The Leap in Logic<\/strong><\/p>\nThe authors\u2019 conclusion is quite provocative. The full trial showed that patients with ischemia did equally well with an initial strategy of PCI or OMT. In the substudy, the authors assert that, given their results, clinicians should seek a target of \u22655% ischemia reduction. The implications are that these patients should undergo MPS, that therapeutic strategies should be guided over time by the MPS results, and that PCI is better than OMT alone in reducing ischemia. How did the authors make this leap? Their reasoning appears to be as follows:<\/p>\n
The PCI strategy was better than OMT in reducing ischemia burden by \u22655%. The authors place emphasis on a significant unadjusted<\/em> association between a reduction in ischemic burden and a reduction in risk (but a critical reader will note that the multivariable analysis was not significant). On the basis of the unadjusted result, the authors conclude that reducing ischemic burden by \u22655% should be a treatment goal and, by implication, that PCI plus OMT would be better than OMT alone for that purpose.<\/p>\nUntangling the Logic<\/strong><\/p>\nThe substudy was not designed to test whether targeting treatment to a certain threshold of ischemia reduction benefits patients; it simply suggested that the PCI strategy was more effective than OMT alone in reducing ischemic burden. [Given that the subjects in this substudy represented a convenience sample of patients and the two treatment groups were not similar it is not clear that they have even demonstrated that PCI reduces ischemic burden more effectively – this is not a comparison of groups that were obtained by randomization – a nuance that is acknowledged but may be easy to miss – and they do not do what is necessary to control for the differences.] Notably, even if PCI reduced ischemic burden, PCI did not significantly reduce the risk for clinical events or substantially affect symptoms in the overall trial. Moreover, in the substudy,the reduction of ischemic burden also did not reduce the risk for events (according to the multivariable analysis in the substudy, which was important since those who had a reduction were likely different at baseline from those who did not – but they do not present this comparison). If ischemic burden reduction had really mattered, the trial should have shown evidence of\u00a0clinical <\/em>differences between the two treatment groups.<\/p>\nAnother issue is that ischemic burden is a\u00a0surrogate<\/em> for the clinical outcomes that affect patients. Surrogate endpoints can be useful when we do not have clinical outcomes to examine. In COURAGE, clinical outcomes were reported. Perhaps the most important finding in this substudy is the failure of ischemic burden\u00a0as<\/em> a surrogate endpoint. If COURAGE had just used ischemic-burden reduction as the primary endpoint, the PCI advocates would have declared victory. However, the trial identified no difference between the groups in the major clinical endpoints that were measured, and the surrogate endpoint would have been useless in predicting the outcome of the trial. This finding suggests to me that treating to a target reduction in ischemic burden is not useful.<\/p>\nThere are also other issues to consider regarding the study design. In order for the trial participants to have their ischemic burden tracked over time, they had to be around for the follow-up study. They are, then, patients who survived at least 6 months and, in some cases, up to 18 months. We do not have information about who in this substudy was lost to follow-up or did not return for a follow-up MPS study \u2014 and whether the time to the follow-up MPS was similar in both intervention groups. That information is essential to evaluating the substudy.<\/p>\n
A Better Line of Inquiry<\/strong><\/p>\nWhat nuclear substudy might have been most useful to a clinician? I personally would have wanted to know whether PCI was better than OMT alone among patients with a large ischemic burden at baseline. Such an analysis would have investigated an interaction \u2014 whether the difference between the PCI and OMT-alone groups varied according to baseline ischemic burden. A reasonable hypothesis would have been that the PCI strategy was superior for patients who initially had the most ischemia according to MPS. Unfortunately, the investigators could not do that analysis, probably due to lack of resources.<\/p>\n
Do you think this COURAGE substudy complements the original trial? How do you assess the authors\u2019 suggestion to target a certain reduction in ischemic burden for patients like those in this trial? How would you have written the conclusion to the abstract?<\/p>\n","protected":false},"excerpt":{"rendered":"
In this journal club, I compare the published data from an original trial with the authors\u2019 conclusions in a substudy from that trial. Often, a substudy provides valuable insights that complement the initial trial findings. Sometimes, however, you need to look closely to identify the additional insight. Case in point: COURAGE. The Original COURAGE Trial […]<\/p>\n","protected":false},"author":211,"featured_media":0,"comment_status":"open","ping_status":"closed","sticky":false,"template":"","format":"standard","meta":{"footnotes":""},"categories":[11,1,9],"tags":[301,373],"class_list":["post-5786","post","type-post","status-publish","format-standard","hentry","category-cardiac-imaging","category-general","category-interventional-cardiology","tag-pci","tag-stable-angina"],"_links":{"self":[{"href":"https:\/\/blogs.nejm.org\/cardioexchange\/wp-json\/wp\/v2\/posts\/5786","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/blogs.nejm.org\/cardioexchange\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/blogs.nejm.org\/cardioexchange\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/blogs.nejm.org\/cardioexchange\/wp-json\/wp\/v2\/users\/211"}],"replies":[{"embeddable":true,"href":"https:\/\/blogs.nejm.org\/cardioexchange\/wp-json\/wp\/v2\/comments?post=5786"}],"version-history":[{"count":0,"href":"https:\/\/blogs.nejm.org\/cardioexchange\/wp-json\/wp\/v2\/posts\/5786\/revisions"}],"wp:attachment":[{"href":"https:\/\/blogs.nejm.org\/cardioexchange\/wp-json\/wp\/v2\/media?parent=5786"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/blogs.nejm.org\/cardioexchange\/wp-json\/wp\/v2\/categories?post=5786"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/blogs.nejm.org\/cardioexchange\/wp-json\/wp\/v2\/tags?post=5786"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}