While many randomized controlled trials (RCTs) of statin therapy in high-risk populations have reported benefit, it may be instructive to review some that did not. For example, coronary artery calcium scores have consistently been shown to identify high-risk patients. The St. Francis Heart Study was an RCT of atorvastatin in 1005 asymptomatic patients with coronary artery calcium scores >80th
percentile for age and gender. Remarkably, no significant reduction in atherosclerotic cardiovascular events was observed after 6 years. Patients with chronic kidney disease are also considered to be at very high risk of atherosclerotic cardiovascular disease. No significant mortality benefit was observed in the 3 RCTs of statin therapy that specifically targeted chronic kidney disease (German Diabetes and Dialysis Study [4D], A Study to Evaluate the Use of Rosuvastatin in Subjects on Regular Hemodialysis: An Assessment of Survival and Cardiovascular Events [AURORA], and Study of Heart and Renal Protection [SHARP]). However, SHARP did report a modest 17% reduction in major atherosclerotic events, while 4D and AURORA reported no significant reduction in major cardiovascular events. In contrast, a Cochrane meta-analysis of statins in patients with chronic kidney disease concluded there was a significant mortality and clinical benefit, but this analysis relied heavily on post hoc subgroup analyses.
- Palmer S.C.
- Navaneethan S.D.
- Craig J.C.
- et al.
HMG CoA reductase inhibitors (statins) for people with chronic kidney disease not requiring dialysis.
While subgroup analysis can provide valuable information, the conclusions of such an analysis can be misleading and should not supersede the results of well-conducted RCTs.
- Wang R.
- Lagakos S.W.
- Ware J.H.
- Hunter D.J.
- Drazen J.M.
Statistics in medicine—reporting of subgroup analyses in clinical trials.
Patients who have undergone coronary artery bypass surgery are also at high risk, yet the Post Coronary Artery Bypass Graft (Post-CABG) trial showed no significant reduction in cardiovascular events in patients randomized to statin therapy. The elderly represent another high-risk population, but only one RCT specifically designed to assess the effect of statins in this population has been reported. The PROspective Study of Pravastatin in the Elderly at Risk (PROSPER) study randomized 5804 patients ages 70-82 years to pravastatin or placebo and observed a significant reduction in combined cardiovascular events, but no significant mortality benefit. Notably, PROSPER patients without prior vascular disease (primary prevention) showed no significant reduction in cardiovascular events or mortality. Similarly, rosuvastatin did not reduce cardiovascular events or mortality in older individuals with ischemic, systolic heart failure in the Controlled Rosuvastatin Multinational Trial in Heart Failure (CORONA). Diabetic patients are considered to have a coronary artery disease risk equivalent, and 3 RCTs of statin therapy specifically in diabetics have been reported (Atorvastatin Study for Prevention of Coronary Heart Disease Endpoints in Non-Insulin-Dependent Diabetes Mellitus [ASPEN], 4D, Collaborative Atorvastatin Diabetes Study [CARDS]). Only one showed a significant reduction in cardiovascular events (CARDS), while all 3 failed to demonstrate a significant mortality benefit. These findings are discordant with the Cholesterol Treatment Trialists (CTT) meta-analysis of statin use in diabetes, which did conclude that statins were beneficial.
Cholesterol Treatment Trialists' (CTT) Collaborators
Efficacy of cholesterol-lowering therapy in 18,686 people with diabetes in 14 randomised trials of statins: a meta-analysis.
However, the CTT meta-analysis relied heavily on subgroup analysis and only one of the 14 studies analyzed was specifically designed and powered for diabetes (CARDS). Finally, patients with peripheral vascular disease represent an additional high-risk population. Although there have been no long-term RCTs specifically designed and powered to assess statin therapy in these patients, a Cochrane meta-analysis of 18 cholesterol-lowering trials (some with statins) in patients with peripheral vascular disease concluded there was no significant reduction in total mortality or cardiovascular events.
- Aung P.P.
- Maxwell H.G.
- Jepson R.G.
- Price J.F.
- Leng G.C.
Lipid-lowering for peripheral arterial disease of the lower limb.