Higher Rates of Myopathy in Chinese Patients: HPS2-THRIVE

August 27, 2012

August 27, 2012 (Munich, Germany) — A prespecified interim safety and tolerability analysis of the Heart Protection Study 2--Treatment of HDL to Reduce Vascular Events (HPS2-THRIVE) study has shown that approximately 75% of patients are compliant with the combination of extended-release niacin and laropiprant after three years of therapy.

Presented here today at the European Society of Cardiology 2012 Congress, Dr Jane Armitage (Oxford Clinical Trial Service Unit, UK) reported that 15.7% of patients treated with niacin/laropiprant withdrew from therapy for medical reasons compared with 7.5% of patients treated with placebo. More patients treated with the active therapy also reported gastrointestinal and skin side effects, mainly pruritus and itching, with a little bit of flushing.

HPS2-THRIVE is the largest study to date of the cardiovascular benefits of raising HDL-C levels. The trial, which includes more than 25 000 patients from Europe and China, is designed to determine whether a combination tablet containing extended-release niacin and laropiprant, a specific blocker of prostaglandin D2 to prevent flushing, reduces the risk of MI, stroke, or revascularization in individuals with existing vascular disease. Patients in the active-treatment and placebo arms are also receiving background LDL-C treatment with simvastatin 40 mg.

Of the more than 12 000 patients treated with niacin/laropiprant, 1.13% developed myopathy compared with 0.18% of subjects treated with placebo. The increased rate of myopathy was largely driven by patients of Chinese descent, however, with 62 of 69 myopathy cases reported in China. Rhabdomyolysis was rare, occurring in 0.05% and 0.02% of niacin/laropiprant- and placebo-treated patients, respectively.

"The most striking thing here is that there is a higher background risk of myopathy among our Chinese participants," said Armitage, "and much of this sixfold excess risk of myopathy is driven by the incidence in China."

The increased risk of myopathy/rhabdomyolysis when simvastatin was coadministered with >1 g/day of niacin was identified by the HPS2-THRIVE independent safety monitoring committee. This resulted in a change to the simvastatin label cautioning physicians not to prescribe Chinese patients simvastatin 80 mg. The Food and Drug Administration has since recommended that physicians restrict prescribing high-dose simvastatin to all patients, given the increased risk of muscle damage, unless the patient has already been taking the drug for 12 months and there is no evidence of myopathy.

Results of HPS2-THRIVE Eagerly Anticipated

The results of HPS2-THRIVE, which are not expected until 2013, are eagerly anticipated, given the recent collapse of the Atherothrombosis Intervention in Metabolic Syndrome with Low HDL Cholesterol/High Triglyceride and Impact on Global Health Outcomes (AIM-HIGH) study. As previously reported by heartwire , the AIM-HIGH study, in which patients with a history of cardiovascular disease, high triglycerides, and low HDL-C levels were treated with high-dose extended-release niacin and statin therapy, was stopped 18 months early because niacin offered no additional benefits in this patient population.

During the clinical-trials-update session at the ESC meeting, Armitage explained that patients were treated with extended-release niacin/laropiprant or placebo during an eight-week run-in phase prior to randomization. During that time, 25.4% of patients in the active-treatment arm withdrew from therapy for various reasons. Of these individuals, 11.3% withdrew because of skin conditions, such as itching and rashes. During the run-in phase, LDL-C levels were reduced by 20% and HDL-C levels increased by 17%. The change in lipid parameters differs from the AIM-HIGH trial, in which LDL-C levels were reduced by just 5.5% and HDL-C levels increased by 13.2%.

Speaking during the update, Dr Ulf Landmesser (University of Zurich, Switzerland) noted that the AIM-HIGH and HPS2-THRIVE studies differ in that AIM-HIGH tested the HDL-C-raising hypothesis alone, with investigators aiming to have minimal differences in LDL-C levels in the treatment arms. As the scheduled discussant, Landmesser said that HDL-C as a treatment goal has increasingly become recognized as a complex target, with some researchers focusing on HDL-C functionality rather than HDL-C levels. Regarding the potential side effects of niacin, while laropiprant is effective, flushing can occur via other pathways, so the agent does not completely stop the common adverse effect, he said.

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