Biotech Values

[DewDiligence]

NIH Pulls Plug on AIM-HIGH Study

[This is an update to the write-up posted by drbio in #msg-63612928. The author added language, which I highlighted in red, that speaks to the point in #msg-63611955—these new data are *not* bullish for AMRN.

ABT issued a PR today suggesting that the stroke imbalance seen in the study was statistical noise insofar as there is no mechanistic reason why niacin should increase the risk of stroke.]

http://www.theheart.org/article/1231453.do

›May 26, 2011
By Lisa Nainggolan

Bethesda, MD - A trial of extended-release niacin (Niaspan, Abbott) given in addition to statin therapy in patients with a history of cardiovascular disease, high triglycerides, and low levels of HDL cholesterol has been halted prematurely, 18 months ahead of schedule, because niacin offered no additional benefits in this patient population.

There was also a small, unexplained increase in ischemic stroke in the high-dose, extended-release niacin group, in the Atherothrombosis Intervention in Metabolic Syndrome with Low HDL Cholesterol/High Triglyceride and Impact on Global Health Outcomes (AIM-HIGH) study, according to a statement from the National Heart Lung and Blood Institute (NHLBI), which sponsored it.

In a media telebriefing today, Dr Susan B Shurin (acting director of the NHLBI) and two investigators from the trial stressed that the findings apply only to the specific patient population studied in AIM-HIGH and that they could not be extrapolated to others.

But others felt this was a nail in the coffin for the whole concept of treating lipid markers associated with CV risk, such as triglycerides and HDL.

FDA will not change labeling for niacin at the moment

Despite treatment with statin therapy for elevated LDL-cholesterol levels, those with low levels of HDL cholesterol remain at significant risk for cardiovascular events, and AIM-HIGH was designed to examine whether raising HDL using extended-release niacin would be beneficial in such patients. AIM-HIGH was a five-year study of almost 3500 patients, and results were originally expected in September 2012.

The decision to stop the trial was made at a regularly scheduled meeting of the study's independent data and safety monitoring board (DSMB) on April 25, 2011. The DSMB concluded that "high-dose, extended-release niacin offered no benefits beyond statin therapy alone in reducing cardiovascular-related complications in this trial. The rate of clinical events was the same in both treatment groups, and there was no evidence that this would change by continuing the trial."

During the telebriefing, Shurin noted that the increased stroke risk did play a role in the decision to stop the trial, but she observed, "The overall frequency of stroke was less than 1%, and previous studies do not suggest that stroke is a potential complication of niacin.

"The FDA is aware of the findings and is recommending no change in labeling or practice [regarding the use of extended-release niacin alone or in combination with simvastatin or other statins] pending further analysis of the data," she said, adding that the NHLBI would soon "begin the important task of analyzing" the findings in detail. Full results of AIM-HIGH will be presented at a major scientific meeting and published in a peer-reviewed journal at a future date, she noted.

Is this the death of the HDL hypothesis? Not quite, say investigators.

AIM-HIGH was based on data from observational studies and a few small clinical studies and the fact that use of high-dose extended-release niacin "is now common practice [but] the evidence did not seem to be as solid as we thought it should be," Shurin explained. "Although we did not see the expected clinical benefit, we have answered an important scientific question about treatment for cardiovascular disease," she noted.

And during the call she stressed—together with investigators from the trial—that patients who were not in the AIM-HIGH trial should not stop taking high-dose, extended-release niacin without talking to their doctor first. "We don't see that the study results here would recommend any general change in the approach to use of niacin, and the FDA concurs with that, at least so far," Shurin commented. "We would strongly recommend that any individual who is taking niacin have that conversation with their physician, but there is nothing in here that would be compelling." The NHLBI is now notifying all primary-care physicians of the findings, she added.

When asked by a reporter what patients should know, AIM-HIGH coinvestigator Dr William B Boden (University at Buffalo, NY) said: "We tell them what the [National Cholesterol Education Program] NCEP recommendations have been for the past decade: the most important determinant of dyslipidemic risk is elevated LDL, and the most important therapeutic imperative is to get the LDL down with statins." [In other words, statins have been proven in long-term studies to reduce the risk of adverse cardiovascular events, while other approaches remain unproven.]

He pointed out that in AIM-HIGH, the extended-release niacin "produced the predicted effects on all lipids measured, increasing HDL levels by 20% and reducing triglycerides by around 25%. While high-dose niacin raised HDL, it did not affect cardiovascular events."

