptor antagonist.
Reviewing: Massó González EL and García Rodríguez LA. Aliment Pharmacol Ther 2008 Sep 1; 28:629
statins en aspirine
Knowledge gap blamed for undertreatment of vascular patients
3 November 2008
MedWire News: A knowledge gap is leading physicians to underprescribe antiplatelet drugs, ACE inhibitors, and statins to high-risk cardiovascular patients, researchers have found.
Underuse of these therapies has been extensively documented, but the reasons physicians fail to prescribe them are unclear, say the authors in the American Journal of Cardiology.
Using two large national outpatient registries, the researchers analyzed the prescription pattern of evidence-based medicine for 6251 patients with high cardiovascular risk, as defined by criteria adapted from the Heart Outcome Prevention Evaluation Study.
Jennifer Tsang (University of Toronto, Ontario, Canada) and co-workers note that despite ample evidence and guideline recommendations “there was suboptimal use of antiplatelet drugs, ACE inhibitors, and statins (78%, 55%, and 75% respectively).” The researchers say this represents “a significant care gap.”
Physicians participating in the registries were asked to complete case-report forms explaining why they chose not to prescribe these agents. For 5%, 14%, and 33% of patients not receiving antiplatelets, ACE inhibitors, and statins, respectively, prescribing physicians did not think these patients were at high enough risk for subsequent events to justify the use of these agents.
The researchers observed that “simply asking physicians why some of their patients were not on a specific therapy led to an approximate 19% to 36% of these patients subsequently being prescribed such therapies.”
They conclude that two important components of the evidence-to-practice care gap are: “a knowledge gap caused by lack of awareness of the evidence and/or familiarity with current guidelines” and “a practice gap in which some physicians responded to a simple patient-specific prompting to reconsider the use of evidence-based therapies.”
The researchers suggest a range of quality enhancement initiatives to help close treatment gaps, including “the use of achievable benchmarks for physician feedback, local medical opinion leaders, community pharmacist intervention, and computer-based clinical decision support systems.”
Am J Cardiol 2008; 102: 1142–1145
catheter ablation
Catheter ablation shows promise in halting AF progression
7 November 2008
MedWire News: Early catheter ablation may be more effective than antiarrhythmic drug therapy for preventing atrial fibrillation (AF) recurrence and delaying disease progression, a 5-year follow-up study has shown.
The research, which appears in the journal Heart Rhythm, also found that older age, diabetes, and heart failure are independent predictors of AF progression.
For the study, Carlo Pappone and colleagues at San Raffaele University Hospital in Milan, Italy, recruited 106 patients with a first AF occurrence and monitored them for 5 years.
At baseline, the patients’ mean age was 57.5 years and 68% were male; 54 patients had lone AF and 52 had comorbidities; and 56 had paroxysmal AF, 24 had persistent AF, and 16 had permanent AF.
During follow-up, 56 patients had recurrent AF episodes occurring, on average, 19 months after the initial episode. These patients were all initially treated with conventional antiarrhythmic drugs; nevertheless AF became persistent in 24 of 45 patients who continued on long-term drug therapy.
A total of 11 patients underwent catheter ablation due to refractoriness or intolerance to antiarrhythmic drugs. No AF recurrences or AF progression occurred after ablation, report Pappone et al.
The main determinants of AF progression were comorbidities and catheter ablation, which increased and decreased the risk for progression, respectively.
Finally, older age, diabetes, and heart failure were all significant independent risk factors for the progression to permanent AF. This finding “indicates a significant role of underlying heart disease in modulating AF progression,” the authors say.
They conclude: “Catheter ablation may be of benefit in preventing AF recurrences and delaying final AF progression, but larger randomized studies are required to confirm this preliminary experience.”
In an accompanying editorial, Hugh Calkins (Johns Hopkins Hospital, Baltimore, Maryland, USA) described the study as “welcome and timely” and “unique for many reasons.”
“The glimmer of hope in this study is that the 11 patients who underwent catheter ablation all had an excellent response with no recurrent AF and no progression during follow-up,” he wrote.
