Background
Prior trials of stable ischemic heart disease (SIHD) have not demonstrated improved clinical outcomes associated with a strategy of percutaneous coronary intervention (PCI) with optimal medical therapy (OMT) compared with OMT alone.^1,2 The principal findings of the Clinical Outcomes Using Revascularization and Aggressive Drug Evaluation (COURAGE) trial was that an initial strategy of OMT alone was as safe and effective as PCI with OMT. There was no between-group difference in the primary outcome of death from any cause and nonfatal myocardial infarction (MI).² The COURAGE findings had significant implications for the prior practice of often recommending PCI  for patients with stable obstructive coronary artery disease (CAD).

However, there were limitations in that there was no predefined threshold for the extent and severity of baseline ischemia as a criterion for randomization, and only one third of patients had moderate to severe ischemia. Thus, an important consideration in the recent ISCHEMIA study was that the subset of patients with moderate to severe ischemia treated with PCI plus OMT would fare better than the OMT-treated patients in terms of a greater ischemic reduction, better quality of life, and improved cardiovascular (CV) outcomes.

This issue, in part, was addressed in a post-hoc analysis of COURAGE, where serial nuclear imaging at baseline and one-year post-randomization revealed that PCI plus OMT led to greater ischemia reductions compared with OMT alone.³ However, there was no difference in CV outcomes by randomized treatment assignment regardless of the severity of ischemia.³

In another COURAGE post hoc study that examined extended follow-up  (median 12 years; range: 0-15 years), in subjects with moderate to severe ischemia (n=130 patients), PCI did not lead to improved survival as compared with OMT alone.⁴ This led to an equipoise on whether the extent or the severity of ischemia had any significant bearing on therapeutic effectiveness with PCI.

The International Study of Comparative Health Effectiveness With Medical and Invasive Approaches (ISCHEMIA) trial was initiated to evaluate the effectiveness of an initial invasive approach (coronary angiography followed by PCI or coronary artery bypass grafting [CABG]) and OMT versus OMT during a median of 3.2 year follow-up. Patients with SIHD were pre-selected with moderate to severe ischemia at baseline.⁵ The primary CV outcome (a composite of death from CV causes, MI, hospitalization for unstable angina, HF, or resuscitated cardiac arrest) in 5,179 patients with moderate/severe ischemia was observed to be no different between the revascularization strategy plus OMT and the OMT alone-treated patients.

Notably, high risk patients including those with advanced kidney disease, ejection fraction (EF) <35%, those with coronary artery revascularization within the past year, as well as those with New York Heart Association functional classification (NYHA) III/IV symptoms despite maximal medical therapy, were excluded from ISCHEMIA.⁵

Prior randomized controlled trials (RCTs) evaluating the survival benefit of CABG versus medical therapy in patients with left ventricular (LV) dysfunction did not include contemporary OMT: high dose, high intensity statin therapy, angiotensin converting enzyme inhibitor (ACEi) or angiotensin receptor blockers (ARBs) and angiotensin neprilysin inhibitors (ARNIs), thus making these older trials less relevant to current practice.^6,7 However, two previous studies addressed outcomes in patients with EF <35%.

The Heart Failure Revascularization Trial (HEART) trial randomized patients with CAD, LVEF, 35% and a substantial volume of viable myocardium assessed by imaging to OMT alone or with early percutaneous/surgical intervention. No difference in all-cause mortality was detected. However, the trial was underpowered and only 138 of the initially planned 800 participants were enrolled.⁸

The larger Surgical Treatment for Ischemic Heart Failure (STICH) trial found an improvement in the primary end point of all-cause mortality at 5 and 10 years of follow-up in patients with EF <35%, randomized to CABG and OMT compared to OMT alone.⁹ During a 6-year follow-up, the primary outcome of all-cause mortality was similar between the medical therapy plus CABG and medical therapy arms (36% vs. 41%, hazard ratio [HR] 0.86, 95% confidence interval [CI] 0.72-1.04, p = 0.12). However, CV mortality was lower in the medical therapy plus CABG arm (28% vs. 33%, HR 0.81, 95% CI 0.66-1.00, p = 0.05), as was all-cause mortality or CV hospitalization (58% vs. 68%, HR 0.74, 95% CI 0.64-0.85, p < 0.001), and all-cause mortality or repeat revascularization (39% vs. 55%, HR 0.60, 95% CI 0.51-0.71, p < 0.001). Although there was no difference in all-cause mortality at 5 years, at 10 years, all-cause mortality and hospitalizations were lower in the CABG group.¹⁰

