Reflexiones suspensión trial Aim High

 

AIM-HIGH: Maybe we should still hold on to our HATS?


I was shocked at the heartwire headline, "NIH pulls plug on AIM-HIGH trial with niacin." Isn't nicotinic acid the essential ingredient in what many consider to be our most potent potion to ward off coronary events? The compound we've spent hours trying to talk patients into "sticking with" despite enduring flushes of rarely the same intensity as 1000 4th-of-July sparklers? How many times have I coaxed my patients, much like any good mother, with a spoonful of unsweetened applesauce and aspirin pressed against closed lips as premedication, practically bribing patients to continue it just to get that great HATSbenefit"? The AIM-HIGH debacle suggests that long-acting niacin might be the greatest heartbreaker in the history of medical trials, ranking right up there with folic acid,torcetrapib, and bosentan. But should we give up on vitamin B3 so soon? What about that June 2010 meta-analysis published in Atherosclerosis? Surely 11 randomized controlled trials can't be wrong! With all the "types" and "antitypes" to be considered in the history of analyses of lipid-trial data, I thought I had an absolute in niacin, so shouldn't we examine a few of the issues before we disconnect it from life support?
No pun intended, but I've hung my hat on HATS for a decade. This was a small placebo-controlled trial consisting of 160 patients with coronary artery disease treated with simvastatin 10–20 mg plus niacin 1000 mg bid. The HATS cohorts had a mean HDL-C of 31 mg/dL, LDL of 127 mg/dL, and TG of 200 mg/dL, a fourth of which possessed "pattern A," or large, buoyant LDL. Quantitative coronary angiography demonstrated regression of coronary obstructive disease on therapy with niacin and statin combination when compared with statin alone. Over three years, a staggering 60% to 90% reduction in death, nonfatal MI, stroke, and revascularization was documented with combination therapy. A 29% increase in HDL and a 61% increase in HDL2-C, (the larger, more buoyant, and beneficial type of HDL) were also noted. The total LDL-C level fell from 132 mg/dL on average to 75 mg/dL, HDL–C rose from 31 mg/dL to 40 mg/dL, and TG fell from 202 mg/dL to 126 mg/dL. Interestingly, the utilization of antioxidants (vitamins E and C, selenium, and beta carotene) blunted the HDL-raising effect of long-acting niacin. Hmm . . . and now we have a new trial, this one demonstrating "futility" of long-acting niacin in combination with statins, with almost one-third of treatment cohorts onezetimibe. Curiously, it's ezetimibe that knocks the crap out of LDL levels but does nothing to halt vascular-disease progression in prior trials. Hmm . . . I wonder, should we be so quick to dismiss niacin? 
And what about ARBITER 6-HALTS, a 12-month study of 167 patients on the combination of statin and niacin with coronary disease and low HDL levels of less than 45 mg/dL. Carotid intima media measurements demonstrated progression in patients treated with a statin alone, with a p value of <0.0001, whereas the statin-plus-niacin group demonstrated a "nonsignificant tendency toward progression." Though there was a trend toward a reduction in cardiovascular events in the combination-therapy group, the trial was small and the p value only 0.20. This trial fit nicely with the niacin hypothesis, and I sank down into it like I would have an overstuffed couch.
Perhaps trial designers should reflect on ENHANCE and ARBITER 6-HALTS for future reference. Ezetimibe, once considered in earlier trials as the much-sought-after "eye of newt" in the witches' brew for combination lipid therapy, has been a major disappointment. Although we won't know for sure until IMPROVE-IT is published, adding ezetimibe to any trial may be like adding a tiny drop of food coloring to a bucket of water. It may taint study results from beginning to end, and only a keen subset analysis (which, by the way, should be included much earlier than is customary in trial presentations today) will be the only way to tease out the issues. Furthermore, controls should really be controls, and cohorts shouldn't already be so well treated that nothing will compare (like the LDL levels of <100 mg in ARBITER 6-HALTS).
Dr Brad Bale, a longtime proponent of combination statin and long-acting niacin therapy, posted a note on the AIM-HIGH study on the Bale-Doneen method website, stating that, "AIM-HIGH was an intent-to-treat study that allows for individuals to be included in the treatment arm without daily compliance monitoring of medication adherence. . . . Niaspan administration requires careful monitoring to ensure compliance with treatment therapy. As we know, if the medication is not taken daily, its treatment benefit is negated." He pointed out that nine of the patients who suffered a stroke were evaluated and found to have stopped their therapy 67 to 1467 days prior to the event. He then stated, "We also do not know the potential relationship of ezetimibe and Niaspan—this remains unclear." 
So what to do with the AIM-HIGH results? I've decided I'm going to "aim higher" than this trial was designed to reach. I'm going to keep patients on long-acting niacin until I know more. There is just too much "good" trial data in support of niacin and statin combination therapy to abandon it due to the results of one study. I think another trial with better design that is allowed to run to completion, with compliance monitoring, without the added zinger of ezetimibe, and with real controls, will prove niacin to be beneficial . . . again. I'm still going to hang on to my HATS, at least for now. 
 

