CardioExchange Archive

Study Raises Questions About Statins for Primary Prevention: A new meta-analysis raises questions about the benefits of statins when given to people without a clinical history of heart disease. Kausik Ray and colleagues, in a paper in Archives of Internal Medicine, analyzed data from 65,229 subjects in 11 studies. There were 2793 deaths in the studies, 1447 among those taking placebo and 1346 among those taking a statin. The risk ratio of 0.91 did not achieve statistical significance (95% CI, 0.83-1.101). They also observed that baseline LDL levels did not appear to have an impact on mortality. The authors acknowledge that a larger benefit might have been observed with more prolonged followup.
Their findings, write the authors, “further reinforce the notion that lowering lipid levels in a very high-risk primary prevention population is not likely to be harmful, but any mortality benefits are likely to be more modest than previously perceived. As a corollary, however, it may be inferred that in even more lower risk populations (such as subjects at low CVD risk prescribed statins for primary prevention of CVD), the benefits of mortality reduction are likely to be even more modest than observed in this meta-analysis, at least in the short term.”

JUPITER Under Attack: Two papers in Archives of Internal Medicine are highly critical of JUPITER. Michel de Lorgeril and colleagues raise a number of troubling questions concerning the conduct of the trial and conflicts of interest. Among their many criticisms, they say the trial should not have been stopped early because this had the effect of magnifying the benefit of the study drug. They also discuss the paucity of data on cardiovascular mortality and troubling inconsistencies with the ratio of fatal MI to nonfatal MI in the trial. They note that 9 of the 14 authors of JUPITER had financial ties to the sponsor. The authors write that “the results of the trial do not support the use of statin treatment for primary prevention of cardiovascular diseases and raise troubling questions concerning the role of commercial sponsors.”
In the second paper on JUPITER, Sanjay Kaul, Ryan Morrissey, and George Diamond offer their own perspective on the trial. They conclude that it does not provide any justification for routine measurement of hsCRP and agree with de Lorgeril et al that the benefit observed in JUPITER was quite likely magnified because of the early termination of the trial. However, they write that the beneficial effect is “real,” although they caution: “do not expect 50% risk reductions in outcomes.”

In response to the addition in March of a boxed warning on the Plavix (clopidogrel) label, the ACC and the AHA have published a clinical alert intended to provide guidance to clinicians. David Holmes, Jr, the chair of the writing group, said in a press release that “the majority of patients do very well with standard guideline-based clopidogrel, but for the small number of patients who have problems, these are big problems.”
The ACC and the AHA do not offer specific recommendations relating to genetic testing. They note that “many questions remain about how and when to use genetic tests, which tests to use, as well as whether they will be reimbursed.” Holmes also noted that newer agents such as prasugrel “appear to have fewer genetic issues, but have the potential for more bleeding and higher costs.”
“Genetic testing, use of alternate drugs or using alternate dosing strategies with clopidogrel might be reasonable in some patients who have taken the drug as directed, but have experienced an adverse event either because the drug did not work or worked too well and caused bleeding,” said Dr. Holmes.

Most of us agree that the limits put on duty hours for physicians-in-training in 2003 were only a partial success. Now, the ACGME Task Force on Quality Care and Professionalism has posted Proposed Standards, which again attempt to improve the working conditions and learning environment for physicians-in-training plus the safety of patients. The proposed standards don’t alter the maximum hours, but do address other workload issues, patient care transitions, the educational and supervisory needs of physicians-in-training, and the particular requirements of different specialties. A newly published Sounding Board in the New England Journal of Medicine  delineates these and discusses the “moral responsibility” of the medical education community.

Do the proposed standards address the problems that you’ve seen on the hospital floor? What would you have included?

Two new studies looking at rosiglitazone seem likely to increase pressure on the drug prior to the July FDA advisory panel that will be making recommendations about its future.

In the first study, published online in JAMA, the FDA’s David Graham, along with colleagues from Acumen and CMS, analyzed data from 227,571 Medicare beneficiaries taking either rosiglitazone or pioglitazone. The group did not find any difference between the drugs in the rate of MI, but did find a 1.25-fold increased risk of heart failure, a 1.27-fold increased risk of stroke, and a 1.14-fold increased risk of death for rosiglitazone when compared with pioglitazone.

