November 15, 2011 (Orlando, Florida) — The AIM-HIGH trial and the future of niacin remained the focus of hot debate following presentation of the full results here at the American Heart Association (AHA) 2011 Scientific Sessions, with the scheduled discussant blasting the study as being far too short and underpowered to change practice.
"This trial disturbs me greatly," HDL guru Dr Philip Barter (The Heart Research Institute, Sydney, Australia) told an AHA press conference. "It cannot be emphasized too much that this trial has not tested the hypothesis of raising HDL or the benefit of niacin. No one should stop taking niacin based on these results."
As announced back in May, the Atherothrombosis Intervention in Metabolic Syndrome with Low HDL Cholesterol/High Triglyceride and Impact on Global Health Outcomes (AIM-HIGH) study was stopped early when niacin (Niaspan, Abbott) showed no signs of additional benefits over placebo in patients already at target levels of LDL; a small, unexplained increase in ischemic stroke was also seen in the niacin group. Full AIM-HIGH results, suggesting that the stroke issue may have just been the play of chance, were published first thing this morning in the New England Journal of Medicine [1] and reported at that time by heartwire .
Arguing Over AIM-HIGH
Barter took issue with the fact that AIM-HIGH was designed to show a 25% reduction in CV events, saying: "This is incredibly ambitious. It would have needed to go on for 15 to 20 years to draw any conclusions."
He pointed out that niacin did increase HDL by 25%, but unfortunately HDL also increased substantially in the placebo group, by 8% to 10%, so that the difference in HDL between the two groups was just 4 mg/dL.
"We know from population studies that this would only give a maximum of 12%--probably closer to 8% to 9%--reduction in events. . . . The confidence intervals in AIM-HIGH are consistent with this."
Finally, said Barter, there looked as if there were a 25% dropout rate, which further underpowered the study.
"We mustn't overreact to a trial that has no ability to answer the question, especially as we have another much larger trial under way (HPS2-THRIVE)," he stressed. "If THRIVE is negative, then niacin will be finished, but until then we should not be taking patients off the drug."
But the chief investigator of AIM-HIGH, Dr William Boden (University at Buffalo School of Medicine, NY), said he stood by the results. "I disagree with Dr Barter. We can't conclude that a 4-mg/dL increase in HDL is insufficient to show an effect on events," he retorted, citing the VA-HIT trial, which showed a 22% reduction in events with just a 2-mg/dL increase in HDL with gemfibrozil.
But Barter shot back that gemfibrozil was "a completely different drug," and the beneficial effect in VA-HIT was almost certainly due to other effects, not the small HDL increase.
Boden, in turn, was adamant that the AIM-HIGH result should not be ignored: "We saw exactly the predicted changes in lipids with niacin, and the fact remains that the event curves for the two groups were spot-on superimposable. I think we can say from these results that if you are able to maintain levels of LDL in the low 60s, then we haven't got the evidence to support using niacin."
Boden said the most likely explanation for the HDL increase in the placebo group was that placebo patients took higher doses of simvastatin to keep their LDL levels at goal, noting that simvastatin has HDL-raising properties. He dismissed the idea that the HDL rise was due to the placebo pills being spiked with a small dose of immediate-release niacin to produce some flushing so that the trial could remain blinded, saying: "This small dose would not have been enough to have any effect on HDL."
The chair of the late-breaking clinical-trial session at which AIM-HIGH was presented, Dr John Kastelein (Academic Medical Center, Amsterdam, the Netherlands), suggested that the study design did not make it easy to show a benefit of niacin. "By allowing uptitration of the statin in the placebo arm and giving them a low dose of niacin, it strikes me that you have really stacked the deck against the chances of this trial showing success. I would have prevented at all costs these types of changes in the placebo group."
Experts Divided
Other lipid experts appeared divided on the argument. Dr Stephen Nicholls (Cleveland Clinic, OH) sided with Barter. "Niacin has many other beneficial effects on lipids as well as raising HDL. It reduces triglycerides and Lp(a), and we have seen regression of atherosclerosis in imaging studies. I agree that we need to wait for THRIVE. In my view, there are patients with lipid abnormalities that should be treated with niacin."
But Dr Roger Blumenthal was not convinced by Barter's arguments. "I think it is pretty clear that if you start off with an LDL of 70, you're not going to see much of a benefit with niacin for at least three years. It would be different possibly if this drug were very well tolerated, but it isn't. We can't say to patients that it is really worth putting up with horrible side effects because we have data that show a definitive benefit."
And Dr Elliott Antman (Brigham and Women's Hospital, Boston, MA), who chaired the morning press conference, said: "I think what we are seeing here is clinical equipoise."
Commenting on the debate for heartwire , Dr Robert Bonow (Northwestern University, Chicago, IL) predicted doctors would be split on how they interpret the results.
"The early release of the neutral results, with talk of an increase in ischemic stroke, has already had an effect, with many doctors stopping prescribing niacin. But now, with the arguments about the study being underpowered we've heard today and the final results suggesting that stroke is not such a concern, I think some doctors will reconsider that action."
Asked what he recommended doctors do, Dr Steve Nissen (Cleveland Clinic) reminded heartwire that full-dose statins should always be the first option to get LDL levels down 70 mg/dL or below.
"Statins should be first-, second-, and third-line treatment. But when we have exhausted this line of thinking, niacin may still be useful. I am perhaps a little bit more reluctant to prescribe niacin now, but I do believe Dr Barter's comments are entirely appropriate, so I don't think AIM-HIGH should change our thinking too much."
Heartwire from Medscape © 2011 Medscape, LLC
Cite this: AIM-HIGH Fallout: Experts Disagree Over Niacin's Niche - Medscape - Nov 15, 2011.