Medical Therapy With Versus Without Revascularization in Stable Patients With Moderate and Severe Ischemia: The Case for Community Equipoise

Abstract

All patients with stable ischemic heart disease (SIHD) should be managed with guideline-directed medical therapy (GDMT), which reduces progression of atherosclerosis and prevents coronary thrombosis. Revascularization is also indicated in patients with SIHD and progressive or refractory symptoms, despite medical management. Whether a strategy of routine revascularization (with percutaneous coronary intervention or coronary artery bypass graft surgery as appropriate) plus GDMT reduces rates of death or myocardial infarction, or improves quality of life compared to an initial approach of GDMT alone in patients with substantial ischemia is uncertain. Opinions run strongly on both sides, and evidence may be used to support either approach. Careful review of the data demonstrates the limitations of our current knowledge, resulting in a state of community equipoise. The ongoing ISCHEMIA trial (International Study of Comparative Health Effectiveness With Medical and Invasive Approaches) is being performed to determine the optimal approach to managing patients with SIHD, moderate-to-severe ischemia, and symptoms that can be controlled medically. (International Study of Comparative Health Effectiveness With Medical and Invasive Approaches [ISCHEMIA]; NCT01471522).

Keywords: angina pectoris; coronary artery bypass; coronary artery disease; guideline-directed medical therapy; percutaneous coronary intervention.

FIGURE 1. Propensity-Matched Analysis in 39,131 Canadian Patients With SIHD Undergoing Early Revascularization (n = 23,992) or Treated Conservatively (n = 15,139)

Over 4 years of follow-up, significant reductions in death (A) and myocardial infarction (B) were observed with revascularization. Adapted with permission from Wijey sundera et al.(18). CI = confidence interval; HR = hazard ratio; SIHD = stable ischemic heart disease.

FIGURE 2. Cardiac Mortality as a Function of Total Ischemic Myocardium at a Mean Follow-Up Time of 1.9 ± 0.6 Years

Cardiac mortality as a function of total ischemic myocardium is shown at a mean follow-up time of 1.9 ± 0.6 years in 10,627 patients at Cedars-Sinai Medical Center without previous myocardial infarction or revascularization who underwent exercise or adenosine thallium 201 single-photon emission computed tomography myocardial perfusion scintigraphy. Outcomes are shown according to whether elective revascularization was versus was not performed within 60 days. Patients with a greater percentage of ischemic myocardium had a greater survival benefit with revascularization. (A) Unadjusted analysis. (B) Log hazard ratio of cardiac mortality for revascularization versus medical therapy as a function of % ischemic myocardium from a Cox proportional hazards regression model. *p < 0.001. Adapted with permission from Hachamovitch et al. (26).

FIGURE 3. Reduction in Inducible Ischemia From Baseline to 6 to 18 Months

Reduction in inducible ischemia from baseline to 6 to 18 months is shown in patients treated with OMT with versus without a strategy of routine upfront PCI, as assessed by myocardial perfusion scintigraphy. Left graph: with routine upfront PCI; right graph: without. The reduction in ischemia in the PCI arm was significant, whereas there was no significant reduction in ischemia with OMT. Adapted with permission from Shaw et al. (27). CI = confidence interval; OMT = optimal medical therapy; PCI = percutaneous coronary intervention.

FIGURE 4. Relationship Between FFR and 1-Year MACE According to Whether or Not Revascularization Was Performed

(A) Study-level meta-regression in 8,418 patients from 90 cohorts. Revascularization was associated with a lower rate of MACE when the FFR was <0.75 in an unadjusted random effects model, and <0.90 in an adjusted model. (B) Patient-level meta-analysis in 5,979 patients. Revascularization was associated with a lower rate of MACE when the FFR was <0.67 in an unadjusted Cox model, and <0.76 in an adjusted model. Reprinted with permission from Johnson et al. (30). CABG = coronary artery bypass graft; FFR = fractional flow reserve; MACE = major adverse cardiac events; MI = myocardial infarction; PCI = percutaneous coronary intervention.