“The results of this study need to be confirmed in much larger multicenter clinical trials. Only then can prevention of progression of AF be considered an appropriate indication for catheter ablation of AF.”
Heart Rhythm 2008; 5: 1501–1507
Friday, November 07, 2008
statins
| To Print: Click your browser's PRINT button. NOTE: To view the article with Web enhancements, go to: http://www.medscape.com/viewarticle/583040  AHA 2008: Eyes Trained on JUPITER: Cardiologists Seek Details to Understand How Statin Use May Expand Shelley Wood Heartwire 2008. © 2008 Medscape
November 5, 2008 (New York, NY) — Cardiologists already know the key result from JUPITER, the opening late-breaking clinical trial at the upcoming American Heart Association (AHA) 2008 Scientific Sessions: rosuvastatin was superior to placebo in reducing hard end points in apparently healthy people with low or normal LDL levels but elevated C-reactive protein (CRP). Still, experts who spoke with heartwire said that as-yet-unreported details from the trial, which has the potential to radically expand the number of people eligible for statin therapy, will be key for understanding how patient screening or statin usage may change. Dr Paul Ridker (Brigham and Women's Hospital, Boston, MA) will present the full results from JUPITER at 3:45 pm November 9 at the AHA 2008 meeting, in New Orleans. As previously reported by heartwire, AstraZeneca, the study sponsor, announced it had stopped the trial last spring, with 17 802 patients enrolled, after an interim analysis showed death, MI, and other adverse events to be reduced among patients randomized to 20-mg rosuvastatin. Critically, JUPITER participants had normal to low LDL levels (less than 130 mg/dL) but increased CRP levels (>2.0 mg/L); depending on nuances in the results, JUPITER could ultimately lead to the expansion of statins to millions of adults currently not eligible for statin therapy. Commenting on the potential impact of the study--without knowing the results--Dr Michael Miller (University of Maryland, Baltimore) pointed out that the anti-inflammatory effects of statins were known already, even in the absence of high LDL, as demonstrated in the ASCOT trial. But in ASCOT, he points out, patients also had risk factors for coronary heart disease other than high CRP--it will be important to see what other risk factors JUPITER patients may have had, Miller notes. "Was the high CRP in JUPITER present by itself, or was it always accompanied by other risk factors? Our analysis of the NHANES database found that a high CRP was present only in one in 2000 [people] in the absence of traditional risk factors, thereby suggesting that high CRP is a biomarker rather than a direct promoter of coronary heart disease," Miller said. "Hence, if the JUPITER paper shows a high prevalence of subjects who had no other risk factors beside high CRP as the basis for the increased event rates, then that would argue for routine CRP screening in this group of middle-aged subjects." Additional Benefit of CRP Also commenting on the potential impact of JUPITER, Dr James Stein (University of Wisconsin, Madison) drew parallels between JUPITER and the METEOR study, which also addressed the question of treating low-risk patients on the basis of a biomarker, not a cholesterol cut point, but he adds that JUPITER was "much more important." "METEOR showed that if you have the biomarker of high carotid [intima media thickness] IMT but LDL cholesterol at a level that would not qualify for treatment, you have less disease progression on rosuvastatin. JUPITER extends that finding to a more widely available biomarker--[high-sensitivity] hs-CRP--and shows the outcome we care most about: cardiovascular events. It is a landmark study. It shows something we all have suspected--that there are people out there who are at higher-than-apparent risk, and if they get identified and treated, they do better." But the question will persist as to how much CRP adds to current screening, Stein suggested. "The rub is that hs-CRP is highly correlated with adiposity and abnormal levels of risk factors, so how many extra people do you identify with screening above just looking at those parameters?" he asked. Participants in JUPITER were older, overweight, with higher-than-normal blood pressure. "They were poster children for a biomarker test to see whether they were at higher-than-apparent risk," Stein said. The question for the medical community will be how to incorporate the JUPITER results into practice guidelines, Stein points out. "That mainly will depend on the magnitude of the benefit in absolute terms, rather than relative terms, as well as the cost of any screening strategies we implement," he said. "Do we screen for hs-CRP in everyone, or just certain subgroups? Or do we just lower our targets for treatment across the population and omit extra