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Universal statin therapy in elderly ‘warrants investigation’

23 July 2009

MedWire News: Patient characteristics cannot reliably identify individuals with elevated C-reactive protein (CRP) levels, report researchers in the American College of Cardiology.

Given the benefits of statin therapy demonstrated in the JUPITER trial, the cost of measuring CRP, and the large percentage of older adults with high CRP levels, they say, universal statin therapy for older US adults “warrants investigation.”

The JUPITER (Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin) results showed that rosuvastatin treatment significantly decreased the risk for cardiovascular disease (CVD) events in older men and women without a history coronary heart disease who had normal cholesterol but elevated CRP.

Paul Muntner (Mount Sinai School of Medicine, New York, USA) and colleagues examined patient characteristics associated with being reclassified for statin therapy based on having a CRP level of 2 mg/l or higher, and whether patient characteristics could be used to identify individuals with such elevated CRP levels.

Using data for 887 older US men and women (aged 50 or 60 years or older, respectively) from the National Health and Nutrition Examination Survey, they report that 90% had elevated CRP.

Individuals with CRP levels of 2 mg/l or higher were more likely to be current smokers, obese, and have chronic kidney disease.

But, among those not meeting criteria for statin therapy, characteristics including demographics, cigarette smoking, obesity, chronic kidney disease, and metabolic syndrome each had low positive predictive values (<70%) for identifying people with elevated CRP and negative predictive values (<60%) for identifying those with CRP levels below 2 mg/l.

Pooling characteristics did not improve the predictive ability.

“Although randomized controlled data demonstrate the benefits of statin therapy for older adults with CRP levels [of 2 mg/l or higher], the cost effectiveness and public health risks and benefits of nearly universal statin therapy for older US adults warrant further investigation,” the authors conclude.

MedWire (www.medwire-news.md) is an independent clinical news service provided by Current Medicine Group, a part of Springer Science+Business Media. © Current Medicine Group Ltd; 2009

Am J Cardiol 2009; 104: 354–358

Summary and Comment Rebound Symptoms After Stopping PPIs The findings are pertinent for patients who take PPIs unnecessarily. Previous research suggests that stopping treatment with proton-pump inhibitors (PPIs) causes rebound hypersecretion of acid. The presumed mechanism is a PPI-induced increase in serum gastrin, which exerts trophic effects on acid-producing gastric cells. When a PPI is withdrawn, these cells are poised to hypersecrete acid. To examine the clinical implications of this phenomenon, Danish researchers conducted a double-blind randomized trial that involved 120 healthy volunteers with no substantial histories of heartburn or dyspepsia; participants received either 12 weeks of placebo or 8 weeks of esomeprazole (40 mg daily) followed by 4 weeks of placebo. For the initial 8 weeks, mean symptom scores were similar in the esomeprazole and placebo groups. Scores diverged after esomeprazole recipients were switched to placebo; between weeks 9 and 12, mean scores for heartburn, regurgitation, and dyspepsia became modestly but significantly higher in the original esomeprazole group than in the continuous placebo group. In addition, during weeks 9 to 12, more people in the original esomeprazole group than in the placebo group reported symptoms (44% vs. 15%). Comment: This study demonstrates that some people develop symptoms consistent with rebound hyperacidity when PPIs are stopped after 2 months of use. The findings are particularly pertinent for the many patients who take PPIs unnecessarily or for unclear indications: When we advise such patients to stop their PPIs, we should warn them about possible rebound. This complication perhaps is best managed with antacids, as rebound has also been described after stopping histamine (H2)-blocker therapy. — Allan S. Brett, MD Published in Journal Watch General Medicine July 14, 2009

July 14, 2009 (Vienna, Austria) — Results of 2 new studies show that both the incidence and prevalence of dementia continue to rise in a linear fashion among the so-called "oldest old," those in their 80s and 90s and even among centenarians.

The results, from the population-based Monzino 80-Plus Study in Italy and the 90+ Study in the United States, would appear to contradict fairly conclusively the previously held idea that conversion to dementia plateaus or even declines in this oldest-old population.

"The prevalence and incidence rates of dementia found in the Monzino 80-Plus study continue to rise also in very advanced ages," Ugo Lucca, MD, from the Laboratory of Geriatric Neuropsychiatry at the Istituto di Ricerche Farmacologiche Mario Negri, in Milan, Italy. "Age remains the most important risk factor for dementia, and we need to further our understanding of its role if effective therapeutic and preventive strategies are to be developed."