The findings of the STICH trial need to be taken into context with regards to patients with severe LV dysfunction, existing comorbidities, and recent advances in medical management of HF. In patients with ischemic LV systolic dysfunction, CABG plus medical therapy resulted in higher mortality at 30 days, but with a significant improvement in long-term mortality (out to 10 years) compared with medical therapy alone.

Only 14 patients needed to be treated with CABG to save one life over 10 years. CV mortality and morbidity were both lower with CABG. There was a high rate of cross-over from the medical therapy arm to CABG (mirroring clinical practice), and on per-protocol analysis, medical therapy plus CABG was associated with a survival benefit over medical therapy alone even earlier.

However, the age-based findings with CABG and medical therapy versus medical therapy suggest that the benefit of CABG may diminish with older age due to competing risks. Also, contemporary medical therapy (OMT) for HF has considerably improved with more frequent the use of ARNI and aldosterone antagonists to achieve maximum symptom reduction; perhaps the benefit of CABG seen in the STICH trial might not be as significant with aggressive medical therapy titrated to maximally tolerated doses.

Study Design
The recent paper by Lopes et al. is a post hoc analysis of the ISCHEMIA trial in a subset of patients with HF and/or reduced EF (35-50%) to discern if outcomes were improved in this high-risk subset.¹¹ The primary outcome for this post hoc analysis was the composite of CV mortality, resuscitated cardiac arrest, MI, or hospitalization for HF or unstable angina. The major secondary outcome was CV mortality or MI.

Results
A subgroup of 398 participants (4.5% of all ISCHEMIA patients) were included: 221 had an EF of 35-45%, and 205 had a prior diagnosis of HF (28 participants with both). Participants who met inclusion criteria tended to have more comorbidities, higher NYHA class symptoms, and were on more beta-blockers, anticoagulation, ACEi or ARB therapy, and diuretics.  Patients randomized to OMT (as per the current contemporary standard of care) alone compared to interventional therapy had greater adverse CV events.

Patients randomized to OMT alone experienced an absolute difference of 12% (95% CI: 1.6-22.6%) more CV adverse events (primary outcome) and 11.4% (95% CI: 1.4-21.4%) more CV mortality/MI (secondary outcome) compared to those randomized to the invasive strategy.

Specifically, participants with both LV dysfunction and history of HF, though extremely limited in number (n=28), seemed to benefit the most from upfront interventional therapy. Patients with normal LV function or no prior history of HF, on the other hand, had no difference in CV events when comparing guideline-directed medical therapy (GDMT) to invasive therapy.

Significance
This is a very small subgroup analysis with a limited number of patients. Unlike the initially published results from the ISCHEMIA trial, this subpopulation analysis suggests that patients with HF/LV dysfunction may potentially derive benefit from an initial primary interventional strategy rather than OMT alone. However, given the post hoc nature of this analysis, the very small sample size, and potential confounding, the findings of this study need to be interpreted with significant caution and restraint. Until more robust prospective data are available in larger populations of stable CAD patients with HF and/or LV systolic dysfunction, clinicians should continue to use their clinical judgment and individualize decision-making for such patients.

Despite no observed improvement in type 2 diabetics randomized to revascularization rather than OMT alone in the BARI 2D trial, in subsequent subgroup analysis, those who were randomized to CABG (not PCI) had better outcomes. The study was not designed to compare CABG to PCI, and choice of revascularization technique was left to the discretion of physicians, leading to a higher-risk population in the CABG group.^12,13

A follow-up analysis of the COURAGE trial studied outcomes after achieving control of six risk factors (systolic blood pressure, LDL-cholesterol, smoking, physical activity, diet, and body mass index).¹⁴ The authors demonstrated that controlling more risk factors has incremental benefits on survival, and that having all six risk factors controlled was associated with 73% lower risk of mortality compared to 0 or 1 risk factor controlled. Therefore, risk factor modification with the aim to control multiple risk factors should be the principal target of individualized management of stable coronary disease regardless of the underlying LV function.

