March 19th, 2014
New Statin Guidelines Recommend Therapy for 12.8 Million More Adults Than The Prior Guideline
Larry Husten, PHD
Millions more people are now eligible for statin therapy under the new cholesterol guideline published last year, according to a new estimate published in the New England Journal of Medicine.
Under the earlier guideline statins were indicated for primary and secondary prevention based largely on LDL cholesterol levels. The new guideline, announced last year, places much less emphasis on LDL and instead puts a much greater emphasis on the future risk of individuals for heart disease and stroke. The most important change is in primary prevention. Now, patients who have LDL cholesterol levels as low as 70 mg dl and no established cardiovascular disease are eligible for statin therapy if they have diabetes or a 10-year estimated risk of CV disease of 7.5%.
There have been many attempts to quantify just how many more people are now eligible for statin therapy under the new guideline. In the new paper in NEJM, Michael Pencina and his colleagues estimate that the new guideline results in a net increase of 12.8 million people presently eligible for statins. Most of the newly eligible people are older adults without cardiovascular disease.
The researchers extrapolated from data from a representative sample of the US population (the National Health and Nutrition Examination Surveys, or NHANES) and calculated the number of adults 40-75 years of age who would be eligible for statin therapy under the old guideline and the new guideline:
- Under the old guideline 43.2 million adults, or 37.5% of the population, were eligible for statins.
- Under the new guideline this increases to 56 million (48.6%). Three out of 5 of the newly eligible patients would be men and their median age would be 63.4 years.
- The net increase in 12.8 million comes mostly from primary prevention– 10.4 million.
- Most of the increase occurs in older adults, between 60 and 75 years. Just under half (47.8%) of this population was eligible for statins in the earlier guideline. Now more than three-quarters (77.3%) of this age group are eligible.
- Lowering the treatment threshold to a 10-year risk starting at 5%, which the guidelines deem “reasonable,” would increase eligibility to 38.4% of adults between 40 and 60 and 87.4% of adults between 60 and 75.
- By increasing the number of people eligible for treatment, the new guideline has increased sensitivity— that is, it will result in more people being treated who would otherwise have gone on to have a cardiovascular event– but also decreased specificity— more people will receive treatment who would not have had an event.
- The authors estimated that the increased number of people taking statins would result in 475,000 fewer events– nearly all (90%) coming from the group of older adults.
In an email interview, Allan Sniderman, one of the senior authors of the paper, said that the increase in the population eligible for treatment “has major consequences for cost and medicalization.” He agreed with other observers that the 7.5% threshold cutoff “is arbitrary.” “The way out is to better define risk. That is where we need to move forward,” he said.
An alternative to the “risk-based approach” of the new guideline, Sniderman said, is “a cause-based approach in which we identify and treat the causes in order to prevent the intramural atherosclerotic disease that will produce the clinical events.” But this approach, he acknowledged, will require more research before being adopted by future guidelines.
The NEJM paper fails to take into account the more subjective side of the new guideline, said Harlan Krumholz in an email. “The guideline recommendation is intended to be just that – a recommendation about a threshold that might make sense to use in a treatment decision. The guidelines are clear that the patient’s preference is what matters most. So it is really impossible to know if more people will be taking statins.”
March 17th, 2014
Happy St. Patrick’s Day!
CardioExchange Editors, Staff
To commemorate the day, the editors and staff at CardioExchange bring you their gallery of adorable Irish children (yes, we are Boston-based). If you are Irish — or feel Irish today! — submit your own photos; we’ll happily add them!
Lá Fhéile Pádraig Sona Daoibh!
John and Sabrina (John Ryan, MD, Editor)
Fergus and Gabriel (Matt O’Rourke, Editor Emeritus)
Lorelei, Catherine, Ciaran, and Conor (Danielle Sullivan-Douglas, Staff Editor)
Nolan (Amy Herman, Staff Editor)
March 17th, 2014
Studies Provide Little Support for Guidelines on Dietary Fats and Supplements
Larry Husten, PHD
The precise cardiovascular effect of dietary fats and supplements has been the subject of heated controversy. Although there is no strong supporting evidence from clinical trials, current guidelines tend to discourage or minimize the role of saturated fats and trans fats and to encourage the intake of omega-3 polyunsaturated fatty acids. Two new studies published today help clarify some of the issues. Both studies demonstrate the shaky underpinnings of the guidelines but are unlikely to provide firm support for a new perspective on these issues.
