HPS2-THRIVE

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Landray MJ et al. "Effects of extended-release niacin with laropiprant in high-risk patients". The New England Journal of Medicine. 2014. 371(3):203-212.
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Clinical Question

Among patients with atherosclerotic disease on statin therapy, does niacin+laropiprant reduce major vascular event when compared to placebo?

Bottom Line

Among patients with atherosclerotic disease on statin therapy, niacin+laropiprant does not reduce incident major vascular events when compared to placebo. The therapy was poorly tolerated.

Major Points

Population studies have identified high LDL-cholesterol and low HDL-cholesterol as independent risk factors for CHD and CHD mortality. The effects of niacin (vitamin B3 or nicotinic acid) are many and are thought to reduce LDL through inhibition of diacylglycerol acyltransferase-2-mediated triglyceride synthesis and increase HDL levels by reducing catabolism of HDL particles.[1] This therapy is particularly attractive for its strong effects on increasing HDL.[2] In the pre-statin era, niacin was found to modestly reduce mortality in patients with CHD.[3] Trials subsequent to the widespread use of statins have had conflicting results. For example, the 2004 ARBITER 2 trial[4] found that niacin added to statin therapy was associated with a reduction in carotid intima-media thickness (a surrogate for atherosclerosis progression) among individuals with known CHD while the 2011 AIM-HIGH trial[5] found no reduction in clinical outcomes (eg, CHD mortality) when niacin was added to statin therapy in patients with CHD. Whether the therapy would benefit a more heterogeneous group of patients with atherosclerotic disease on statin therapy was unknown.

Published in 2014, the Heart Protection Study 2-Treatment of HDL to Reduce the Incidence of Vascular Events (HPS2-THRIVE) trial enrolled 25,673 adults with atherosclerotic disease (eg, prior MI, PAD) on statin therapy+/-ezetimibe. Participants who tolerated a run-in phase of niacin+laropiprant therapy were randomized to niacin extended release 2g+laropiprant 40 mg PO qdaily or placebo. (Laropiprant is a prostaglandin inhibitor that reduces niacin-related flushing.)[6] With a median follow-up of 3.9 years, there was no difference in the primary outcome of major vascular events (niacin+laropiprant 13.2% vs. placebo 13.7%; P=0.29). Niacin therapy was poorly-tolerated as it was associated with increased incidence of serious adverse events (GI, musculoskeletal, skin, infection, and bleeding), higher risk of new-onset diabetes, and worsening glucose control among those with prevalent diabetes.

The failure of niacin therapy in this trial has led some to suggest abandoning the medication except in highly-selected individuals who don't tolerate statins.[7][2] Combining the outcomes of HPS2-THRIVE with the negative outcomes of trials of novel agents that increase HDL cholesterol (eg, torcetrapib in ILLUMINATE[8] and dalcetrabib in dal-OUTCOMES[9]) suggest that the previous understanding of HDL as an independent risk factor for CHD is incorrect or is an oversimplification of the complex molecule's true role.[10]

Guidelines

As of April 2015, no guidelines have been published that reflect the results of this trial.

Design

  • Multicenter, randomized, placebo-controlled trial
  • N=25,673 (51,698 were screened, 42,424 entered the prerandomization run-in phase)
    • Niacin-Laropiprant (n=12,838)
    • Placebo (n=12,835)
  • Setting: 245 centers in the the UK, Scandinavia, and China
  • Enrollment: 2007-2010
  • Median follow-up: 3.9 years
  • Analysis: Intention-to-treat
  • Primary outcome: Major vascular event

Population

Inclusion Criteria

  • Age 50-80 years
  • Prior MI, CVD, PAD, or DM with symptomatic CAD

Exclusion Criteria

  • Liver disease (eg, ALT >1.5x ULN), CKD (creatinine >2.3 mg/dL), inflammatory muscle disease,
  • Prior adverse reaction to a study medication
  • Active PUD
  • Treatment with a fibrate, niacin, ezetimibe with simvastatin 80 mg, atorvastatin ≥20 mg, or rosuvastatin ≥10mg PO qday
  • Use of CYP3A4 inhibitor, cyclosporine, amiodarone, verapamil, or danazol
  • <3 months since MI, ACS, or stroke
  • Planned revascularization in the next 3 months
  • SOB
  • Poor compliance
  • Other significant medical comorbidity likely to reduce compliance

Baseline Characteristics

From the Niacin-Laropiprant group.

  • Demographics: Age 64.9 years, male sex 83%, Europe 57%, China 43%
  • PMH: MI 68%, non-MI CHD 66%, CVD 32%, PAD 13%, DM 32%
  • Labs: LDL 64 mg/dL, TChol 128 mg/dL

Interventions

  • Prerandomization run-in:
    • Simvastatin 40 mg PO qday for 4 weeks, if inadequate lipid control (eg, Tchol >135 mg/dL) then ezetimibe 10 mg PO qday was added
    • Niacin extended-release 1g+laropiprant 40 mg PO, 1 tablet PO daily for 4 weeks then 2 tablets daily for 3-6 weeks
    • Those without clinically-significant side effects were randomized to a study group
  • Study:
    • Niacin-laropiprant - Same dosing as above, 2 tablets PO daily
    • Placebo

Outcomes

Presented as niacin-laropiprant vs. placebo.

