What Future for Niacin After AIM-HIGH?

AIM-HIGH Fallout

July 05, 2011

July 4, 2011 (New York, NY) — It is now a month after the surprise announcement by the US National Heart, Lung, and Blood Institute (NHLBI) that it was stopping the AIM-HIGH trial of extended-release niacin (Niaspan, Abbott) for patients with low HDL and high triglycerides because of futility, and, as expected, sales of Niaspan have started to fall.

Although it is believed that raising HDL will be beneficial, no large outcome trial has actually shown a reduction in clinical events with this approach, and the first major HDL-raising drug to be tested in a large trial--Pfizer's torcetrapib--spectacularly failed a few years ago. This was attributed by many to an off-target effect of torcetrapib on raising blood pressure, and the focus therefore shifted to other HDL-raising drugs, of which niacin is one. This agent has been around for a long time and is known to effectively raise HDL and lower LDL and triglycerides. But it is hard to tolerate, with the main side effect of flushing causing many patients to discontinue treatment. Niaspan is an extended-release formulation of niacin claimed to reduce the flushing side effects of the drug.

While the stopping of AIM-HIGH for futility will inevitably make doctors think more carefully about prescribing niacin, what is actually happening out there in clinical practice? But how has the lipid community reacted to the results? heartwire asked several lipid experts and general cardiologists if they had changed their practice since the disappointing, albeit preliminary, results were reported.

AIM-HIGH highlights

AIM-HIGH enrolled 3414 patients with a history of cardiovascular disease, low HDL cholesterol, and high triglycerides who were all prescribed simvastatin and then randomized to Niaspan in gradually increasing doses up to 2000 mg/day or placebo. Of the patients, 515 were given a second LDL-lowering drug, ezetimibe (Zetia, Merck/Schering-Plough), in order to maintain LDL levels at the target range of 40–80 mg/dL. At the time the trial was stopped, the primary end point (a composite of fatal or nonfatal MI, stroke, ACS, or revascularization) had occurred at an annualized rate of 5.8% in the niacin group vs 5.6% with placebo. During the 32-month follow-up period, there were 28 strokes (1.6%) in the niacin group vs 12 strokes (0.7%) in the control group, but nine strokes in the niacin group occurred after the drug had been discontinued.

20% fall in Niaspan sales forecast this year

For the week ending June 17, the third full week after the NHLBI announcement, total Niaspan sales fell 5.3% compared with the same week last year, but new prescriptions were down 9.5%, according to analysts Larry Biegelsen and Lei Huang from Wells Fargo Securities, who are forecasting a 20% fall in prescriptions over the year.

Niaspan has shown a sharp growth in sales in recent years, correlating with growing enthusiasm for raising HDL. The Niaspan franchise, which includes Advicor (Niaspan and generic lovastatin) and Simcor (Niaspan and generic simvastatin), recorded sales of $1.1 billion in 2010, with 8.2 million prescriptions written.

Leading cardiologists polled by heartwire had a mixed response on whether they would be changing their practice based on the AIM-HIGH announcement. Many want to know more details about the study before making any decisions.

One of these is Dr Steven Nissen (Cleveland Clinic, OH), who was a lead investigator in the torcetrapib trials. He commented to heartwire : "Circumstances under which the [NHLBI] stopped AIM-HIGH are not very clear. The reporting of the reasons was obscure and difficult to understand. It was stopped for futility, not harm. We don't know if the stroke risk was significant or not. We have been left in a quandary. There are no published results. As the dust settles, many people, including me, want to wait to see the published paper and even then maybe for more data before changing practice. We shouldn't be changing practice based on a press conference or a press release."

Less use in patients with low LDL

However, almost all experts questioned said they would not be using niacin so much now in patients with low LDL. AIM-HIGH was different from other studies in that patients were receiving aggressive LDL lowering, and mean LDL was very low--an average of 71 mg/dL. Many doctors believe that because of this, patients were at such a low risk that it would have been hard to show an additional benefit.

Dr William Boden (University at Buffalo Schools of Medicine, NY), co-chief investigator of AIM-HIGH, said he has changed his practice regarding the subset of stable CHD patients with low HDL who have achieved the aggressive levels of LDL reduction attained in the study. "In my experience, this is about 10–20% of all patients I see who can get (and maintain) these sustained low levels of LDL control. For all other patients (and in higher risk patients like those with MI or ACS who were excluded, by design, from AIM-HIGH), my approach and practice has not changed, and I continue to aggressively seek both LDL lowering and HDL raising/TG lowering with either Niaspan and/or fibrates," he added.

