Journal of the American College of Cardiology Vol. 61, No. 15, 2013© 2013 by the American College of Cardiology Foundation ISSN 0735-1097/$36.00Published by Elsevier Inc. http://dx.doi.org/10.1016/j.jacc.2013.01.046

EDITORIAL COMMENT

Revascularizationfor Silent Ischemia?Another Piece of the Puzzle*

David J. Maron, MD,† Judith S. Hochman, MD‡

Nashville, Tennessee; and New York, New York

There are 2 reasons to perform coronary revascularization:1) improve survival; and 2) improve symptoms. By defini-tion, revascularization cannot improve the symptoms ofpatients with asymptomatic (“silent”) ischemia, leaving im-provement in survival as the only justifiable reason toperform revascularization in an asymptomatic person.

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Several studies have suggested that silent ischemia wors-ens prognosis in patients with stable ischemic heart disease(SIHD) (1–3). Evidence from 2 small, randomized con-trolled trials—1 in SIHD (ACIP [Asymptomatic CardiacIschemia Pilot study] and 1 in post-myocardial infarctionpatients (SWISSI II [Swiss Interventional Study on SilentIschemia Type II])—suggests that revascularization im-proves survival in patients with silent ischemia (4,5). Thesestudies were limited by their small size (ACIP was a pilotstudy) and conduct before contemporary guideline-directedmedical therapy (MT). There was a small subset of patientswith silent ischemia enrolled in the COURAGE (ClinicalOutcomes Utilizing Revascularization and Aggressive DrugEvaluation) trial (6). Consistent with the overall trial results,there was no significant difference in the small number ofdeaths between the percutaneous coronary intervention(PCI) and the optimal MT groups, but when combinedwith the 2 small previous studies, the role of routinerevascularization for asymptomatic SIHD patients withischemia comes into question.

In this issue of the Journal, Aldweib et al. (7) report asingle-site observational study that adds to the available

*Editorials published in the Journal of the American College of Cardiology reflect theviews of the authors and do not necessarily represent the views of JACC or theAmerican College of Cardiology.

From the †Departments of Medicine and Emergency Medicine, VanderbiltUniversity School of Medicine, Nashville, Tennessee; and the ‡CardiovascularClinical Research Center, Leon Charney Division of Cardiology, New York Univer-sity School of Medicine, New York, New York. The paper refers to work supportedby National Institutes of Health grant 1U01HL105907. Dr. Hochman has acted as

a consultant for GlaxoSmithKline. Dr. Maron has reported that he has no relation-ships relevant to the contents of this paper to disclose.

evidence on managing SIHD patients who have silentischemia. The authors compared survival of asymptomaticpatients with previous revascularization and documentedischemia at later follow-up, who were then selected by theirtreating physicians to undergo repeat revascularization orcontinue on MT. Ischemia was documented with single-photon emission computed tomography 5 years after theinitial revascularization. The authors selected asymptomaticpost-revascularization patients because appropriate-use cri-teria have deemed functional testing to be appropriate forasymptomatic patients �5 years after coronary artery bypassgraft (CABG) but uncertain �5 years after CABG or at anytime for asymptomatic patients with previous PCI (8). Theauthors identified 6,750 consecutive patients with previousrevascularization (CABG or PCI) who underwent stresssingle-photon emission computed tomography between2005 and 2007, then excluded symptomatic patients and/orthose without ischemia, leaving 769 patients with silentischemia. Patients were followed up over 5.7 years forall-cause death. Patients were separated into those selectedfor MT (n � 654) or revascularization (n � 115). Thosewho underwent repeat revascularization realized no survivalbenefit over those who received MT either in propensity-matched groups or unadjusted and adjusted analyses. Noneof the imaging variables, including severity of ischemia, wasassociated with all-cause death.

The study by Aldweib et al. (7) is discordant withACIP and SWISSI II results (4,5) and supports theposition that (repeat) revascularization of asymptomaticpost-revascularization patients does not improve survival.The study is subject to selection bias because unlike arandomized trial, assignment to treatment was not randombut was due to unmeasured variables, including physicianand patient preferences. To mitigate bias, the authorsdeveloped a propensity score to adjust for nonrandomiza-tion, modeled the decision to refer to revascularization, andused a Cox proportional hazards model to assess theassociation of revascularization with mortality, with andwithout adjustment for the propensity score.

Observational studies, however, cannot account for un-measured confounding variables that may affect the out-come of interest. Patients selected for conservative therapyare often sicker than patients selected for invasive therapy,and observational studies most often report better outcomeswith revascularization. (In contrast, randomized trials inSIHD have not shown superiority for a strategy of routinerevascularization [9–11].) A remarkable finding in thecurrent report (7) is that, despite selection bias, unadjustedand adjusted outcomes were not superior for those selectedfor revascularization. Another important limitation is thatonly patients who survived an average of 5 years after theirinitial revascularization were included, thereby introducingsurvival bias. Although the findings are intriguing, ulti-mately the only way to know whether a treatment strategy is

effective is by performing a randomized controlled trial.

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1625JACC Vol. 61, No. 15, 2013 Maron and HochmanApril 16, 2013:1624–5 Revascularization for Silent Ischemia

These findings (7) also seem to contradict another obser-vational study from Cedars-Sinai that found patients withmyocardial ischemia �10% who underwent revasculariza-ion had lower cardiac mortality than patients who werereated medically (12). That analysis, however, excludedatients with previous revascularization and included symp-omatic patients. Importantly, the nuclear substudy ofOURAGE patients with at least moderate ischemia ataseline, with or without angina, found no reduction ineath or myocardial infarction from PCI (13).What is the take-home point for the clinician? Most

vidence suggests that more severe ischemia is associatedith worse outcomes, probably because severe stenoses that

ause ischemia are a marker of greater atheroscleroticurden. Whether revascularization for ischemia-producingtenoses improves survival beyond the benefit of aggressive

T to stabilize vulnerable plaques is unknown. The currenteport (7) calls into question the association of ischemia andutcome in patients with remote revascularization. Thetrength of the current data may not be sufficient to reclassifyhe appropriateness score for post-revascularization stress test-ng in asymptomatic patients (5 years after CABG; noecommendation after PCI), but it calls into question itstility. The ongoing National Heart, Lung, and Bloodnstitute–funded ISCHEMIA (International Study ofomparative Health Effectiveness With Medical and Invasivepproaches; NCT01471522) randomized controlled trial will

provide further evidence. The trial is enrolling SIHDpatients with at least moderate ischemia who are eitherasymptomatic or symptomatic, with or without previousrevascularization, and testing whether a routine invasivestrategy with revascularization improves prognosis. As trialleaders, we believe there is equipoise regarding the optimalmanagement strategy for patients with ischemia who do notrequire revascularization for symptoms and encourage supportfor answering this important clinical question. In the mean-time, it is reasonable to follow existing guidelines for SIHDpatients with high-risk ischemia and participate in shareddecision making with such patients (14).

Reprint requests and correspondence: Dr. David J. Maron,Vanderbilt Heart and Vascular Institute, 1215 21st Avenue South,MCE, 5th Floor South Tower, Nashville, Tennessee 37232-8800.E-mail: david.maron@vanderbilt.edu.

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Key Words: ischemia y outcome y revascularization y single-photonemission myocardial perfusion scintigraphy.