JAMA Weighs In on CVD Guidance, Statins in Primary Prevention

Shelley Wood

November 25, 2013

CHICAGO, IL – Another week and another flurry of insights and opinions on the new CVD prevention guidelines, this time in the journal that once cornered the market on cholesterol guidance.

Back in 2001, when the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults released their third report (ATP III), it was the Journal of the American Medical Association (JAMA) that published the report. Ditto the previous edition, ATP II, in 1993.

This time around, in the wake of the partnership struck between the American Heart Association (AHA), American College of Cardiology (ACC), and the original guidelines developer, the National Heart, Lung, and Blood Institute (NHLBI), the new guidelines and accompanying risk calculator were simultaneously published in the flagship journals of the two cardiology organizations.

Seemingly keen to get in on a piece of the action, JAMA has today published online a Clinical Evidence Synopsis[1], accompanied by a commentary by Dr Jennifer Robinson, vice chair for the new cholesterol guidelines and a coauthor of the guidelines for assessing CV risk[2]. Both the clinical evidence synopsis and Robinson's commentary zero in on what has emerged as the most controversial aspect of the new four-part CVD guideline packet: the use of statins in primary prevention. Specifically, experts have raised concerns that too many patients will be swept into drug therapy by the new CV risk calculator.

The clinical evidence synopsis, by Dr Fiona Taylor (London School of Hygiene and Tropical Medicine) and colleagues, sums up their 2013 Cochrane meta-analysis that updated a 2011 meta-analysis reviewing the evidence on statin use in primary prevention[3]. Taylor et al's analysis included 18 trials conducted between 1994 and 2008 and published between 2011 and 2013, enrolling almost 57 000 patients. Compared with placebo, statins reduced LDL by 39 mg/dL, all-cause mortality by 14%, fatal and nonfatal CVD by 22%, coronary heart disease by 27%, stroke by 22%, and coronary revascularization by 38%. Risk of cancer, myalgia, rhabdomyolysis, liver-enzyme elevations, renal dysfunction, or arthritis were no different between the patients taking statins and those on placebo, nor was drug discontinuation. An increased risk of diabetes with statins was seen "in one of the two trials reporting this outcome."

Dr Rita Redberg (University of California, San Francisco), who recently coauthored a New York Times Op-Ed expressing concern that the new cholesterol guidelines would lead to statin overtreatment, commented on the JAMA articles for heartwire .

Redberg pointed out that this latest Cochrane analysis comes to starkly different conclusions than the 2011 Cochrane review, despite having many of the same authors. That may be in part due to the "elimination of major trials," something also at odds with a 2009 meta-analysis by Ray et al that found no benefit of statins in reducing all-cause mortality.

In her commentary, Robinson notes that the 2013 Cochrane meta-analysis was one of the pieces of evidence reviewed by the ACC/AHA guideline writers, along with other "high-quality randomized trials and systematic reviews and meta-analyses of randomized trials." These included the 2010 and 2012 Cholesterol Treatment Trialists meta-analyses, as well as the AFCAPS/TexCAPS, MEGA , and JUPITER trials. It was from these studies, she notes, that the cut points of a 5% and 7.5% or greater 10-year risk of atherosclerotic cardiovascular disease were derived, and not plucked from thin air, as some critics have alleged.

The recent studies, writes Robinson, "provide evidence that largely refutes the major criticisms against statins used for primary prevention. Statins are well tolerated in properly selected individuals. Statins reduce total mortality as well as atherosclerotic cardiovascular disease events in lower-risk individuals. Concerns about cost are no longer relevant with five of the currently available statins available as generic drugs. . . . The accumulated evidence should convince those with a philosophical aversion to statin therapy for primary prevention to reconsider their stance."

To heartwire , Robinson pointed out that much of the criticism of the new guidelines and risk calculator has centered on the idea that millions more Americans will be encouraged to take statins. In fact, she points out, "in 2005, 35 million Americans were already on a statin, so if you apply our CV risk calculator, you'd see 32 million on a statin. There are [still] a lot of people being treated, but [with these new guidelines] you are not going to see more people being treated, it may just not be the same people."