Claudia Kawas, MD, from the University of California, Irvine, showed a linear increase in dementia risk from 10% in the 90- to 95-year-olds to a "whopping" 41% for centenarians in the 90+ Study.

"I for one just spent about 2 decades of my career suggesting that the incidence rates of dementia go down after age 85," she said. "This just goes to show that you really don't know what you think you know."

The results of both studies were presented here at the 2009 Alzheimer's Association International Conference on Alzheimer's Disease (ICAD 2009).

Monzino 80-Plus Study

Patients with dementia included in clinical research are systematically younger than those in the general population, and this may limit the generalizability of the findings to the oldest old, Dr. Lucca told a press conference here. Because the numbers of these older patients who have been studied in epidemiological surveys have been small, incidence estimates fluctuate widely, he noted, "and the evidence is often insufficient to reach confident conclusions."

Dr. Ugo Lucca

There is also growing evidence that the classical pathology of amyloid plaques and neurofibrillary tangles do not correlate with cognitive status in these oldest-old patients. For example, a study published just this year in the New England Journal of Medicine (NEJM) from the Medical Research Council Cognitive Function and Ageing Study found that the association between pathological features of AD and dementia was stronger in "younger-old" subjects than in the older old (Savva GM et al. N Engl J Med 2009;360:2302-2309).

The Monzino 80-Plus study is a prospective, door-to-door population-based survey of all residents 80 years of age and older living in 8 municipalities of Varese province in Italy. Of 2436 eligible residents, information could be gathered for 2138 subjects, a response rate of 87.8%, making this among the largest studies of dementia in this population, Dr. Lucca noted.

On the first visit, prevalent dementia was found in 25% of this population of over-80-year-olds, with an almost 4-fold increase with age, increasing from approximately 14% at 80 to 84 years to about 55% over 90 years of age, he said. More women were affected than men, with dementia seen in 27% of women vs 18% of men.

Of 1085 surviving participants, 995, or 91%, were reevaluated after an average follow-up of 3 years. Incident dementia among those not demented at baseline occurred at a rate of about 8 new cases per 100 persons, he noted, and here the rate also rose with age, from about 6 cases per 100 persons among those aged 80 to 84 years to 19 cases per 100 among those 95 years of age or older. "Thus, from 80 to 95 years of age, the proportion of new cases triples," Dr. Lucca said.

Monzino 80-Plus Study: Prevalence and Incidence of Dementia

Age Group (y)	Prevalence (95% CI)	Incidence (95% CI)
80 – 84	14.6 (12.1 – 17.5)	6.3 (4.6 – 8.4)
85 – 89	32.8 (29.2 – 36.6)	8.2 (6.7 – 10.0)
90 – 94	40.6 (36.7 – 44.6)	15.6 (13.0 – 18.6)
95+	55.5 (47.5 – 63.2)	19.2 (13.7 – 26.2)
80+*	24.3 (22.5 – 26.2)	7.9 (6.9 – 8.9)

*Standardized to the Italian population

Incident dementia was about 30% higher in women than in men, occurring in about 8.5% of women vs 6.5% in men. However, he noted, "Since the number of men at these extreme ages becomes very small, the interpretation of the gender difference should be cautious."

"With almost one-fourth of over-80s and almost half of over-90s affected, the results of our study confirm that dementia is widespread among the older olds and strengthen the need to shift the focus of clinical research to this segment of the elderly population," Dr. Lucca concluded. "In fact, evidence drawn from younger olds cannot necessarily be generalized to the older olds."

Findings of the NEJM paper and other research suggest the pathology of dementia in the oldest old may be different from classical AD, he said. "Probably dementia is a common expression of many diseases, where several rivers flow together into the lake of the disease, and each person has a different river."

90+ Study: Epidemiology and Autopsy Findings

Dr. Kawas similarly reported a high incidence of dementia in the oldest old, particularly centenarians, with results from the 90+ Study, also a population-based study of the oldest old. In this study, 330 participants underwent in-person neurological examination and were determined to be nondemented at baseline. Blood and DNA were also collected, and over follow-up, many of the participants agreed to donate their brain upon their death. "We now have over 100 brains in the brain bank," Dr. Kawas noted.