Dr James Stein (University of Wisconsin School of Medicine and Public Health, Madison) told heartwire : "I really do wonder, if you get LDL and total cholesterol low enough, whether HDL matters any more. One expert I know always said that the main problem with low HDL is LDL particle excess. I have always suspected, based on secondary analyses, that the observed benefit of niacin was reducing LDL particles, not the HDL increases we have focused on. Maybe the residual risk is just too low to make a difference, or maybe the LDL particle effects of niacin are not enough to make a difference once we get to this low a level."

I really do wonder, if you get LDL low enough, whether HDL matters any more.

He added: "Right now, this has not affected my practice in a major way. I might be a little less inclined than I was previously to add niacin to a statin if someone's LDL is very low. But I always have tried to maximize the statin and lifestyle intervention before adding in other agents."

Dr Prediman Shah (Cedars Sinai Hospital, Los Angeles, CA) commented to heartwire : "There are so many outstanding questions about the trial it is very difficult to make any decisions based on the limited information we have now. It is possible that the LDL was so low that the patients' risk would be low, and that means it would take much longer follow-up to show any benefit of raising HDL. I suppose the results are telling us that if LDL is well-controlled, we could consider discontinuing niacin if it is being used only for its HDL-raising properties. Until more detailed data become available, we are telling our patients that if they are doing well on niacin not to stop taking it. But we are not starting new patients on it at the moment, especially if their LDL is well-controlled. We still have considerable uncertainty about the AIM-HIGH result, but I am not going to jump to put people on niacin as soon as I see a low HDL level after these results. So, yes, I will be using less niacin now. Although we are still operating in the dark with regard to the AIM-HIGH details, the information we do have does cause us to pause for thought on the use of niacin."

I am not going to jump to put people on niacin as soon as I see a low HDL after these results.

Dr Roger Blumenthal (Johns Hopkins University School of Medicine, Baltimore, MD) and Dr Christie Ballantyne (Methodist DeBakey Heart and Vascular Center, Houston, TX) seem to be taking a similar stance. Blumenthal said: "I am now much less apt to prescribe niacin in persons whose LDL cholesterol is well-controlled, such as to a level of 70 mg/dL, which was the approximate mean in the AIM-HIGH trial. I am still prescribing niacin in persons who can't get to their LDL goal on the maximally tolerated dose of a statin. I tell my patients on niacin that I will keep them on niacin until the final data are published, and we can see if there are some subgroups that may have had a trend for benefit."

Ballantyne commented: "We have to be careful to examine the design of the AIM-HIGH trial. The results imply that if we have LDL to our target levels, adding niacin does not appear to be of significant benefit in these patients, and thus I will be using less niacin in such cases than before. However, niacin may still be of benefit if patients are not able to achieve goals for LDL, non-HDL-cholesterol, or [apolipoprotein B] apoB. I have many patients who continue to have elevated LDL or non-HDL cholesterol levels on maximally tolerated statin therapy (many patients cannot tolerate high doses of statins), and niacin may still have benefit in such patients. In addition, some patients cannot tolerate statins at all, and finally, we need data about the patients with very high levels of [lipoprotein(a)] Lp(a) from these studies to see whether they benefit from niacin."

What to make of the stroke data

The experts are also unsure of what to make of the suggested increase in stroke in the niacin arm. Shah commented: "The stroke situation is murky. Many of the strokes appeared to occur after the patient stopped taking niacin, but as it was an intention-to-treat analysis, they had to be included." But Blumenthal noted: "I find that patients are now much less likely to want to try niacin or stay off it, since they are concerned by the small excess number of strokes in the niacin group."

Boden says the p value for stroke was nominally significant at < 0.05, but the numbers "will continue to shift until the database is completed, cleaned up, and locked in late summer or early fall." He adds "that this unexpected signal of ischemic stroke with niacin (not seen in any earlier studies) likely also contributed to the NIH's decision to stop the trial."

Trial was underpowered

But many experts warned not to make any hasty decisions on this one study that was actually underpowered to show a benefit in events.

Lipid expert Dr Scott Grundy (University of Texas Southwestern Medical Center, Dallas) said: "Considering the relatively small number of patients in the trial and the fact that their LDL was already reduced to 70 mg/dL, it is not surprising that the trial was underpowered. I assume that the data safety and monitoring board recognized that the trial was underpowered so they decided not to continue it. It is likely that the number of events in the nonniacin arm was so small that it was clear that it will be very difficult to obtain enough events to give a positive result. But this is speculation. We will have to see the full results of the study before we can make a judgment."

