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

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

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

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

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

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

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

SUMMARY AND COMMENT

ARISTOTLE: Another Competitor Beats Warfarin Free!

August 29, 2011 | Mark S. Link, MD

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

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

Mega JL. N Engl J Med 2011 Aug 28;

Learning Objectives

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

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

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

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

Study Synopsis and Perspective

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

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

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

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

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

The Rotterdam Study

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

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

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

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

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

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

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

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

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

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

Interesting, but no Clinical Effect at Present

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

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

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

What Is Old Is New Again

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

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

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

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

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

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

Pregabalin Reduced Pain from Chronic Pancreatitis

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

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

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

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

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

— Chris E. Forsmark, MD

Published in Journal Watch Gastroenterology September 9, 2011

Rivaroxaban versus Warfarin in Nonvalvular Atrial Fibrillation

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

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

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

Clinical Context

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

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

Study Synopsis and Perspective

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

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

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

Portfolio Diet vs Diet Low in Saturated Fat

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

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

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

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

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

To Treat or Not to Treat With a Statin

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

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

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

Medscape, LLC, encourages Authors to identify investigational products or off-label uses of products regulated by the US Food and Drug Administration, at first mention and where appropriate in the content.

Laurie Barclay, MD
Freelance writer and reviewer, Medscape, LLC
Disclosure: Laurie Barclay, MD, has disclosed no relevant financial relationships.

Brande Nicole Martin
CME Clinical Editor, Medscape, LLC
Disclosure: Brande Nicole Martin has disclosed no relevant financial relationships.

Charles P. Vega, MD
Associate Clinical Professor, Residency Program Director, Prime-LC, University of California-Irvine, Orange, California; Department of Family Medicine, University of California-Irvine, Orange, California
Disclosure: Charles P. Vega, MD, has disclosed no relevant financial relationships.

Sarah Fleischman
CME Program Manager, Medscape, LLC
Disclosure: Sarah Fleischman has disclosed no relevant financial relationships.

Laurie E. Scudder, DNP, NP
Nurse Planner, Continuing Professional Education Department, Medscape, LLC; Clinical Assistant Professor, School of Nursing and Allied Health, George Washington University, Washington, DC
Disclosure: Laurie E. Scudder, DNP, NP, has disclosed no relevant financial relationships.

Learning Objectives

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

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

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Clinical Context

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

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

Study Synopsis and Perspective

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

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

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

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

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

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

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

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

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

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

Lancet. Published online August 16, 2011.

Abstract

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

Introduction

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

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

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

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

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

ASCOT-LLA and the Long-Term Effects of Atorvastatin

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

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

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

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

Serious Decision for Primary Prevention Patients

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

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

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

SUMMARY AND COMMENT

ARISTOTLE: Another Competitor Beats Warfarin Free!

August 29, 2011 | Mark S. Link, MD

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

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

Mega JL. N Engl J Med 2011 Aug 28;