Dr. Claudia Kawas [Source: University of California, Irvine]

They were followed from January 2003 through December 2007, for a total of 770 person-years. Assessments in this study were done every 6 months. There were 140 cases of incident dementia identified over 770 person-years, for an overall incidence rate of 18.2% per year. Of these cases, 20 occurred among the centenarians, she noted.

Interestingly, she noted, men and women had almost identical rates of incident dementia: 17.9% in men and 18.3% in women. Their previous findings in this same cohort showed a prevalence of dementia among women that was double that of men, Dr. Kawas noted.

"The fact that we have an identical incidence rate for men and women in the incidence study I think tells us that the risk for dementia in women is not higher, but once they become demented, they live longer than men who are demented, just as women without dementia live longer than men without dementia," she said.

The effect of age on incidence was linear on the log scale, such that dementia incidence doubled every 5.5 years overall and in both sexes, strikingly similar to what has been seen for those under 85 years of age. "Essentially the rate goes from 10% for the 90- to 94-year-olds to 20% in the 95- to 99-year-olds and a whopping 41% for our centenarians, unfortunately," she said.

"I'm very convinced by these results," Dr. Kawas concluded. "I think the doubling time being completely consistent with younger ages and the dead-on similar rate for men and women are very striking and convince me that unfortunately the risk of this dreadful disorder does not go down with age."

In an interview with Medscape, Dr. Kawas speculated that the difference between their findings of no sex difference in incident dementia and those of Dr. Lucca's group may relate to the sampling frequency, which was 6 months in their study and 3 years in the Monzino 80-Plus study. "The longer your interval, the greater the likelihood of missing short-duration cases, and the short-duration cases are going to be the men," she said. This same issue may also explain why previous studies have suggested dementia declines in older age, she added.

Poor Correlation

Also at this meeting, Dr. Kawas presented autopsy data of the brains donated to date in the 90+ Study. Interestingly, there was again very little correlation between the clinical assessment of dementia or no dementia and what was found at autopsy. "If we said somebody was demented who came to autopsy, there was a 50% chance that the pathologist would call them normal elderly brain," she said.

There is a very poor relationship of cognition with amyloid measures, Dr. Kawas added, and only a slightly better relationship with neurofibrillary tangles and tau. "Far and away the best correlation for cognition in this sample turned out to be, so far, synaptophysin," she said, a way of measuring the integrity of synapses, that had an almost linear correlation with cognition. However, the actual disease process is unclear. "That's the million-dollar question — what is the pathology?" she said.

Pathologists are now examining a variety of measures, including other isomers of amyloid and tau, to see whether these other specific forms might be related to cognition. Their group is also doing neuronal counting in the hippocampus of these brains, as well as looking at the size of the neurons to see if this is relevant. "It might be that you might not lose neurons but lose size, and that could account for brain shrinkage." Finally, they are looking at other types of vascular pathology.

Work Just Beginning

Dr. Kristine Yaffe

Asked for comment on these findings, Kristine Yaffe, MD, professor of psychiatry, neurology, and epidemiology and associate chair of research for the department of psychiatry at the University of California, San Francisco, pointed out that work among the oldest old is still a burgeoning area of research.

Until recently, there were not that many people of this age around, and now it is actually the fastest-growing segment of the population, she said. "You don't see that many people in their 90s as a physician, but I think what we're talking about here is, what is it about the pathology in that group, and is the dementia in that group different from dementia in the earlier group?"

These people are not even generally included in trials, Dr. Yaffe noted. "If we're understanding that the neuropathology is different, maybe we need a trial of the oldest old."

There may also be differences in risk factors for dementia in this group, she added. "So, for example, whether this is due to survival bias or other reasons — we don't know — it looks like some of the traditional risk factors that we think of for dementia don't bear out in the oldest old. And again, I think we're just starting to understand why that is."

Dr. Yaffe added that she has just been funded by the Alzheimer's Association to look at risk factors in this group of oldest old.

The 90+ Study was funded by the National Institute on Aging. Dr. Kawas reports no conflicts of interest. The Monzino 80-Plus Study is supported by the nonprofit Monzino Foundation. Dr. Lucca reports no conflict of interest.

2009 Alzheimer's Association International Conference on Alzheimer's Disease (ICAD 2009): Abstracts P3-168, 02-02-08. Presented July 14, and 13, 2009.