The first study, published in Annals of Internal Medicine, is a systematic review and meta-analysis of 76 randomized and observational studies that looked at either dietary fat consumption, dietary fat biomarkers, or dietary fat supplements. Among the chief findings:
- Omega-3 and omega-6 fatty acids: There were trends for modest benefits associated with dietary intake or supplements, but these did not achieve statistical significance. There was some evidence that people with high circulating levels of omega-3 fatty acids may have a reduced risk of coronary disease.
- Saturated fatty acids: There was no discernible effect of total saturated fat as measured by either dietary intake or circulating biomarkers. There was a signal suggesting different effects for individual saturated fatty acids as measured by biomarkers, but the authors noted that circulating levels of these are often only poorly determined by dietary intake. There was a suggestion of benefit for saturated fats derived from milk or dairy consumption.
- Monunsaturated fatty acids: No effect was found, either harmful or beneficial.
- Trans dietary fats: A harmful effect was confirmed.
The authors stated that “the pattern of findings from this analysis did not yield clearly supportive evidence for current cardiovascular guidelines that encourage high consumption of polyunsaturated fatty acids and low consumption of saturated fats.” The conclusions are consistent with a recent editorial in Open Heart that urged revision of guidelines advocating low-fat diets, especially when saturated fats are replaced with carbohydrates or omega-6 fatty acids.
The second study, published in JAMA Internal Medicine, reports the cardiovascular outcomes of patients who participated in AREDS2 (Age-Related Eye Disease Study 2). A total of 4,203 patients with age-related macular degeneration were randomized twice, to either omega-3 fatty acids (DHA 350 mg and EPA 650 mg) or placebo and also to lutein and zeaxanthin (carotenoids found in the eye) or placebo. After 4.8 years of followup there was no significant reduction in cardiovascular outcomes in either of the treatment groups.
The authors concluded that their “results are consistent with a growing body of evidence from clinical trials that have found little CVD benefit from moderate levels of dietary supplementation.”
In an invited commentary, Evangelos Rizos and Evangelia Ntzani write that after many years of investigation it is now clear that omega-3 supplements “with daily doses close to 1 g in patients with or without established CVD shows no clear, considerable benefit.” Future trials “should focus on the remaining gaps of knowledge such as high-dose omega-3 supplementation (definitely more than 1 g daily) with various EPA/DHA ratios” in patients with high triglyceride levels. For now, omega-3 supplements should only be prescribed for patients with severe hypertriglyceridemia, “an extreme minority of the general population.”
March 17th, 2014
Phase 4 Actelion Study Misses Primary Endpoint
Larry Husten, PHD
Actelion announced today that a phase 4 study with its blockbuster drug bosentan (Tracleer) had failed to meet its primary endpoint.
The COMPASS-2 trial was a prospective, randomized, double-blind, placebo-controlled trial evaluating the effect of bosentan on the time to first confirmed event in patients with symptomatic pulmonary arterial hypertension (PAH) already receiving treatment with sildenafil.
According to the company, a 17% risk reduction in the primary endpoint of the time to first event did not reach statistical significance (p=0.25). Actelion reported that an exploratory analysis showed a significant increase in the 6-minute walking distance in the combination group and “and a placebo-corrected incidence of 15.4%” in elevated liver enzymes over 23 months of treatment.
The press release quoted the University of Michigan’s Vallerie McLaughlin, chair of the trial’s steering committee: “While the observed risk reduction of 17% did not reach statistical significance, I am convinced that this study provides important information for the scientific community and we are committed to perform all the necessary analyses to fully understand the outcome of the study.”
The company said that the full results of the study will be presented at future congresses and in peer-reviewed publications.
