Long-term Safety of Statins
Abstract & Commentary
By Andrew J. Boyle, MBBS, PhD, Assistant Professor of Medicine, Interventional Cardiology, University of California, San Francisco, CA.
This article originally appeared in the February issue of Clinical Cardiology Alert. At that time it was peer reviewed by Ethan Weiss, MD, Associate Professor of Medicine, Division of Cardiology, University of California, San Francisco, CA. Dr. Weiss is an advisory board member for Bionovo. Dr. Boyle reports no financial relationships relevant to this field of study.
Synopsis: There do not appear to be any safety issues with the long-term use of statins.
Source: Heart Protection Study Collaborative Group. Effects on 11-year mortality and morbidity of lowering LDL cholesterol with simvastatin for about 5 years in 20,536 high-risk individuals: A randomised controlled trial. Lancet 2011;378:2013-2020.
Statins reduce the incidence of adverse cardiovas-cular events. Some observational non-randomized studies have suggested that low cholesterol levels and/or statins may increase the risk of cancer or other non-cardiovascular diseases. To determine the long-term effects of simvastatin on cancer and death, the investigators from the Heart Protection Study reviewed the outcomes of their trial participants over an extended follow-up time after the original 5-year clinical trial had ended.
You may remember that the Heart Protection Study (HPS) was a trial of 20,536 patients at high risk of vascular events who were randomized to receive simvastatin 40 mg daily vs placebo. The study ran over 5 years and showed a reduction in LDL cholesterol of 1 mmol/L (39 mg/dL), which was associated with a 23% reduction in major vascular events. This paper extends the follow-up period to 11 years. Over the original 5-year study period, 85% of the simvastatin-allocated patients, and 17% of the placebo-allocated patients, were taking statins. Over the extended follow-up period of this study, approximately 74% of patients in each group were taking statins. Correspondingly, LDL cholesterol was lower in the simvastatin-allocated group after the original 5-year study period, but was the same between groups after the extended follow-up period. Thus, the long-term follow-up represents a 5-year period of randomized treatment (statin vs placebo), followed by 6 years of high rates of statin treatment in both groups. The particular focus of this study was on cancer and mortality, so the authors not only followed up the patients but also cross-referenced with the national cancer registry and with the national death index in the United Kingdom.
Patients allocated to simvastatin had a significant reduction in vascular events during the 5-year trial period. During this extended follow-up period from years 5-11, there were no differences between groups in terms of vascular events. This was to be expected because the rates of statin therapy and the lipid levels were the same in both groups. During the extended follow-up period, there were no differences between groups in terms of any of the components of the primary endpoint: stroke, major coronary events, and revascularization rate.
There was a significant reduction in mortality in the statin-allocated group during the initial 5-year study period. Mortality from vascular and non-vascular causes remained the same in each group during the extended trial follow-up period. The incidence of cancer was the same in each group, as was the body region where the cancer occurred. There were no differences in mortality between treatment groups in those with lower baseline lipid levels or in the elderly.
Commentary
This is more good news for patients in need of statin therapy. The reports that suggested a link between statin therapy, or low LDL, and cancer or increased non-cardiovascular mortality appear to be unfounded. They were based on epidemiological observational studies, but analyses of randomized placebo-controlled trials like this one refute this hypothesis quite resoundingly. This study is congruous with the growing body of literature on long-term statin follow-up. The WOSCOPS study of pravastatin versus placebo was initially a 5-year study, and the extended follow-up of an additional 10-years showed continued reduction in cardiovascular mortality, with no increase in cancer or in non-cardiac mortality.1 Similarly, the extended follow-up of the ASCOT-LLA study of atorvastatin 10 mg vs placebo (initial trial stopped early after 3 years for highly positive effect, extended follow-up to 11 years) showed continued reduction in mortality with no excess cancer and a decrease in non-cardiac mortality.2
In all these studies, a period of statin use for several years conferred a mortality reduction that continued for many more years. This continued legacy of treatment benefit has been consistent throughout these studies and appears to be a class effect of the statins. This confirms that statin therapy should be given early to those in whom it is warranted. There do not appear to be any long-term safety issues, at least out to 11 years. In particular, there does not seem to be an increased risk in those with low baseline LDL or in the elderly.
This long-term follow-up following an initial period of treatment and then open-label treatment is not the most robust clinical trial design. However, it is the best data we are ever likely to have. It is not ethical to have a long-term statin vs placebo trial in those who are at risk for vascular events, as the benefits of statins are clear and randomizing patients to placebo would be unethical. I am reassured by this paper, and other long-term follow-up papers, that statins are safe in the long-term. Hopefully, this paper puts the issue to rest.
References
1. Ford I, et al. N Engl J Med 2007;357:1477-1486.
2. Sever PS, et al. Eur Heart J 2011;32:2525-2532.
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