Opposing View, Proton-Pump Inhibitors Better Option

However, David A. Johnson, MD, FACG, FACP, professor of medicine and chief of gastroenterology at Eastern Virginia Medical School in Norfolk and past president of the American College of Gastroenterology, disagrees. "The problems I have [with the study] are the applications to real life," Dr. Johnson told Medscape Gastroenterology. "This patient group was just taking low-dose aspirin. And in real life, a lot of people take more than that. So applications beyond just low-dose aspirin or patients taking some other NSAIDs on a sporadic or even on a concomitant basis would not be appropriate from the data they did in this trial, where they were very restricted."

He said that both the American College of Gastroenterology's guidelines and the consensus statement that the American College of Gastroenterology wrote with the American College of Cardiology in fall 2008 say that proton-pump inhibitors are still the preferred strategy. "In comparative trials, not just low-dose aspirin but for patients taking regular NSAIDs, [PPIs] are just more effective."

Dr. Johnson said that an H₂ receptor antagonist may have some benefit if looking only at cost factors. However, "This study was dated at a time when H₂ receptor antagonists were being compared to prescription costs of PPIs. Now, with the availability of generics and over the counter PPIs, I think the cost strategy needs to be re-evaluated. From the standpoint of compliance and efficacy, I still see that the proton pump inhibitor recommendation stands as the most viable for patients deemed at risk."

This study was funded by Merck Laboratories and Astellas Pharma. The study drugs (famotidine and placebo) were donated by Merck Laboratories, United Kingdom. Dr. Taha has received research grants and travel expenses from Astellas, AstraZeneca, Merck, and Yamanouchi. The other study authors have disclosed no financial relationships.

Dr. Hawkey has received research funding and/or honoraria from Bayer, Logical Therapeutics, Albireo AB, Novartis Pharma, Pfizer, and NicOx.

Dr. Johnson has received grants for clinical research and served as an advisor or consultant for AstraZeneca Pharmaceuticals LP and TAP Pharmaceutical Products Inc. He has also served as an advisor or consultant for Dynogen Pharmaceuticals, Inc.

Lancet. Published online July 6, 2009.

MIDAS Study

Dr. Karin Yurko-Mauro

Karin Yurko-Mauro, PhD, associate director of clinical research at Martek Biosciences, makers of the DHA supplement derived from algae used in this as well as the AD trial, presented more promising results with supplementation in healthy subjects 55 years of age and older with age-related cognitive decline. This kind of cognitive decline is described in Diagnostic and Statistical Manual of Mental Disorders, 4th ed (DSM-IV) as "decline in cognitive functioning consequent to the aging process that is within normal limits given a person's age."

The Memory Improvement with DHA Study (MIDAS) was also a double-blind, placebo-controlled trial including 485 subjects from 19 US centers stratified by age, randomized to receive 900 mg/day of DHA or placebo for 6 months. The primary end point was cognitive testing of memory and learning using the CANTAB Paired Associate Learning (PAL) test, a computerized cognitive battery measuring visuospatial and memory recall that has been shown to discriminate well between aging, mild cognitive impairment, and AD and to be sensitive to early changes in episodic memory.

"So in terms of our primary end point, the Paired Associate Learning test, what we found was that there significantly fewer errors made on this test with algal DHA for 6 months vs placebo," she said. Subjects taking DHA had almost double the reduction in errors on the PAL test, with a mean reduction of 4.5 errors from a baseline of 13.4, vs a reduction of 2.4 errors from a baseline of 12.1 in the placebo group (P = .032).

The net benefit is roughly equivalent to having the learning and memory skills of someone 3 years younger, Dr. Yurko-Mauro said. Plasma levels of DHA doubled with supplementation and a decrease in heart rate in treated patients correlated with the increased DHA levels, suggesting a potential cardiac benefit.

Finally, there was no difference in adverse events between groups, and the supplements were well tolerated, she noted.

"In conclusion, this MIDAS study is the first large randomized placebo-controlled study to demonstrate the benefits of algal DHA in maintaining and improving brain health in older adults," Dr. Yurko-Mauro concluded. The dose used improved learning and memory recall in these subjects with age-related cognitive decline and appeared to have a significant impact on early episodic memory changes.