FIGURE 5. Network Meta-Analysis Comparing Different Revascularization Modalities With MT

Estimated risk rate ratios (95% credible intervals) are shown for death, MI, and the composite of death or MI. Compared with MT, a reduction in death was observed with EES, R-ZES, and CABG; a reduction in MI was observed with CABG; and a reduction in the composite of death or MI was observed with EES and CABG. Adapted with permission from Windecker et al. (47). BMS = bare-metal stent(s); CrI = credible interval; EES = everolimus-eluting stent(s); E-ZES = fast-release zotarolimus-eluting stent(s); MT = medical therapy; PES = paclitaxel-eluting stent(s); PTCA = percutaneous transluminal coronary angioplasty; R-ZES = slow-release zotarolimus eluting stent(s); SES = sirolimus-eluting stent(s); other abbreviations as in Figure 4.

FIGURE 6. Effect of OMT on Clinical Outcomes in Patients Undergoing PES Implantation and CABG in the SYNTAX Trial

OMT significantly lowered the risk of death throughout the 5-year follow-up. In a Cox regression model, OMT as a time-dependent covariate was independently associated with improved survival throughout follow-up both in PCI patients (HR: 0.70; 95% CI: 0.48 to 0.998) and CABG patients (HR: 0.65; 95% CI: 0.49 to 0.86; p_interaction = 0.44). Adapted with permission from Iqbal et al. (57). SYNTAX = Synergy Between Percutaneous Coronary Intervention With TAXUS and Cardiac Surgery; other abbreviations as in Figures 1, 3, 4, and 5.

FIGURE 7. Baseline Severity of Ischemia and Outcomes by Treatment Group in the COURAGE Trial

Cumulative rates of all-cause death or MI are shown according to randomized treatment assignment in patients with no-to-mild ischemia and moderate-to-severe ischemia on myocardial perfusion imaging at baseline in the COURAGE (Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation) trial. (A) No-to-mild ischemia. (B) Moderate-to-severe ischemia. Ischemia severity was determined by the participating sites, and was not associated with risk of death or MI. PCI did not reduce death or MI in patients with moderate or severe ischemia. Adapted with permission from Shaw et al. (48). Abbreviations as in Figures 3 and 4.

FIGURE 8. Ischemia Severity, Anatomic Burden, and Outcomes in COURAGE

Freedom from death, MI, or NSTE-ACS is shown by percent ischemic myocardium and burden of angiographic atherosclerosis. (A) Percent ischemic myocardium. (B) Burden of angio-graphic atherosclerosis. The number of patients pertaining to each colored curve is shown per year of follow-up. The Cedars-Sinai Nuclear Core Laboratory determined the percent ischemic myocardium at baseline. Atherosclerotic burden was determined by a custom score, accounting for the number and specific diseased coronary arteries, and proximal versus nonproximal location. Ischemic burden was not associated with events, in contrast to anatomic burden, which was. PCI did not reduce the event rate in patients with high ischemic or anatomic burden. Adapted with permission from Mancini et al. (65). NSTE-ACS = non-ST-segment elevation acute coronary syndrome; other abbreviations as in Figures 3, 4, and 7.

FIGURE 9. Meta-Analysis of PCI and MT Versus MT Alone in Patients With Documented Myocardial Ischemia

(A) Death. (B) Nonfatal MI. This meta-analysis required 50% statin use and only included studies of SIHD that directly compared the 2 randomized groups. The addition of PCI to MT did not reduce the incidence of death or MI as compared with MT alone. Adapted with permission from Stergiopoulos et al. (73). OR = odds ratio; other abbreviations as in Figures 3, 4, and 5.

CENTRAL ILLUSTRATION. Ischemia Revascularization Equipoise: The ISCHEMIA Trial Design

CCTA may not be performed in participants with estimated glomerular filtration rate <60 ml/min. Participants in whom CCTA shows significant left main disease (≥50% stenosis) or no obstructive disease are excluded. CCTA results are otherwise kept blinded. Cath = catheterization; CCTA = coronary computed tomographic angiography; CKD = chronic kidney disease; eGFR = estimated glomerular filtration rate; OMT = optimal medical therapy; SIHD = stable ischemic heart disease.