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AIM-HIGH: Maybe we should still hold on to our HATS?Jun 1, 2011 17:27 EDT
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 HATS benefit"? 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 on ezetimibe. 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.