Impact of Repeat Myocardial Revascularization in Silent Ischemia After Previous Revascularization
Editor's Note: Based on Aldweib N, Negishi K, Hachamovitch R, Jaber WA, Seicean S, Marwick TH. Impact of repeat myocardial revascularization on outcome in patients with silent ischemia after previous revascularization. J Am Coll Cardiol 2013;61:1616-23.
Numerous studies indicate that silent ischemia is associated with an increased risk of coronary events1 and patients with prior coronary artery bypass graft (CABG) and percutaneous coronary intervention (PCI) are at risk for silent ischemia.2,3 Though current guidelines indicate that it is appropriate to use single-photon emission computed tomography (SPECT) to screen certain patients post-revascularization for asymptomatic disease,4 the optimal management strategy for silent ischemia, once discovered, is unclear.
In the study performed by Aldweib et al. published in JACC, the authors sought to determine whether repeat revascularization in asymptomatic patients with prior CABG or PCI found to have silent ischemia on SPECT myocardial perfusion scintigraphy (MPS) would result in a survival benefit when compared to medical therapy.
This single-site, observational study included 769 asymptomatic patients with prior CABG or PCI found to have inducible ischemia on routine exercise or adenosine SPECT MPS. Gated SPECT single- or two-day technetium-99m tracer protocols were utilized and the consensus of two observers was used to determine whether the study was positive or negative for ischemia. The extent and severity of perfusion defects in the left ventricle were assessed using the 17-segment model of the left ventricle along with a five-point scoring system to grade the degree of radiotracer uptake.
Of the 769 patients with silent ischemia, 115 patients underwent repeat revascularization and the remaining 654 patients were treated without revascularization. These remaining patients are said to have undergone "medical therapy" but the use of cardiac catheterization in these patients was not reported and the details of medical therapy in both groups were not discussed. The study cohort was followed for a median of 5.7 years for all-cause mortality. The two groups were compared in an unadjusted analysis and in a multivariate model using a propensity score to adjust for selection bias associated with revascularization in addition to other baseline characteristics. A propensity-matched survival analysis was also performed. Deaths were confirmed by reviewing death certificates along with hospital charts or physician records. The Social Security Death Index was used to confirm the survival status of all patients at the end of the follow-up period.
At the time of stress testing, patients who went on to receive repeat revascularization had greater ischemic burden and lower exercise capacity, and were more likely to have a history of transient ischemic attack, pulmonary embolism, or ventricular fibrillation. Approximately 35% of included patients had undergone prior CABG and the remainder prior PCI. The average time from revascularization to SPECT was just over 5 years. Both the type of prior revascularization and the time from prior revascularization to SPECT MPS were similar between revascularization and medical therapy groups.
The propensity score included male sex, stress test characteristics (maximum rate-pressure product and summed difference score) and historical characteristics. Among the latter, diabetes and congestive heart failure were associated with increased utilization of revascularization and history of atrial or ventricular fibrillation, prior TIA, and hypothyroidism were associated with decreased utilization of revascularization. The model c-index was 0.842, indicating that most of the variability in use of revascularization in this cohort was explained by the score.
There was no association between repeat revascularization and all-cause mortality on either unadjusted or propensity score-adjusted comparison of all patients. Over the 5.7-year follow up period, there was no difference in mortality between those patients with silent ischemia who received medical therapy compared to those who had repeat revascularization (18.3% vs. 19.1% respectively, p = 0.84). Propensity-matched analysis comparing patients receiving medical therapy versus repeat revascularization also showed no difference in survival (n=230), however, the sample size calculation was based on a large hypothesized risk reduction (66%) and the comparison was therefore likely underpowered.
A clinical risk score for all-cause mortality was developed using a Cox proportional hazards model and this identified the following predictive variables: age, sex, cancer, anemia, smoking, and end-stage renal disease. Propensity for selection for revascularization was not a predictor of death. The combination of patient age and sex also predicted increased risk of death. None of the imaging variables, including extent of myocardial ischemia, extent of myocardial scar or LVEF, were predictors of mortality on multivariate analysis, even when the number of variables was limited. After adjusting for the propensity score, a Cox proportional hazards model revealed that pharmacologic stress testing and the clinical risk score were the most important predictors of all-cause death while revascularization showed no association with mortality.
Patients with prior CABG or PCI found to have silent ischemia on routine SPECT MPS who were selected for revascularization did not have lower all-cause mortality as compared to those selected for treatment without revascularization, even when compared using propensity matching or multivariate adjustment.
