ARBITER 6 and Combining Therapies with Statins

The results from ARBITER 6 were released this week.

The interpretation is less clear.

I've been in a minority who has doubted that most drugs that lower LDL are actually beneficial in primary prevention. Statins clearly show benefit, but really no other agents have shown a reduction in all cause mortality or, in primary prevention, in cardiovascular mortality. As such, I'd been raising concerns about ezetimibe even before ENHANCE was published, and have been unconvinced that anyone should be treated with combination therapy to achieve LDL goals, since there is little to suggest added benefit when other lipid-lowering drugs are combined with a statin.

Recently, the Oxford Niaspan Study found that CIMT was improved when niacin was combined with a statin, but CIMT is a surrogate marker and it's not so clear that changes in CIMT will predict clinical benefits. However, of all the non-statin therapies, niacin has been the one that looks most promising for reducing cardiovascular mortality, at least in secondary prevention.

Now, soon after that study, we have ARBITER 6, showing that niacin plus a statin seemingly reduced cardiovascular events compared with ezetimibe plus a statin. There were 2 events in the niacin arm (1%) and 9 in the ezetimibe arm (5%) and this was statistically significant. So, what can we conclude from this?

One possibility is that niacin actually does add some clinical benefit to a statin in secondary prevention, while ezetimibe does not.

Another possibility is that ezetimibe is actively harmful, while niacin is neutral. There were slightly more events in ENHANCE in the ezetimibe arm, but the numbers were tiny.

A third possibility is that this was due to chance. The actual results are quite "fragile" in the sense that only a few events moving from one arm to the other would make the difference disappear. While, in theory, a statistical test captures this, there's been a sense in the EBM world that very small event numbers create a fragility of results not adequately captured by a p value. It seems extremely unlikely that niacin really reduces events by 80%, since this should have been obvious in prior trials of niacin. As such, either niacin combined with a statin is much superior to niacin alone, or these results are in part due to the play of chance. (It's not likely that ezetimibe raises events by this degree when used with a statin, since we would likely have noticed this in other trials.)

ARBITER 6 was stopped early for benefit, based on CIMT results. This seems like an odd decision to say the least, since change in CIMT is not a clinical outcome requiring an ethical decision to stop a trial. The early stopping was unfortunate since with more events we might be more certain about whether the reduction in events was real.

I'll be interested to see how others interpret ARBITER 6. So far I've communicated with one lipid expert (who has not shared my views about non-statin therapy) and he doesn't believe that ezetimibe is clearly to be avoided, while another expert (who does share my views about non-statin therapy) doesn't feel that ARBITER 6 means that niacin should be used. Apparently neither one found ARBITER 6 substantially reshaped their positions on this.

My best guess is that niacin reduces events a bit, though not as much as ARBITER 6 suggests. If so, for the highest risk patients, such as those who have CV events while on a statin, adding niacin might make sense. Given the side effects with niacin (36% of patients in ARBITER 6 had  flushing, and many more in the niacin arm than the ezetimibe arm discontinued therapy), I'd hesitate to use niacin in lower risk patients even for secondary prevention, out of concern that they might discontinue both niacin and the statin.

I'd be quite hesitant to treat anyone with ezetimibe at this point. While I was a skeptic that ezetimibe did anything beneficial even before ARBITER 6, I'm now substantially more concerned that it could be causing real harm.

Comments

[Marilyn Mann]

A fourth possibility is that niacin adds a small cardiovascular benefit *and* ezetimibe adds a small cardiovascular harm.

Question: you seem to be saying that ARBITER was a secondary prevention trial. Yet some of the patients did not have known vascular disease. The trial included patients with a calcium score over 200 for women or 400 for men or Framingham risk scores over 20%. (There were also patients with diabetes who did not have known vascular disease, although diabetes is usually classified as a coronary risk equivalent.) Admittedly the primary prevention patients were *very* high risk. Still, if someone is totally asymptomatic but either has multiple risk factors giving them a high FRS or known extensive atherosclerosis as indicated by a high calcium score, isn't that still primary prevention?

In my view, the issue of whether ezetimibe promotes cancer and/or cancer death is still unresolved, although I know you are a skeptic on that issue. This trial does not tell us anything about that.

[Dan Hackam MD PhD]

David, I am inclined to agree with your analysis. The only non-statin lipid-lowering agent that has shown event reduction in the primary prevention setting is gemfibrozil.

Having said this, drugs which prevent events in secondary prevention, usually also prevent events in primary prevention, although the NNTs are inflated. Again another reason why I rely on my atherosclerosis imaging to determine if a "primary prevention" patient is truly "primary", or rather actually a secondary prevention patient whose disease has not yet been unmasked by an event (worryingly, >30% of first MI are fatal).

I guess we'll have to wait for AIM-HIGH, HPS2-THRIVE, and IMPROVE-IT before we really know the truth on this.

Great blog.

[David Rind]

Marilyn Mann's point is of course correct about the possibility of some harm from ezetimibe plus some benefit from niacin.

The "secondary prevention" issue is really just one of terminology. Since the definitions in ATP-III, a lot of people writing about lipids have called things "secondary prevention" if the patients have cardiac risk equivalents -- that is, if they have a condition or combination of conditions that gives them as high an event rate as if they had known CHD. This isn't truly secondary prevention, but it has become an acceted shorthand.

From my point of view it works because the relative risk reductions with statins are essentially the same whether patients are being treated for primary or secondary prevention, and so combining very high risk primary prevention patients with secondary prevention patients doesn't really alter the meaning of the discussion.

Dan is referring to the Helsinki Heart Study, I assume, which did show a decrease in cardiac events, but had no mortality benefit and had a concerning trend toward more cancers. I remain nervous about rates of noncardiac deaths in trials of nonstatin lipid lowering agents.

David Rind

[Acai Berry]

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