October 1st, 2010
A Case of Exuberance About a Subgroup in a Clinical Trial
In many clinical trials, researchers investigate whether an overall effect of an intervention is consistent across various subgroups, as I discussed in this Journal Club Series last week. Such subgroup analyses require assessment of what is called an interaction — that is, whether the effect in one group differs from that in another. Do the benefits differ, for example, between older and younger patients — or between men and women? That may sound like an easy issue to explore, but penetrating it demands an appetite for methodological nuance. Are you ready? Here we go . . .
The basic principle of subgroup analysis is that before you assess the effect of an intervention in each subgroup of interest, you must assess whether there is strong evidence of statistically meaningful differences among the subgroups. If older patients and younger patients benefit similarly from a drug, for example, there is no reason to look at one group alone, because the overall trial outcomes apply to both groups.
This week, I focus specifically on a study showing that bleeding risk was significantly greater with prasugrel than with clopidogrel in ACS patients scheduled for PCI. The researchers published a subsequent article focusing just on the patients with ST-segment–elevation MI (STEMI) and concluded that there was no excess risk for bleeding in that subgroup, even though the difference in that risk between STEMI and unstable angina/non–STEMI (UA/NSTEMI) patients was not significant. These studies are instructive for thinking about how to interpret subgroup analyses accurately.
The articles are a 2007 NEJM paper and a 2009 Lancet paper from the industry-funded TRITON-TIMI 38 trial, in which 13,608 patients with moderate-to-high risk ACS who were scheduled for PCI were randomized to receive prasugrel or clopidogrel. Incidence of the primary endpoint — death from cardiovascular causes, nonfatal MI, or nonfatal stroke at 15 months — was significantly lower in the prasugrel group than in the clopidogrel group (9.9% vs. 12.1%), mostly because of fewer nonfatal MIs. However, the incidences of major and life-threatening bleeding were significantly higher with prasugrel. In a 2009 NEJM perspective piece, an FDA official characterized the data as follows:
“For each 1000 patients who were given prasugrel instead of clopidogrel, 24 end-point events were prevented — 21 nonfatal myocardial infarctions and 3 cardiovascular deaths. (The rate of stroke was essentially the same with either drug.) The cost was 10 excess major or minor bleeding events, 2 of which were fatal.”
What the Authors Analyzed
It’s important to emphasize that this trial reported analyses for 7 subgroups on the primary outcome, as well as several secondary outcomes including safety outcomes — quite a few comparisons in all. When there are multiple subgroup comparisons, P values for analyses beyond the primary endpoint must be adjusted to more stringent levels than the usual P<0.05, in order to account for the likelihood that the differences may be due to chance. A common approach is to divide 0.05 by the number of tests performed, but there are other ways to do this adjustment.
When the NEJM findings were published, the authors reported the significant difference between prasugrel and clopidogrel in the overall cohort and reported no evidence of a difference (interaction) between treatment group and type of MI. They then looked specifically at the primary outcome in the UA/NSTEMI and STEMI subgroups and found an advantage of prasugrel, at the P<0.05 level of significance, in each.
In their 2009 Lancet article, the authors focused only on the STEMI subgroup. They declared the primary-endpoint advantage of prasugrel in STEMI patients, reiterating the finding earlier reported in the NEJM. So far, so good: There was no interaction reported in the NEJM paper, and the Lancet paper said the same thing — the result is similar. It’s important to note that even if the effect had been reported as nonsignificant in the Lancet paper, the drug should not be considered ineffective in STEMI patients. Given that the interaction was negative, the efficacy of the intervention in the underpowered STEMI subgroup should be considered the same as it was in the overall cohort. In short, we have no evidence of an intervention-related difference between STEMI and UA/NSTEMI patients.
The authors also looked at safety endpoints. Specifically, they reported in the Lancet that the type of MI did not influence the excess risk for bleeding conferred by prasugrel (P=0.4). Therefore, the interaction between the bleeding risk with prasugrel and type of MI was negative (i.e., no evidence of heterogeneity for type of MI). However, the authors went on to assess the STEMI group alone and did not find a significantly increased risk for bleeding. They write, “TIMI major bleeding unrelated to CABG surgery was similar in the prasugrel and clopidogrel groups at both 30 days and 15 months.” This statement suggests that unlike patients with UA/NSTEMI, those with STEMI are not at increased risk for bleeding.
The problem is twofold: (1) the interaction, as noted, was not significant; and (2) the prasugrel versus clopidogrel hazard ratio for TIMI major bleeding unrelated to CABG was hardly reassuring (HR, 1.11; 95% CI, 0.70–1.77). That HR is not statistically significant, but it is in the direction of harm, and a 77% higher risk with prasugrel cannot be excluded. The best inference is that the excess bleeding risk in the STEMI subgroup is no different than that reported for the overall cohort.
How the Authors Interpreted Their Analyses
The authors conclude their Lancet abstract with this sentence: “In patients with STEMI undergoing PCI, prasugrel is more effective than clopidogrel for prevention of ischaemic events, without an apparent excess in bleeding.” And they end the entire Lancet article with this sentence: “Our findings suggest that prasugrel is an especially attractive alternative to clopidogrel to support PCI in the course of management of patients with STEMI.”
At the conclusion of your journal club, participants can decide whether the evidence from these articles is strong enough to say that STEMI patients gain a particular benefit from prasugrel. For now, please share your perspective with your colleagues here on CardioExchange.