Coronary artery disease (CAD) continues to be the leading cause of heart failure (HF) globally.¹ The concept of salvaging hibernating myocardium in order to improve morbidity and mortality in patients with HF has been a topic of discussion for many years.

In 2011, the investigators of the Surgical Treatment in Ischemic Heart Failure (STICH) trial hypothesized that coronary artery bypass grafting (CABG) in addition to optimal medical therapy (OMT) would benefit patients with CAD and left ventricular systolic dysfunction (LVSD) compared to OMT alone.² Although the primary outcome of all-cause mortality at the end of the initial 5-year follow-up period was not different between the groups, a 16% lower risk of death was observed at the extended 10-year follow-up in the CABG plus OMT group.³

The investigators of the Revascularization for Ischemic Ventricular Dysfunction (REVIVED) trial hypothesized that coronary artery revascularization using percutaneous coronary intervention (PCI) in patients with severe ischemic LVSD with viable myocardium would improve event-free survival compared to OMT alone.⁴ Their secondary hypothesis was that PCI would improve LVSD.

Methods
The REVIVED trial was an open-labelled, prospective, randomized, multicenter trial that took place across 40 institutions within the United Kingdom.⁵ It included patients with a left ventricular ejection fraction (LVEF) of ≤35%, extensive anatomic CAD, and ≥4 viable segments amenable to PCI. Extensive CAD was defined as a British Cardiovascular Intervention Society Jeopardy Score of ≥6. Viability was assessed using dobutamine stress, cardiac magnetic resonance imaging (cMRI), single photon emission computerized tomography (SPECT), or positron emission tomography (PET).⁶

The primary outcome was all-cause death or hospitalization secondary to HF within 24 months of randomization. Secondary outcomes consisted of LVEF at 6 and 12 months, Kansas City Cardiomyopathy Questionnaire (KCCQ) score, EuroQol Group 5-Dimensions 5-Level Questionnaire (EQ-5D-5L) score, and New York Heart Association (NYHA) Functional Classification.

Results
Between August 2013 and March 2020, 700 patients were randomized in a 1:1 ratio to either PCI plus OMT versus OMT alone. Both groups were matched well: 77% of the PCI group and 71% of OMT group were NYHA class I or II, while 66% and 67% of PCI and OMT groups, respectively, had no angina. The primary outcome was observed in 37% of the PCI group and 38% of OMT group with a hazard ratio of 0.99 (95% confidence interval [CI], 0.78 to 1.27, P=0.96).

Changes in LVEF did not vary significantly between both groups with a mean difference of -1.6 percent points at 6 months (95% CI, -3.7 to 0.5) and 0.9 percent points at 12 months (95% CI, -1.7 to 3.4). The KCCQ score at 6 months was in favor of PCI group with a mean difference of 6.5 points (95% CI, 3.5 to 9.5); however, OMT group scores improved over time with a mean difference of only 2.6 points (95% CI, -0.7 to 5.8) at the end of the 24-month follow-up period with similar results observed in the EQ-5D-5L score. The distribution of patients based on NYHA class remained stable in both groups throughout the 41-month follow-up.

Conclusion
In patients with ischemic LVSD with an LVEF ≤35% and viable myocardium, PCI when added to contemporary OMT did not reduce incidence of death or hospitalization from HF, or significantly improve LVEF versus OMT alone.

Perspectives
The results of REVIVED are not surprising given the small mortality benefit seen in STICH and the dramatic improvements in OMT over the past two decades, including medications associated with reduced risk of mortality.

In STICH, no improvement in HF symptoms was noted with CABG over OMT after 36 months, questioning the hypothesis of improving myocardial function with revascularization. In BARI-2D and FREEDOM, CABG was superior to PCI for improving patient outcomes. Unlike PCI, which treats only stenotic segments with stents, CABG provides new nutritive antegrade coronary blood flow with arterial and/or venous conduits, while providing upstream cardioprotection against new plaque ruptures in more proximal coronary segments with non-flow-limiting stenoses and vulnerable plaques, thus effectively reducing disease burden. In contrast, PCI does not reduce risk of myocardial infarction versus OMT alone.^7-9

At the time STICH took place, 2002 to 2007, the only class I recommended medical therapies for HF with reduced ejection fraction (HFrEF) were angiotensin converting enzyme inhibitors (ACE-I), beta blockers, and digitalis.¹⁰ In 2013 when REVIVED initiated patient recruitment, angiotensin II receptor blockers (ARB), mineralocorticoid receptor antagonists (MRA), hydralazine and isosorbide dinitrate had been added as new class I recommendations.¹¹ This was followed by the addition of angiotensin receptor/neprilysin inhibitors (ARNI) and sodium/glucose co-transporter-2 inhibitors (SGLT-2i) as class I recommendations, while digitalis became a class IIa recommendation.¹²

Hence, a significant difference can be appreciated in both the intensity and breadth of medical therapy used with ACE-I employed in 84% versus 80%, beta blockers in 83% versus 88% and digitalis in 20% versus 21% of the CABG and OMT arms of STICH, respectively. ACE-I were used in 61% versus 57%, ARB in 17% and 19%, ARNI 26% and 33%, MRA in 49% and 57%, beta blocker in 93% and 94%, and oral hypoglycemic agents in 28% and 29% in PCI versus OMT arms of REVIVED, respectively.^13,4 Additionally, devices including cardiac resynchronization therapy (CRT) and intracardiac defibrillators (ICD) were more frequently employed in REVIVED versus STICH and was considered a critical part of OMT.

