Do Guidelines Underestimate the Harms of Statins?

Patrice Wendling

December 05, 2018

A new modeling study suggests that 10-year risk thresholds used in current guidelines to prescribe statins for primary prevention of heart disease are likely substantially too low.

"Instead of 7.5% to 10% 10-year risks, we found at least 14%, and depending on the age, even much higher risk thresholds where the benefits of statins exceed the harms," senior author Milo Puhan, MD, PhD, University of Zurich, told | Medscape Cardiology.

Guidelines emphasize the benefits of statins for cardiovascular disease (CVD), but fail to take into account the full array of potential harms, the authors argue in the study, published online in the Annals of Internal Medicine December 3.

"The second major finding is that one size doesn't fit all," Puhan said. "So the benefit/harm balance depends quite a bit on age and gender, but also the type of statin. The recommendations are not granulated to take these factors into account."

Using an approach originally developed by the National Cancer Institute to look at tamoxifen for breast cancer prevention, the investigators show that statins provide a net benefit starting at a CVD risk of 14% for men aged 40 to 44 years. The risk threshold, however, increased to 21% for aged 70 to 75.

For women, the risk thresholds were higher at 17% and 22%, respectively. Individuals at high risk for CVD (>21%) were likely to benefit from statins, regardless of sex or age.

Among four commonly used statins, atorvastatin had the most favorable benefit–harm balance, followed by rosuvastatin, especially for younger adults with low or medium CVD risk. For example, among men aged 45 to 49 years, net benefits were seen at a 10-year CVD risk of 15% for atorvastatin but at 18%, 19%, and 21% for rosuvastatin, pravastatin, and simvastatin, respectively.

"The primary concern with this paper is that the harms used by the authors in their benefits-versus-harms analysis is based on work that has not yet been published," Kirsten Bibbins-Domingo, PhD, MD, MAS, Lee Goldman, MD Endowed Chair in Medicine, professor and chair of the Department of Epidemiology and Biostatistics, Vice Dean for Population Health and Health Equity, UCSF School of Medicine, University of California, San Francisco, said in an email to | Medscape Cardiology.

"This unpublished work includes a variety of harms — unfortunately most of these have not been substantiated in other meta-analyses," she said. "Since this is the primary input that leads to the authors' findings, this work would be critical to review and assess."

Nevertheless, Bibbins-Domingo said the authors' approach of understanding the benefit–harms calculus by age and competing risks is the right one.

"All of the guidelines have continued to move toward an approach that seeks to take the benefits–harms observed across the entire adult population and tailor it to a more specific benefits–harms calculation that might apply to the individual patients," she said. "This paper suggests that such an approach does make a difference in whether statin medications can be recommended."

In 2016, the USPSTF gave a grade B recommendation for primary-prevention statins in adults aged 40 to 75 years who have at least one CVD risk factor and a 10-year risk of 10% or higher. A grade C recommendation suggests statins also can be selectively offered to patients in the same age group with a 10-year risk of 7.5% to 10% after discussion with the patient.

The newly released American College of Cardiology/American Heart Association cholesterol guidelines use a risk threshold of 7.5%, but also emphasize the use of coronary artery calcium testing and patient preference.

Puhan acknowledged that it is difficult for guideline creators and others to bring together all of the evidence on treatment effects, as harm outcomes from randomized trials might be incomplete because of short follow-up and observational data are often inherently biased.

Their approach combined data from both sources for the benefits of statins on fatal and nonfatal CVD events and for the harms of myopathy, hepatic and renal dysfunction, cataracts, hemorrhagic stroke, type 2 diabetes, any cancer, nausea or headache, and treatment discontinuation.

"What we did was kind of a combination but we weighted it according to the information in the data," Puhan said. "The estimates we used are much closer to the RCTs than to the observational studies."

