One-quarter of patients with occlusive arterial disease who received extended release niacin in addition to statins discontinued treatment, primarily due to adverse reactions. Results, published online Feb. 27 in European Heart Journal , showed a four-fold excess risk of myopathy in patients taking the combination therapy, with patients in China facing even higher risks.
High doses of the vitamin niacin modify lipids and consequently may help reduce the risk of cardiovascular events. In combination with statins, extended release niacin has been shown to increase high-density lipoprotein cholesterol (HDL-C) levels and reduce low-density lipoprotein cholesterol (LDL-C), for instance (Int J Clin Practice 2008;62:1959-1970). But niacin has many side effects, including skin reactions such as flushing that make its tolerability limited. Laropiprant taken with extended release niacin reduces flushing, though.
Researchers at the University of Oxford in the U.K. conceived the randomized controlled clinical trial HPS2-THRIVE (Heart Protection Study 2—Treatment of HDL to Reduce the Incidence of Vascular Events) as a way to evaluate extended release niacin and laropiprant in addition to statins in patients who are at high risk of major vascular events. The primary endpoint was the assessment of daily dose extended release niacin and laropiprant compared with placebo in patients with pre-existing occlusive arterial disease who were already receiving statin treatments to lower their LDL-C. The primary outcome was the first major vascular event (composite non-fatal MI, coronary death, stroke or arterial revascularization).
The study involved a run-in phase and then randomization. In collaboration with researchers in Europe and China, the Oxford team enrolled patients from 72 hospitals and clinics in China, 89 in the U.K., 22 in Denmark, 10 in Finland, 21 in Norway and 31 in Sweden. Patients with a history of MI, cerebrovascular atherosclerotic disease, peripheral artery disease or diabetes with any of those conditions or evidence of symptomatic coronary heart disease were eligible. Exclusion criteria included previous significant adverse reaction to statins, ezetimibe, niacin or laropiprant.
Of the 38,369 patients from China, the U.K. and Scandinavia enrolled in the one-month run-in phase, approximately one-third were excluded, mainly due to side effects from niacin. A total of 25,673 patients then were randomized between April 2007 and July 2010 to receive either daily 2 g extended release niacin and 40 mg laropiprant or placebo. All patients received LDL-C lowering therapy with simvastatin, and if necessary, ezetimibe and were followed for a median of 3.9 years.
Among the key results:
- The proportion of patients reporting they took 80 percent of the treatment decreased over time, from 92 to 89 to 85 percent at one, two and three years of follow-up. At the 3.9-year follow-up mark, 25.4 percent of the niacin/laropiprant group had stopped taking treatment compared with 16.6 percent of the placebo group;
- 5.4 percent of the niacin/laropiprant group cited skin-rated issues for their withdrawal compared with 1.2 percent in the placebo group;
- 3.9 percent of the niacin/laropiprant group reported gastrointestinal issues compared with 1.7 percent in the placebo group;
- 0.9 percent of the niacin/laropiprant group reported diabetic complications compared with 0.4 percent in the placebo group; and
- 1.8 percent of the niacin/laropiprant group cited musculoskeletal reasons for stopping treatment compared with 0.4 percent in the placebo group. The niacin/laropiprant group had fourfold higher risk of any myopathy, and the risk was 10 times higher for patients in China compared with Europe.
“The mechanism for this myopathy-related interaction between niacin and simvastatin is not clear,” the authors wrote. “Nor is it clear why the rate of myopathy on simvastatin alone is higher among Chinese individuals.”
They cautioned that statin therapy remained a potent weapon against cardiovascular risks. “[I]it should be noted that—even among Chinese individuals—this small absolute excess of myopathy with simvastatin 40 mg daily (with or without niacin) is likely to be greatly outweighed by its cardiovascular benefits in the sort of high-risk patients included in HPS2-THRIVE.”
Looking at the data from another angle, they pointed out that three-quarters of the randomized patients remained on the treatment through follow-up. “Based on this compliance and the lipid changes observed during the prerandomization run-in, it was estimated prior to unblinding the trial that study average differences in LDL-C of approximately 0.25 mmol/L and HDL-C of approximately 0.13 mmol/L would have been achieved,” they wrote.
The large number of participants will provide sufficient power to analyze outcomes, they concluded. This study focused on prespecified muscle outcomes and participants’ reasons for stopping treatment. More findings will be presented at a late-breaking clinical trial presentation March 9 at the American College of Cardiology’s Scientific Session in San Francisco.
In an accompanying editorial, Ulf Landmesser, MD, of the University Hospital Zurich in Switzerland, reviewed the bumpy path of research involving niacin and laropiprant. The AIM-HIGH (Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglycerides: Impact on Global Health) trial, which evaluated the use of niacin therapy on HDL cholesterol, was stopped early for futility.
HPS2-THRIVE is a much larger study but also may miss its mark. “The sponsor of the trial has recently communicated that the study did not meet its primary endpoint of reduction of major vascular events, although the detailed data presentation is still expected,” Landmesser wrote.
He described the efficacy findings from both studies as disappointing, writing that “niacin has failed as a valuable ‘partner’ of statin therapy in lipid-targeted approaches to reduce major cardiovascular events further in high-risk patients.”
HPS2-THRIVE is sponsored by Merck.