New USPSTF Guidelines Recommend Statins in ‘Appropriately Selected’ Primary-Prevention Patients
The USPSTF document is bound to spark debate over when and in whom statins should be started, and at what strength.
The United States Preventive Services Task Force (USPSTF) has issued new guidelines on the use of statins for the primary prevention of cardiovascular disease, recommending a similar treatment approach to existing US clinical guidelines, albeit with some slight differences including a slightly higher threshold for initiating statin therapy. And, as with guidance that has come before, the USPSTF document is already sparking debate over when and in whom statins should be started, and at what strength.
“We review our guidelines periodically, and we previously had guidelines for the screening of high cholesterol,” task force member Douglas Owens, MD (Stanford University, CA), told TCTMD. “When it came up for periodic review, our thinking was that most people are getting their cholesterol screened as part of their care—that’s not really the most important question now. Now the question has really changed to who should take a statin.”
The thrust of the new USPSTF statin primary-prevention recommendations, said Owens, is that in “appropriately selected patients, statins can help prevent heart attacks, stroke, and even death.”
The USPSTF recommends low-to-moderate-dose statin therapy in adults 40 to 75 years old without a history of cardiovascular disease who have at least one cardiovascular risk factor and a 10-year event risk of 10% of greater (B recommendation). In addition, the task force recommends physicians “selectively offer” a low-to-moderate-dose statin in adults with at least one cardiovascular risk factor and a calculated 10-year event risk of 7.5% to 10% (C recommendation). In both recommendations, the cardiovascular risk factors are defined as the presence of dyslipidemia, diabetes, hypertension, or smoking.
Like clinical guidelines from other organizations, the USPSTF document concludes the evidence is insufficient to recommend the use of statins in adults 76 years of age and older.
Rita Redberg, MD (University of California, San Francisco), who wrote an editorial accompanying the USPSTF recommendations along with Mitchell Katz, MD (Department of Health Services, Los Angeles, CA), told TCTMD she was “disappointed” with the new report. For Redberg and Katz, the data supporting statins in primary prevention do not warrant a C recommendation, let alone a B recommendation.
“Overall, I still think that most people taking a statin will have absolutely no benefit and much more chance of harm,” Redberg told TCTMD. “If you have a very small chance of benefit and a greater chance of harm, but there are other things you can do that are more beneficial that don’t cause harm, I think that would be the wiser choice.”
The new recommendations, as well as a series of editorials and viewpoints, were published today in the Journal of the American Medical Association as part of a themed issue focusing on statins and cardiovascular health.
Differences and Similarities With Other Guidelines
The USPSTF recommendations are based on an evidence review of 19 clinical trials with 71,344 participants. In these primary-prevention studies, which included trials such as AFCAPS/TexCAPS, WOSCOPS, ASCOT-LLA, CARDS, JUPITER, MEGA, and HOPE-3, among others, statin therapy was associated with relative reductions of 14% in the risk of all-cause mortality, 31% in the risk of cardiovascular mortality, 36% in the risk of MI, and 29% in the risk of stroke.
The absolute risk reductions were small, ranging from a 0.40% reduction in all-cause mortality among statin-treated patients to a 0.81% reduction in the risk of MI.
Overall, the benefits were observed in all demographic and clinical subgroups, with higher absolute benefits seen in patients at higher baseline risk. In the evidence review, led by Roger Chou, MD (Oregon Health and Science University, Portland), statins were not associated with an increased risk of serious adverse events, myalgias, or liver-associated side effects. In addition, the pooled analysis did not show evidence of an increased risk of diabetes with statin therapy, although the reviewers say there was heterogeneity across the trials. One study, in fact, showed statin therapy was associated with as much as a 25% increased risk of new-onset diabetes mellitus.
In 2013, the American College of Cardiology (ACC) and American Heart Association (AHA) published guidelines for the treatment of cholesterol, including recommendations for individuals without cardiovascular disease. For primary prevention, the ACC/AHA recommended a moderate-to-high-dose statin in individuals with a 10-year risk of clinical events greater than 7.5% and an LDL cholesterol level between 70 and 189 mg/dL.
To TCTMD, Owens said the USPSTF and ACC/AHA recommendations are “quite similar in many respects.” He said that individuals with a 10-year event rate of 7.5% to 10% have a lower baseline risk of cardiovascular disease and as result the USPSTF encourages shared decision-making based on a discussion between the clinician and patient.
Owens said the USPSTF recommends low-to-moderate-dose statin therapy, because this was the dose used in the majority of randomized clinical trials in primary prevention. “We recognize that there are some situations where a higher-intensity statin might be appropriate,” he said. “Again, the dose of statins should be based on a conversation between the patient and their clinician.”
Like the ACC/AHA cholesterol guidelines, the USPSTF report makes no recommendations on treating to a specific LDL cholesterol target. The task force took a similar approach as the ACC/AHA in their rationale for not recommending a “treat to target” approach as there is little evidence supporting the goals, said Owens. Most of the randomized clinical trials used a fixed-dose statin instead of titrating to an LDL cholesterol target, he added.
