Optimal medical therapy for initial management of stable angina: a call to action

Over one million percutaneous coronary interventions (PCIs) and coronary artery bypass graft (CABG) surgeries are performed annually worldwide in patients with stable coronary artery disease (CAD), more inclusively defined now as non-acute myocardial ischaemic syndromes (NAMIS) according to a newly proposed nomenclature.1 Initial revascularization is frequently performed despite clinical outcome data from multiple randomized controlled trials (RCTs) that upfront revascularization, most often with PCI, does not impart a significant incremental reduction in mortality or myocardial infarction (MI) in NAMIS patients with or without left ventricular dysfunction2,3 over guideline-directed optimal medical therapy (OMT) alone. One of the central arguments to pursue PCI as the initial therapeutic strategy of choice—rather than awaiting an adequate empirical trial of OMT to prove inadequate for effective symptom control—is that PCI, regardless of prognostic equipoise, would provide more immediate symptom relief (Graphical Abstract). This has increasingly become part of a ‘personalized’ patient-centric approach4 wherein the immediacy of achieving symptom relief often supersedes an initial conservative approach with OMT alone, which prioritizes both cardiac event reduction and symptomatic improvement. Despite no confirmatory evidence of prognostic benefit, upfront PCI alone is still favoured by many as the preferred initial management before first attempting OMT, even in asymptomatic patients after non-invasive detection of myocardial ischaemia or obstructive CAD. We believe that upfront PCI (as well as CABG surgery) should be discouraged in NAMIS patients as an initial default strategy, based on four evidence-based tenets, as detailed below. The view that PCI improves symptoms dates to the early balloon angioplasty era5 and has always been a common perception despite the recognition that many causes of angina (and ischaemia) are non-obstructive. Since then, OMT has improved dramatically as has revascularization with modern stents and more refined PCI/CABG techniques. While prior—albeit not placebo-controlled—randomized comparisons of OMT with or without PCI as an initial treatment approach showed comparable outcomes and symptom relief during long-term follow-up, the symptomatic improvement over time observed in both COURAGE6 and ISCHEMIA2 trials occurred—importantly–without penalty (i.e. no increase in clinical events).2 However, until recently, no placebo-controlled RCTs have been performed in NAMIS patients to assess symptomatic improvement alone. Such a placebo-controlled study design is not feasible for CABG, nor had it been employed in any prior vascular intervention/surgery trials. The Objective Randomised Blinded Investigation With Optimal Medical Therapy of Angioplasty in Stable Angina (ORBITA) trial for the first time assessed efficacy of PCI vs placebo to improve exercise capacity (and symptoms) in CAD patients receiving OMT7 and demonstrated no PCI benefit vs sham PCI (placebo) on either anginal symptom severity or angina score during a short (6-week) follow-up, largely in patients with single-vessel CAD or single-territory ischaemia.7 Such a finding may have simply reflected the small size and limited statistical power of the study. The subsequent sham-controlled ORBITA-2 trial,8 in which, by design, robust OMT was not fully implemented during a 12-week follow-up, showed the superior symptomatic improvement of PCI on angina relief and the emergence of a statistically significant, albeit modest (net 59 s), increment in exercise time during an abbreviated 12-week follow-up. Nevertheless, these results may fuel a resurgent, ‘PCI-first’ strategy in many NAMIS patients. Although revascularization is believed to reduce long-term medication interactions and side effects, a PCI-first strategy does not absolve the need for multifaceted OMT targeted to reducing elevated lipids, blood pressure, and metabolic/glycaemic, thrombotic, and inflammatory residual risk. Revascularization also entails, however, both