Physicians' Academy for Cardiovascular Education

HPS2-THRIVE: design and reason for stopping

Literature -

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.

HPS2-THRIVE Collaborative Group.
Eur Heart J. 2013 Feb 26. [Epub]


Cardiovascular risk remains elevated in some high-risk patients even after lowering low-density lipoprotein cholesterol (LDL-C) with statins, controlling blood pressure and diabetes, and stopping smoking [1,2]. Additional cardiovascular risk reduction might be achieved by targeting other aspects of lipid metabolism, such as high-density lipoprotein cholesterol (HDL-C), triglycerides, and lipoprotein (a) [Lp(a)], as well as lowering LDL-C further [3,4].
In patients already receiving a statin, extended release (ER) niacin 2 g daily is reported to increase HDL-C by ~20% and apolipoprotein A1 (apoA1) by ~7%, as well as reducing LDL-C, apolipoprotein B (apoB), and Lp(a) levels by ~20% and triglycerides by ~25% [5].
The HPS2-THRIVE (Heart Protection Study 2-Treatment of HDL to Reduce the Incidence of Vascular Events) study compared extended-release niacin and laropiprant, an anti-flushing agent, plus statin therapy versus statin therapy alone in 25,673 patients at high risk for cardiovascular events.
The trial was stopped in December 2012, as it did not meet its primary endpoint. Full results of the HPS2-THRIVE study will be presented by lead investigator Dr Jane Armitage (Oxford University, UK) on March 9, 2013 at American College of Cardiology 2013 Scientific Sessions in San Francisco, CA.

Main results:

  • The combination of niacin and laropiprant did not significantly reduce the risk of the combination of coronary deaths, nonfatal MI, strokes, or coronary revascularizations compared with statin therapy
  • More than a quarter of all patients who were randomized to the niacin arm stopped their treatment, compared with only 16.6% who were randomized to placebo.
  • The most common reasons for stopping treatment were skin-related (chiefly pruritus, rash, or flushing): 5.4% in the combination group versus 1.2% in the placebo group.
  • Gastrointestinal problems (mostly indigestion and diarrhea) were the second most common cause: 3.9% versus 1.7%.
  • Musculoskeletal problems occurred in 1.8% and 1%; the risk of myopathy was small but occurred more than four times as often in the combination group, while there is no proposed mechanism by which niacin could cause myopathy. The risk of myopathy was significantly higher in randomized patients from China than in patients from Europe.


These data shed some light on the adverse events associated with extended-release niacin and the antiflushing agent laropiprant in HPS2-THRIVE. The HDL-raising therapy when added to statins was associated with a significantly increased risk of definite myopathy.

Editorial comment [6]:

“The failure of niacin is a finding in the difficult search to find a drug that can work together with statins to further lower vascular events. Data from the HPS2-THRIVE study raise the question as to whether or not laropiprant is really biologically inert with respect to atherosclerosis and thrombosis. The effects of inhibition of the prostaglandin D2 receptor-1 by laropiprant on thrombosis and atherosclerosis in humans in vivo are probably difficult to predict and complex, since it has been observed that on the one hand laropiprant at low concentrations prevented the inhibitory effects of prostaglandin D2 on platelet function, including effects on platelet aggregation and thrombus formation, but on the other hand laropiprant at higher concentrations attenuated platelet activation induced by thromboxane and inhibited thrombus formation"


1. Cholesterol Treatment Trialists’ (CTT) Collaborators. Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials. Lancet 2010;376:1670–1681.
2. Perk J, De Backer G, Gohlke H, et al. European Guidelines on cardiovascular disease prevention in clinical practice (version 2012). The Fifth Joint Task Force of the European Society of Cardiology and Other Societies on Cardiovascular Disease Prevention in Clinical Practice (constituted by representatives of nine societies and by invited experts). Developed with the special contribution of the European Association for Cardiovascular Prevention & Rehabilitation (EACPR). Eur Heart J 2012;33:1635–1701.
3. Di Angelantonio E, Sarwar N, Perry P, et al. Major lipids, apolipoproteins, and risk of vascular disease. JAMA 2009; 302:1993–2000.
4. Bennet A, Di Angelantonio E, Erqou S, et al. lipoprotein(a) levels and risk of future coronary heart disease: large-scale prospective data. Arch Intern Med 2008;168:598–608.
5. Maccubbin D, Bays HE, Olsson AG, et al. Lipid-modifying efficacy and tolerability of extended-release niacin/laropiprant in patients with primary hypercholesterolaemia or mixed dyslipidaemia. Int J Clin Practice 2008;62:1959–1970.
6. Landmesser U. The difficult search for a 'partner' of statins in lipid-targeted prevention of vascular events: the re-emergence and fall of niacin. Eur Heart J. 2013 Feb 26.


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.

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.