She also addressed the controversial Ridker and Cook analysis, which came out with much fanfare during last week's AHA meeting, as well as its call to treat only subjects who are similar to those enrolled in the major clinical trials rather than use an untested global risk-prediction score.

"We tried that," Robinson said, "and what you get when you apply clinical-trial inclusion criteria is that you fail to identify about 40% of high-risk people [who would benefit from statin therapy] and you overtreat about 35% of people who have less than a 5% 10-year risk of CVD."

Criticisms Don't Hold Up: Robinson

The four major criticisms of the guidelines as they pertain to statin therapy are concerns about adverse effects, lack of a total mortality benefit, cost, and a "philosophical aversion to drug therapy," Robinson writes.

"None of these really stand up under the light of evidence anymore," she told heartwire . "It's fine to have a philosophical aversion to statins, but when all the evidence flies in the face of that, it seems like that's an attitude that should fall by the wayside."

Asked if she's concerned that all the focus on statins in the cholesterol guidelines has eclipsed important information in the lifestyle and obesity guidelines, released the same day, Robinson maintained that statins deserve the attention they've been basking in over the last few weeks.

"Only 10% of Americans have optimal CV health: that's why we need statins. We've been telling people to diet and exercise for at least 50 years; this is not a new thing. I think the problem with this approach is that if we wait until people do what we tell them to do for diet and exercise and smoking cessation, we are going to be withholding a lifesaving therapy from exactly the people who will benefit. Of course, keep telling people to diet, exercise, and quit smoking, but when people can't or won't do that, we can't withhold therapy."

Redberg for her part, remains adamant that the focus of primary-prevention efforts should be on promoting healthy lifestyle, not prescribing drugs. "Healthy-lifestyle measures such as healthy diet, regular physical activity, and smoking cessation . . . have been shown to reduce heart disease and cancer and are associated with living longer as well as better. The multiple adverse effects—fatigue, weakness, muscle problems, memory loss, and diabetes risk—and concern for underreporting of adverse events in current trials noted in the current and previous Cochrane meta-analysis (all industry-sponsored [based on] data that are not publicly available) all mean that the chance of benefit from statins in primary prevention is still dwarfed by the chance of harms. "

Robinson, however, pointed to the fact that one of the most vocal critics of specific high-profile drugs and their expanded use was also invited by JAMA to respond to the new cholesterol guidance. The ViewPoint by Dr Bruce Psaty with Dr Noel S Weiss (University of Washington, Seattle) was published online in JAMA last week on a day many cardiologists were traveling home from the AHA meeting[4].

In it, notes Robinson, Psaty was "highly supportive" of the new guidelines. He writes: "Overall, the revised 2013 ACC/AHA guidelines represent a strong fit with the clinical-trial evidence: treatment thresholds resemble eligibility criteria of the trials; statins are clearly identified as the first-line drug therapy; and treatment targets are abandoned."

"We were pretty pleased," Robinson told heartwire .

That's not enough to reassure Redberg, who insists all research into statins in primary prevention should be reviewed "by groups that do not have conflicts of interest and that make their data freely available to the research community and clinicians for independent analysis."

Taylor had no disclosures; disclosures for the coauthors are listed in the paper. Robinson disclosed receiving grants to her institution from Amarin, Amgen, AstraZeneca, Daichi Sankyo, Eli Lilly, GlaxoSmithKline, Pfizer, Regeneron, Roche, Sanofi, and Takeda; and consulting for Amgen, Pfizer, and Sanofi. Psaty disclosed serving on the data and safety monitoring board for a clinical trial of a device funded by Zoll LifeCor; working on a manuscript describing the development of the risk assessment tool; serving as a reviewer of a draft of the Adult Treatment Panel IV guidelines for the NHLBI; and is a member of the NHLBI advisory council. Weiss reported no disclosures.


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