When calculating the 10-year cardiovascular risk score, the USPSTF urges clinicians to use the global risk assessment tool developed by the ACC/AHA. The 2013 pooled cohort equations—which have been controversial in the past—take into account age, sex, race, cholesterol levels, systolic blood pressure, antihypertension treatment, presence of diabetes, and smoking. The outcomes of interest in the ACC/AHA risk calculator include MI, death from coronary heart disease, ischemic stroke, and stroke-related death.
“There have been studies that suggest the ACC/AHA calculator may overestimate risk in some groups,” said Owens. “We were aware of that, and that’s why we feel the estimation of risk with the calculator should be the beginning of a conversation with the patient about the benefits and potential harms and whether or not a statin would make sense for them.”
Lifestyle First, Not Statins
In their editorial, Redberg and Katz emphasize that the absolute reduction in mortality and cardiovascular mortality with statin therapy is very small. Despite the small absolute benefit, the editorialists suggest this number might even be inflated, noting that the evidence review included some patients taking statins for secondary prevention, a group with a higher baseline risk of cardiac events who would be more likely to benefit from statin therapy. Inclusion of such individuals “inflates the benefit attributed to a primary prevention population,” according to the editorialists.
They note that even if the estimation of benefit is accurate in the USPSTF evidence review, 244 patients would need to take a statin for 5 years to prevent one death. Redberg and Katz point out that for every 100 individuals who take a statin for 5 years, only two will avoid an MI and there will be no survival benefit for any of those 100 individuals. Yet, five to 20 of the 100 statin users will experience muscle aches, weakness, fatigue, cognitive dysfunction, and an increased risk of diabetes.
“I think people have a very inflated idea of what the benefits are with statins,” she told TCTMD. “I’m sure that everyone taking a statin assumes they are the one who is going to avoid a heart attack. I don’t think they realize their chances are very slim in terms of being that person.”
As part of the JAMA issue, Paul Thompson, MD (Hartford Hospital, CT), published an article on “what to believe and do about statin-related adverse effects.” He notes there is considerable debate over whether or not statins produce mild muscle-related symptoms, such as myalgias. While reviews of the randomized clinical trial data suggest myalgias are rare, even nonexistent, most doctors “are convinced these symptoms exist and are caused by statins,” he says. In some observational studies, it has been estimated that the incidence of statin myalgia is as high as 10%.
“Many patients can ultimately tolerate these drugs, but doing so requires acknowledging the possible relationship of statins with primarily muscle symptoms and developing with the patient a collaborative treatment plan,” according to Thompson.
Instead of statin therapy, Redberg argues that it is time to refocus on lifestyle, and she said that even small changes can go a long way in altering a patient’s risk. In clinical practice, if she encounters a patient without cardiovascular disease but with one of the four cardiovascular risk factors and 10-year risk greater than 10%, her first step is to encourage a Mediterranean-style diet, increase physical activity, have them quit smoking, and to treat their high blood pressure, if necessary. “I don’t recommend statins,” said Redberg.
Such individuals are very responsive to the lifestyle recommendations, mainly because patients in general don’t like to take pills and particularly don’t like to take medication that makes them feel poorly, said Redberg.
Now Five Clinical Guidelines
In a second editorial, Philip Greenland, MD, and Robert Bonow, MD (Northwestern University Feinberg School of Medicine, Chicago, IL), point out that the USPSTF recommendations are yet another document on how to use statins in primary prevention. Other recommendations come not only from the ACC/AHA, but also the Canadian Cardiovascular Society, the UK National Institute for Health and Care Excellence (NICE), and the European Society of Cardiology.
While there is “considerable agreement” among the five guidelines, there are aspects where the organizations differ, they say. Specifically, the organizations have different approaches on whether or not to treat to a specific LDL cholesterol target—the Canadian and European guidelines recommend a treat-to-target approach—and each have their own treatment initiation thresholds. Overall, the ACC/AHA document has the lowest threshold for starting treatment, note Greenland and Bonow.
Speaking with TCTMD, Neil Stone, MD (Northwestern University Feinberg School of Medicine), who chaired the 2013 ACC/AHA expert panel that drafted the cholesterol guidelines, said the two documents—the ACC/AHA and USPSTF recommendations—are consistent, mainly because both drew from the same evidence.
While the ACC and AHA use a lower threshold for initiating statins than the USPSTF, Stone said, the decision to start statins in a patient with a 10-year risk of cardiovascular disease exceeding 7.5% is not automatic. Instead, the ACC/AHA guidelines advise a discussion about the risks and benefits of treatment. Like the ACC/AHA, the USPSTF recommends shared decision-making between physicians and patients.
“The fact that both guidelines agree on shared decision-making is important,” said Stone. “One of several good reasons for shared decision making is because, if a patient jogs into your office with optimal risk factors and his or her parents died at 102 years old, that person doesn’t get a statin under the ACC/AHA or USPSTF guidelines. This is the idea about the discussion. The benefit from the statin is not going to be very high in this low-risk primary-prevention group, and the patient needs to decide if that benefit is enough for me.”