Silent ischemia carries a risk of adverse cardiac events similar to that of symptomatic ischemia in patients with coronary artery disease (CAD).1,5 The optimal treatment strategy for patients with silent ischemia has yet to be elucidated, both overall and in patients with prior revascularization. Studies suggest that patients with prior CABG or PCI are at risk of silent ischemia following revascularization,2,3 so it is important to determine an evidence-based approach to management. Aldweib et al. approached this question with a single-site, observational study and found no benefit associated with selection for revascularization among patients with prior revascularization and silent ischemia, identified at an average of five years after revascularization.
The findings in the study by Aldweib et al. are consistent with results from the post hoc analysis of the silent myocardial ischemia subgroup of the COURAGE (Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation) trial.6 This substudy of the COURAGE randomized trial assessed whether PCI, in addition to aggressive medical therapy, resulted in improved outcomes in asymptomatic patients when compared to optimal medical therapy alone. 27% of the patients in this substudy had undergone prior CABG or PCI. Medical therapy included both anti-ischemic and anti-hypertensive medications along with aggressive lipid-lowering therapy with a target low-density lipoprotein (LDL) level of 60 to 85 mg/dl. In the observational study by Aldweib et al. it is unclear what medications were prescribed to the patients selected for medical therapy alone and whether treatment targets were achieved. Though this information is lacking, it seems likely that most patients in this study were prescribed guideline recommended therapy, which includes beta-blockers and statin therapy titrated to optimal LDL levels.7
Revascularization was previously shown to reduce the risk of major cardiac events in patients with CAD when compared to medical therapy in the Swiss International Study on Silent Ischemia Type II (SWISSI II).8 Though all patients in this study received aspirin and a statin, the statin dose was not aggressively uptitrated according to current guideline recommendations. Revascularization was also superior to medical therapy in patients with silent ischemia in the Asymptomatic Cardiac Ischemia Pilot (ACIP) Study.8 This study specifically assessed the effect of medical therapy versus revascularization in patients with CAD found to have silent ischemia on stress testing and ambulatory ECG monitoring. Similar to SWISSI II, the patients randomized to medical therapy in the ACIP study were not medically optimized according to current guidelines. Though they all received ASA and anti-ischemic medications, lipid-lowering medications were not included in the protocol since enrollment for this study began prior to the publication of secondary prevention trials using statins.10,11 This is likely a major reason for the differing results as compared to the COURAGE analysis and the observational study by Aldweib et al.
This study by Aldweib et al. attempts to answer an important question, which is whether patients with silent ischemia and prior CABG or PCI realize a survival benefit from repeat revascularization. The primary endpoint was all-cause mortality and though this is a clinically meaningful endpoint, it would have been useful to determine if either medical therapy or repeat revascularization affected other clinically significant endpoints such as the rate of cardiac death, nonfatal MI, freedom from angina and/or hospitalization for unstable angina. This study is also limited by the fact that the power and sample size calculations were based on the assumption of a large treatment effect, determined partly by the COURAGE silent ischemia substudy,6 which was also an underpowered analysis. Selection bias was addressed carefully using propensity scoring but there remains the possibility that unmeasured confounders affected results in this observational study.
Patients with silent ischemia post-revascularization represent a subset of those patients with ischemia. Some observational studies have suggested an association between the extent and severity of myocardial ischemia and the risk of cardiac death and myocardial infarction (MI), with patients with moderate to severe ischemia at highest risk.12,13 This association was not observed in the study by Aldweib et al., in which extent of myocardial ischemia was not a predictor of mortality on multivariate analysis. Prior observational studies suggested that treatment of patients with moderate to severe ischemia with revascularization is associated with lower risk of death and MI.14,15 Analysis of a subset of patients in COURAGE trial with ischemia imaging at baseline, however, did not identify an interaction between higher ischemia severity and the trial outcome; that is, there was no benefit of PCI even in those patients with moderate-severe ischemia at baseline in that underpowered analysis.16 Additionally, a recently published trial assessing the outcomes of patients with CAD and ejection fraction ≤35% randomized to CABG or medical therapy in the STICH trial found that inducible myocardial ischemia did not identify patients with poorer prognosis or a benefit from CABG compared with medical therapy.17
The ongoing ISCHEMIA (International Study of Comparative Health Effectiveness With Medical and Invasive Approaches) trial18 is currently testing whether an initial invasive approach will improve clinical outcomes in patients with stable ischemic heart disease. In this randomized controlled trial, patients with moderate to severe ischemia will be randomized to either optimal medical therapy and cardiac catheterization with intended complete revascularization or optimal medical therapy alone, with cath reserved for failure of medical therapy. This trial will likely give us more definitive insight on the ideal treatment strategy for patients with moderate to severe ischemia, including silent ischemia, and will shed additional light on the questions raised by the excellent study by Aldweib et al.