screening? Also, how do we account for the high intra-individual variability in hs-CRP? We can't begin to answer these questions until we see the final data and some of the subgroup analyses." Other Trials at AHA 2008 The JUPITER trial is expected to steal the show at this year's meeting, although a range of other trials should also help cardiologists to fine-tune treatments for both primary and secondary prevention of cardiovascular disease. Day two of the meeting features trials of clopidogrel, rivaroxaban (ATLAS ACS-TIMI 46), and an "intervention timing" trial for non-STE ACS (TIMACS). Diabetes is the focus of three late-breakers spread across different days of the meeting: two studies address atherosclerosis prevention in diabetic patients (the JPAD trial using aspirin and the APPROACH trial with rosiglitazone), while a third is a registry analysis of drug-eluting stents vs bare-metal stents in diabetic patients from the Massachusetts registry. Speaking with heartwire about the upcoming meeting, Dr Gordon Tomaselli (Johns Hopkins University, Baltimore, MD), chair of the program committee, pointed out that JPAD may provide some much-needed new information. "The utility of aspirin specifically in patients with diabetes really has been difficult to sort out, so the trial will help us understand whether there really is any effect," he said. The third late-breaking clinical-trial session, on Tuesday, is devoted to heart-failure trials: of these, the I-PRESERVE study, looking at the use of irbesartan in patients with preserved ejection fraction, has the power to pack the most punch, if positive, given the dearth of drugs for this form of heart failure. According to Tomaselli, "I-PRESERVE is really the first properly designed trial to address this question, so it could be very interesting." Additional late-breakers include results of a home INR-monitoring study (THINRS), the FIT study exploring a family-based exercise intervention for heart-disease prevention, and two randomized comparisons of vitamin-related strategies vs placebo for primary and secondary prevention. Of these last, Tomaselli highlighted the SEARCH study, looking at effects of secondary prevention using both statins and folic acid. "The homocysteine hypothesis hasn't been abandoned, we just haven't figured out the correct way to reduce homocysteine. . . . I think that it may further confirm the recent trials that suggest using folic acid to lower homocysteine levels is not the right way to go, but I don't think it's going to firmly put the nail in the biological plausibility of the homocysteine hypothesis." The complete contents of Heartwire, a professional news service of WebMD, can be found at www.theheart.org, a Web site for cardiovascular healthcare professionals.
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Wednesday, November 05, 2008
CRP en artheosclerosis
C-Reactive Protein and Atherosclerosis: No Case for Causality
But a genetics study confirms CRP’s role as a marker for cardiovascular events.
Elevated plasma C-reactive protein levels are associated with increased risk for cardiovascular events. However, scientists debate whether elevated CRP levels are a causative factor in — or just a marker of — ischemic vascular disease.
To assess the effects of genetically determined lifelong elevated CRP levels, investigators studied more than 50,000 Danish individuals from the general population of Copenhagen, including one large prospective cohort, one large cross-sectional cohort, and two small case-control groups. The researchers measured high-sensitivity plasma CRP levels and genotyped individuals for four single nucleotide polymorphisms (SNPs) in the CRP gene and for two SNPs in the apolipoprotein E gene (positive controls). All of the genetic variants are known to affect plasma levels of their respective gene products.
The investigators found an association of ischemic heart or cerebrovascular disease with elevated CRP levels, as expected. They also confirmed that the four CRP polymorphisms were associated with increases in CRP levels by up to 64%, which would amount to an increase in predicted risk for ischemic vascular disease of up to 32% for heart disease and up to 25% for cerebrovascular disease, independent of other risk factors. However, none of the CRP genotypes was associated with an increase in risk for either heart or cerebrovascular disease. By contrast, the apolipoprotein E genotypes were associated with both elevated cholesterol levels and increased risk for ischemic heart disease.
Comment: These findings strongly suggest that genetic variants associated with lifelong elevations of CRP levels are not associated with an increase in cardiovascular risk. Thus, increased CRP levels appear to be simply a marker for atherosclerosis or cardiovascular events, and future drugs targeting CRP are unlikely to provide any preventive benefit.