early and late procedural risks, which may have important clinical consequences. Large peri-procedural MIs with important biomarker elevations, electrocardiographic changes, and clinical symptoms are widely accepted as prognostically important. Type 4b and 4C MIs, while uncommon, may likewise be consequential. Finally, while ISCHEMIA, COURAGE, and ORBITA did not show a detrimental prognostic impact of PCI, these studies were conducted largely in high-volume centres, and uncertainties about the long-term impact of peri- and post-procedural events persist.9 Both revascularization methods—PCI and CABG—increase bleeding risks. Stenting obstructive CAD entails the need for dual antithrombotic therapy (DAPT), typically with aspirin and a P2Y12 inhibitor (usually clopidogrel) for at least 1 month and up to 6 months. Dual antithrombotic therapy inevitably associates with more bleeding, not only in the skin and mucosae, but also may rarely result in intracranial haemorrhage.10 Clinically significant bleeding has been shown to be an independent predictor of 1-year mortality (hazard ratio: 6.93; 95% confidence interval: 4.53–10.60; P < .0001).10 Similarly, fear of DAPT-related bleeding also interferes with any surgical timing where such bleeding may be fatal in cases of trauma or accidents.10 The promise of complete angina relief in all patients remains a largely unachieved goal, as shown in the sham-controlled ORBITA-2 trial, where approximately 20% of patients still reported Canadian Cardiovascular Society (CCS) Class 3 angina and 30% had persistent CCS Class 2 angina post-PCI during the 12-week follow-up.8 This is, indeed, one of the central arguments to propose a nomenclature of myocardial ischaemic syndromes that does not focus solely on obstructive epicardial CAD.1 If we cannot fully promise (and achieve) angina relief even in the short term, we should then clearly discuss with patients the occurrence of microvascular disease, vasospasm, and other chest pain causes beyond the ‘classic’ obstructive CAD paradigm before proceeding to an initial PCI default strategy, which addresses only one cause for symptoms. There are some high-risk categories largely excluded from recent RCTs that may derive benefit from upfront revascularization (most frequently PCI, but also CABG), including patients in whom clinical stability is uncertain or questionable (e.g. recent worsening of angina or minor troponin release); those with left main CAD; those limited by essential components of OMT, e.g. low blood pressure, bradycardia, or intolerable side effects; or unwillingness to wait even a few weeks for symptom relief, e.g. those seeking to quickly re-engage in sport activities. In addition to invasive coronary angiography, prediction of high-risk coronary anatomy can now be reasonably performed using coronary computed tomography angiography, also informing on the likelihood of improvement with a possible revascularization. However, while maximal exercise testing may rule out left main CAD in some conditions, submaximal exercise or provocative pharmacologic testing alone is less diagnostic. Yet even when invasive coronary angiography is performed, the usual practice of ad hoc PCI should be discouraged in most such NAMIS patients. All too often, relevant information on the benefits and risks of PCI is not fully disclosed to the patient in understandable evidence-based terms prior to ad hoc intervention, wherein a careful, deliberate, and fully transparent process of shared decision-making is critically important. We therefore strongly advocate implementation of upfront OMT as the initial clinical approach to managing most NAMIS patients. This includes significant lifestyle interventions, best if implemented in an optimized programme of cardiac rehabilitation that addresses modifiable risk factors (e.g. smoking cessation and dietary modifications). This should be combined with both disease-modifying agents (with intensive lipid-lowering, antihypertensive, antithrombotic and—most recently—metabolic interventions for pre/diabetes or obesity, such as glucagon-like peptide-1 receptor agonists), and