If the Fates Allow: The Zero-Sum Game of ISCHEMIA-EXTEND.

HomeCirculationVol. 147, No. 1If the Fates Allow: The Zero-Sum Game of ISCHEMIA-EXTEND Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBIf the Fates Allow: The Zero-Sum Game of ISCHEMIA-EXTEND Steven M. Bradley and Ty J. Gluckman Steven M. BradleySteven M. Bradley Correspondence to: Steven M. Bradley, MD, MPH, Minneapolis Heart Institute, 920 E 28th St, Ste 300, Minneapolis, MN 55407. Email E-mail Address: [email protected] https://orcid.org/0000-0003-4006-6760 Allina Health Minneapolis Heart Institute and Minneapolis Heart Institute Foundation, MN (S.M.B.). Search for more papers by this author and Ty J. GluckmanTy J. Gluckman https://orcid.org/0000-0002-7187-6822 Center for Cardiovascular Analytics, Research and Data Science (CARDS), Providence Heart Institute, Providence Research Network, Portland, OR (T.J.G.). Search for more papers by this author Originally published6 Nov 2022https://doi.org/10.1161/CIRCULATIONAHA.122.063033Circulation. 2023;147:20–22This article is a commentary on the followingSurvival After Invasive or Conservative Management of Stable Coronary DiseaseOther version(s) of this articleYou are viewing the most recent version of this article. Previous versions: November 6, 2022: Ahead of Print Article, see p 8According to the ancient Greeks, the lives of the gods and mortals were immutably determined by 3 Fates: sisters Clotho, who spins the thread of life; Lachesis, who assigns each their destiny; and Atropos, whose scissors snip the thread of life at its end. Among the goals of medicine is to bend the will of fate by forestalling death. The extent to which coronary revascularization alters the fate of patients with stable ischemic heart disease (IHD) remains an important question.The ISCHEMIA randomized controlled trial (International Study of Comparative Health Effectiveness with Medical and Invasive Approaches) sought to determine the effect of adding coronary angiography and revascularization when feasible to medical therapy in patients with stable IHD and moderate or severe ischemia.1 Over a median follow-up of 3.2 years, there was no difference in the risk of ischemic cardiovascular events or death from any cause between the treatment strategies. However, the rate of cardiovascular events was sensitive to the definition applied, with more procedural and fewer spontaneous (nonprocedural) myocardial infarctions noted in those randomized to an initial invasive strategy. Given the stronger association between spontaneous myocardial infarction and subsequent cardiovascular mortality,2,3 an initial invasive strategy might prove favorable over a longer period of time. Extended follow-up of participants from ISCHEMIA may therefore inform whether an initial invasive strategy affects the long-term fate of patients with stable IHD.In this issue of Circulation, Hochman et al.4 present an interim analysis from ISCHEMIA-EXTEND, representing follow-up of ISCHEMIA participants out to a median of 5.7 years. In contrast to the primary trial results, patients treated with an initial invasive strategy experienced an estimated 2.2% absolute reduction in cardiovascular mortality at 7 years (estimated number needed to treat 45). This benefit was offset by an estimated 1.2% absolute increase in noncardiovascular mortality over the same time frame (estimated number needed to harm 83). Relative to optimal medical therapy alone, no association was observed between an initial invasive strategy and all-cause mortality, with a hazard ratio of 1.0. Although the hypothesized long-term benefit of an invasive strategy on cardiovascular mortality is evident, its effect on overall mortality is negated by a higher rate of noncardiovascular death. In short, we have not altered fate for all-cause mortality; the net effect in this regard is a zero-sum game.For patients with coronary artery disease, an emphasis on cardiovascular mortality is understandable. However, previous studies remind us of the implications of noncardiovascular mortality in this population. In a single-center study that evaluated trends in long-term survival over a span of nearly 2 decades in 19 077 patients who underwent percutaneous coronary intervention, a 33% temporal decline in cardiac deaths at 5 years was offset by a 57% increase in noncardiovascular deaths over the same time period.5 In a pooled analysis of 32 882 patients undergoing percutaneous coronary intervention from 21 randomized clinical trials, cardiovascular and noncardiovascular mortality contributed approximately equally to total mortality at 5 years (4.2% and 5.2%).6The tradeoffs in cardiovascular and noncardiovascular mortality observed in ISCHEMIA-EXTEND raise many important questions. For example, can we identify patients with stable IHD treated with an initial invasive strategy for whom the cardiovascular mortality benefit meaningfully exceeds the risk of noncardiovascular death? What are the ways in which an initial invasive strategy confers increased risk of noncardiovascular mortality and how can this risk be mitigated? Can we identify patients at greatest risk of noncardiovascular death after an