Dr. Yurko-Mauro anticipates there will be further study in this population. "I think at this point it's premature to talk about the future plans, but we are closely looking at these results," she said. "There are actually some more data that are coming in from the [National Institutes of Health] NIH trial, and we definitely will be looking toward future development clinically."

During discussion of the trial results at the press conference, Dr. Thies suggested to Dr. Yurko-Mauro that DHA may "just cry for a mild-cognitive-impairment trial," which is the population between age-related cognitive decline and frank Alzheimer's disease. "I think that would be a logical next step," she agreed.

The Alzheimer's study was supported by the National Institute on Aging; the age-related cognitive-decline study was supported by Martek Biosciences. Dr. Yurko-Mauro is an employee of Martek Biosciences; Dr. Quinn reports no disclosures.

2009 Alzheimer's Association International Conference on Alzheimer's Disease (ICAD 2009): Abstracts 01-04-01, 01-04-02. Presented July 12, 2009

Benefits of extra BP lowering disputed

17 July 2009

MedWire News: Researchers claim lowering blood pressure (BP) beyond standard targets is not beneficial to any hypertensive patient, after conducting a review of seven trials involving more than 22,000 participants.

Lowering BP beyond standard targets neither prolonged survival nor reduced the risk fora range of cardiovascular outcomes, they report in the Cochrane Database of Systematic Reviews.

Jose Agustin Arguedas (University of Costa Rica, San Pedro de Montes de Oca) initially searched for trials comparing different systolic BP targets but could not find any.

However, they did identify seven trials, including 22,089 individuals, which compared different diastolic BP targets.

Attempting to achieve lower targets of 135/85 mmHg or less led to a significantly greater BP reduction of 4 mmHg systolic and 3 mmHg diastolic compared with standard targets of 140–160 mmHg systolic and 90–100 mmHg diastolic.

However, this did not significantly affect the relative risk for total mortality, myocardial infarction, stroke, congestive heart failure, major cardiovascular , or end-stage renal disease.

The researchers acknowledge that the net health effect of lower targets cannot be fully assessed due to a lack of information on all serious adverse events and withdrawals due to adverse effects in six of the seven trials.

A sensitivity analysis in patients with diabetes and those with chronic renal disease also did not show a reduction in any of the mortality and morbidity outcomes with lower targets.

The researchers conclude: “More trials are needed, but at present there is no evidence to support aiming for a [BP] target lower than 140/90 mmHg in any hypertensive patient.”

However, they add: “Because guidelines are recommending even lower targets for diabetes mellitus and chronic renal disease, we are currently conducting systematic reviews in those groups of patients.”

MedWire (www.medwire-news.md) is an independent clinical news service provided by Current Medicine Group, a part of Springer Science+Business Media. © Current Medicine Group Ltd; 2009

Cochrane Database Syst Rev 2009; 3: CD004349

Optimal level of anticoagulant therapy determined for heart conditions

15 July 2009

MedWire News: Patients with mechanical heart valve prostheses or atrial fibrillation should be treated with oral anticoagulant therapy (OAT) to an optimal international normalized ratio (INR) of 3, results of an observational study suggest.

Those patients recovering from a myocardial infarction (MI) meanwhile should be maintained at a slightly higher INR of 3.5, say Frits Rosendaal and colleagues from the Leiden University Medical Center in The Netherlands.

Oral anticoagulant therapy with vitamin K antagonists is recommended for the primary and secondary prevention of arterial thromboembolism.

Specifically, for patients with mechanical heart valve prostheses, OAT protects from valve thrombosis, while in patients with atrial fibrillation or ischemic heart disease it prevents ischemic stroke and recurrent MI.

However, the major drawback of OAT is the increased risk for hemorrhage, which is associated with the intensity of anticoagulation.

In the present study, the researchers evaluated 4202 patients visiting the Leiden Anticoagulation Clinic with mechanical heart valve prostheses, atrial fibrillation, or MI from 1994 to 1998.

During follow-up they recorded incidences of major hemorrhage and thromboembolism (untoward events) and took venous blood samples to determine prothrombin times expressed as an INR.

The optimal intensity of oral anticoagulation was calculated as the INR level that provided the lowest overall incidence of untoward events.

Incidence rates of untoward events were around 4% per year for all indications: 4.3 for patients with mechanical heart valve prostheses, 4.3 for patients with atrial fibrillation, and 3.6 per year for patients treated after MI.