In an accompanying editorial, David Juurlink concluded that “the epilogue of the rosiglitazone story has yet to be written, but a few observations can now be made with confidence. First, there is no direct evidence that rosiglitazone prevents vascular events in patients with diabetes. Second, converging lines of evidence suggest that rosiglitazone is less safe than pioglitazone, whereas no data suggest that the converse might be true. Third, because the evidence to date is not conclusive, differing views have emerged on how to proceed in the face of uncertainty. … Whether rosiglitazone and pioglitazone really do have different cardiovascular safety profiles is an intriguing question but one with a misplaced focus. Accumulating concerns about rosiglitazone make it difficult to advance a cogent argument why, exactly, a patient might want to receive the drug or why a physician would choose to prescribe it when there is an available and quite possibly safer alternative.”

In the second study, published online in Archives of Internal Medicine, Steve Nissen and Kathy Wolski update their famous 2007 meta-analysis that first ignited the rosiglitazone controversy. In the new analysis, the authors analyzed 56 trials involving 35,531patients, 19,509 of whom received rosiglitazone and 16,022 who received other medications, and found a significant 28-39% increased risk of myocardial infarction associated with the use of rosiglitazone. There was no increase in the risk of cardiovascular death, however.

Nissen and Wolski conclude that “because no unique benefits of rosiglitazone use have been identified, administration of this agent solely to lower blood glucose levels is difficult to justify.”

Diabetes Doubles the Risk of Vascular Disease: An international group of investigators analyzed data from nearly 700,000 subjects without previous vascular disease enrolled in 102 prospective studies and found that diabetes appeared to double the risk of coronary disease, stroke, and other vascular deaths. In a presentation at the annual meeting of the American Diabetes Association and in a paper in The Lancet, the researchers estimated that diabetes accounts for 10-12% of all vascular deaths.

Once-Weekly Exenatide Performs Well in Study:  DURATION-3 was also published in The Lancet and presented at the ADA meeting. The trial randomized 456 type-2 diabetics with suboptimal glycemic control to either once-weekly exenatide or insulin glargine for 26 weeks. Exenatide treatment resulted in a greater reduction in HbA1c than insulin glargine, and was also associated with a mean weight loss of 2.6 kg per patient. But in an accompanying comment, Anoop Misra and Shashank Joshi write that “enthusiasm about this drug is similar to that seen in the initial phase of development and use curve of any new drug. Historical data that show novel and prohibitive adverse reactions with approved drugs have taught us to be cautiously optimistic. In particular, it will take time and specifically designed trials for accrual of valid cardiovascular safety data.”

New Agent to Control Glucose: Also presented at the ADA meeting and published in The Lancet were the results of a phase-3, double-blind, parallel-group, placebo-controlled trial of dapagliflozin, a novel agent that is a selective sodium-glucose cotransporter-2 inhibitor, in 546 type-2 diabet with inadequate glycemic control despite taking metformin. Clifford Bailey and colleagues report that the drug improves glycemic control independently of insulin and also causes weight loss. HbA1c decreased in a dose-dependent manner in the dapagliflozin groups, without causing any increase in hypoglycemia. On the worrisome side, genital infections occurred more frequently in the dapagliflozin groups, which may be a result of the increased glucose in the urine.
Vernakalant Gains Recommendation for Approval in Europe: The Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) has recommended marketing approval for vernakalant (Brinavess, Merck, Cardiome), a novel IV anti-arrhythmic agent. The approved indication is for the “rapid conversion of recent onset of atrial fibrillation to sinus rhythm in adults” for non-surgery patients with atrial fibrillation of seven days or less and for post-cardiac surgery patients with atrial fibrillation of three days or less.

30% of Echocardiograms Misread: A Milwaukee hospital found that nearly 30% of diagnostic echocardiograms were misread, according to an article by John Fauber in the Journal-Sentinel. An internal review of 235 echocardiograms performed at Aurora St. Luke’s Medical Center turned up 5 cases in which patients “actually went into the operating room with a faulty diagnosis, although the problem was discovered before surgery was done.” In addition, 18 patients unnecessarily underwent transesophageal echocardiography and 19 patients unnecessarily underwent cardiac catheterization. The hospital is hiring 4 “internationally known experts” to bolster its echo lab and has asked 2 cardiologists to stop reading echoes, Fauber reports. The review was presented at the recent American Society of Echocardiography meeting.