Published in Journal Watch Cardiology October 29, 2008
Citation(s):
Zacho J et al. Genetically elevated C-reactive protein and ischemic vascular disease. N Engl J Med 2008 Oct 30; 359:1897.
atenolol hoge bloeddruk
October 24, 2008 — Slowing the heart rate with beta blockers in people with hypertension is associated with an increased risk of cardiovascular events and death, a new systematic review shows [1]. Furthermore, the slower the heart rate, the greater the risk, report Dr Sripal Bangalore (St Luke's Roosevelt Hospital, New York) and colleagues in the October 28, 2008, issue of the Journal of the American College of Cardiology.
Senior author Dr Franz Messerli (St Luke's Roosevelt Hospital) told heartwire: "Slowing heart rate is known to prolong life expectancy, and with beta blockers post-MI [myocardial infarction] and in heart failure, the slower you can make the heart rate, the better. But this new paper goes against the grain. What we show is that in hypertension, when you slow down the heart rate with a beta blocker, it actually shortens your life expectancy, it causes more heart attacks, more heart failure, and more strokes." Messerli says he and his team believe the likely explanation for this is "that slowing the heart rate with beta blockers increases the central pressure, and obviously the latter is one of the determinants of stroke and heart attack."
Another hypertension expert sees things slightly differently, however. Dr John Cockcroft (Wales Heart Institute, Cardiff, UK) argues that in this review, the studies included almost exclusively used atenolol — something the authors do point out — and that it is this drug per se that is likely the culprit here.
What is vitally important to determine in this setting, he adds, "is whether it's atenolol that's bad or whether it's reduction of heart rate that's bad." This is crucial because there are other drugs that aren't beta blockers that lower heart rate, he explained, such as the new agent ivabradine (Procoralan, Servier). "This issue needs resolving because if it's heart-rate reduction [that is the cause], then that's bad news, and we need to know about it.
Tuesday, November 04, 2008
polypill
A single pill to prevent cardiovascular disease sounds like a perfect solution, but little progress has been made since the idea was first suggested. Geoff Watts investigates why.
When Nicholas Wald, head of London's Wolfson Institute of Preventive Medicine, and his colleague Malcolm Law published their case for the prevention of heart disease using a "polypill",[1] an accompanying editorial described it as "one of the boldest claims for a new intervention."[2] The substance of the claim was that, if taken by everyone with established cardiovascular disease and -- most importantly -- all those aged 55 or over, the polypill could reduce rates of heart attack and stroke by more than 80%.
Now, more than five years later, you might imagine that a clutch of research groups would be eagerly competing to test this innovative suggestion. Not so.
As conceived by Professors Wald and Law, the polypill comprised a statin, aspirin, three types of blood pressure lowering drug, and folic acid -- intended to lower serum homocysteine concentrations. The logic was that most people in Western society are at raised risk, that cardiovascular disease is consequently common, and that the drugs to treat it are effective and safe. "No other preventive method," they wrote, "would have so great an impact on public health in the Western world." Since that time, Professor Wald says, nothing has happened to change his mind.
The few trials that have been planned lack the scope and ambition of Professor Wald's original proposal. One, for example, is being organised by Anthony Rodgers of the University of Auckland's clinical trials research unit. His pilot study is recruiting 400 participants from New Zealand, Brazil, India, and elsewhere for a 12 week placebo controlled trial of a pill containing blood pressure and cholesterol lowering drugs together with aspirin.[3] But all his participants are selected because they are at increased risk of heart attack or stroke; they are not intended to reflect a section of the population at large.
Another study is being led by Valentin Fuster of Mount Sinai Hospital in New York. He is also the scientific director of Spain's National Centre for Cardiovascular Research, the body through which the trial is being organised. His polypill variant comprises aspirin, a statin, an angiotensin converting enzyme inhibitor, and a beta blocker. But all the participants have had a myocardial infarction, and his intention is to learn whether having to swallow only a single pill will improve compliance. At present, he says, only one third to half of patients take all the drugs necessary to prevent a second heart attack.
