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HPS2-THRIVE: Treatment of HDL to Reduce the Incidence of Vascular Events



Presenter: Jane Armitage | see Discussant report


Discussant: Ulf Landmesser | see Presenter abstract



The HPS2-THRIVE (Treatment of HDL to Reduce the Incidence of Vascular Events) study examines the effects of ER-niacin/laropiprant treatment in addition to simvastatin (40 mg) therapy on cardiovascular events in patients with established occlusive arterial vascular disease. This trial has randomized 25`673 patients in the UK, Scandinavia and China and is adequately powered to address the question of whether adding ER-niacin/laropiprant therapy to statin treatment can further lower the risk of adverse cardiovascular events.
With the overwhelming evidence of a net clinical benefit of statin therapy in patients with high vascular risk, clinical studies examining efficacy of lipid-targeted therapies to reduce cardiovascular events are now largely performed in addition to statin therapy. Several lipid-targeted therapies are currently examined in large clinical outcome trial programs, either resulting in further LDL-cholesterol lowering (ezetimibe; monocloncal PCSK9-antibody) or a combined LDL-cholesterol lowering and HDL-cholesterol raising (niacin; potent CETP-inhibitors anacetrapib and evacetrapib).
Niacin was the first lipid-lowering drug. In 1955, Dr Altschul and colleagues observed that high doses of vitamin B3 (niacin) lowered serum cholesterol levels. The Coronary Drug Project (CDP), a randomized clinical trial performed in the seventies, suggested that niacin therapy reduced the risk of myocardial infarction (without statin therapy). It was only in 2003, that the niacin receptor (GPR-109A) was discovered.
This resulted in a better understanding of molecular mechanisms of well-known skin side effects of niacin, e.g. flushing. These side effects are partly mediated by GPR-109A-dependent activation of skin immune cells leading to production of PGD2, stimulating vascular DP1 receptors resulting in vasodilation. In addition, niacin can also stimulate GPR-109A-dependent PGE2 production of keratinocytes activating prostaglandin E2/E4 receptors. In 2009, it was observed that addition of laropiprant, a DP1 receptor antagonist, to niacin-treatment reduced flushing.
The observations from the HPS2-THRIVE study suggest that approximately 2/3 of patients can tolerate long-term niacin/laropiprant treatment. The carefully presented safety analysis suggests that myopathy occurs in 0.5 % of patients treated with simvastatin 40 mg and niacin/laropiprant, however, the vast majority of these cases were observed in patients with Chinese descent. These observations have resulted in a FDA-approved label change for simvastatin, indicating that patients of Chinese descent should not receive simvastatin 80 mg with cholesterol-modifying doses of niacin-containing products and that caution is recommended when such patients are treated with simvastatin 40 mg or less in combination with cholesterol-modifying doses of niacin-containing products.
The HPS2-THRIVE study is a substantially larger study with a longer follow-up (4 years) as compared to the AIM-HIGH study, presented in 2011, where no significant effect of ER-niacin therapy on cardiovascular events was observed in 1718 vs. 1696 patients. Notably, in AIM-HIGH higher doses of statins and ezetimibe were more frequently used in the control group, since the study aimed to have similar LDLcholesterol levels in the active treatment and control arms, making the interpretation of the results more difficult. The data in HPS2-THRIVE on the effects of niacin/laropiprant treatment on vascular events are expected to be presented in 2013.


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Clinical Trial & Registry Update I: Updates on Prevention and Markers

The content of this article reflects the personal opinion of the author/s and is not necessarily the official position of the European Society of Cardiology.