For primary prevention, statins provide net benefits at higher than recommended 10-year risks
Finding the Balance Between Benefits and Harms When Using Statins for Primary Prevention of Cardiovascular Disease: A Modeling Study
Introduction and methods
Statins are recommended for primary prevention of CVD if 10-year risk exceeds 7.5-10.0%, often in addition to other criteria such as high cholesterol or presence of at least one specific risk factor [1-5]. None of the current guidelines, however, used a systematic assessment of the benefit-harm balance of statins , and it remains unclear whether the currently recommended thresholds for initiation of statin therapy are justified.
This quantitative modeling study assessed the balance of benefits and harms of four statins (atorvastatin, simvastatin, pravastatin, and rosuvastatin) for primary prevention of CVD and determined age- and sex-specific 10-year risk thresholds at which the net benefits of statins outweigh the net harms in individuals aged 40-75 years without a history of CVD events.
Benefit and harm outcomes were selected from systematic reviews [7,8] and quantified in a preference-eliciting survey . 10-Year risk was estimated by extrapolating the data of the RCT follow-up of less than five years, with the assumption of smaller CVD risk accumulation and that the effects of statins remains similar in low- to moderate risk persons in this period.
Beneﬁt outcomes for statin use were defined as fatal and non-fatal CVD events. Harm outcomes were defined as myopathy, hepatic and renal dysfunction, cataracts, hemorrhagic stroke, T2DM, any cancer, nausea or headache, and treatment discontinuation due to adverse effects.
Benefit and harm outcome events
- Without statin use, the expected number of events increased for T2DM, any cancer, and hemorrhagic stroke with age, whereas in statin users these events were increased due to the effect of statins in addition to age.
- In both groups, the expected increase in events accounted for the competing risk for non-CV death, the effect of which on attenuation of the outcome risks was smaller than the effect of age on risk for T2DM, any cancer, and hemorrhagic stroke.
- Because the expected number of myopathies, cataracts, or renal and hepatic dysfunction per age-category was based on average estimates, because age-specific estimates were not available, it did not increase with age; instead, risks decreased slightly with age due to the competing risk.
Benefit-harm balance and risk threshold
- Net beneﬁts with statins were seen at a CVD risk of 14% for men aged 40-44 years, and the threshold increased to 21% for those aged 70-75 years. Similar results were observed for women, but the risk thresholds were higher (17% for women aged 40-44 years and 22% for those aged 70-75 years).
- Persons at high risk for CVD (>21%) were likely to beneﬁt from statins, regardless of sex or age.
- As a result of differences in preventive effects on beneﬁt or harm outcomes, atorvastatin had the most favorable beneﬁt–harm balance, followed by rosuvastatin, especially for persons with low or medium CVD risk and age <60 years. The other statins did not demonstrate beneﬁts at the same risk level for any of the age groups.
In a quantitative modeling study, statins provided net benefits for primary prevention at higher 10-year risks for CVD than are recommended in most current guidelines. In addition, the level of risk at which net benefit occurs depends on age, sex, and statin type. These data suggest that guidelines should use higher 10-year risk thresholds and should consider different recommendations based on sex, age, and statin type.
Richman and Ross note that the recommendation to use statins for primary prevention of CVD in adults with 10-year risk of at least 7.5% in the 2013 update of the ACC/AHA guidelines was particularly controversial. In the 2018 update of these guidelines, the approach was affirmed, albeit with emphasis on the importance of patient preference. The U.S. Preventive Services Task Force released guidelines in 2016, in which statins for primary prevention was recommended for adults with 10-year CVD risk of at least 10%, or at lower risk thresholds (starting at 7.5%) considering individual circumstances.
Yebyo and colleagues now challenge these risk thresholds, ‘through a careful accounting of long-term risks and benefits of statins’, according to Richman and Ross. ‘The authors assigned weights to treatment outcomes so that benefits and harms could be quantified on a single scale and summed over a 10-year horizon to determine the risk threshold at which benefits outweighed harms.’ Richman and Ross express their surprise that the authors consistently found that harms outweighed benefits until 10-year CVD risk thresholds substantially exceeded those recommended in current guidelines. That raises the question whether physicians should reconsider implementing the guideline recommendations into practice. Richman and Ross consider why the estimates in this article differ from those in current guidelines. Firstly; different methodological approaches were used to estimate net benefit, with a more elaborate method used in the article. Especially taking into account competing mortality risk contributed to the decreasing probability of net benefit of statins with increasing age.
Yebyo et al. included a long list of potential adverse events, derived from an as yet unpublished network meta-analysis by the same authors, which inevitably tips the balance further away from net benefit and toward harm. Opinions may differ as to whether or not it is justified to include these harms. Richman and Ross conclude that it is the patient who has to decide on the CVD risk threshold for initiation of statin therapy. It is up to ‘physicians to fairly summarize the evidence and guide patients through the decision-making process’.