The optimal intensity of anticoagulation for patients with mechanical heart valve prostheses was an INR of 2.5 to 2.9; for patients with atrial fibrillation, an INR of 3.0 to 3.4; and for patients after MI, an INR of 3.5 to 3.9.

“Our study suggests target INRs of 3.0 for patients with mechanical heart valve prostheses and atrial fibrillation and 3.5 after myocardial infarction as a starting point in future clinical trials,” Rosendaal and colleagues conclude in the Archives of Internal Medicine.

MedWire (www.medwire-news.md) is an independent clinical news service provided by Current Medicine Group, a part of Springer Science+Business Media. © Current Medicine Group Ltd; 2009

Arch Intern Med 2009; 169: 1203–1209

Over the past three decades, data from major clinical trials support the view that aspirin, beta blockers, angiotensin-converting enzyme inhibitors, and statins each reduce cardiovascular risk significantly. Treating patients with pills from each of these classes presents a challenge due to the cost and the difficulty of taking four pills each day. As the incidence of cardiovascular disease increases in the developing world, these challenges become more profound but, if addressed adequately, can have a significant impact on the global incidence of cardiovascular disease.

The concept of a combination pill that contains a drug from each of these four classes—a polypill—has been considered since the early part of this decade. Estimates of the population effect of such a pill suggest that its use can reduce cardiovascular events in individuals without regard for prior cardiovascular disease or risk factor status by more than 80% (Wald, Law, 2003). Before a major prospective trial is undertaken, however, the efficacy of the polypill in risk factor reduction, ease of use, and tolerability must first be assessed. For this reason, a phase II, double-blind, randomized trial was designed to determine the magnitude of the effect of a combination pill on blood pressure and lipid lowering, the tolerance of such a combination pill, and possible adverse interactions among its components. In The Indian Polycaps Study (TIPS) (2009), 2053 middle-aged (54.0 + 7.9 years) individuals without previous cardiovascular disease and with one risk factor were recruited from 50 centers in India and randomized to one of nine treatment regimens: (1) 100 mg aspirin; (2) 12.5 mg thiazide; (3) 5 mg ramipril + 12.5 mg thiazide; (4) 50 mg atenolol + 12.5 mg thiazide; (5) 50 mg atenolol + 5 mg ramipril; (6) 50 mg atenolol + 5 mg ramipril + 12.5 mg thiazide; (7) 50 mg atenolol + 5 mg ramipril + 12.5 mg thiazide + 100 mg aspirin; (8) 20 mg simvastatin; or (9) the Polycap (50 mg atenolol + 5 mg ramipril + 12.5 mg thiazide + 100 mg aspirin + 20 mg simvastatin). As shown in this listing, three different antihypertensive regimens were included in the trial (diuretic, angiotensin-converting enzyme inhibitor, and beta blocker) in various combinations. The active treatments were maintained for 12 weeks, and effects of the therapies on risk factors were measured at 4-week intervals, including one follow-up measurement 4 weeks after treatments were discontinued.

The principal results of the study can be summarized as follows. First, the magnitude of the reduction in blood pressure increased with increasing numbers of antihypertensive agents, with the Polycap achieving the greatest reduction (systolic pressure reduction, 7.4 mmHg; diastolic pressure reduction, 5.6 mmHg). Second, simvastatin and Polycap achieved significant reductions in LDL cholesterol, but the magnitude of reduction by Polycap was marginally significantly less than that of simvastatin used alone (27 vs. 32 mg/dL, p = .04). Third, all atenolol-containing regimens lowered heart rate by ~7 beats per minute compared with regimens not containing atenolol, and, fourth, all aspirin-containing regimens lowered 11-dehydrothromboxane B2 (a stable metabolite of platelet-derived thromboxane A2) equivalently compared with regimens not containing aspirin. Drugs were permanently discontinued in 303 patients overall (14.8%), and there appeared to be no relationship between the number of agents used in combination and the frequency of discontinuation.

These results are encouraging in that they demonstrate the short-term efficacy of a polypill, the Polycap, in reducing cardiovascular risk factors significantly and show that these effects are achieved with minimal adverse effects or intolerability. The true benefits of this approach with respect to hard clinical endpoints, long-term safety and tolerability, and overall patient adherence remain to be demonstrated in an adequately sized, prospective, longer term, randomized, controlled trial.

