Optimizing Management of Stable Angina

A Patient-Centered Approach Integrating Revascularization, Medical Therapy, and Lifestyle Interventions

Rocco A. Montone, MD, PHD; Riccardo Rinaldi, MD; Giampaolo Niccoli, MD, PHD; Giuseppe Andò, MD, PHD; Felice Gragnano, MD, PHD; Raffaele Piccolo, MD, PHD; Francesco Pelliccia, MD, PHD; Elisabetta Moscarella, MD, PHD; Marco Zimarino, MD, PHD; Enrico Fabris, MD, PHD; Salvatore de Rosa, MD, PHD; Paolo Calabrò, MD, PHD; Italo Porto, MD, PHD; Francesco Burzotta, MD, PHD; Francesco Grigioni, MD, PHD; Emanuele Barbato, MD, PHD; Alaide Chieffo, MD, PHD; Davide Capodanno, MD, PHD; Rasha Al-Lamee, MD, PHD; Tom J. Ford, MD, PHD; Salvatore Brugaletta, MD, PHD; Ciro Indolfi, MD, PHD; Gianfranco Sinagra, MD; Pasquale Perrone Filardi, MD, PHD; Filippo Crea, MD, PHD; the Interventional Cardiology Working Group of the Italian Society of Cardiology

Disclosures

J Am Coll Cardiol

Abstract and Introduction

Abstract

Angina pectoris may arise from obstructive coronary artery disease (CAD) or in the absence of significant CAD (ischemia with nonobstructed coronary arteries [INOCA]). Therapeutic strategies for patients with angina and obstructive CAD focus on reducing cardiovascular events and relieving symptoms, whereas in INOCA the focus shifts toward managing functional alterations of the coronary circulation. In obstructive CAD, coronary revascularization might improve angina status, although a significant percentage of patients present angina persistence or recurrence, suggesting the presence of functional mechanisms along with epicardial CAD. In patients with INOCA, performing a precise endotype diagnosis is crucial to allow a tailored therapy targeted toward the specific pathogenic mechanism. In this expert opinion paper, we review the evidence for the management of angina, highlighting the complementary role of coronary revascularization, optimal medical therapy, and lifestyle interventions and underscoring the importance of a personalized approach that targets the underlying pathobiology.

Introduction

Angina pectoris is the most common symptom of ischemic heart disease (IHD), affecting >100 million people worldwide.^[1] The primary mechanism underlying angina is a mismatch between myocardial oxygen demand and supply, originating from the presence of an obstructive epicardial coronary artery disease (CAD) or even in the absence of significant epicardial CAD (ischemia with nonobstructed coronary arteries [INOCA]).^[2]

Obstructive CAD is characterized by significant coronary artery stenosis, typically defined as an angiographic reduction in the luminal diameter of 50% or more, although this threshold may vary, particularly when evaluating the left main (LM) coronary artery or incorporating functional assessments such as fractional flow reserve (FFR) or instantaneous wave-free ratio.^[3] However, up to 50% of patients undergoing coronary angiography for angina or myocardial ischemia may have unobstructed coronary arteries. INOCA encompasses a heterogeneous group of disorders, including coronary microvascular dysfunction (CMD) and vasospastic angina (VSA), where ischemia occurs without significant epicardial stenoses seen on coronary angiography.^[4]

Distinguishing between obstructive CAD and INOCA represents a significant clinical challenge because they may present with similar symptoms, yet each necessitates distinct diagnostic approaches and therapeutic strategies. At the same time, both require the same intensive interventions on risk factors, especially when obstructive CAD and functional disorders coexist within the same patient. For obstructive CAD, treatment involves a combination of lifestyle modifications promoting a healthy diet and regular physical exercise, cardiovascular (CV) prevention targeting traditional and emerging risk factors, and symptom control; revascularization procedures should be reserved for specific subsets of patients.^[5] In INOCA, the focus shifts toward the management of multiple functional alterations of coronary circulation encompassing both epicardial arteries and microcirculation, along with risk factor control and secondary preventive measures.^[6]

This review offers a comprehensive analysis of the current landscape of antianginal therapy for stable IHD, with a specific focus on the most recent evidence regarding the management of obstructive CAD and INOCA. In addition, it provides a patient-centered, evidencebased approach to patients presenting with angina symptoms, highlighting the importance of tailoring treatments based on individual patient mechanisms of disease.

