Heart Protection Study 2–Treatment of HDL to Reduce the Incidence of Vascular Events - HPS2-THRIVE

Description:

The goal of the trial was to evaluate treatment with extended-release niacin/laropiprant compared with placebo among high-risk patients treated with statin therapy. Laropiprant is a prostaglandin D2 receptor antagonist, which reduces niacin-associated flushing.

Hypothesis:

To determine the side-effect profile and efficacy of extended-release niacin/laropiprant.

Study Design

  • Parallel
  • Randomized
  • Placebo Controlled
  • Stratified

Patient Populations:

  • Patients ≥50 years of age with atherosclerotic vascular disease defined by the following:
    - History of myocardial infarction
    - History of stroke, transient ischemic attack, or carotid revascularization
    - History of claudication or revascularization
    - Diabetes and symptomatic coronary artery disease

    Number of screened applicants: 51,698
    Number of enrollees: 25,673 participants
    Duration of follow-up: Median 3.9 years
    Mean patient age: 65 years
    Percentage female: 17%

Exclusions:

  • Age >80 years
  • Myocardial infarction or stroke within the last 30 days
  • Planned revascularization procedure within the next 30 days
  • Chronic liver or renal disease
  • Dyspnea for any reason
  • Active inflammatory muscle disease
  • Adverse reaction to one of the study medications
  • Peptic ulcer disease
  • Concurrent treatment with a medication that could increase the risk of an adverse drug reaction
  • Noncompliant
  • Limited life span

Primary Endpoints:

  • Cardiovascular death, myocardial infarction, stroke, or revascularization

Secondary Endpoints:

  • Cardiovascular death
  • Myocardial infarction
  • Stroke
  • Revascularization

Drug/Procedures Used:

High-risk patients with documented atherosclerosis were randomized to extended-release niacin/laropiprant 2 g/40 mg (n = 12,838) versus placebo (n = 12,835) after two run-in phases. The first run-in phase was to simvastatin 40 mg ± ezetimibe (11% of participants withdrew at this stage), and the second to extended-release niacin/laropiprant for 1 month titrated up to target dose (33% of participants withdrew at this stage).

Concomitant Medications:

 

Principal Findings:

Overall 25,673 patients were randomized. The mean age was 65 years, 17% were women, 32% had diabetes, mean body mass index was 28 kg/m2, and 18% were current smokers. Mean low-density lipoprotein cholesterol (LDL-C) was 63 mg/dl and the mean high-density lipoprotein cholesterol (HDL-C) was 44 g/dl. Coronary disease was reported in 78%, cerebrovascular disease in 32%, peripheral arterial disease in 13%, and diabetes in 33%.

During the treatment period, the mean reduction in LDL-C was 10 mg/dl and the mean increase in HDL-C was 6 mg/dl.

Cardiovascular death, myocardial infarction, stroke, or revascularization at a mean of 3.9 years occurred in 13.2% of the extended-release niacin/laropiprant group vs. 13.7% of the placebo group (p = 0.29). This outcome was similar among patients with coronary, cerebrovascular, or peripheral arterial disease. There was a marginally enhanced benefit of niacin compared with placebo among patients in the highest tertile of LDL-C (i.e., ≥77 mg/dl). Regarding individual components of the primary outcome, extended-release niacin/laropiprant was associated with a reduction in any revascularization procedure (p = 0.03).

The study drug was stopped in 25% of patients in the extended-release niacin/laropiprant group vs. 17% of the placebo group. This was mostly due to the following reasons:

- Dermatologic: 0.7% vs. 0.4% (p = 0.003), respectively, for niacin vs. placebo

- Gastrointestinal: 4.8% vs. 3.8% (p < 0.001), respectively, for niacin vs. placebo

- Musculoskeletal reasons: 3.7% vs. 3.0% (p < 0.001), respectively, for niacin vs. placebo

- Infection: 8.0% vs. 6.0% (p < 0.001), respectively, for niacin vs. placebo

- Bleeding event: 2.5% vs. 1.9% (p < 0.001), respectively, for niacin vs. placebo

- Definite myopathy: 0.16%/year vs. 0.04%/year (p < 0.001), respectively, for niacin vs. placebo

Any myopathy was more common among Chinese participants (0.66%/year vs. 0.13%/year) compared with European participants (0.07%/year vs. 0.04%/year), respectively, for niacin vs. placebo.

- New-onset diabetes: 5.7% vs. 4.3% (p < 0.001), respectively, for niacin vs. placebo

- Disturbed diabetes control: 11.1% vs. 7.5% (p < 0.001), respectively, for niacin vs. placebo

Interpretation:

Among high-risk patients who went through two run-in phases to demonstrate tolerability to study medication, extended-release niacin/laropiprant did not reduce the frequency of major adverse events. Moreover, 25% of participants still terminated niacin therapy during the treatment period for a variety of side-effects, mostly due to skin, gastrointestinal, musculoskeletal, and diabetes-related reasons. Myopathy was more common among Chinese participants compared with European participants.

Unexpected findings were an increase in serious infections and bleeding events among niacin-treated patients. This large study with long-term follow-up complements the AIM-HIGH trial, which also failed to demonstrate benefit from niacin therapy.

References:

The HPS2-THRIVE Collaborative Group. Effects of extended-release niacin with laropiprant in high-risk patients. N Engl J Med 2014;371:203-12.

Editorial: Lloyd-Jones DM. Niacin and HDL cholesterol — time to face facts. N Engl J Med 2014;371:271-3.

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;Feb 26:[Epub ahead of print].

Presented by Dr. Jane Armitage at ACC.13, San Francisco, March 9, 2013.

Clinical Topics: Dyslipidemia, Vascular Medicine, Atherosclerotic Disease (CAD/PAD), Lipid Metabolism, Nonstatins, Statins

Keywords: Myocardial Infarction, Stroke, Ischemic Attack, Transient, Follow-Up Studies, Receptors, Immunologic, Lipoproteins, Peripheral Arterial Disease, Simvastatin, Cholesterol, Complement System Proteins, Body Mass Index, Indoles, Receptors, Prostaglandin, Niacin, Muscular Diseases, Diabetes Mellitus


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