Implementation of statin therapy in practice for primary prevention of cardiovascular disease is controversial due to concerns over costs and side-effects with broader use and uncertainty regarding LDL goals in the primary prevention population. Previous primary prevention trials suggest a reduction in cardiovascular outcomes in largely white patients with significant risk factors for coronary disease. The HOPE-3 trial randomized a diverse population of 12,000 individuals over 55 years of age (women over 60) with 1-2 relatively modest risk factors for cardiovascular disease (annual risk ~1%) but otherwise no indication for statin therapy to 10 mg of rosuvastatin daily vs placebo. The composite primary outcome was death from cardiovascular causes, non- fatal MI or stroke. Nearly 13% of patients were excluded following roll-in based on side-effects or lab abnormalities. For remaining patients, over median follow of 5.6 years there was a significant reduction in the primary endpoint: 3.7% vs 4.8% favoring treatment (HR 0.76 [CI 0.64-0.91]) with a NNT of 91. An expanded ‘co-primary’ outcome which also included heart failure, revascularization and resuscitated cardiac arrest resulted in a NNT of 73. Of note, there was a significant increase in muscle aches and weakness in the rosuvastatin group (5.8% vs 4.7%) but this did not clearly impact drug discontinuation, which was common at 23.7%. In fact, therapy discontinuation was 2.5% higher in the placebo group. Myopathy or rhabdomyolysis events were very rare, but there was a significant increase in cataracts in the rosuvastin group.

Conclusions: Using a simplified, fixed-dose statin therapy approach without specific lipid goals, the authors demonstrate meaningful reductions in cardiovascular outcomes in an intermediate-risk, primary prevention population without severe hyperlipidemia. Statin compliance and tolerance remain significant obstacles to broader adoption but reports of statins mixing with fluoride in the tap water of the western world are seeming increasingly less satirical.

Yusuf S, Bosch J, Dagenais G, Zhu J, Xavier D, Liu L, Pais P, López-Jaramillo P, Leiter LA, Dans A, Avezum A, Piegas LS, Parkhomenko A, Keltai K, Keltai M, Sliwa K, Peters RJG, Held C, Chazova I, Yusoff K, Lewis BS, Jansky P, Khunti K, Toff WD, Reid CM, Varigos J, Sanchez-Vallejo G, McKelvie R, Pogue J, Jung H, Gao P, Diaz R, and Lonn E, for the HOPE-3 Investigators. Cholesterol Lowering in Intermediate-Risk Persons without Cardiovascular Disease N Engl J Med 2016; 374:2021-2031 May, 2016 DOI: 10.1056/NEJMoa1600176

Authors: Kate Kearney, James M. McCabe