John Ryan, a pulmonary hypertension expert at the University of Utah, offered the following perspective:
“The COMPASS-2 trial assessed the efficacy of a common clinical practice, namely the addition of bosentan (an endothelia receptor antagonist, ERA) to patients with pulmonary arterial hypertension (PAH) already taking sildenafil (phosphodiesterase 5 inhibitor, PDE5i). The safety and benefit (or otherwise) of this combination therapy has been largely unknown. But because this disease process can advance so rapidly with a limited life expectancy, if patients are deemed to be failing monotherapy with clinical deterioration, most PAH providers are aggressive in adding on a second agent. Therefore the COMPASS-2 trial represents a marked advance in our knowledge of the merits of dual therapy. Looking forward, it will be important to perform similar combination trials with the other classes of agents available, especially ERAs and the new soluble guanylate cyclase stimulators (riociguat being the only currently available agent).”
March 17th, 2014
Selections from Richard Lehman’s Literature Review: March 17th
Richard Lehman, BM, BCh, MRCGP
CardioExchange is pleased to reprint this selection from Dr. Richard Lehman’s weekly journal review blog at BMJ.com. Selected summaries are relevant to our audience, but we encourage members to engage with the entire blog.
Lancet 15 Mar 2014 Vol 383
Comparison of the Efficacy and Safety of New Oral Anticoagulants with Warfarin in Patients with AF (pg. 955): “And God saw every thing that he had made, and, behold, it was very good.” Gen 1.31. This meta analysis of new oral anticoagulants for atrial fibrillation breathes a similar air of contentment. They are, quite simply, better than warfarin, especially when INR control is suboptimal. In an overall comparison with warfarin, they decrease all-cause mortality by about 10%, and reduce stroke and other embolic events by about 19%. What’s not to like? Well, a bit more gastrointestinal bleeding and a lot more cost. So if you have AF and feel strongly, you should follow the advice of the director of NICE and march along to your GP and demand some dabigatran. Or apixaban. Or rivaroxaban. Or wait a bit, until edoxaban has been approved. Why should you worry about cost to the NHS? When did anyone ever ask you about how much the nation should spend on health, or fulfil an electoral promise about the NHS?
Mortality from Ruptured Abdominal Aortic Aneurysms (pg. 963): It’s blood-in-the-boots time again folks. In the UK, more than 90% of ruptured abdominal aortic aneurysms are repaired by open surgery, whereas in the USA, the figure is 79%. Over there, they offer surgery to a lot more people too: 80% of those with ruptured AAA as opposed to 58% here. Yet their in-hospital mortality is somewhat better than ours, at 53 versus 66%. So we must learn lessons from America, but it isn’t quite clear what these are. The main one seems to be to rush off people with rAAA to high volume centres.
Metabolic Mediators of the Effects of BMI, Overweight, and Obesity on CHD and Stroke (pg. 970): As an aging man who likes food and doesn’t get much time away from a desk, I puzzle about the importance of overweight. It seems to me that the main problem is the tightness of one’s clothes. This is somewhat confirmed by this Lancet analysis, which concludes that “Interventions that reduce high blood pressure, cholesterol, and glucose might address about half of excess risk of coronary heart disease and three-quarters of excess risk of stroke associated with high BMI. Maintenance of optimum bodyweight is needed for the full benefits.” The last has to be true. Taking losartan and a statin has made no difference whatever to the tightness of my clothes.
The Framingham Heart Study and the Epidemiology of Cardiovascular Disease (pg. 999): In a few weeks’ time, all who can should visit Framingham, Mass. The Woodland Garden there will be full of the most wonderful erythroniums, trilliums, and sanguinarias. Others may wish to make the pilgrimage because it is 65 years since the first subjects were recruited to the Framingham Heart Study, marking the beginning of a new era in epidemiology. Here is a fascinating history of the project, which was stimulated in part by F.D. Roosevelt’s death from galloping hypertension. It’s a wonderful reminder of how much good work could be done by means of messages written on rickety typewriters, simple paper charts, and card indexes. No internet for the first 40 years.
BMJ 15 Mar 2014 Vol 348
Exclusion of DVT Using the Wells Rule in Clinically Important Subgroups: When faced with a possible deep vein thrombosis, I try to apply the Wells rules and do a d-dimer test, but I’m constantly frustrated at how often they simply don’t apply to the clinical situation. This individual patient data meta-analysis, whose authors include the great Professor Wells himself, concludes that “Combined with a negative D-dimer test result (both quantitative and qualitative), deep vein thrombosis can be excluded in patients with an unlikely score on the Wells rule. This finding is true for both sexes, as well as for patients presenting in primary and hospital care. In patients with cancer, the combination is neither safe nor efficient. For patients with suspected recurrent disease, one extra point should be added to the rule to enable a safe exclusion.” Add to this pregnant women and elderly people with fragility bruises, and you find yourself giving a lot of LMW heparin until you can get a scan, just in case.
