HPS2-THRIVE randomized placebo-controlled trial in 25 673 high-risk patients of ER niacin/laropiprant: trial design, pre-specified muscle and liver outcomes, and reasons for stopping study treatment

Eur Heart J. 2013 May;34(17):1279-91. doi: 10.1093/eurheartj/eht055. Epub 2013 Feb 26.

Abstract

Aims: Niacin has potentially favourable effects on lipids, but its effect on cardiovascular outcomes is uncertain. HPS2-THRIVE is a large randomized trial assessing the effects of extended release (ER) niacin in patients at high risk of vascular events.

Methods and results: Prior to randomization, 42 424 patients with occlusive arterial disease were given simvastatin 40 mg plus, if required, ezetimibe 10 mg daily to standardize their low-density lipoprotein (LDL)-lowering therapy. The ability to remain compliant with ER niacin 2 g plus laropiprant 40 mg daily (ERN/LRPT) for ~1 month was then assessed in 38 369 patients and about one-third were excluded (mainly due to niacin side effects). A total of 25 673 patients were randomized between ERN/LRPT daily vs. placebo and were followed for a median of 3.9 years. By the end of the study, 25% of participants allocated ERN/LRPT vs. 17% allocated placebo had stopped their study treatment. The most common medical reasons for stopping ERN/LRPT were related to skin, gastrointestinal, diabetes, and musculoskeletal side effects. When added to statin-based LDL-lowering therapy, allocation to ERN/LRPT increased the risk of definite myopathy [75 (0.16%/year) vs. 17 (0.04%/year): risk ratio 4.4; 95% CI 2.6-7.5; P < 0.0001]; 7 vs. 5 were rhabdomyolysis. Any myopathy (definite or incipient) was more common among participants in China [138 (0.66%/year) vs. 27 (0.13%/year)] than among those in Europe [17 (0.07%/year) vs. 11 (0.04%/year)]. Consecutive alanine transaminase >3× upper limit of normal, in the absence of muscle damage, was seen in 48 (0.10%/year) ERN/LRPT vs. 30 (0.06%/year) placebo allocated participants.

Conclusion: The risk of myopathy was increased by adding ERN/LRPT to simvastatin 40 mg daily (with or without ezetimibe), particularly in Chinese patients whose myopathy rates on simvastatin were higher. Despite the side effects of ERN/LRPT, among individuals who were able to tolerate it for ~1 month, three-quarters continued to take it for ~4 years.

Keywords: ER niacin/laropiprant; HDL-cholesterol; LDL-cholesterol; cardiovascular disease; secondary prevention.

Publication types

  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Arterial Occlusive Diseases / drug therapy*
  • Chemical and Drug Induced Liver Injury / etiology*
  • Death, Sudden, Cardiac / prevention & control
  • Delayed-Action Preparations
  • Drug Therapy, Combination
  • Female
  • Humans
  • Hypolipidemic Agents / administration & dosage*
  • Hypolipidemic Agents / adverse effects
  • Indoles / administration & dosage*
  • Indoles / adverse effects
  • Male
  • Middle Aged
  • Muscular Diseases / chemically induced*
  • Myocardial Infarction / prevention & control
  • Myocardial Reperfusion / statistics & numerical data
  • Niacin / administration & dosage*
  • Niacin / adverse effects
  • Simvastatin / administration & dosage
  • Stroke / prevention & control

Substances

  • Delayed-Action Preparations
  • Hypolipidemic Agents
  • Indoles
  • MK-0524
  • Niacin
  • Simvastatin