antianginal agents for symptom relief (e.g. beta-blockers, calcium antagonists, nitrates, ranolazine). Such an initial approach does not adversely impact life expectancy, allows more time to assess the effectiveness of OMT, and permits better prioritization and more judicious use of revascularization options, if subsequently needed, in accordance with existing international guidelines. In conclusion, a defendable default strategy should include, with few relevant exceptions, an initial empiric trial of fully implemented OMT. We believe this should constitute the new current standard of care, which, at present, remains a largely unrealized goal. R.D.C. reports fees, honoraria, and research funding from Sanofi-Aventis, Boehringer Ingelheim, Bayer, BMS/Pfizer, Daiichi Sankyo, Novartis, Merck, Portola, Roche, AstraZeneca, Menarini, Guidotti, Milestone, Amarin, Noventure, and Amgen. D.L.B. discloses the following relationships: advisory board: Angiowave, Antlia Bioscience, Bayer, Boehringer Ingelheim, CellProthera, Cereno Scientific, E-Star Biotech, High Enroll, Janssen, Level Ex, McKinsey, Medscape Cardiology, Merck, NirvaMed, Novo Nordisk, Repair Biotechnologies, Stasys, and Tourmaline Bio; board of directors: American Heart Association New York City, Angiowave (stock options), Bristol Myers Squibb (stock), DRS.LINQ (stock options), and High Enroll (stock); consultant: Alnylam, Altimmune, Broadview Ventures, Corcept Therapeutics, Coursera, GlaxoSmithKline, Hims, SERB, SFJ, Summa Therapeutics, and Worldwide Clinical Trials; data monitoring committees: Acesion Pharma, Assistance Publique-Hôpitaux de Paris, Baim Institute for Clinical Research, Boston Scientific (Chair, PEITHO trial), Cleveland Clinic, Contego Medical (Chair, PERFORMANCE 2), Duke Clinical Research Institute, Mayo Clinic, Mount Sinai School of Medicine (for the ABILITY-DM trial, funded by Concept Medical; for ALLAY-HF, funded by Alleviant Medical), Novartis, Population Health Research Institute, and Rutgers University (for the NIH-funded MINT Trial); honoraria: American College of Cardiology (Senior Associate Editor, Clinical Trials and News, ACC.org; Chair, ACC Accreditation Oversight Committee), Arnold and Porter law firm (work related to Sanofi/Bristol Myers Squibb clopidogrel litigation), Baim Institute for Clinical Research (AEGIS-II executive committee funded by CSL Behring), Belvoir Publications (Editor in Chief, Harvard Heart Letter), Canadian Medical and Surgical Knowledge Translation Research Group (clinical trial steering committees), CSL Behring (AHA lecture), Duke Clinical Research Institute, Engage Health Media, HMP Global (Editor in Chief, Journal of Invasive Cardiology), Medtelligence/ReachMD (CME steering committees), MJH Life Sciences, Oakstone CME (Course Director, Comprehensive Review of Interventional Cardiology), Philips (Becker’s Webinar on AI), Population Health Research Institute, WebMD (CME steering committees), and Wiley (steering committee); other: Clinical Cardiology (Deputy Editor) and Progress in Cardiovascular Diseases (Deputy Editor); patent: Sotagliflozin (named on a patent for sotagliflozin assigned to Brigham and Women’s Hospital who assigned to Lexicon; neither I nor Brigham and Women’s Hospital receive any income from this patent); research funding: Abbott, Acesion Pharma, Afimmune, Alnylam, Amarin, Amgen, AstraZeneca, Atricure, Bayer, Boehringer Ingelheim, Boston Scientific, CellProthera, Cereno Scientific, Chiesi, Cleerly, CSL Behring, Faraday Pharmaceuticals, Fractyl, Idorsia, Janssen, Javelin, Lexicon, Lilly, Medtronic, Merck, MiRUS, Moderna, Novartis, Novo Nordisk, Pfizer, PhaseBio, Regeneron, Reid Hoffman Foundation, Roche, Sanofi, Stasys, and 89Bio; royalties: Elsevier (Editor, Braunwald’s Heart Disease); and site co-investigator: Cleerly. W.E.B. reports research grant support from the VA Cooperative Studies Program and the National Heart, Lung, and Blood Institute and has received research funding from AbbVie, Amarin Pharmaceuticals Inc., Amgen, AstraZeneca, and Sanofi-Aventis and speaking honoraria from Amarin, Amgen, Janssen Pharmaceuticals, Pfizer, and Servier.