Additional key differences between REVIVED and STICH are found in the patient populations studied. REVIVED was mainly composed of patients with NYHA I and II symptoms and little to no angina, while patients in STICH were more symptomatic with 86% of CABG arm and 85% of OMT arm reporting NYHA functional class II or III symptoms, and 43% of both arms reporting Canadian Cardiovascular Society angina class II symptoms. On the other hand, REVIVED included an older patient population with a mean age of 70 and 69 years in the PCI and OMT groups, respectively, while the mean age in the STICH trial was 60 and 59 years in the CABG and OMT groups, respectively.

The natural history of CAD depends on our ability to blunt disease progression and reduce thrombotic complications. This can be achieved with lifestyle and risk factor modifications and multifaceted OMT. The role of coronary artery revascularization in patients with stable CAD has been shrinking with the increasing effectiveness of OMT and is largely confined to symptom control in patients' refractory to adequate medical management. It is unlikely that future clinical trials will show a mortality benefit with revascularization in patients with stable CAD, regardless of whether CABG or PCI is being used. The true challenge exists in optimizing medical therapy in these patients. Even in ISCHEMIA, only 40% received true OMT according to current standards. Our efforts and resources should be directed to closing this gap between evidence derived from multiple trials and current practice, where OMT usage remains disappointingly low.¹⁴

References

1. Pagliaro BR, Cannata F, Stefanini GG, Bolognese L. Myocardial ischemia and coronary disease in heart failure. Heart Fail Rev 2020;25:53–65.
2. Velazquez EJ, Lee KL, Deja, MA, et al. Coronary-artery bypass surgery in patients with left ventricular dysfunction. N Engl J Med 2011;364:1607–16.
3. Velazquez EJ, Lee KL, Jones RH, et al. Coronary-artery bypass surgery in patients with ischemic cardiomyopathy. N Engl J Med 2016;374:1511–20.
4. Perera D, Clayton T, O'Kane PD, et al. Percutaneous revascularization for ischemic left ventricular dysfunction. N Engl J Med 2022;387:1351-60.
5. Perera D, Clayton T, Petrie MC, et al. Percutaneous revascularization for ischemic ventricular dysfunction: rationale and design of the REVIVED-BCIS2 trial: percutaneous coronary intervention for ischemic cardiomyopathy. JACC Heart Fail 2018;6;517–26.
6. Allman KC, Shaw LJ, Hachamovitch R, Udelson JE. Coronary revascularization myocardial viability testing and impact of revascularization on prognosis in patients with coronary artery disease and left ventricular dysfunction: a meta-analysis. J Am Coll Cardiol 2002;39:1151-58.
7. 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.
8. Farkouh ME, Domanski M, Sleeper LA, et al. Strategies for multivessel revascularization in patients with diabetes. N Engl J Med 2012;367:2375-84.
9. Soares A, Boden WE, Hueb W, et al. Death and myocardial infarction following initial revascularization versus optimal medical therapy in chronic coronary syndromes with myocardial ischemia: a systematic review and meta-analysis of contemporary randomized controlled trials. J Am Heart Assoc 2021;10:e019114.
10. Hunt SA, Baker DW, Chin MH, et al. ACC/AHA guidelines for the evaluation and management of chronic heart failure in the adult: executive summary. A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (committee to revise the 1995 guidelines for the evaluation and management of heart failure) J Am Coll Cardiol 2001;38:2101-13.
11. Yancy CW, Jessup M, Bozkurt B, et al. 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association task force on practice guidelines. J Am Coll Cardiol 2013;62:e147-239.
12. Heidenreich PA, et al. 2022 AHA/ACC/HFSA guideline for the management of heart failure: a report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. J Am Coll Cardiol 2022;79:e263-e421.
13. Velazquez EJ, Lee KL, Jones RH, et al. Coronary-artery bypass surgery in patients with ischemic cardiomyopathy. N Engl J Med 2016;374:1511–20.
14. 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.

Clinical Topics: Arrhythmias and Clinical EP, Cardiac Surgery, Cardiovascular Care Team, Dyslipidemia, Heart Failure and Cardiomyopathies, Invasive Cardiovascular Angiography and Intervention, Noninvasive Imaging, Atherosclerotic Disease (CAD/PAD), Implantable Devices, SCD/Ventricular Arrhythmias, Aortic Surgery, Cardiac Surgery and Arrhythmias, Cardiac Surgery and Heart Failure, Lipid Metabolism, Acute Heart Failure, Heart Failure and Cardiac Biomarkers, Interventions and Coronary Artery Disease, Interventions and Imaging, Computed Tomography, Magnetic Resonance Imaging, Nuclear Imaging

Keywords: Angiotensin Receptor Antagonists, Angiotensin-Converting Enzyme Inhibitors, Cardiomyopathies, Confidence Intervals, Constriction, Pathologic, Coronary Artery Bypass, Coronary Artery Disease, Coronary Vessels, Defibrillators, Cost of Illness, Digitalis, Dobutamine, Disease Progression, Follow-Up Studies, Glucose, Heart Failure, Hospitalization, Hydralazine, Hypoglycemic Agents, Ischemia, Incidence, Isosorbide Dinitrate, Magnetic Resonance Imaging, Life Style, Mineralocorticoid Receptor Antagonists, Morbidity, Myocardial Infarction, Neprilysin, Myocardium, Patient Selection, Percutaneous Coronary Intervention, Positron-Emission Tomography, Progression-Free Survival, Random Allocation, Prospective Studies, Receptors, Angiotensin, Stents, Risk Factors, Stroke Volume, Sodium, Symporters, Tomography, Emission-Computed, Single-Photon, Ventricular Function, Left, Ventricular Dysfunction

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