Recently, the study by Lee et al. showed the addition of high-dose extended-release niacin (niacin ER, Niaspan) to simvastatin therapy resulted in regression of atherosclerotic plaque size measured by MRI of the common carotid artery.1 The results seem to indicate that raising HDL with niacin ER can induce further disease regression in patients on a statin with an LDL-C < 100. The ARBITER 6-HALTS study, recently published in New England Journal of Medicine,2 and the NIA Plaque study presented at the 2009 AHA Scientific Sessions in Orlando, have added new and conflicting information on this topic.3
The Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol 6: HDL and LDL Treatment Strategies in Atherosclerosis (ARBITER 6-HALTS) study was a randomized controlled trial comparing the effect of a statin combined with either ezetimibe (Zetia®) or niacin ER 2000 mg daily on carotid intima media thickness (CIMT) measured by ultrasonography. Patients enrolled in this study had established coronary heart disease (CHD) or CHD risk equivalent, had been taking a stable dose of a statin and had an LDL-C < 100 mg/dL (mean ~ 84 mg/dL overall) and HDL < 50 mg/dL for males and < 55 mg/dL for females (mean ~ 44 mg/dL overall) at baseline. At 14 months the statin combined with ezetimibe reduced LDL-C (-17.6 ± 20.1 mg/dL) and HDL (-2.8 ± 5.7mg/dL); niacin also reduced LDL-C (-10 ± 24.5 mg/dL) but increased HDL (7.5 ± 9.2 mg/dL). The trial was halted early with only 208 of 363 randomized patients completing the study due to achievement of a statistically significant difference in mean CIMT favoring the statin plus niacin ER combination. Significant CIMT measured plaque size regression was observed in the niacin ER treated patients; mean CIMT in the ezetimibe group was essentially unchanged at 14 months. In an interesting post hoc analysis, the authors found a significant correlation between high LDL-C reductions and plaque size progression in the ezetimibe group; this relationship was not seen in the niacin ER group. These results suggest not only an incremental benefit of raising HDL with niacin ER when added to a statin but also that LDL-C reductions with ezetimibe are ineffective at best and harmful at worst. The hypothesis that raising HDL in patients at goal on a statin may provide additional cardioprotection is also supported by a meta-analysis presented at the recent 2009 AHA Scientific Sessions that showed patients taking statins had 9.7 fewer CHD events per 1000 patient years for every 10 mg/dL increase in HDL levels.4
While the ARBITER 6-HALTS results simultaneously support the results of the ENHANCE trial and also the study by Lee and colleagues, questions have been raised about the validity its findings.5,6 In two accompanying editorials the trial was criticized for terminating early thereby ignoring the possibility that beneficial effects with ezetimibe may take longer than 14 months to develop.7,8 Additionally, the recently presented NIA Plaque study showed no difference in CIMT in patients treated with a statin plus niacin versus a statin plus placebo after a longer follow-up period of 18 months. It bears mentioning, however, that the NIA Plaque study used a smaller niacin dose (1500 mg) than either the ARBITER 6-HALTS trial or the trial by Lee et al., and also included higher-risk patients than those two trials. Both of these could potentially explain the difference in outcome.
So what lessons can be learned from all of this new information? At the heart of this debate is an important clinical question: In patients at high risk for CHD events with an LDL-C that is at or below goal, will targeting further LDL reduction, or targeting HDL increase prevent more cardiovascular events and deaths? The answer to that question of course is tied very closely to whether add-on therapy with either ezetimibe or niacin ER will provide the most incremental benefit over statin therapy. Some studies have suggested maximizing statin therapy to achieve a more aggressive LDL-C goal < 70 can better prevent CHD events in very high-risk patients.9 This strategy was not tested in these trials but could also be considered as an option to further reduce LDL-C in lieu of add-on therapy.
Obviously since none of these trials directly evaluated the clinical endpoints of interest they do not directly answer the clinical question. Fortunately, there are ongoing large scale clinical trials that will answer the question: the AIM-HIGH (April 2011) and HPS2-THRIVE (January 2013) trials with niacin ER and the IMPROVE-IT (June 2012) trial with ezetimibe. It will be years, however, before any of these trials are ...