March 17th, 2014
Meta-Analysis Finds Few Side Effects Caused by Statins
Larry Husten, PHD
Although clinical trials have consistently demonstrated the benefits of statins, especially in secondary prevention, the perception that the drugs can cause serious side effects has prompted some patients to discontinue or not take the drugs. Now, in a paper published in the European Journal of Preventive Cardiology, a new meta-analysis of existing trials offers some reassurance that most of the side effects that have been tied to statins do not appear to be actually caused by the drugs.
Researchers in the U.K. analyzed data from more than 83,00 patients randomized to statin therapy or placebo and found “little evidence of incremental symptomatic side effects beyond placebo,” though they did find a small absolute increase of 0.4% in people taking statins who had asymptomatic liver enzyme elevations.
The authors reported that although there were many reports of side effects often linked to statins, including myopathy, fatigue, muscle aches, and rhabdomyolysis, none occurred more often in the statin patients than in the placebo patients.
In 14 primary prevention trials, which included 46,262 randomized subjects, there was a small absolute 0.5% increase in the risk of diabetes in the statin group, but there was an absolute reduction of the same size in the risk of death. Overall, serious adverse events were reported in 14.6% of the statin group versus 14.9% of the placebo group.
In 15 secondary prevention trials, which included 37,618 randomized subjects, there was an absolute 1.4% decrease in the risk of death in the group taking statins. Overall, serious adverse events occurred in 9.9% of the statin group versus 11.2% of the placebo group.
In a separate analysis, the researchers analyzed data from five randomized trials that compared low-dose to high-dose statins. High-dose statins were associated with small but significant increases in asymptomatic liver enzymes, myopathy symptoms, and muscle aches. But high-dose statins were also associated with significant reductions in myocardial infarction and stroke.
The researchers acknowledge in their paper that the clinical trials used for their analysis may not fully reflect real-life clinical experience. Trials differ in the degree to which they search for and document side effects, and some investigators or sponsors “may not be motivated to search exhaustively for potential side effects.” In addition, people who qualify for or choose to participate in clinical trials may differ in important ways from real-life patients.
The authors concluded that “only a small minority of symptoms reported on statins are genuinely due to the statins: almost all reported symptoms occurred just as frequently when patients were administered placebo.”
March 14th, 2014
Apixaban Gains Indication for DVT Prophylaxis After Knee and Hip Replacement Surgery
Larry Husten, PHD
The FDA has approved a new indication for apixaban (Eliquis), the anticoagulant drug manufactured by Bristol-Myers Squibb and Pfizer. The new indication is for the prophylaxis of deep vein thrombosis (DVT) and pulmonary embolism in patients who have undergone hip or knee replacement surgery. The DVT prophylaxis indication joins the previously approved indication of stroke prevention in patients who have nonvalvular atrial fibrillation.
According to the companies, approximately 719,000 total knee replacement surgeries and 332,000 hip replacement surgeries are performed each year in the US. The use of anticoagulants is recommended in these patients because they are at elevated risk for developing DVT and PE.
The new indication is based on results of the ADVANCE clinical trial program in which apixaban was compared to enoxaparin in more than 11,000 patients.
Among the new oral anticoagulants only rivaroxaban (Xarelto, Johnson & Johnson) had been approved previously for DVT prophylaxis in orthopedic patients.
March 13th, 2014
rAAA Patients More Likely to Get Surgery and Survive in the U.S. Than in England
Larry Husten, PHD
Patients with a ruptured abdominal aortic aneurysm (rAAA) have better outcomes in the United States than in England according to a new study published in the Lancet.
Researchers at the University of London compared hospital data from 11,799 rAAA patients in England with 23,838 rAAA patients in the U.S. They found that U.S. patients were more likely than English patients to have a procedure to repair the rAAA and to survive their hospital stay.
- The in-hospital mortality rate was 53.05% in the U.S. compared with 65.9% in England.