- Gehi AK, Ali S, Na B, et al. Inducible Ischemia and the Risk of Recurrent Cardiovascular Events in Outpatients With Stable Coronary Heart Disease. Arch Intern Med 2008;168:1423-1428.
- Weiner DA, Ryan TJ, Parsons L, et al. Prevalence and prognostic significance of silent and symptomatic ischemia after coronary bypass surgery: A report from the Coronary Artery Surgery Study (CASS) randomized population. J Am Coll Cardiol 1991;18:343-348.
- Pfisterer M, Rickenbacher P, Kiowski W, et al. Silent ischemia after percutaneous transluminal coronary angioplasty: Incidence and prognostic significance. J Am Coll Cardiol 1993;22:1446-1454.
- Hendel RC, Berman DS, Di Carli MF, et al. ACCF/ASNC/ACR/AHA/ASE/SCCT/ SCMR/SNM 2009 appropriate use criteria for cardiac radionuclide imaging: a report of the American College of Cardiology Foundation Appropriate Use Criteria Task Force, the American Society of Nuclear Cardiology, the American College of Radiology, the American Heart Association, the American Society of Echocardiography, the Society of Cardiovascular Computed Tomography, the Society for Cardiovascular Magnetic Resonance, and the Society of Nuclear Medicine. J Am Coll Cardiol 2009;53:2201-29.
- Tzivoni D, Gavish A, Zin D, et al. Prognostic significance of ischemic episodes in patients with previous myocardial infarction. Am J Cardiol 1988;62:661.
- Gosselin G, Teo KK, Tanguay JF, et al. Effectiveness of percutaneous coronary intervention in patients with silent myocardial ischemia (post hoc analysis of the COURAGE trial). Am J Cardiol 2012;109:954-9.
- Fihn SD, Gardin JM, Abrams J, et al. 2012 ACCF/AHA/ACP/AATS/PCNA/SCAI/STS Guideline for the Diagnosis and Management of Patients With Stable Ischemic Heart Disease: A Report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines, and the American College of Physcicians, American Association for Thoracic Surgery, Preventive Cardiovascular Nurses Association, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons. Circulation 2012;126:e354-e471.
- Erne P, Schoenenberger AW, Burckhardt D, et al. Effects of percutaneous coronary interventions in silent ischemia after myocardial infarction: the SWISSI II randomized controlled trial. JAMA 2007;297:1985-1991.
- Davies RF, Goldberg AD, Forman S, et al. Asymptomatic Cardiac Ischemia Pilot (ACIP) study two-year follow-up: outcomes of patients randomized to initial strategies of medical therapy versus revascularization. Circulation 1997;95:2037-43.
- Scandinavian Simvastatin Survival Study Group. Randomised trial of cholesterol lowering in 444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet 1994;344:1383-1389.
- Sacks FM, Pfeffer MA, Moye LA, et al. The effect of prava-statin on coronary events after myocardial infarction in patients with average cholesterol levels. N Engl J Med 1996;335:1001-1009.
- Beller GA, Zaret BL. Contributions of nuclear cardiology to diagnosis and prognosis of patients with coronary artery disease. Circulation 2000; 101:1465-78.
- Califf RM, Armstron PW, Carver JR, et al. 27th Bethesda conference: Matching the intensity of risk factor management with the hazard for coronary disease events. Task Force 5. Stratification of patients into high, medium and low risk subgroups for purposes of risk factor management. J Am Coll Cardiol 1996; 27:1007-19.
- Hachamovitch R, Hayes SW, Friedman JD, et al. Comparison of the short-term survival benefit associated with revascularization compared with medical therapy in patients with no prior coronary artery disease undergoing stress myocardial perfusion single photon emission computed tomography. Circulation 2003;107:2900-7.
- Moroi M, Yamashina A, Tsukamoto K, et al. Coronary revascularization does not decrease cardiac events in patients with stable ischemic heart disease but might do in those who showed moderate to severe ischemia. Int J Cardiology 2012;158:246-52.
- Shaw LJ, Weintraub WS, Maron DJ, et al. Baseline stress myocardial perfusion imaging results and outcomes in patients with stable ischemic heart disease randomized to optimal medical therapy with or without percutaneous coronary intervention. Am Heart J 2012;164:243-250.
- Panza JA, Holly TA, Asch FM, et al. Inducible Myocardial Ischemia and Outcomes in Patients with Coronary Artery Disease and Left Ventricular Dysfunction. J Am Coll Cardiol 2013; 61:1860-70.
- Available from: http://clinicaltrials.gov/show/NCT01471522
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