Asked to comment on the study, Michael Pencina, PhD, professor of biostatistics and informatics at Duke Clinical Research Institute, Durham, North Carolina, said that "on the positive side, a study like this finally attempting to formally quantify the risks of statins is long overdue."

Digging deeper, however, Pencina had reservations about the methodology, specifically the use of only one benefit but all of the possible harms, many of which failed to reach statistical significance. This, he said, "creates an overly negative perspective on the impact of statins."

That said, Pencina noted that evidence for both harms and benefits of statins beyond CVD is hard to come by, highlighting a recent review of meta-analyses in the Annals that failed to find convincing evidence of an association between statins and more than 250 unique non-CVD outcomes. Suggestive associations with statin use were found only for incident diabetes and myopathy.

Puhan countered that it's important to be inclusive of potential harms because, in general, these harms tend to be underestimated. They included cancer, for example, because this is a concern for some patients.

"Cancer has a risk ratio of 1.01, so this doesn't have an effect on the overall benefit–harm balance," he said. But, "it's better than eliminating outcomes beforehand, because then no one knows what the impact was. So I think it's good to be explicit about that."

Pencina also pointed out that the population preferences used in the study are based on a previous Swiss and Ethiopian survey conducted by the authors. Although these patients might be less willing, for example, to deal with myalgia to avoid CVD, the same might not be true for Americans.

"What we learned is that it's worthwhile to try to quantify the benefit versus the risks, but I do have a hard time reading this study and thinking, 'Oh, the guidelines have it wrong; the risk at which statins should be given is too low, it should be higher'," Pencina said. "So in that sense, I see this study as discussion-generating. We need to sit down and start thinking about quantifying these things in a more rigorous way than we have done today."

Sensitivity analyses performed for the United States and United Kingdom showed similar results, noted Puhan, who also agrees that explicit methods are needed to determine risks, which will depend to some extent on the individual country. He noted that there are more than 300 prediction models for CVD around the world, but that they did not make any recommendation for a particular model.

"The bottom line is that we shouldn't be that naïve to think that one result applies to the entire world," he said. "So each country should probably consider what the risks are, determine risk thresholds accordingly, and then make recommendations accordingly."

In an accompanying editorial, Ilana Richman, MD, and Joseph S. Ross, MD, MHS, both from Yale University School of Medicine, New Haven, Connecticut, write that the methodology used in the analysis is "much more elaborate" than the calculus used in either the USPSTF or ACC/AHA guidelines, and importantly, incorporates the competing risk for death.

"The effect of this approach was immediately apparent: within every CVD risk stratum, as age increased, the probability of net benefit from statin therapy decreased, reflecting both competing mortality and age-related risk for adverse events," they write.

"The results paint a nuanced — if less optimistic — picture of the net benefits of statins, particularly in older adults who may not live long enough to benefit."

Whether the inclusion of such a wide range of adverse events is justified is sure to be debated by both sides of the statin debate. The editorialists conclude, however, that patient preferences must play a role in statin initiation and that "the onus is on physicians to fairly summarize the evidence and guide patients through the decision-making process."

Bibbins-Domingo reiterated this point. "It's important to remember that we are talking about statins for primary prevention — a pill patients take daily when they don't have signs or symptoms of disease to avoid something bad happening in the future. For any given patient, it's important that we are able to give them our best understanding of the likelihood that they will benefit and the likelihood that they will experience some harms."

"It's also important to listen to patients to understand how they value these potential benefits and harms, how risk averse they are in each of these domains, and even whether taking a daily pill for prevention itself poses a burden," she said.

The study was funded by grants from the Swiss Government Excellence Scholarship Office and the North-South Cooperation at the University of Zurich , and by the Béatrice Ederer-Weber Foundation. The authors report no relevant financial conflicts of interest. Pencina reports grants to his institution from Sanofi/Regeneron and Amgen and consulting fees from Merck and Boehringer Ingelheim.

Ann Intern Med. Published online December 3, 2018. Abstract, Editorial

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