AIM-HIGH study release - Bale/Doneen Response
26-May-2011
NHLBI announced that the AIM-HIGH study has been stopped.  AIM-HIGH, a randomized, multicenter clinical trial sponsored by the NHLBI was designed to answer the question of whether raising high-density lipoprotein cholesterol (HDL-C) in patients with a history of stable, non-acute pre-existing cardiovascular disease and well controlled low-density lipoprotein cholesterol (LDL-C) would lower the rate of CV events. 

All AIM-HIGH participants were treated with simvastatin, with the possible addition of ezetimibe, to achieve an LDL-C between 40 and 80 mg/dL.  Patients were randomly assigned to also receive either Niaspan or placebo. 

The AIM-HIGH data and safety monitoring board recommended stopping the trial as of May 25, 2011 because of lack of efficacy.  The data from the interim analysis indicated that the trial does not show a significant difference in cardiovascular outcome event rates between the two study arms.  There were 249 primary outcome events (15%) in the simvastatin arm and 262 (15%) in the Niaspan plus simvastatin (p=0.561).  There were a total of 28 ischemic strokes (1.6%) in the Niaspan plus simvastatin arm and a total of 12 such events (0.7%) reported in the simvastatin arm. 

Bale/Doneen Method thoughts: 

This AIM-HIGH announcement and trial cessation allows the opportunity to propose several relevant and important questions.  We must recognize that AIM-HIGH was slated to validate many of our observations of previous clinical trials and certain clinical observations.  The NHLBI’s decision to halt this trial is based on a lack of efficacy, not an increase risk for clinical events.  Regardless, we await the full disclosure with much anticipation.  In the meantime, we are left to search for potential meaning of these preliminary findings, knowing that the full release will hopefully provide the needed information to formulate a clinical decision for our patients.  We have listed several thoughts below that detail our current thoughts on the early release.  We, like you, anticipate the full release by the AIM-HIGH study investigators to fully appreciate the depth and limitation of this complicated issue.   The highlighted areas of discussion below represent our thoughts today, which will surely reformulate as further data is released. 

Intent to treat: AIM HIGH was designed as an “intent to treat” study, which allows for individuals to be included in the treatment arm without daily compliance monitoring of medication adherence.  Nine of  the ischemic stroke events reported in the Niaspan arm occurred after the subjects had stopped taking Niaspan for 67-1467 days.  Niaspan administration requires careful monitoring to insure compliance with treatment therapy.  As we know, if the medication is not taken daily, its treatment benefit is negated. 

Confounding therapies: Ezetimibe was used in 515 participants as an add-on therapy to the statin therapy with the intent to get LDL to the treated goal of 40-80. It remains yet unclear how many  participants in the Niacin/statin ischemic stroke arm were also taking ezetimibe.   The potential interaction between Niaspan and ezetimibe has never been formally evaluated.  We do know from the ENHANCE trial and ARBITER 6, that ezetimibe is an effective add-on to statin therapy to lower LDL.  It has been determined, however, that the addition of ezetimibe to a statin falls short of improving atherosclerosis, as measured by carotid intima-media thickness.  We also do not know the potential relationship of ezetimibe and Niaspan – this remains unclear. 

Population:  Inclusion criteria for the study subjects included established cardiovascular disease and atherogenic  dyslipidemia.  This demographic possesses a multi-factorial treatment challenge, often including obesity, hypertension, insulin resistance and metabolic syndrome.  This study was designed to treat the lipid portion of this risk factor profile.  In this difficult to treat population, therapy beyond the lipids is essential.  Treatment issues include blood pressure management, psychosocial management, exercise support, diet support, sleep management and optimal treatment of insulin resistance.  Clearly, this trial perhaps supports the opportunity to recognize the multi-factorial treatment necessary to treat stroke risk in this complicated patient population. 

Stroke Prevention: The INTERSTROKE trial provides the best insight into the most common causes of ischemic stroke.  The most common cause of ischemic stroke, worldwide, was determined to be blood pressure.  We do not know how well BP was controlled in these patients. 

Heart Attack Prevention:  The INTERHEART trial looked at a worldwide population and it was determined that lipids were the number one risk factor for heart attacks.  AIM-HIGH is a lipid trial and, according to the preliminary release, heart attack concerns were not raised by the NHLBI safety board.

Arterial Inflammation:  Events are triggered by inflammation.  Eradication of arterial inflammation in individuals who are resistant to insulin frequently requires therapy beyond statin and niacin.  It will be interesting to see the trial results in regards to biomarkers of inflammation.

The story is yet to unfold and we will be watching the daily press releases with the intent to determine the true reason for this rather surprising announcement.  We share the same concerns as many providers who are dedicated to the prevention of heart attacks, ischemic stroke and diabetes.  The story will continue….

Respectfully,

Amy Doneen and Bradley Bale 

 

 

Dr. Pablo Corral.
Tel/Fax : (0223) 451-5475 / 451-6803
Rawson 1006.
Mar del Plata.
Argentina.

www.icm-mdp.com