Landmark study results presented at ACC.13 reveal patients with vascular disease treated with niacin therapy face increased risk of myopathy and other adverse events.
The late-breaking HPS2-THRIVE (Heart Protection Study 2-Treatment of HDL to Reduce the Incidence of Vascular Events) trial was an early highlight of ACC.13, the 62nd Annual Scientific Session & Expo of the American College of Cardiology.
The randomized placebo-controlled trial combined extended-release (ER) niacin and laropiprant (Tredaptive) with lipid-lowering therapy (simvastatin or simvastatin/ezetimibe) in 25,673 patients from the UK, Scandinavia, and China. Jane Armitage, FFPH, FRCP, professor of clinical trials at the University of Oxford, presented the trial results.
Eligible participants included men and women age 50-80 with a prior history of: myocardial infarction, ischemic stroke, or transient ischemic attack (TIA); peripheral arterial disease; or diabetes with other coronary heart disease; with no myocardial infarction (MI) or stroke within the past 30 days, or revascularization procedure planned within 30 days; no contraindication to study treatments; and no significant liver, kidney, or muscle disease.
Patients at high risk of cardiovascular disease were screened and standardized with background LDL-lowering therapy with simvastatin (with or without ezetimibe). Compliance was tested with ER niacin 2 grams and laropiprant (reducing niacin’s flushing) 40 mg daily for at least one month. Finally, 25,673 patients tolerating the daily dose were randomized with placebo, with a median follow-up of 3.9 years.
Participants on average were men (83%), aged 65, with prior coronary (78%), cerebrovascular (32%), or peripheral arterial disease (13%), or diabetes (32%). Some were current smokers (18%). Mean LDL was 63 mg/dl and mean HDL was 44 g/dl. During the treatment period, the mean reduction in LDL was 10 mg/dl and the mean increase in HDL was 6 mg/dl.
Primary endpoints were cardiovascular death, MI, ischemic or hemorrhagic stroke, or arterial revascularization (angioplasty, bypass surgery, or peripheral procedure). Cardiovascular death, MI, stroke, or revascularization occurred in 14.5% of the treatment group vs. 15.0% of the placebo group (P = 0.29). This outcome resembled that of patients with coronary, cerebrovascular, or peripheral arterial disease. Drugs were stopped in 25% of patients in the treatment group vs. 17% of the placebo group. Largely, this was for these reasons:
Serious adverse events (including hospitalization or significant unwellness) observed with this treatment included a significant 3% absolute excess: about 30 people in 1000 treated had at least one side effect. Most are well recognized niacin side effects (eg, increased risk in diabetics of glucose control issues); however, there was also a significant increase among non-diabetics of developing diabetes, and increased risk (1% absolute excess) of GI problems like indigestion, peptic ulcer, or diarrhea. There were also two side effects not usually recognized with niacin: a 20% increased risk of infection ranging from chest to kidney and beyond (a statistically significant increase due to the study’s large size); and an increased risk of bleeding, including intracranial bleeding, and an increased risk of hemorrhagic stroke (although a decreased risk of ischemic stroke). Key findings showed no significant benefit of treatment on major vascular events when added to statin therapy to lower LDL.
The study was unable to identify any participant type for whom benefits might outweigh risks. The result is nevertheless clear and reliable, due to the size of the study, with good follow-up. “In light of these findings,” said Armitage, “the role of ER niacin in preventing cardiovascular disease needs reconsideration.”