invasive strategy to reduce the likelihood of a zero-sum game or even net harm?The primary outcome of a clinical trial reflects the mean treatment effect for an average trial participant. As such, the absolute magnitude of benefit or harm of a given intervention is not uniform for all trial participants. Instead, the benefits of a given intervention are usually proportional to the underlying risk of the disease being treated and trial participants represent a spectrum of underlying risk. In trials with a treatment effect, some participants will benefit more and some will benefit less, partly as a function of their underlying risk. This concept of heterogeneity of treatment effect is relevant as we seek to apply trial results to individual patients.7The concept of heterogeneity of treatment effect does not appear to inform the interim findings of ISCHEMIA-EXTEND. It might be expected that an initial invasive strategy would have a larger effect on cardiovascular mortality among patients with higher cardiovascular risk. Support for this comes from observations of higher cardiovascular mortality and cardiovascular risk among individuals with greater severity of coronary artery disease or ischemic myocardium.8 However, no treatment heterogeneity for all-cause mortality was identified in subgroup analyses from ISCHEMIA-EXTEND that would favor an early invasive strategy, including those with multivessel coronary artery disease and greater ischemic burden. Possible explanations include insufficient power to identify this heterogeneity and the potential need for even longer follow-up to identify subgroups for whom an invasive strategy results in an overall mortality benefit.A nuance in the classification of cause of death in ISCHEMIA and ISCHEMIA-EXTEND warrants attention. Deaths of undetermined cause were classified as cardiovascular deaths in both the original trial and extended follow-up. This creates a potential misclassification of noncardiovascular deaths as cardiovascular deaths and may bias the treatment effect of an invasive strategy on cardiovascular mortality toward the null. This is evident when comparing the estimated hazard ratios for cardiovascular mortality in sensitivity analyses in which undetermined deaths were instead categorized as noncardiovascular deaths. This nuance does not have implications for overall mortality.Understanding what drives noncardiovascular mortality after an invasive strategy also has important implications. In a previous analysis of ISCHEMIA, deaths attributable to malignancy were more common after an invasive strategy.9 The authors found this risk increased with greater procedural exposure to radiation and this risk was not modified by extent of dual antiplatelet therapy. Although exploratory, and biologically challenging to rectify given the short time interval between radiation exposure and death from malignancy, this analysis raises questions about the potential noncardiovascular implications of an invasive strategy in the management of coronary artery disease. A major limitation of the current analysis is the lack of detail on causes of noncardiovascular mortality, precluding our ability to further understand mechanisms and potential strategies to identify and mitigate the noncardiovascular risk associated with an initial invasive strategy.In ISCHEMIA-EXTEND, vital status was captured by directly contacting participants or their designated surrogate; in a limited number of participating countries, this information was collected from central data. Capture of nonfatal end points (eg, nonfatal myocardial infarction, congestive heart failure, coronary revascularization) may have further informed mechanisms by which an invasive strategy affects cardiovascular and noncardiovascular death. Because the current publication represents an interim analysis from ISCHEMIA-EXTEND, exploration of nonfatal endpoints in continued follow-up may be warranted.Are these findings from ISCHEMIA-EXTEND likely to change clinical practice? Consistent with results from the original ISCHEMIA, we now know that for individuals with stable IHD, without left main disease or a left ventricular ejection fraction <35%, an initial invasive strategy does not improve all-cause mortality out to 7 years. For many individuals with stable IHD, mortality is not the only outcome of importance. A reduction in symptom burden and improvement in health status are additional goals in the management of IHD. Analyses from ISCHEMIA,10 and COURAGE before it,11 have demonstrated a time-dependent effect of an invasive strategy on patient-reported health status, most notably symptom burden among patients with more severe anginal symptoms at baseline. ISCHEMIA-EXTEND lacks insight on patient-reported health status, including symptom burden, functional status, and health-related quality of life. Whereas ISCHEMIA-EXTEND represents an important contribution to the literature as it relates to the effects of an invasive strategy on mortality, continued attention to patient-centered outcomes remains paramount as we strive to help patients choose a treatment strategy that bends the will of fate to meet their goals of care.Article InformationSources of FundingNone.Disclosures None.FootnotesThe opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.For Sources of Funding and Disclosures, see page 22.Circulation is available at www.ahajournals.org/journal/circCorrespondence to: Steven M. Bradley, MD, MPH, Minneapolis Heart Institute, 920 E 28th St, Ste 300, Minneapolis, MN 55407. Email steven.