HPS2-THRIVE Trial of ER Niacin/Laropiprant
HPS2-THRIVE Trial of ER Niacin/Laropiprant
HPS2-THRIVE is the largest ever randomized trial of ER niacin treatment and the present report provides uniquely reliable information about its tolerability and side-effect profile. About one-third of the potentially eligible individuals who started the 2-month ERN/LRPT run-in phase were excluded prior to randomization, with many reporting known side effects of niacin. Consequently, HPS2-THRIVE is assessing the clinical efficacy and safety of ERN/LRPT among the types of patient at high risk of vascular events who are likely to be able to take it long term, which is the relevant question in clinical practice.
Known side effects of niacin on the skin, gastrointestinal system and diabetes account for most of the excess of medical reasons given for stopping ERN/LRPT during both the pre-randomization run-in and post-randomization follow-up phases. Skin side effects account for about half the excess, with itching, rashes, and flushing all reported more frequently. Flushing has been a major cause of niacin intolerance but was less frequently reported than itching or rash in HPS2-THRIVE, perhaps due to laropiprant blocking prostaglandin D2 signalling (whereas itching and rash are mediated by prostaglandin E). ERN/LRPT was also associated with an excess of indigestion and diarrhoea, but there was no apparent excess of hepatobiliary side effects.
A meta-analysis of niacin trials (predominantly among Caucasians not on a statin) did not find any evidence of an excess of muscle problems, and niacin is not thought to cause myopathy in the absence of statin therapy. However, during development of lovastatin, it was noted that the frequency of myopathy rose from 0.2% with lovastatin alone to 2% when co-administered with niacin. An important finding from the present analyses in HPS2-THRIVE is the highly significant four-fold excess risk of any myopathy with the addition of ERN/LRPT to simvastatin 40 mg daily (with or without ezetimibe 10 mg daily). This excess risk was particularly marked among the participants in China, where the background rate of myopathy with the study LDL-lowering therapy alone was higher than among the participants in Europe. During 2009, after definite myopathy had been recorded in 52 (including 34 after randomization) participants in China (and only 4 in Europe), the independent Data Monitoring Committee advised the investigators that it was substantially more frequent in the participants allocated active ERN/LRPT and the prescribing information was updated accordingly.
The mechanism for this myopathy-related interaction between niacin and simvastatin is not clear. Nor is it clear why the rate of myopathy on simvastatin alone is higher among Chinese individuals. Niacin does not inhibit cytochrome P450 3A4 or interfere with statin-glucuronidation, but it has been found to increase simvastatin blood concentrations by about one-third, and statin-induced myopathy is known to be associated with higher blood statin levels. Asian subjects are also recognized to have higher blood levels than Caucasians following a given statin dose and this too may be a contributory factor. However, it should be noted that—even among Chinese individuals—this small absolute excess of myopathy with simvastatin 40 mg daily (with or without niacin) is likely to be greatly outweighed by its cardiovascular benefits in the sort of high-risk patients included in HPS2-THRIVE.
Niacin has a variety of effects on lipids, including lowering LDL-C, apoB, and Lp(a) and raising HDL-C and apoA1, which might be expected to translate into reductions in vascular events. Over 25 000 people at high risk of vascular events were randomized in HPS2-THRIVE and three-quarters remained compliant with ERN/LRPT after 3.9 years' median follow-up. Based on this compliance and the lipid changes observed during the pre-randomization run-in, it was estimated prior to unblinding the trial that study average differences in LDL-C of ~0.25 mmol/L and HDL-C of ~0.13 mmol/L would have been achieved. Based on previous observational studies and randomized trials, it was anticipated that such lipid differences might translate into a 10–15% reduction in vascular events. At least 3400 of these high-risk participants were expected to have confirmed MVEs during an average of ~4 years of follow-up, so HPS2-THRIVE has excellent statistical power to detect or exclude effects of this magnitude.
Discussion
HPS2-THRIVE is the largest ever randomized trial of ER niacin treatment and the present report provides uniquely reliable information about its tolerability and side-effect profile. About one-third of the potentially eligible individuals who started the 2-month ERN/LRPT run-in phase were excluded prior to randomization, with many reporting known side effects of niacin. Consequently, HPS2-THRIVE is assessing the clinical efficacy and safety of ERN/LRPT among the types of patient at high risk of vascular events who are likely to be able to take it long term, which is the relevant question in clinical practice.
Known side effects of niacin on the skin, gastrointestinal system and diabetes account for most of the excess of medical reasons given for stopping ERN/LRPT during both the pre-randomization run-in and post-randomization follow-up phases. Skin side effects account for about half the excess, with itching, rashes, and flushing all reported more frequently. Flushing has been a major cause of niacin intolerance but was less frequently reported than itching or rash in HPS2-THRIVE, perhaps due to laropiprant blocking prostaglandin D2 signalling (whereas itching and rash are mediated by prostaglandin E). ERN/LRPT was also associated with an excess of indigestion and diarrhoea, but there was no apparent excess of hepatobiliary side effects.
A meta-analysis of niacin trials (predominantly among Caucasians not on a statin) did not find any evidence of an excess of muscle problems, and niacin is not thought to cause myopathy in the absence of statin therapy. However, during development of lovastatin, it was noted that the frequency of myopathy rose from 0.2% with lovastatin alone to 2% when co-administered with niacin. An important finding from the present analyses in HPS2-THRIVE is the highly significant four-fold excess risk of any myopathy with the addition of ERN/LRPT to simvastatin 40 mg daily (with or without ezetimibe 10 mg daily). This excess risk was particularly marked among the participants in China, where the background rate of myopathy with the study LDL-lowering therapy alone was higher than among the participants in Europe. During 2009, after definite myopathy had been recorded in 52 (including 34 after randomization) participants in China (and only 4 in Europe), the independent Data Monitoring Committee advised the investigators that it was substantially more frequent in the participants allocated active ERN/LRPT and the prescribing information was updated accordingly.
The mechanism for this myopathy-related interaction between niacin and simvastatin is not clear. Nor is it clear why the rate of myopathy on simvastatin alone is higher among Chinese individuals. Niacin does not inhibit cytochrome P450 3A4 or interfere with statin-glucuronidation, but it has been found to increase simvastatin blood concentrations by about one-third, and statin-induced myopathy is known to be associated with higher blood statin levels. Asian subjects are also recognized to have higher blood levels than Caucasians following a given statin dose and this too may be a contributory factor. However, it should be noted that—even among Chinese individuals—this small absolute excess of myopathy with simvastatin 40 mg daily (with or without niacin) is likely to be greatly outweighed by its cardiovascular benefits in the sort of high-risk patients included in HPS2-THRIVE.
Niacin has a variety of effects on lipids, including lowering LDL-C, apoB, and Lp(a) and raising HDL-C and apoA1, which might be expected to translate into reductions in vascular events. Over 25 000 people at high risk of vascular events were randomized in HPS2-THRIVE and three-quarters remained compliant with ERN/LRPT after 3.9 years' median follow-up. Based on this compliance and the lipid changes observed during the pre-randomization run-in, it was estimated prior to unblinding the trial that study average differences in LDL-C of ~0.25 mmol/L and HDL-C of ~0.13 mmol/L would have been achieved. Based on previous observational studies and randomized trials, it was anticipated that such lipid differences might translate into a 10–15% reduction in vascular events. At least 3400 of these high-risk participants were expected to have confirmed MVEs during an average of ~4 years of follow-up, so HPS2-THRIVE has excellent statistical power to detect or exclude effects of this magnitude.
