CardioExchange Archive

CardioExchange welcomes this guest post reprinted with permission from Dr. David Rind, an academic primary care physician and medical editor in Boston. This piece originally appeared on his blog, Evidence in Medicine. For more on the CREST trial, see the NEJM article and editorial, the Journal Watch summary by Dr. Howard Herrmann, and an Interventional Cardiology blog by Dr. Richard Lange.

In recent years, a common practice in clinical trials is to make the primary endpoint a composite endpoint. That is, the primary endpoint is a combination of various clinical events that might happen, such as heart attack or death or stroke, where any one of those events would count as part of the composite endpoint.

There can be good reasons for composite endpoints. If a single therapy is likely to have similar effects on a number of different related endpoints (such as cardiovascular events), creating a composite can help achieve adequate power. For instance, if statins decrease nonfatal strokes, nonfatal MIs, and cardiac deaths by about 25%, then creating these endpoints as a composite may make it possible to run an adequately powered trial with fewer patients. Additionally, there may be situations where a therapy might decrease an outcome by killing patients off before they can reach that outcome, and so a composite may be a way of evaluating safety.

Composites can quickly get you into trouble, though, if you combine events of very different importance to patients. Sometimes this appears to have been done with the intention of obscuring the real outcome of a trial or to make a therapy look far better than it really is. The primary outcome of DREAM, for instance, was “the development of diabetes or death”. DREAM was a randomized trial that looked at the effects of rosiglitazone in patients at high risk for developing diabetes. The article states in the Discussion:

This large, prospective, blinded international clinical trial shows that 8 mg of rosiglitazone daily, together with lifestyle recommendations, substantially reduces the risk of diabetes or death by 60% in individuals at high risk for diabetes.

A reasonable person reading this might conclude that rosiglitazone had had a rather dramatic and important effect on the risk of death in patients in the DREAM trial. In reality, however, the study found no effect of rosiglitazone on mortality (and was always much too small to find any difference), and the primary outcome was driven entirely by development of diabetes.

Additionally, since development of diabetes was assessed while patients were taking rosiglitazone (a drug that reduces blood sugar), it was virtually certain that the arm taking rosiglitazone would appear to have a lower rate of “diabetes and death” simply because development of diabetes is based on blood sugar and A1c measurements. Even if rosiglitazone had no effect on the natural history of diabetes, it could be counted on to reduce blood sugar and A1c during the time patients were taking it, and thus appear to delay the onset of laboratory-diagnosed diabetes. Worse, rosiglitzaone has harmful cardiac effects that could be minimized by focusing on a dramatic reduction of a primary endpoint that included the word “death.”

It hardly seems fair or true to conclude that rosiglitazone decreased “diabetes and death,” but by making that the primary composite endpoint, the trial can claim that this is the only statistically fair way to report the results.

With this in mind, we are now faced with the CREST trial, published online in the New England Journal of Medicine. CREST was a randomized trial that compared two methods of dealing with carotid vascular disease: carotid endarterectomy and carotid stenting. The primary endpoint was a composite of periprocedural stroke, myocardial infarction, or death, or ipsilateral stroke in the following four years.

CREST found no difference between the procedures in the primary endpoint, but this obscures what really happened. Unsurprisingly, patients treated with stenting, a less invasive procedure, had lower rates of periprocedural MI than those treated with endarterectomy (1.1%  versus 2.3%). But they also had higher rates of periprocedural stroke ( 4.1% versus 2.3%), as well as a trend toward higher mortality.

I suspect most people undergoing a procedure to avoid having a stroke (the rationale behind both endarterectomy and stenting) would hesitate to accept a 1.2% gain in the form of a lower risk of MI in return for a 1.8% loss in the form of a higher rate of stroke. As such, the apparent equivalence on the primary endpoint obscures the importance of the underlying components of the composite.

The article was much more upfront about these individual outcomes than the DREAM article, but this did not alter a general buzz in the press (presumably traceable back, in some fashion, to the way the results were promoted) that CREST had shown equivalence between stenting and endarterectomy, and that stenting had now proven itself in a randomized trial.

Hopefully, though, when doctors talk to patients about the choice between carotid endarterectomy and carotid stenting, they will focus on the comparative risks of stroke and MI, and not on the composite outcome, since I suspect very few patients would consider a stroke and an MI to be outcomes that could be fairly equated and thus lumped into a single basket.