[email protected].comReferences1. Maron DJ, Hochman JS, Reynolds HR, Bangalore S, O’Brien SM, Boden WE, Chaitman BR, Senior R, Lopez-Sendon J, Alexander KP, et al. Initial invasive or conservative strategy for stable coronary disease.N Engl J Med. 2020; 382:1395–1407. doi: 10.1056/NEJMoa1915922CrossrefMedlineGoogle Scholar2. Bangalore S, Pencina MJ, Kleiman NS, Cohen DJ. Prognostic implications of procedural vs spontaneous myocardial infarction: results from the Evaluation of Drug Eluting Stents and Ischemic Events (EVENT) registry.Am Heart J. 2013; 166:1027–1034. doi: 10.1016/j.ahj.2013.09.008CrossrefMedlineGoogle Scholar3. Chaitman BR, Alexander KP, Cyr DD, Berger JS, Reynolds HR, Bangalore S, Boden WE, Lopes RD, Demkow M, Perna GP, et al. Myocardial infarction in the ISCHEMIA trial: impact of different definitions on incidence, prognosis, and treatment comparisons.Circulation. 2021; 143:790–804. doi: 10.1161/CIRCULATIONAHA.120.047987LinkGoogle Scholar4. Hochman JS, Anthopolos R, Reynolds HR, Bangalore S, Xu Y, O’Brien SM, Mavromichalis S, Chang M, Contreras A, Rosenberg Y, et al. Survival after invasive or conservative management of stable coronary disease.Circulation. 2023; 147:8–19. doi: 10.1161/CIRCULATIONAHA.122.062714LinkGoogle Scholar5. Spoon DB, Psaltis PJ, Singh M, Holmes DR, Gersh BJ, Rihal CJ, Lennon RJ, Moussa ID, Simari RD, Gulati R. Trends in cause of death after percutaneous coronary intervention.Circulation. 2014; 129:1286–1294. doi: 10.1161/CIRCULATIONAHA.113.006518LinkGoogle Scholar6. Brener SJ, Tarantini G, Leon MB, Serruys PW, Smits PC, von Birgelen C, Crowley A, Ben-Yehuda O, Stone GW. Cardiovascular and noncardiovascular death after percutaneous coronary intervention: insights from 32,882 patients enrolled in 21 randomized trials.Circ Cardiovasc Interv. 2018; 11:e006488. doi: 10.1161/CIRCINTERVENTIONS.118.006488LinkGoogle Scholar7. Yeh RW, Secemsky EA, Kereiakes DJ, Normand SLT, Gershlick AH, Cohen DJ, Spertus JA, Steg PG, Cutlip DE, Rinaldi MJ, et al; DAPT Study Investigators. Development and validation of a prediction rule for benefit and harm of dual antiplatelet therapy beyond 1 year after percutaneous coronary intervention.JAMA. 2016; 315:1735–1749. doi: 10.1001/jama.2016.3775CrossrefMedlineGoogle Scholar8. Reynolds HR, Shaw LJ, Min JK, Page CB, Berman DS, Chaitman BR, Picard MH, Kwong RY, O’Brien SM, Huang Z, et al. Outcomes in the ISCHEMIA trial based on coronary artery disease and ischemia severity.Circulation. 2021; 144:1024–1038. doi: 10.1161/CIRCULATIONAHA.120.049755LinkGoogle Scholar9. Sidhu MS, Alexander KP, Huang Z, O’Brien SM, Chaitman BR, Stone GW, Newman JD, Boden WE, Maggioni AP, Steg PG, et al; ISCHEMIA Research Group. Causes of cardiovascular and noncardiovascular death in the ISCHEMIA trial.Am Heart J. 2022; 248:72–83. doi: 10.1016/j.ahj.2022.01.017CrossrefMedlineGoogle Scholar10. Spertus JA, Jones PG, Maron DJ, O’Brien SM, Reynolds HR, Rosenberg Y, Stone GW, Harrell FE, Boden WE, Weintraub WS, et al; ISCHEMIA Research Group. Health-status outcomes with invasive or conservative care in coronary disease.N Engl J Med. 2020; 382:1408–1419. doi: 10.1056/NEJMoa1916370CrossrefMedlineGoogle Scholar11. Weintraub WS, Spertus JA, Kolm P, Maron DJ, Zhang Z, Jurkovitz C, Zhang W, Hartigan PM, Lewis C, Veledar E, et al; COURAGE Trial Research Group. Effect of PCI on quality of life in patients with stable coronary disease.N Engl J Med. 2008; 359:677–687. doi: 10.1056/NEJMoa072771CrossrefMedlineGoogle Scholar eLetters(0)eLetters should relate to an article recently published in the journal and are not a forum for providing unpublished data. Comments are reviewed for appropriate use of tone and language. Comments are not peer-reviewed. Acceptable comments are posted to the journal website only. Comments are not published in an issue and are not indexed in PubMed. Comments should be no longer than 500 words and will only be posted online. References are limited to 10. Authors of the article cited in the comment will be invited to reply, as appropriate.Comments and feedback on AHA/ASA Scientific Statements and Guidelines should be directed to the AHA/ASA Manuscript Oversight Committee via its Correspondence page.Sign In to Submit a Response to This Article Previous Back to top Next FiguresReferencesRelatedDetailsRelated articlesSurvival After Invasive or Conservative Management of Stable Coronary DiseaseJudith S. Hochman, et al. Circulation. 2023;147:8-19 January 3, 2023Vol 147, Issue 1 Advertisement Article InformationMetrics © 2022 American Heart Association, Inc.https://doi.org/10.1161/CIRCULATIONAHA.122.063033PMID: 36335920 Originally publishedNovember 6, 2022 Keywordsischemiacoronary angiographymyocardial ischemiaEditorialsmortalityPDF download Advertisement SubjectsChronic Ischemic Heart Disease