Is niacin ineffective? Or did AIM-HIGH miss its target?
ABSTRACTThe AIM-HIGH trial (Atherothrombosis Intervention in Metabolic Syndrome With Low HDL/High Triglycerides: Impact on Global Health Outcomes) found, in an interim analysis, no cardiovascular benefit from taking extended-release niacin (Niaspan). In fact, there was a trend toward a greater risk of ischemic stroke, which did not reach statistical significance. But questions remain about this complex trial, which included intensive statin therapy in the active-treatment group and the control group.
KEY POINTS
- The study was stopped early because of the concerns raised by the interim analysis.
- The AIM-HIGH results can be interpreted in several ways: perhaps niacin is no good as a preventive agent; perhaps raising levels of high-density lipoprotein cholesterol (HDL-C) is flawed as a preventive strategy; perhaps AIM-HIGH had methodologic flaws; or perhaps statins are so good that, once you prescribe one, anything else you do will not make much of a difference.
- It seems reasonable to continue niacin treatment in patients who need its multiple lipid-modifying effects. It is uncertain if clinicians will be less likely to prescribe niacin therapy until we have clear evidence of clinical benefit. As for HDL-C, it remains to be determined whether any therapy targeting quantitative or qualitative changes will be beneficial.
Is raising HDL-C a flawed strategy?
The failure of HDL-C-raising therapies in clinical trials15,16 has fueled concern that HDL may not be the magic elixir that many have sought. Given that niacin is the most effective HDL-C-raising agent currently available, its lack of efficacy in AIM-HIGH could be perceived as another nail in the coffin of the hypothesis that raising the HDL-C level with pharmacologic agents is beneficial.
AIM-HIGH was designed to examine the effects of raising HDL-C. To this end, it was performed exclusively in patients with low HDL-C levels, and the investigators tried to isolate the potential effects of raising HDL-C by equalizing the LDL-C levels in the treatment groups.
However, the HDL-C changes observed in AIM-HIGH are likely to have undermined the study objective. While niacin predictably increased HDL-C levels by 25%, an unexpected increase in HDL-C of 9.8% in the placebo-treated patients resulted in a difference in achieved HDL-C levels of only 4 mg/dL between the groups. This was far less than anticipated, and it likely had a major impact on an already underpowered study.
AIM-HIGH was designed to have 85% power to demonstrate a 25% reduction in clinical events, which was an optimistic estimate. On the basis of population studies, a difference of 4 mg/dL in HDL-C would be anticipated to result in no more than a 10% lower rate of clinical events, far beyond AIM-HIGH’s limit of detection.
The reasons for the increase in HDL-C in the placebo group are unknown, but they likely reflect the use of higher doses of simvastatin, some regression to the mean, and, possibly, the small doses of immediate-release niacin that the placebo contained. (Contrary to the belief of the investigators, there have been some reports of lipid changes with such doses,17 which may have contributed to the observed HDL-C-raising.)
Given that the HDL-C difference between the groups was relatively small and that niacin has additional effects beyond raising HDL-C and lowering LDL-C, it is unlikely that the futility of AIM-HIGH reflects a major indictment of HDL-C-raising. For the time being, the jury is still out on this question.
Was AIM-HIGH methodologically flawed?
A number of methodologic issues may have affected AIM-HIGH’s ability to adequately address its objectives.
The wrong cohort? In planning a study such as AIM-HIGH, the need for a relatively small sample size and the need to detect the greatest relative risk reduction with niacin would require enrollment of patients at the highest risk of cardiovascular events despite the use of statins. These needs were satisfied by only including patients who had atherosclerotic cardiovascular disease and low HDL-C levels. The inclusion of patients with low levels of HDL-C was also expected to promote greater increases in this lipid, and potentially event reduction, with niacin.
But no benefit was observed. It remains to be determined whether the inclusion of a high proportion of patients with the metabolic syndrome adversely affected the ability to detect a benefit with niacin. While post hoc analyses of studies of carotid intimal-medial thickness demonstrated no relationship between raising HDL-C with niacin and slowing of disease progression in patients with the metabolic syndrome,18 it remains to be determined whether this would translate to any effect on cardiovascular event rates.
Inadequate statistical power? An underpowered study would leave very little room for error, a pertinent point given the variability in therapeutic response in both actively treated and placebo-treated patients typically encountered in clinical trials. Giving low doses of immediate-release niacin and titrating the simvastatin dose to control LDL-C, resulting in imbalances in lipid-modifying therapies, represent additional flaws in the study design.
Stopped too soon? The early cessation of the study was somewhat questionable. The study crossed the prespecified boundary for lack of efficacy at the time of the interim analysis, and initial review by the data and safety monitoring board suggested an excess rate of ischemic stroke with niacin. The inclusion of this latter finding in the press release prompted considerable speculation regarding potential mechanisms and also concern among patients currently taking niacin. The subsequent finding that this signal was not statistically significant serves as an important warning for those conducting clinical trials not to prematurely overstate preliminary observations.
The implications for agents used in clinical practice are considerable: negative findings should not be overemphasized without robust evidence.
Do statins make everything else irrelevant?
The final factor to consider is the relative modifiability of residual clinical risk in statin-treated patients.
While residual risk is often cited as the reason to develop new antiatherosclerotic therapies, it is unknown how many of these ongoing events can be prevented. Several nonmodifiable factors such as age and concomitant disease are likely to contribute to these clinical events, which may limit our ability to further reduce event rates in patients who have already achieved low LDL-C levels with statin therapy. This may underscore the observation that no major clinical trial has demonstrated clinical benefit of an antiatherosclerotic agent on top of background medical care that included statins.
The finding that atherosclerosis continues to progress in many patients even though they take statins in high doses or achieve low LDL-C levels suggests that there is still room for improvement.
WHAT FUTURE FOR NIACIN?
So what does the future hold for niacin? The ongoing HPS2-THRIVE study provides another opportunity to evaluate the potential clinical efficacy of niacin in statin-treated patients. For now, we must wait for the results of this study.
In the meantime, it would seem reasonable to continue treatment with niacin in patients who need it for its multiple lipid-modifying effects. Whether clinicians will be less likely to initiate niacin therapy until there is clear evidence of clinical benefit remains uncertain. As for HDL-C, it remains to be determined whether any therapy targeting either quantitative or qualitative changes will be beneficial.
Over the last 3 decades, clinical trials have provided important insights into the prevention of cardiovascular events and have had a profound impact on clinical practice. Such studies simply evaluate whether one strategy is better or worse than the existing standard of care. They do not provide mechanistic insights, and when attempts have been made to address mechanisms in the study design, the trial, as in the case of AIM-HIGH, leaves more questions than answers.
Future trials will provide more clarity as to the optimal way to treat patients, but they must be based on a robust design that permits the study question to be adequately addressed.