AHA and ACCME Kiss and Make Up: Following a controversial ruling which would have prevented industry employees from making presentations at CME-accredited meetings, including the AHA’s scientific sessions, the AHA and ACCME held “in-depth discussions.” The result is that “there will be no variance from past Scientific Sessions and CME will be available for all presentations within the scientific program,” according to an AHA press release.

Lowering Homocysteine Fails Again to Reduce Events: U.K. investigators randomized 12,064 MI survivors to folic acid and vitamin B12 or placebo. No difference was observed between the two groups in either major vascular events or in the incidence of cancer. In their report in JAMA, the SEARCH (Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine) investigators concluded that “taken together with the previous homocysteine-lowering trials, the results of SEARCH indicate that folic acid supplementation has no significant adverse effects on cancer or other major health outcomes, even if it also produces no beneficial effects on cardiovascular disease.”

European Atherosclerosis Society Will Recommend Lp(a) Screening and Niacin: In a consensus statement not yet published, the EAS will recommend that patients at high to moderate risk of cardiovascular disease should be screened for elevated Lp(a) levels. Details of the statement were presented at the EAS Congress in Hamburg, Germany, and reported on TheHeart.Org by Reed Miller. The statement will also recommend the use of niacin to bring Lp(a) levels below 50 mg/dL. Although the consensus panel “acknowledges that there have not been randomized, controlled trials selectively targeting plasma levels of Lp(a),” consensus panel cochair Dr. John Chapman said: “We consider the level of evidence to be sufficient to warrant the identification of Lp(a) as a causal, independent cardiovascular risk.”

Aggrenox Fails to Beat Aspirin in Japanese Study: Aggrenox, the combination of extended-release dipyridamole and aspirin, is indicated for the reduction of subsequent stroke in patients who have had a TIA or ischemic stroke. But results from JASAP (Japanese Aggrenox Stroke Prevention vs. Aspirin Programme), which compared Aggrenox to aspirin in 1294 patients, found that Aggrenox failed to cause a significant reduction in recurrent stroke; in fact, there was a trend toward more strokes in the Aggrenox group than in the aspirin group (45 vs. 32, P=0.097).

The manufacturer of Aggrenox, Boehringer Ingelheim, has not publicized the results, which were first received on February 16, 2010 and posted on ClinicalTrials.gov in March. News of JASAP was first reported on Pharmalot. Boehringer Ingelheim provided Pharmalot with a statement: “Because neither non-inferiority nor superiority of either treatment could be demonstrated, we cannot draw conclusions from this study about the relative efficacy of either agent.” Aggrenox’s initial approval was based on the results of the second European Stroke Prevention Study.

Livalo Now Available in the U.S.: Livalo (pitavastatin) is now available in the United States, according to the drug’s manufacturer, Eli Lilly. However, as noted on Pharmalot, Wall Street analysts question whether the drug will find a large commercial market.

New York Times Spotlights ICDs with Benefits: A feature article in the New York Times by Gina Kolata provides a mostly sunny view of ICDs with remote monitoring features. Although the article quotes Lynne Warner Stevenson as saying that “information overload is a very serious problem,” most of the comments in the story, including others by Stevenson, Leslie Saxon, and Richard Page, take a positive view of the devices. Page calls the new technology “potentially transformative.”

Coffee and Tea: Go Ahead and Have a Cup: Moderate consumption of both coffee and tea was associated with a reduction in coronary heart disease (CHD) in a Dutch study that followed 37,514 people for 13 years. The paper appears in Arteriosclerosis, Thrombosis, and Vascular Biology. Compared to people who drank less than 1 cup of tea per day, people who drank more than 6 cups of tea per day had a 36% lower risk of developing CHD, and people who drank 3-6 cups per day had a 45% lower risk. (Most of the tea consumed in the Netherlands is black tea, according to the authors.) Compared to people who drank less than 2 cups or more than 4 cups of coffee, people who drank 2-4 cups of coffee per day had a 20% reduction in the risk of CHD. The incidence of stroke did not appear to be affected by coffee or tea consumption. The authors concluded that their study strengthens “the evidence on the lower risk of CHD associated with coffee and tea consumption,” although they acknowledge that neither was seen to have an effect on either stroke or all-cause mortality.