The results from AIM-HIGH "clearly underscore the importance of LDL reduction, and the fact that these patients were so incredibly well-treated with respect to LDL [average LDL at baseline was 71 g/dL] that we could not, in that subpopulation, demonstrate incremental benefit of HDL raising. That doesn't mean that there aren't patients out there who might benefit from HDL raising, it's just that we don't have evidence from trials to guide us," he noted.

"The AIM-HIGH study population was not the very highest-risk population, and that clearly is why we can't generalize these findings to patients we didn't study in the AIM-HIGH trial," Boden added.

"Many patients in the real world have far higher LDL levels at baseline than we encountered. There is an enormous unmet need of increased residual risk, even among patients who take statins, and one of the challenges we as physicians and cardiologists face is to try to address that unmet need therapeutically," he said, noting, "It's difficult to speculate about whether HDL therapies are completely ineffective."

Another AIM-HIGH investigator, Dr Jeffrey Probstfield (University of Washington, Seattle), concurred: "We have to focus specifically on the fact that we had a very special population in this study. The only thing that we can say about alteration of HDL is in relation to the population we addressed in this study. There may be other populations who will respond differently."

But others disagree . . .

When asked whether she thought these findings meant the "death" of the HDL hypothesis, Shurin replied: "This sends us a bit back to the drawing board in terms of trying to figure out how to approach this hypothesis. Either the approach to raise HDL was not effective or HDL is just not a good target for therapy in the setting of other lipid-lowering agents."

Dr Darren McGuire (UT Southwestern Medical Center at Dallas) told heartwire: "In the absence of data to the contrary, clinicians accepted possibilities that led to niacin and other drugs being used to treat biomarkers associated with CV risk, such as triglycerides and HDL."

But now, "in the wake of negative trials of fibric acids, we have a futility finding with niacin and, in this case, at least some chance of a possibly serious adverse risk for stroke. In this setting, I think there is no justification to continue niacin therapy. I don't understand why patients should not stop the drug. There is no danger to stopping the drug to my knowledge and no withdrawal syndrome requiring tapering or other management."

"We can await findings from [the Heart Protection Study 2 Treatment of HDL to Reduce the Incidence of Vascular Events] HPS-2-THRIVE to make any further clinical decisions," McGuire adds.

HPS-2-THRIVE is another large international trial of high-dose, extended-release niacin, which is still ongoing, with results expected in 2013. Probstfield said that although the dose of niacin used in this trial is "comparable" to that employed in AIM-HIGH, the preparation is different and the patient population "is quite a bit different; it's a whole panorama of HDL levels, all-comers."

Study details

AIM-HIGH enrolled 3414 participants in the US and Canada with a history of cardiovascular disease, low HDL cholesterol, and high triglycerides, who were all prescribed simvastatin and who were also randomized to either high-dose, extended-release niacin in gradually increasing doses up to 2000 mg per day (n=1718) or placebo (n=1696). Of the participants, 515 were given a second LDL-cholesterol-lowering drug, ezetimibe (Zetia, Merck/Schering-Plough), in order to maintain LDL-cholesterol levels at the target range between 40 and 80 mg/dL.

However, the combination treatment did not reduce the five-component end point—fatal or nonfatal MI, strokes, hospitalizations for acute coronary syndrome, or revascularization procedures; the primary end point was an annualized rate of 5.8% in the high-dose-niacin group vs 5.6% in placebo group.

Most of the primary-end-point events were hospitalizations or revascularizations (around 140 events), although there were also a "substantial" number of nonfatal MIs and around 40 deaths, the telebriefing was told.

The investigators said they did not have sufficient information yet to determine the role that ezetimibe played in the subgroup that also received that drug.

During the 32-month follow-up period, there were 28 strokes (1.6%) reported among participants taking high-dose, extended-release niacin vs 12 strokes (0.7%) in the control group. [See comments in prologue of this post.] Nine of the 28 strokes in the niacin group occurred in participants who had discontinued the drug at least two months and up to four years before their stroke.

All AIM-HIGH study participants have been informed of the results and will be scheduled for clinic visits within the next 2.5 months, the doctors said. Participants will be followed for an additional 12 to 18 months.

Does niacin have effects on different subgroups of HDL?

Asked during the telebriefing about niacin's possible effects on different subgroups of HDL, Boden said: "Niacin is thought to raise the more beneficial subgroups of HDL. We have a very extensive substudy within the trial that remains under analysis, so at some point in the future we can give you much more detail about this."

Extended-release formulations of niacin are being used in these trials because the immediate-release form of niacin is associated with a high incidence of flushing, the doctors noted during the telephone briefing.‹