HPS2-THRIVE randomized placebo-controlled trial in 25,673 high-risk patients of ER niacin/laropiprant

HPS2-THRIVE Collaborative Group. 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;34(17):1279-1291.

Background 

Residual risk for cardiovascular disease is seen among many high-risk patients despite LDL-C lowering with statins, and controlling blood pressure and diabetes. Niacin (nicotinic acid) is commonly prescribed as an add-on to statin therapy for incremental lowering of LDL-C, apoB, Lp(a), and triglycerides (TG); and incremental increasing of HDL-C and apoA1.

The use of niacin, particularly the extended-release (ER) formulation, is limited in clinical practice due to many adverse events, namely flushing. Laropiprant is an antagonist of DP1, the prostaglandin D2 receptor that mediates flushing; it has been shown to improve niacin tolerability.

The efficacy of niacin in reducing vascular risk among high-risk patients is unclear, particularly given the discontinuation in 2011 of the Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglycerides: Impact on Global Health Outcomes (AIM-HIGH) study due to perceived lack of benefit in the treatment group allocated ER niacin 1.5-2.0 g/day plus statin. (Click here for more on AIM-HIGH) 

The HPS2-THRIVE study assessed the effects of ER niacin 2 g + laropiprant 40 mg daily vs placebo on the time to first major vascular event among patients at high risk for vascular disease who are receiving effective statin-based LDL-lowering therapy. (Click here for slide) 

Design  

HPS2-THRIVE assessed the effects of ER niacin + laropiprant among patients at high risk for vascular events. A total of 25,673 patients from China and Europe were randomized to ER niacin 2 g plus laropiprant 40 mg daily versus matching placebo. Background LDL-lowering therapy with simvastatin 40 mg or ezetimibe/simvastatin 10/40 mg was continued. All participants had occlusive arterial disease. 

Select baseline characteristics in HPS2-THRIVE are shown below: (Click here for slide) 

   Study Population (N=25,673) 
Mean age, yrs (SD)     
 
64.9 (7.5)
Male      21,229 (82.7%)
Vascular History  
   Coronary disease 20,137 (78.4%)
   Cerebrovascular disease 8,170 (31.8%)
   Peripheral artery disease 3,214 (12.5%)
   Diabetes 8,299 (32.2%)
Medications  
   Simvastatin 40 mg  13,542 (52.7%)
   Ezetimibe/simvastatin 10/40 mg 12,131 (47.3%)
   Aspirin 22,159 (86.3%)

 

The primary endpoint was time to a first major vascular event, a composite of nonfatal myocardial infarction (MI), cardiovascular (CV) mortality, stroke, or arterial revascularization. 

HPS2-THRIVE was stopped after 3.9 years (median) due to significant adverse events in the ER niacin + laropiprant group. (Click here for slide) 

Results  

The proportion of patients who reported taking ≥80% of their study LDL-lowering treatment was 92% in Year 1, 89% in Year 2, and 85% in Year 3. The proportion of patients who stopped taking study LDL-lowering treatment was significantly higher in the extended-release niacin/laropiprant (ERN/LRPT) group: 13.7% vs 11.7% placebo (P<0.0001). (Click here for slide) 

The proportion of subjects who stopped randomized treatment was significantly higher in the ERN/LRPT group: 25.4 vs 16.6% placebo (P<0.0001).  Adverse events leading to treatment discontinuation in each group were as follows: (Click here for slide) 

  • Skin-related reasons were four times more common for ERN/LRPT: 5.4% vs 1.2% (P<0.0001)
  • Gastrointestinal-related reasons were twice more common for ERN/LRPT: 3.9% vs 1.7% (P<0.0001)
  • Musculoskeletal reasons were slightly more common for ERN/LRPT: 1.8% vs 1.0% (P<0.0001)
  • Diabetes-related reasons were about twice as common for ERN/LRPT: 0.9% vs 0.4% (P<0.0001)

The risk for definite myopathy with ERN/LRPT was 4.4 (95% confidence interval [CI], 2.6-7.5; P<0.0001; 0.16%/yr vs 0.04%/yr). All patients who experienced myopathy had LDL-lowering and randomized treatments stopped. The excess risk was greater in Year 1 than in subsequent years.

Allocation to ERN/LRPT nearly doubled the incidence of raised transaminases: alanine aminotransaminase (ALT) >3x upper limit of normal was 0.30%/yr for ERN/LRPT and 0.14%/yr for placebo (P<0.0001). (Click here for slide) 

Related content: 

Slide: AIM-HIGH: Niacin + Statin Therapy for Cardiovascular Risk Reduction  

Slide: AIM-HIGH: Design  

Slide: AIM-HIGH: Baseline Characteristics  

Slide: AIM-HIGH: Lipid Values at Baseline and 2 Years  

Slide: AIM-HIGH: Rate of the Primary Endpoint  

Slide: AIM-HIGH: Rate of Secondary Endpoints   

 

March 2013 

This overview was created by KnowledgePoint360 Group, LLC, and was not associated with funding via an educational grant or a promotional/commercial interest.  

Last Modified: 8/5/2014