July 6, 2009 — Proton-pump inhibitor (PPI) therapy for 8 weeks induces acid-related symptoms in healthy volunteers after withdrawal, according to the results of a randomized, double-blind, placebo-controlled trial reported in the July issue of Gastroenterology.

"Rebound acid hypersecretion (RAHS) has been demonstrated after 8 weeks of treatment with a proton-pump inhibitor (PPI)," write Christina Reimer, from Køge University Hospital, Copenhagen University in Copenhagen, Denmark, and colleagues. "If RAHS induces acid-related symptoms, this might lead to PPI dependency and thus have important implications."

PPIs Induce Acid-Related Symptoms

In this study, 120 healthy volunteers were randomized to receive placebo for 12 weeks or esomeprazole 40 mg/day for 8 weeks followed by 4 weeks of placebo. Clinically relevant acid-related symptoms were defined as a score of 2 or higher on one of the questions regarding heartburn, acid regurgitation, or dyspepsia on the Gastrointestinal Symptom Rating Scale (GSRS), which was completed weekly.

At baseline, GSRS scores were statistically similar in both groups. Compared with the placebo group, the PPI group had significantly higher GSRS scores for acid-related symptoms at week 10 (1.4 ± 1.4 vs 1.2 ± 0.9; P = .023), week 11 (1.4 ± 1.4 vs 1.2 ± 0.9; P = .009), and week 12 (1.3 ± 1.2 vs 1.0 ± 0.3; P = .001).

Of volunteers receiving PPI, 44% (26/59) reported at least 1 relevant, acid-related symptom in weeks 9 to 12, as did 15% (9/59; P < .001) in the placebo group. In the PPI group, the proportion reporting dyspepsia, heartburn, or acid regurgitation was 13 (22%) of 59 at week 10, 13 (22%) of 59 at week 11, and 12 (21%) of 58 at week 12 vs 7% (P = .034), 5%, and 2% (P = .001), respectively.

"PPI therapy for 8 weeks induces acid-related symptoms in healthy volunteers after withdrawal," the study authors write. "This study indicates unrecognized aspects of PPI withdrawal and supports the hypothesis that RAHS has clinical implications."

Limitations of this study include the use of healthy volunteers, which prevents determining whether symptoms develop as a consequence of RAHS to the same degree in patients with dyspeptic symptoms. In addition, the randomly skewed assignment of most subjects infected with Helicobacter pylori to the placebo group prevented determining whether the acid rebound phenomenon is clinically significant in infected subjects.

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

Inform Patients of Potential Risks

In an accompanying editorial, Kenneth E. L. McColl, MD, and Derek Gillen, MD, from the University of Glasgow Gardiner Institute, Glasgow, United Kingdom, note that findings from this study challenge current liberal PPI prescribing patterns and suggest changes in prescribing habits that should be considered.

"More effort should be made to identify contributory lifestyle factors and to utilize milder medications such as antacids or alginates," Drs. McColl and Gillen write. "Patients often ask about the safety and likelihood of side effects from [PPI] therapy. Now that rebound acid secretion has been demonstrated to induce symptoms, we are probably obliged to inform them about rebound acid hypersecretion and its potential effects."

The Danish Medical Research Council, Københavns Amts Research Foundation, and Region Sjællands Research Foundation supported this study. AstraZeneca provided the medication and placebo. Two of the study authors have disclosed relevant financial relationships with AstraZeneca, Nycomed, Eisai, and/or Wyeth. Drs. Mccoll and Gillen have disclosed no relevant financial relationships.

Gastroenterology. 2009;137:20-39, 80-87.

From Reuters Health Information

Exercise Did Not Improve Cognition in Elderly Dementia Patients: Study

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NEW YORK (Reuters Health) Jul 07 - A short-term walking program did not improve cognition in older nursing home patients with moderate dementia, reports an article in the Journal of Neurology, Neurosurgery, and Psychiatry for July.

"Physical activity can increase brain volume and benefit cognition in healthy sedentary older people," the authors note. Furthermore, they say, treadmill running led to reduced beta-amyloid accumulation in a mouse model of Alzheimer's disease.