Primary Outcome

Major vascular event
Nonfatal MI, coronary mortality, stroke, arterial revascularization.
13.2% vs. 13.7% (RR 0.96; 95% CI 0.90-1.03; P=0.29)

Secondary Outcomes

Components of the primary outcome
Nonfatal MI: 3.1% vs. 3.4%
Coronary mortality: 2.4% vs. 2.3%
Any major coronary event: 5.2% vs. 5.4% (RR 0.96; 95% CI 0.87-1.07; P=0.51)
Nonhemorrhagic stroke: 3.0% vs. 3.2%
Hemorrhagic stroke: 0.9% vs. 0.7%
Any stroke: 3.9% vs. 3.9% (RR 1.00; 95% 0.88-1.13; P=0.56)
Coronary revascularization: 4.6% vs. 5.2%
Noncoronary revascularization: 1.8% vs 2.0%
Any revascularization: 6.3% vs. 7.0% (RR 0.90; 95% CI 0.82-0.99; P=0.03; NNT 143)

Additional Outcomes

Difference in lipid levels from baseline
Change in placebo group minus change in niacin/laropiprant group.
TChol: -5 mg/dL
LDL: -10 mg/dL
HDL: +6 mg/dL
TG: -33 mg/dL

Adverse Events

Detailed in the supplementary appendix[11]

All-cause mortality
8.2% vs. 6.7% (RR 1.08; 95% CI 0.99-1.21; P=0.08)
Serious
GI event: 4.8% vs. 3.8% (RR 1.28; 95% CI 1.13-1.44; P<0.001; NNH 100)
Musculoskeletal event: 3.7% vs. 3.0% (RR 1.26; 95% CI 1.10-1.44; P<0.001; NNH 143)
Skin-related event: 0.7% vs. 0.4% (RR 1.67; 95% CI 1.20-2.34; P=0.003; NNH 333)
Infection event: 8.0% vs. 6.6% (RR 1.22; 95% CI 1.12-1.34; P<0.001; NNH 71)
Bleeding event: 2.5% vs. 1.9% (RR 1.38; 95% CI 1.17-1.62; P<0.001; NNH 167)
New-onset diabetes
5.7% vs. 4.3% (RR 1.32; 95% CI 1.16-1.51; P<0.001; NNH 71)
Worsening glucose control among those with prevalent diabetes
11.1% vs. 7.5% (RR 1.55; 95% CI 1.34-1.78; P<0.001; NNH 28)
Discontinuation of of study medication
25.4% vs. 16.6% (P<0.001)

Criticisms

  • The participants may have had too high of an HDL level or too low of an LDL level to benefit from the intervention[10]
  • Laropiprant may have increased atherogenesis as has been seen in prostaglandin D2 receptor DP1 knockout mice[10]
  • The incidence of adverse events was higher in this trial than in AIM-HIGH and may be unique to the novel formulation studied here[12]

Funding

  • Merck, the manufacturers of Tredaptive (the brand name of the niacin formulation used in this study)
  • UK Medical Research Council
  • British Heart Foundation and Cancer Research UK
  • British Heart Foundation Centre of Research Excellence

Further Reading

  1. Kamanna VS and Kashyap ML. "Mechanism of action of niacin." The American Journal of Cardiology. 2008;101(8A):20B-26B.
  2. 2.0 2.1 Lloyd-Jones DM. "Niacin and HDL cholesterol -- Time to face facts." The New England Journal of Medicine. 2014;371(3):271-273.
  3. Carlson LA. "Nicotinic acid: The broad-spectrum lipid drug. A 50th anniversary review." Journal of Internal Medicine. 2005;258:94-114.
  4. Taylor AJ, et al. "ARBITER 2: a double-blind, placebo-controlled study of extended-release niacin on atherosclerosis progression in secondary prevention patients treated with statins." Circulation. 2004;110(23):3512-3517.
  5. Boden WE, et al. "Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy." The New England Journal of Medicine. 2011;365(24):2255-2267.
  6. Lai E, et al. "Suppression of niacin-induced vasodilation with an antagonist to prostaglandin D2 receptor subtype 1." Clinical Pharmacology & Therapeutics. 2007;81(6):849-857.
  7. Bloomfield HE. "ACP Journal Club: Adding niacin plus laropiprant to statins did no reduce vascular events and increased serious adverse events." Annals of Internal Medicine. 2014;161(10):JC8.
  8. Barter PJ, et al. "Effects of torcetrapib in patients at high risk for coronary events." The New England Journal of Medicine. 2007;351(21):2109-2122.
  9. Schwartz GG, et al. "Effects of dalcetrapib in patients with a recent acute coronary syndrome." The New England Journal of Medicine. 2012;367(22):2089-2099.
  10. 10.0 10.1 10.2 Multiple authors. "Correspondence: Niacin for reduction of cardiovascular risk." The New England Journal of Medicine. 2014;371:1940-1944.
  11. Supplementary Appendix
  12. Anderson TJ, et al. "Correspondence: Safety profile of extended-release niacin in the AIM-HIGH trial." The New England Journal of Medicine. 2014;371:288-290.