Professor Fuster is particularly keen to explore the relevance and affordability of a polypill in low income countries. One of his hopes when full trials start -- subject to US Food and Drug Administration approval -- is to show how secondary prevention of heart disease can be made available in the developing world.
Primary Concerns
Professor Wald knows of no plans to run a trial of the polypill on a general healthy population. So, mindful of its potential impact on public health, why the reluctance?
It is likely that Professor Fuster speaks for others besides himself when he explains why his study is limited to secondary prevention. "This is not the solution for primary prevention," he says. "Primary prevention requires education of the public. As a priority this is much more important than any polypill."
It's a view that Professor Wald has been confronting ever since he published his BMJ paper. "Yes, in an ideal world our saturated fat intake would be lower and we'd exercise more, and we'd have less salt and sugar in our diet. But this is not going to happen tomorrow." He is puzzled that people seem to regard these strategies as mutually exclusive. "It's a mistake to think that when you can do things two ways it has to be one or the other."
The polypill concept is also accused of "medicalising" whole populations. "Quite the reverse," Professor Wald insists. "If you test people to see if they've got high blood pressure or high cholesterol, give them a disease label, and then have them come back regularly to find out if things have changed, you've created a patient." This, he argues, is the real medicalisation -- not universal access to a pill.
Does he sense a moral objection of some kind to the use of drugs rather than lifestyle changes? He does. "There's an unstated view that if you're not a patient, taking pills may be regarded as a weakness. Once you're a patient you're relieved of that burden." Such a view, he thinks, is unreasonable. "Is getting vaccinated a moral weakness?"
The only people currently contemplating a trial in a population defined by age seem to be Professor Wald and his colleagues. With a polypill developed by the Indian generics company Cipla he hopes to set up a project in the developing world. This choice of location would be partly to minimise cost, but also because guidelines on cardiovascular screening in the UK would require participants in the placebo group with problems identified by baseline tests to get some treatment, so making it harder to show the polypill's effects.
At present no polypill formulation has been licensed in Europe or America. But if and when a combined pill for treating hypercholesterolaemia and hypertension as part of secondary prevention wins regulatory approval, new possibilities will open up. "Once a polypill is on the market, doctors can prescribe it as they see fit." It's this, Professor Wald suspects, that will eventually lead to a wider exploration of its benefits.
References
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Sunday, November 02, 2008
aspirin
Age Thresholds for Routine Aspirin Use Defined
Information from Industry ADHD in Adults: How common is it? Dr Lenard Adler explores the symptoms and prevalence of ADHD in adults. Watch video presentation |
NEW YORK (Reuters Health) Oct 29 - If aspirin is to be used routinely for primary prevention of cardiovascular disease, it should begin at age 48 in men and 57 in women, according to a report in the November issue of Heart.
Below these thresholds, the authors conclude, the risks of chemoprophylaxis with aspirin likely outweigh the benefits. Still, they emphasize, these thresholds only apply to individuals without cardiovascular risk factors; when such factors are present, the age thresholds are lower.
The findings are based on a study of 11,232 patients drawn from 304 general practices in England and Wales. Eligibility criteria included age between 30 and 75 years, no prior treatment with lipid-lowering agents, and no history of diabetes or cardiovascular disease.
The focus of the study was the age at which subjects developed an estimated 10-year heart disease risk of 10% or higher, senior author Dr. I. Idris, from Sherwood Forest Hospitals in Sheffield, UK, and colleagues note. For men, that occurred at 47.8 years and for women, at 57.3 years.
In a related editorial, Dr. Peter Elwood, from Cardiff University, UK, and Dr. Gareth Morgan, from Welsh Aspirin Group, Swansea, UK, comment that the idea of basing routine aspirin use on age alone was probably first put forth in 1991. However, they note, this proposal is still hotly debated.
"Before aspirin prophylaxis is widely recommended," they add, "work should be done to identify the safest and best absorbed formulation of the drug, and to examine the effect of taking it with food, or perhaps with milk."
Heart 2008;94:1364-1365,1429-1432.
