In 2006, about 80 million people in the United States had one or more forms of cardiovascular disease: hypertension, coronary heart disease, stroke, heart failure.1 Guidelines have established treatment goals for low-density lipoprotein (LDL) and recommend intensive treatment for high-risk patients to reduce the risk of coronary heart disease (CHD). It is recommended to initiate HMG Co-A reductase inhibitors (statins) after dietary and lifestyle changes to lower LDL.2 However, it is unclear as to whether high-dose statin monotherapy or combination lipid-modifying therapy is superior with respect to clinical outcomes.
Sharma and colleagues3 conducted a systematic review of 102 trials that examined the effectiveness and harms of combination lipid-modifying therapy versus high-dose statin monotherapy. The questions addressed in this review are the comparative long-term benefits and rates of serious adverse events of coadministration of different lipid-modifying agents compared to high-dose statin monotherapy and the difference of achievement in low-density lipoprotein (LDL) cholesterol targets, short-term side effects, tolerability, or adherence. Studies included in the review were randomized controlled trials that compared combinations of statins plus bile-acid sequestrants, fibrates, ezetimibe, niacin, or omega-3 fatty acids with statin monotherapy. The main analyses were conducted in patients requiring intensive lipid-lowering therapy (10-year CHD risk >20%, mean baseline LDL >190 mg/dL, or both).
The main outcomes of interest in this systematic review were all-cause mortality and vascular death. Other clinical outcomes included myocardial infarction, acute coronary syndrome, stroke, transient ischemic attack, and revascularization procedures. The surrogate outcomes included achievement of LDL cholesterol goals per ATP III guidelines, LDL and high-density lipoprotein (HDL) levels, and measurement of carotid or coronary atherosclerosis. Harms outcomes evaluated in this review included serious adverse events, cancer, withdrawals due to adverse effects, elevated serum aminotransferase levels, hepatitis, myalgias, creatine kinase levels > 10 times the upper limit of normal, and rhabdomyolysis.
Mortality was rare, with no differences between treatments noted. There were no trials comparing combination lipid-modifying therapy with high-dose statin monotherapy that reported the occurrence of other clinical outcomes. A review of the trials showed no statistically significant differences in the rate of adverse events. The incidence of cancer was also nonsignificant between treatments. In trials comparing statin-ezetimibe versus high-dose statin monotherapy in patients requiring intensive lipid-lowering therapy, the patients receiving statin-ezetimibe experienced a higher chance of achieving the LDL goal than patients receiving high-dose statin monotherapy (OR 7.21; CI 4.3-12.8). In the 23 trials comparing statin-ezetimibe versus statin therapy without regard to dose, there were a higher proportion of patients in the statin-ezetimibe group that attained the LDL goal, compared to the statin monotherapy group, in all but one trial.
Although the results for the mean additional LDL reduction for statin-bile acid sequestrants, statin-fibrate, and statin-niacin were inconsistent in trials using various doses of statin monotherapy; the combination of statin-ezetimibe resulted in a mean additional LDL reduction of 4% to 27%. In comparison, statin monotherapy was superior in LDL reduction compared to omega-3 fatty acids (mean difference in LDL reduction, 5.26%; CI 1.79% to 8.74%). The percentage ...