Shah added: "The study was too small and follow-up too short to see any clinical benefit; after all, the Coronary Drug Project [CDP] showed benefits of niacin after 10 to 15 years. And the rigorously controlled LDL would make it even harder to show an incremental benefit. I would think AIM-HIGH was stopped because the [NHLBI] didn't want to invest any more money in a study that wasn't going to show a definite result. This was a government-funded trial and the US economy is in a bad state. The [National Institutes of Health] will be under pressure not to spend unnecessarily."

Stein points out that AIM-HIGH is just one study. "To make bold statements about niacin's 'failure' is just a way to grab attention and does not serve medical science or our patients. There is no doubt that niacin as used in other studies (CDP, Stockholm, HATS, FATS) is an effective agent for reducing CVD events. And there are a lot of physiological and imaging data to support its benefits as well." But Shah counters that previous trials with niacin suggesting benefit have been even smaller with a shorter follow-up than AIM-HIGH.

Some have little use for niacin

One doctor who won't be changing his practice based on these results is Dr Raymond Gibbons (Mayo Clinic, Rochester, MN). But that's because he doesn't use niacin very much anyway. He told heartwire : "I won't be changing my practice, as I was never an enthusiast for the idea of raising HDL. I focus on the primary target of LDL in my practice. I would use niacin only if the patient couldn't tolerate statins or was on the maximum dose of statins and still needed additional LDL reduction. So these new data do not affect my practice. I think people who believed in a benefit of raising HDL and were using niacin for this action will probably change their practice now and stop using it so much. But I tend to believe that given resources are so restricted in medicine that we should be using those resources to do the things we know work. And the benefit of raising HDL with niacin or anything else has not been proven."

Everyone agreed that any definite decisions about the place of niacin must wait for the results of the much larger HPS2-THRIVE study, currently under way. This study has 25 000 patients and so is much more likely to be able to show a real result. The trial has completed enrollment, with results expected in 2013.

Questions about the study design

Nissen is particularly critical of the design of AIM-HIGH, saying that, in addition to being underpowered, it allowed active LDL management in both arms of the trial, which may have biased the results. "When you test a drug you need to be able to test all actions of that drug, not just one. They allowed liberal use of other agents, which makes it difficult to interpret the results. As niacin lowers LDL as well as raises HDL, it is likely that the placebo group took more LDL-lowering therapies. Niacin also lowers triglycerides, and so it may be that the placebo group took more fish oils. Until we see the paper, we will not know these things. I would have designed the trial differently. It should have been usual care for everyone with niacin or placebo added on top. The question we want to know the answer to is 'Does niacin provide incremental benefits over usual standard of care?' But if you allow active LDL lowering in both arms, you are asking the question 'Does the HDL-raising action of niacin make a difference when LDL is also actively being lowered?' Those are two different things."

He adds: "AIM-HIGH was poorly designed and poorly exercised. A bad-quality trial shouldn't change practice."

But Shah thinks this is unfair. "I don't think you can fault the design of the trial. It was trying to answer the question 'Once LDL is under control, is there incremental benefit of raising HDL with niacin?' Obviously, if a patient is not at target LDL when adding niacin it makes sense to use additional LDL lowering."

Boden reinforces this view. He commented to heartwire : "We were sensitive to the need to achieve an aggressive on-treatment LDL, as the entire field of dyslipidemia therapeutics has increasingly shifted toward 'lower is better' for LDL control. Had we not [done this], it is likely that we would have been highly criticized for not getting the LDL down low enough, as many lipid experts and opinion leaders have stated that if LDL is intensively treated, then HDL-raising will have little impact. In fact, our trial result settles this scientific question--and it is an important one, even though it is a disappointing one from the perspective of what we set out to demonstrate."

Boden says if they conducted the trial Nissen's way, this would have likely resulted in varying statins and doses, higher LDL values in placebo patients, and lower LDL values in Niaspan patients. "This would have triggered an endless debate as to whether the event reduction was due to the LDL or the HDL effects."

He stands by the decision to stop the trial, noting that when the DSMB met, there had been 249 events with treatment A (placebo) and 262 events with treatment B (Niaspan), with a hazard ratio of 1.05, and there was a <1:10 000 chance that they would see a positive result for Niaspan if the trial continued.


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