- A procedure to repair the rAAA, either surgical or endovascular, was performed in 80.43% of the U.S. patients compared with 58.45% of the English patients.
- U.S. patients were much more likely to receive an endovascular repair (20.88% versus 8.54%).
The intervention rate appeared to play a key role in the outcome, since the mortality rate was 41% in both countries among the patients who received an intervention. U.S. patients had shorter hospital stays and were more likely to be discharged to a skilled nursing facility. These factors may have partly skewed the data to favor the U.S.. The authors did not have access to 30-day mortality rates.
In both countries patients were at higher risk when they were admitted to the hospital on a weekend or to smaller or non teaching hospitals — probably a reflection of the reduced availability of a prompt intervention.
“The large mortality difference is concerning”, said co-author Peter Holt in a Lancet press release. “Our data suggest that failure to deliver proven life-saving surgery is a key reason why in-hospital survival for patients with rAAA is lower in England.”
The study suffers from the limitations of all observational studies, the differences between the groups, and the shorter followup period in the U.S., write Martin Björck and Kevin Manian in an accompanying editorial. But, they state, because of the large difference in outcome “the conclusions would probably not have been changed even if these issues had been addressed.”
However, they point out, the short-term perspective of the study probably masks a grimmer view of rAAA: “With modern intensive care, many patients with rAAA do survive the early postoperative period, but fail to recover fully. This is shown by the fact that mortality remains high up to 90 days following surgery after rAAA.”
Although efforts to improve access to appropriate treatment should be encouraged, appropriate screening and prevention is more important: “Prevention will prolong the lives of many more patients with AAA in the future than efforts to improve treatment of ruptured AAA.”
March 13th, 2014
Achieving Consensus for the 2014 ACC/AHA Valvular Heart Disease Guideline
Catherine M. Otto, MD and Rick Akira Nishimura, MD
With the recent release of the 2014 AHA/ACC Guideline for the Management of Patients with Valvular Heart Disease, CardioExchange editors were interested to know how, in the present climate of rapid change and controversy, the writing committee achieved consensus on the future treatment of valvular disease. We asked committee co-chairs Rick Nishimura, Professor of Medicine at the Mayo Clinic College of Medicine, and Catherine Otto, Professor of Medicine at the University of Washington School of Medicine, to discuss how the guideline was updated.
Our basic approach for updating the guideline was to start with the evidence, basing recommendations on the published body of knowledge for each clinical issue. First, we made a detailed outline for the scope of the document, including each valve lesion as well as prosthetic valves, endocarditis, noncardiac surgery, and pregnancy in women with valvular heart disease.
Within this outline, a parallel structured format was used with sub-headers for each type of valve disease for diagnosis and testing, medical therapy, and the timing and type of intervention. This outline was refined and expanded early in the writing process, but the parallel structure was rigorously maintained to ensure that recommendations were complete and consistent throughout the document.
Next, committee members were assigned as primary or secondary writers for each section, ensuring the absence of potential conflicts of interest for that specific topic.
The first responsibility of the primary writer was to:
- Identify the clinical issues we needed to answer for each section.
- Perform a systemic review of the published evidence with preparation of detailed evidence tables (which are published as an online supplement to the guidelines).
- Draft initial recommendations based on the evidence.
- List the references justifying a Level of Evidence A or B for each recommendation. Our goal was to provide recommendations with a Level of Evidence A or B; if there was no evidence to support a recommendation, we did not write one. This approach decreased the number of Class C recommendations from over 70% in the 2006 guidelines to less than 50% in the 2014 document — still not optimal, but better than before given the paucity of randomized controlled clinical trials for valve disease.
The committee was split into two groups under the leadership of the co-chairs to facilitate discussion and consensus building for the draft recommendations. Once each group achieved consensus, the entire committee discussed each recommendation again.
Consensus was achieved by writing recommendations that accurately reflected the published evidence, were congruent with the clinical expertise of the committee, and were worded precisely and unambiguously. Although we often had to rely on observational or nonrandomized data, we based definitions of disease severity and criteria for intervention on published study entry criteria and clinical outcome data whenever these data were available. All of the committee members were willing to modify opinions based on their personal clinical experience when the published data were convincing.
