Last November the initial presentation at the AHA and simultaneous publication in the New England Journal of Medicine of the ARBITER 6-HALTS trial resulted in a storm of confusion and controversy. Now the final results of the trial have been published in the Journal of the American College of Cardiology. The data appear to provide strong confirmation that niacin was effective in inducing atherosclerosis regression as measured by CIMT while ezetimibe had no such effect.
Of the 315 patients randomized in the trial, 208 had a final CIMT measurement after the protocol specified 14 month endpoint. Following the early termination of the trial, an additional 107 patients had a final CIMT measurement after a mean followup of 7 months. As expected, patients on ezetimibe achieved lower total cholesterol, LDL, and HDL levels than niacin patients. Adherence to drug treatment was over 80% in both groups, but significantly higher in the ezetimibe group (87.5% for ezetimibe versus 82.1% for niacin).
Compared to baseline, niacin treatment resulted in a significant regression in mean CIMT (-0.0102 + 0.0026 mm; p < 0.001) and maximal CIMT (-0.0124 + 0.0036 mm; p < 0.001). By contrast, compared to baseline, ezetimibe had no significant effect on mean CIMT (-0.0016 + 0.0024 mm; p = 0.88) or maximal CIMT (-0.0005 + 0.0029 mm; p = 0.88).
The investigators, led by Allen Taylor, reported an exploratory analysis based on the cumulative drug exposure based on the differences in drug treatment period due to the early termination of the trial: “Increased cumulative drug exposure resulted in regression of CIMT with niacin, and progression of CIMT with ezetimibe,” they wrote.
Steve Nissen sent the following comment to CardioBrief:
This updated report on the results of ARBITER 6 continues to raise concerns about the effectiveness of ezetimibe, particularly in comparison to niacin. The difference in CIMT progression originally reported is now confirmed in a larger population. The study shows a highly significant reduction in HDL-C with ezetimibe treatment (p<0.001), which was unexpected. Even more concerning is the relationship between drug exposure and CIMT, which shows an increase in CIMT with greater exposure to ezetimibe and a decrease with greater exposure to niacin. These findings suggest an unexpected adverse effect of ezetimibe on disease progression. Although, hypothesis generating, not definitive, these results further emphasize the need to reserve ezetimibe as a drug of last resort. Unfortunately, the first clinical outcome trial with ezetimibe will not be completed before 2013, more than a decade after introduction of this drug.
Roger Blumenthal sent the following comment to CardioBrief:
This is a very well done study that answers nearly all of the concerns that were raised in our editorial. [Blumenthal was the co-author of an NEJM editorial accompanying the original publication of ARBITER 6.] It is clear that with this last observation carried forward analysis that all of the IMT studies in aggregate are consistent in showing that Niaspan does reduce carotid IMT more than ezetimibe does. Since we lack outcome data with ezetimibe, most clinicians now favor using extended release niacin as the preferred second line agent. However, the official guideines won’t change until the ongoing clinical trial results are available for AIM-HIGH and HPS2-Thrive. Drs. Taylor and Villenes should be congratulated on this superb analysis, which is very helpful in better understanding this very important paper in the field of Preventive Cardiology.