Future Directions
Since the ISCHEMIA trial was not specifically designed to assess outcomes in patients with HF, these preliminary findings should be considered hypothesis-generating. Multiple newer medications have demonstrated cardiovascular benefit in this group of participants including SGLT2 inhibitors and ARNI therapy, and the goal blood pressure and lipid levels recommendations have changed. It would be important to see how these factors may affect outcomes in future randomized trials comparing an interventional approach to OMT alone.

References

1. Weintraub WS, Spertus JA, Kolm P, et al. Effect of PCI on quality of life in patients with stable coronary disease. N Engl J Med 2008;359:677-87.
2. Boden WE, O'Rourke RA, Teo KK, et al. Optimal medical therapy with or without PCI for stable coronary disease. N Engl J Med 2007;356:1503-16.
3. 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;164:243-50.
4. Sedlis SP, Hartigan PM, Teo KK, et al. Effect of PCI on long-term survival in patients with stable ischemic heart disease. N Engl J Med 2015;373:1937-46.
5. Maron DJ, Hochman JS, Reynolds HR, et al. Initial invasive or conservative strategy for stable coronary disease. N Engl J Med 2020;382:1395-1407.
6. Mock MB, Ringqvist I, Fisher LD, et al. Survival of medically treated patients in the coronary artery surgery study (CASS) registry. Circulation 1982;66:562-8.
7. VA Coronary Artery Bypass Surgery Cooperative Study Group. Eighteen-year follow-up in the Veterans Affairs cooperative study of coronary artery bypass surgery for stable angina. Circulation 1992;86:121-30.
8. Cleland JGF, Calvert M, Freemantle N, et al. The Heart Failure Revascularisation Trial (HEART). Eur J Heart Fail 201113:227-33.
9. Velazquez EJ, Lee KL, Deja MA, et al. Coronary-artery bypass surgery in patients with left ventricular dysfunction. N Engl J Med 2011364:1607-16.
10. Petrie MC, Jhund PS, She L, et al. Ten-year outcomes after coronary artery bypass grafting according to age in patients with heart failure and left ventricular systolic dysfunction: an analysis of the extended follow-up of the STICH Trial (Surgical Treatment for Ischemic Heart Failure). Circulation 2016;134:1314-24.
11. Lopes RD, Alexander KP, Stevens SR, et al. Initial invasive versus conservative management of stable ischemic heart disease patients with a history of heart failure or left ventricular dysfunction: insights from the ISCHEMIA trial. Circulation 2020;Aug 29:[Epub ahead of print].
12. Dagenais GR, Lu J, Faxon DP, et al. Effects of optimal medical treatment with or without coronary revascularization on angina and subsequent revascularizations in patients with type 2 diabetes mellitus and stable ischemic heart disease. Circulation 2011;123:1492-500.
13. Frye RL, August P, Brooks MM, et al. A randomized trial of therapies for type 2 diabetes and coronary artery disease. N Engl J Med 2009;360:2503-15.
14. Maron DJ, Mancini GBJ, Hartigan PM, et al. Healthy behavior, risk factor control, and survival in the COURAGE trial. J Am Coll Cardiol 2018;72:2297-2305.

Clinical Topics: Diabetes and Cardiometabolic Disease, Dyslipidemia, Heart Failure and Cardiomyopathies, Invasive Cardiovascular Angiography and Intervention, Noninvasive Imaging, Atherosclerotic Disease (CAD/PAD), Nonstatins, Novel Agents, Statins, Heart Failure and Cardiac Biomarkers, Interventions and Coronary Artery Disease, Interventions and Imaging, Angiography, Nuclear Imaging

Keywords: Dyslipidemias, Coronary Artery Disease, Percutaneous Coronary Intervention, Coronary Angiography, Mineralocorticoid Receptor Antagonists, Angiotensin Receptor Antagonists, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Neprilysin, Diuretics, Angiotensins, Confidence Intervals, Maximum Tolerated Dose, Drug Evaluation, Stroke Volume, Follow-Up Studies

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