The next steps for each primary writer were to:
- Write concise text for each recommendation, referring to the evidence tables and expanding on details as needed for clinical implementation.
- Add key references to each text section.
- Prepare flow chart diagrams for each major valve lesion to ensure the recommendations were internally consistent.
The text was reviewed by the entire committee with discussion, revision, and re-review as needed to ensure that all agreed with the final version.
After the committee members voted on all the recommendations, the entire document was sent for external review. Reviewers were selected both by the organizations collaborating on the document and from suggestions by the writing group. We received a total of 1463 comments from 49 reviewers — we responded to each of these comments before sending the document to the American College of Cardiology Board of Trustees (BOT). After the very rigorous review from the reviewers and the BOT, any resulting changes in the Class Recommendations went back to the entire committee for approval. We hope this process of iterative internal review and extensive external review will ensure rapid and widespread acceptance of the guideline recommendations.
The modular format of these new valve disease guidelines will improve quick access to the specific information needed for patient care, particularly when these guidelines are available in an interactive digital format. In addition, this format allowed us to make rapid changes, even at the end of the review process; individual recommendations can be updated in the future, without rewriting the entire document, as justified by new published data.
We look forward to seeing these guidelines become a “living” evidence-based document with continuous updates to reflect the rapidly changing knowledge base in valvular heart disease.
March 12th, 2014
Clinical Trials For Diabetes Drugs Need To Consider Heart Failure
Larry Husten, PHD
Is heart failure the missing 800 pound gorilla in diabetes trials? That’s the argument proposed by a group of prominent cardiovascular and diabetes researchers.
It was long believed that by virtue of their glucose-lowering properties diabetes drugs would confer substantial cardiovascular benefits. That belief is no longer widely held, however, and the FDA now requires cardiovascular outcome trials for new diabetes drugs. But, write the researchers in an article published in the Lancet Diabetes & Endocrinology, these trials are failing to track and analyze one key cardiovascular endpoint, thereby diminishing the value of these trials in assessing the cardiovascular effects of diabetes drugs.
John McMurray, Hertzel Gerstein, Rury Holman, and Marc Pfeffer write that heart failure is “a cardiovascular outcome in diabetes that can no longer be ignored.” In response to the firestorm over rosiglitazone (Avandia) the FDA and the EMA have insisted that cardiovascular outcomes trials be performed with new diabetes drugs. But for the most part these trials, which now include about 150,000 patients, have been designed to track a traditional MACE (major adverse cardiovascular events) endpoint, which includes cardiovascular death, MI, and stroke, but which does not include heart failure.
This omission could have serious repercussions, they write, because the available evidence from epidemiological studies and clinical trials indicates that heart failure occurs quite frequently in patients with diabetes (though they acknowledge that it is unclear whether there is a precise causal relationship). Further, the occurrence of heart failure is clearly related to a poor prognosis. It was once believed that the heart failure symptoms associated with one class of diabetes drugs– the thiazolidinediones (which includes rosiglitazone)– was an artifact that did not have the same prognostic significance as heart failure in other patients. But, McMurray and colleagues write, evidence from the RECORD trial “suggests otherwise.” Equally ominous is that recent trials of a newer class of diabetes drugs, the DPP-4 inhibitors, appeared to have resulted in a clear heart failure signal.
Summarizing their position, they write that “hospital admission for heart failure is one of the most common and prognostically important cardiovascular complications of diabetes, and the one cardiovascular outcome for which the risk has been shown unequivocally to be increased by certain glucose-lowering therapies.” They propose that heart failure should be “systematically evaluated” in these outcome trials.
Sanjay Kaul provided the following comment about the Lancet paper:
I agree with the authors that the evidence linking some, but not all, antidiabetic drugs to increased risk of heart failure is stronger than the evidence linking to increased risk of atherothrombotic MACE events. However, the underlying mechanisms remain unclear. Nonetheless, the authors make a defensible case for including heart failure as an outcome of special interest in future diabetes trials. Rather than combining it with MACE as a primary composite outcome, I prefer heart failure to be included as a separate coprimary endpoint, or a key secondary endpoint as it might not lie on the same pathophysiologic pathway as MACE (primarily an atherothrombotic event), and the treatment might potentially yield divergent effects on these endpoints, thereby challenging the interpretation of the composite endpoint.
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