Does niacin plus laropiprant improve cardiovascular outcomes or reduce mortality in patients with vascular disease?
This large, adequately powered trial did not find any clinically meaningful benefit to the use of niacin in patients who are already taking a statin, even with several study design features that should bias the result in favor of niacin. Niacin should not be prescribed to reduce the risk of cardiovascular events, even in high-risk patients and in patients with known vascular disease. The combination of niacin and laropiprant, marketed as Tredaptive in the United States, has been removed from the market after the preliminary results of this study showed no benefit. (Level of Evidence = 1b)
Although niacin is widely used for its effects on high-density lipoprotein (HDL) cholesterol—and, to a lesser extent, low-density lipoprotein (LDL) cholesterol—its benefit has never been proved in clinical trials. The recent AIM-HIGH trial in patients with metabolic syndrome found no benefit, and the current study was intended to evaluate niacin in patients with known vascular disease. The researchers recruited patients 50 to 80 years of age with a history of myocardial infarction, cerebrovascular disease, peripheral arterial disease, or diabetes mellitus with symptomatic coronary heart disease. Lipid levels were not part of the inclusion criteria, although patients receiving high-intensity statin therapy were excluded. During an initial run-in period, all patients received simvastatin (Zocor; 40 mg) once daily, and if their total cholesterol level remained higher than 135 mg per dL (3.50 mmol per L), ezetimibe (Zetia; 10 mg) was added. They were then given a single tablet with niacin (1 g) plus laropiprant (20 mg) once daily for four weeks, and then twice daily (laropiprant is added to reduce flushing).
Of the 51,698 patients who were initially screened, approximately one in nine withdrew during the simvastatin run-in period, and another one-third withdrew during the niacin run-in period (primarily because of adverse drug effects). This design would tend to select patients who tolerate the study medications, introduces a bias in favor of finding an effect, and also risks unmasking patients to their treatment assignment if they had mild but noticeable adverse effects while taking the drug, which then went away when taking placebo.
The final study population consisted of 25,673 patients; 83% were men, 57% were recruited in England or Scandinavia (the rest in China), and the average age was 65 years. The mean LDL level was 64 mg per dL (1.66 mmol per L) and the mean HDL level was 44 mg per dL (1.14 mmol per L). Groups were balanced at the start of the study, and analysis was by intention to treat. Patients were randomized to receive the active drug or a placebo and were observed for a median of 3.9 years. The drug successfully lowered LDL levels by 10 mg per dL (0.25 mmol per L) and raised HDL levels by 6 mg per dL (0.16 mmol per L) more than the placebo. However, there was no significant effect on major vascular events, major coronary events, stroke, cardiovascular mortality, or all-cause mortality. There was a borderline significant reduction in the likelihood of requiring revascularization (an outcome that might be affected by failure to mask) and a significant increase in the likelihood of new-onset diabetes (5.7% vs. 4.3%; number needed to treat to harm = 71) and in disturbed diabetes control (11.1% vs. 7.5%; number needed to treat to harm = 28). An increase in all-cause mortality occurred with the active drug, but it was not statistically significant (6.2% vs. 5.7%; P = .08).
Study design: Randomized controlled trial (double-blinded)
Funding source: Industry
Reference: LandrayMJHaynesRHopewellJCet alHPS2-THRIVE Collaborative Group. Effects of extended-release niacin with laropiprant in high-risk patients. N Engl J Med2014; 371( 3): 203– 212.