In their randomized trial of a walking intervention in 97 elderly men and women (mean age, 85.4 years) with a mean Mini-Mental State Examination score of 17.7, however, Dr. L. H. P. Eggermont of VU University in Amsterdam and colleagues did not observe any benefit on cognition.

Patients assigned to the experimental group walked for 30 minutes, 5 days a week, for 6 weeks. The control group received one-on-one social visits on the same schedule.

The researchers used a linear mixed model to calculate differences "in a broad range of cognitive functions" between the groups at baseline, after the six-week program, and again six weeks later. "No positive effects on cognition were found, and treatment outcome was not influenced by apolipoprotein E genotype," the investigators said.

"Possible explanations for the lack of a beneficial effect...could be the level of physical activation of the intervention or the high frequency of comorbid cardiovascular disease in the present population of older people with dementia," the authors conclude.

J Neurol Neurosurg Psychiatry 2009;80:802-804

From Heartwire

Statin-Induced Myopathy Reflects Structural Muscle Damage, New Study Shows

Michael O’Riordan

Authors and Disclosures

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July 7, 2009 (Boston, Massachusetts) — Persistent muscle pain in patients taking statins reflects structural muscle damage, and this microscopic damage can occur in the absence of elevated creatine phosphokinase levels, according to the results of a new study [1].

"It's clear that a patient with statin-induced myopathy can have microscopic muscle damage, but the damage is not sufficient to break the cell open, and that means that it doesn't release creatinine phosphokinase into the blood," said study investigator Dr Richard Karas (Tufts-New England Medical Center, Boston, MA). "So to say that the other way around, we have clear evidence that there is ongoing damage to the muscle at the microscopic level, but it's not revealed in the blood tests that we use to check for muscle damage."

Speaking with heartwire , Karas said that muscle-related adverse effects limit statin use, despite the drugs being part of the foundation of cardiovascular risk reduction. He added that although these muscular side effects are well documented, little is known about the mechanisms of myopathy.

In this study, which is published online July 7, 2009 in the Canadian Medical Association Journal, Karas, along with lead investigator Dr Marcus Mohaupt (University of Bern, Switzerland), obtained biopsy samples from the vastus lateralis muscle of 83 patients. Overall, 44 subjects had clinically diagnosed statin-associated myopathy, and of these, 29 were currently taking a statin, while 15 had discontinued statin therapy for at least three weeks. Among the 83 patients, 19 were currently taking a statin but had no myopathy and 20 patients served as healthy controls.

Among the 44 individuals with myopathy, 57% had muscle injury defined by structural abnormalities in the muscle fibers, as did one patient without clinically diagnosed myopathy. Interestingly, just one patient with structural muscle injury had circulating creatine phosphokinase levels that exceeded 10 times the upper limit of normal, or >1950 U/L.

"This is clinically relevant because when a patient is on a statin and they come in complaining that their muscles hurt, we check the blood test for creatinine phosphokinase," said Karas. "If it's normal we tell them not to worry about it, that it's not the statin. This study tells us that in this group of patients, that clinical assumption is not true."

Not Your Average Patient on a Statin

Karas stressed that the patients included in this study are not typical patients on statins, but rather individuals with clinically identified statin-related myopathy. This distinction is important because patients treated with statins who feel fine and who have normal creatine phosphokinase levels should not worry they are damaging their muscles with the LDL-cholesterol-lowering medications.

The researchers point out, however, that patients with clinically diagnosed statin-induced myopathy who had stopped their statins for at least three weeks also had persistent microscopic evidence of muscle damage. Although he is cautious in interpreting results, saying it needs further study, Karas said that muscle problems might not go away among individuals with persistent muscle pain.

The researchers also performed a gene-expression analysis in 57 patients to look for association between muscle damage and genes that encode proteins located in T-tubule membrane or the adjacent sarcoplasmic reticulum and that are involved in the release of intracellular calcium. One of those proteins, ryanodine receptor 3, was significantly upregulated among patients with structural muscle damage when compared with individuals without muscle damage.

"The problem is that we don't know if this was elevated in the first place, and then this makes people susceptible to statin-induced myopathy, or whether it is elevated as a result of them having statin-induced myopathy," Karas explained to heartwire . "This is the first step, as it tells us that it's a gene that should be focused on in studies going forward. What we'd like to do is take a huge group of people and get their levels of expression and see if it predicts them getting myopathy