Regarding statin intensity, Stone said that in primary prevention, the ACC/AHA guidelines recommend starting with a moderate-intensity statin. However, in one trial, JUPITER, there was a significant benefit in treating patients with rosuvastatin 20 mg, a high-intensity statin. For that reason, the ACC/AHA recommendations leave the option to treat primary-prevention patients with a high-intensity statin following the physician-patient discussion. Individuals with significantly elevated LDL cholesterol levels and a family history of cardiovascular disease might be good candidates for higher-intensity statin therapy, said Stone.
In addition to the USPSTF recommendations and editorials, Jerry Gurwitz, MD (University of Massachusetts Medical School, Worcester), Alan Go, MD (University of California, San Francisco), and Stephen Fortmann, MD (Oregon Health and Science University, Portland), published a viewpoint on statins for primary prevention in older adults, noting there is an absence of clear benefit in those older than 75 years and uncertainty about the risks.
Robert Harrington, MD, and Fatima Rodriguez, MD (Stanford University, CA), meanwhile, published a forward-looking viewpoint on the future of LDL-cholesterol lowering, including the use of PCSK9 inhibitors. And finally, Ann Marie Navar, MD, and Eric Peterson, MD (Duke Clinical Research Institute, Durham, NC), highlight two case vignettes and delve into the questions that can arise in the “gray areas” when trying to treat patients who might not fit into existing clinical guidelines.
US Preventive Services Task Force. Statin use for the primary prevention of cardiovascular disease in adults: US Preventive Services Task Force recommendation statement. JAMA. 2016;1997-2007.
Chou R, Blazina I, Daeges M, Jeanne TL. Statins for the prevention of cardiovascular disease in adults evidence report and systematic review for the US Preventive Services Task Force. JAMA. 2016;316:2008-2024.
Redberg RF, Katz MH. Statins for primary prevention: the debate is intense, but the data are weak. JAMA. 2016;316:1979-1981.
Thompson PD. What to believe and do about statin-associated adverse effects. JAMA. 2016;316:1969-1970.
Greenland P, Bonow RO. Interpretation and use of another statin guideline. JAMA. 2016;316:1977-1979.
Gurwitz JH, Go AS, Fortmann SP. Statins for primary prevention in older adults: uncertainty and need for more evidence. JAMA. 2016;316:1971-1972.
Rodriguez F, Harrington RA. Cholesterol, cardiovascular risk, statins, PCSK9 inhibitors, and the future of LDL-C lowering. JAMA. 2016;316:1967-1968.
Navar AM, Peterson ED. Evolving approaches for statins in primary prevention: progress but questions remain. JAM.A 2016;316:1981-1983.
- Disclosures of the USPSTF members are available in the paper (Owens reported no conflicts of interest).
- Chou and colleagues report no conflicts of interest.
- Thompson reports that he has spoken for Regeneron, Sanofi, Amgen, and Amarin; consulted for Amgen, Regeneron, Merck, Esperion, and Sanofi; received research support from Genomas, Roche, Sanofi, Regeneron, Esperion, Amarin, and Pfizer; and owns stock in Abbvie, Abbott Labs, CVS, General Electric, Johnson & Johnson, Medtronic, and Sarepta.
- Greenland and Bonow report no conflicts of interest.
- Gurwitz reports receiving research funding from the National Institute on Aging and the Agency for Healthcare Research and Quality.
- Go reports receiving research funding through his institution from the National Institute on Aging, the National Heart, Lung, and Blood Institute, the National Institute of Diabetes and Digestive and Kidney Diseases, and Sanofi.
- Fortmann reports receiving support through his institution from the National Heart, Lung, and Blood Institute, the National Institute of Diabetes and Digestive and Kidney Diseases, the Agency for Healthcare Research and Quality, and the Health Resources and Services Administration, and previously from AstraZeneca for an observational study of diabetes mellitus.
- Navar reports receiving grant funding from Sanofi and Regeneron and consulting fees from Sanofi.
- Peterson reports receiving grant funding from American College of Cardiology, American Heart Association, and Janssen; and consulting fees from Bayer, Boehringer Ingelheim, Merck, Valeant, Sanofi, AstraZeneca, Janssen, Regeneron, and Genentech.
- Harrington reports receiving grants from CSL as steering committee co-chair and from Sanofi-Aventis as an executive committee member; receiving grants and personal fees from Merck as steering committee chair and for regulatory consulting and from The Medicine Company as steering committee co-chair and for regulatory consulting; receiving personal fees from Amgen for clinical development consulting; receiving research grants to his institution from AstraZeneca, GlaxoSmithKline, Janssen, Novartis, and Portola; serving as an advisor or consultant to Adverse Events, Element Science, Gilead, MyoKardia, Vida Health, and WebMD; and serving on the board of directors for the American Heart Association, Stanford Healthcare, Scanadu, and SignalPath.