Best evidence for drugs used alone or in combination with statins
| DRUG STUDIES | EFFECT* USED ALONE | EFFECT* COMBINED WITH STATIN | STRENGTH OF EVIDENCE | CONCLUSION |
|---|---|---|---|---|
| Niacin | ||||
| • CDP106 | 3 g/d reduced mortality by 11% on 15-y follow-up; secondary prevention following MI | NA | Large RCT in men only; follow-up for 9 y after trial ended | Significant (P = .0004) mortality benefit only on extended follow-up; only trial not confounded by other drug treatment |
| • HATS107 | NA | 60%–90% reduction in events or mortality for combination of simvastatin and niacin | Small RCT; confounding of niacin effect by administration with statin | Mortality reduction exceeds that expected with statin alone; trial against statin alone needed |
| • AIM-HIGH108 | NA | No benefit of addition of niacin in patients maximally treated with statins; secondary prevention | Large RCT using 1.5–2.0 g of niacin; trial stopped early for futility at 3 y | No evidence for effect of niacin on event or mortality reduction with statin combination |
| • Bruckert et al109 | Benefit based on the CDP trial only | Benefit, with substantial heterogeneity; old trials had variable statin use | 2009 meta-analysis; did not include AIM-HIGH, which has best evidence | Probable benefit used alone; evidence for combination therapy probably no longer valid |
| • Duggal et al110 | Benefit based on the CDP trial only | Small reduction in events but not mortality based on infrequent use of statins in old trials | 2010 meta-analysis; did not include AIM-HIGH, which has best evidence | Probable benefit used alone; evidence for combination therapy probably no longer valid |
| Fibrates | ||||
| • Helsinki Heart Study111 | Gemfibrozil produced 34% reduction in events or mortality; 71% if TG levels elevated and HDL levels low; 78% if obese | NA | Large RCT of primary prevention; no confounding from use of other drugs; benefit found on post hoc analysis | Moderate evidence for gemfibrozil used alone; especially if obese, high TG levels, low HDL levels |
| • BIP112 | Benzafibrate produced 39% reduction in events if TG levels were elevated, but no effect overall | NA | Large RCT of secondary prevention; TG effect found on post hoc analysis | Moderate evidence for benzafibrate used alone if TG levels elevated |
| • VA-HIT113 | Gemfibrozil produced 24% reduction in events overall | NA | Large RCT of secondary prevention | Good evidence for gemfibrozil used alone |
| • FIELD114 | Fenofibrate produced no difference overall but reduced events by 11% if metabolic syndrome present; adjusted for statins | Fenofibrate gave no added benefit when given with statins | Large RCT of patients with diabetes and secondary prevention; metabolic syndrome analysis was post hoc | Moderate evidence for fenofibrate used in metabolic syndrome |
| • ACCORD103 | NA | Fenofibrate showed no benefit overall when given with statins; benefit shown in subgroup with high TG and low HDL | Large RCT of patients with diabetes in primary and secondary prevention | No evidence for benefit overall; good evidence for benefit if high TG levels and low HDL levels; no fenofibrate-statin interaction |
| • Bruckert et al100 | Fibrates no benefit overall, but 30% event reduction if high TG and low HDL levels | Fibrates no benefit overall, but 30% event reduction if high TG and low HDL levels | 2011 meta-analysis based on post hoc subgroup analysis | Fibrates beneficial with or without statins only with high TG and low HDL levels |
| • Lee et al101 | Fibrates no benefit overall, but 30% event reduction if high TG and low HDL | Fibrates no benefit overall, but 30% event reduction if high TG and low HDL | 2011 meta-analysis based on post hoc subgroup analysis | Fibrates beneficial with or without statins only if TG high and HDL low |
| Fish oil | ||||
| • Kwak et al115 | No evidence for benefit | No evidence for benefit | 2012 meta-analysis | Insufficient evidence; largest older studies are observational or open ended |
| • Delgado-Lista et al116 | Reduction of cardiovascular events by 10%; no mortality reduction | More difficult to demonstrate benefit when used with statins | 2012 meta-analysis | Moderate evidence when used alone; study dosages quite variable |
| • Rizos et al117 | No evidence for benefit | No evidence for benefit | 2012 meta-analysis | Insufficient evidence for benefit |
| Resins | ||||
| • LRC-CPPT118 | 19% reduction in events or mortality with cholestyramine | NA | Large RCT | Good evidence for benefit used alone; there are no studies in combination with statins |
| • CDP106 | No evidence for benefit with cholestyramine | NA | Large RCT in men only; follow-up for 9 y after trial ended | No evidence for benefit used alone |
| • Bucher et al119 | Benefit for mortality using resins of “borderline significance” | NA | 1999 systematic review of RCTs with mortality data | Weak evidence for benefit used alone |
| Other | ||||
| • Ezetimibe: None | There have been no trials evaluating hard CVD outcomes or mortality; all trials to date involved either surrogate outcomes or a fixed combination with statin; IMPROVE-IT, due in 2014, will evaluate ezetimibe against a simvastatin combination | No reliable evidence of improvement in hard outcomes | ||
| • CETP inhibitors93,104 | Torcetrapib trial was terminated early for harm; dalcetrapib trial terminated early for futility; these drugs may lead to production of “dysfunctional” HDL with changed, and perhaps harmful, properties; anacetrapib is the subject of ongoing trials | No evidence of improved outcomes despite remarkable increases in HDL | ||
ACCORD—Action to Control Cardiovascular Risk in Diabetes, AIM-HIGH—Atherothrombosis Intervention in Metabolic Syndrome with Low HDL and High Triglycerides, BIP— Benzafibrate Infarction Prevention, CETP—cholesterol ester transfer protein, CDP—Coronary Drug Project, CVD—cardiovascular disease, FIELD—Fenofibrate Intervention and Event Lowering in Diabetes, HATS—HDL Atherosclerosis Treatment Study, HDL—high-density lipoprotein, IMPROVE-IT—Improved Reduction of Outcomes: Vytorin Efficacy International Trial, LRC-CPPT—Lipid Research Clinics Coronary Primary Prevention Trial, MI—myocardial infarction, NA—not applicable, RCT—randomized controlled trial, TG— triglyceride, VA-HIT—Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial.
↵* Evidence presented only for hard cardiovascular end points or mortality. Surrogate end points such as lipid changes or vascular imaging are not included.