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Next Section

Abstract and Introduction
Treatment Strategies for Obstructive CAD
Antianginal Therapy in INOCA
Comprehensive Management of Patients Presenting with Angina
Conclusions and Future Directions
References

Table 1. RCTs Comparing Coronary Revascularization Plus OMT vs OMT Alone in Chronic Coronary Syndromes
Trial Name	First Author(Publication Year)	No. of Subjects andInclusion Criteria	Exclusion Criteria	Design	Principal Findings
Cardiovascular events reduction
COURAGE	Boden¹⁵ (2007)	2,287 patients with ≥70% coronarystenosis and evidenceof myocardialischemia or ≥80% coronary stenosis withangina	Persistent CCS Class IV angina A markedly positive stress test Refractory HF or CS,LVEF <30% Recent revascularization (<6 mo) Coronary anatomy not suitablefor PCI	Randomization to eitherPCI with OMT (n = 1,149)or OMT alone (n = 1,138) Primary endpoint: deathfrom any cause andnonfatal MI during amedian follow-up of4.6 y	No significant difference in thecumulative primary-event rates(PCI 19.0% vs OMT: 18.5%; HR:1.05, 95% CI: 0.87-1.27; P = 0.62) Similar rates of the composite ofdeath, MI, and stroke (20.0% vs 19.5%; HR: 1.05; 95% CI: 0.87-1.27; P = 0.62), hospitalization for ACS (12.4% vs 11.8%; HR: 1.07;95% CI: 0.84-1.37; P = 0.56), and MI (13.2% vs 12.3%; HR: 1.13;95% CI: 0.89-1.43; P = 0.33)between the 2 groups
BARI 2D	Frye¹⁶ (2009)	2,368 patients with both T2DM and CAD(≥ 50% coronarystenosis and a positivestress test or ≥70% coronary stenosis andangina)	Need of immediaterevascularization LM coronary disease Creatinine level >2.0 mg/dL or Hb1_Ac level >13.0% Class III or IV HF or hepaticdysfunction Recent PCI or CABG (<12 mo)	Randomization to eitherprompt PCI or CABG withOMT or OMT alone and toeither insulin-sensitization or insulin-provision therapy Primary endpoint: rate ofdeath and a composite ofdeath, MI, and stroke	At 5 y, no significant difference insurvival between the 2 groups(88.3% in the revascularizationgroup vs 87.8% in the medical-therapy group; P = 0.97) In the CABG stratum, lower rate ofMACE in the revascularizationgroup (22.4%) vs the medical-therapy group (30.5%; P = 0.01;P = 0.002 for interaction betweenstratum and study groups).
FAME 2	Xaplanteris¹⁸(2018)	888 patients with stableangina and at least1 coronarystenosis ≥50% eligible for PCI and with FFR ≤0.80	CABG as the preferredtreatment LM coronary disease Recent ACS (<1 wk) Previous CABG Contraindication to DAPT,LVEF <30%, or planned needfor concomitant valvular oraortic surgery	Randomization to eitherFFR-guided PCI plusmedical therapy(n = 447) or to medical Primary endpoint: compos-ite of death, MI, and urgentrevascularization	At 5 y, lower rate of the primaryendpoint in the PCI group comparedwith the medical-therapy group(13.9% vs 27.0%; HR: 0.46;95% CI: 0.34-0.63; P < 0.001) No difference between the 2 groupsin the rates of death (5.1% and5.2%; HR: 0.98; 95% CI: 0.55-1.75)or MI (8.1% and 12.0%; HR: 0.66;95% CI: 0.43-1.00)
ISCHEMIA	Maron¹⁹ (2020)	5,179 patients withmoderate to severeischemia on stressimaging or severeischemia onnonimaging exercisetolerance testing	eGFR <30 mL/min/1.73 m² Recent ACS (within theprevious 2 months) Unprotected LM stenosis ≥50% NYHA functional class III or IVHF or LVEF <35% Unacceptable angina despitethe use of medical therapy atmaximum acceptable doses	Randomization to aninitial invasive strategy(angiography and revas-cularization by PCI orCABG) and OMT or to aninitial conservative strat-egy of OMT alone andangiography if medicaltherapy failed Primary endpoint: com-posite of CV death, MI,and hospitalization forUA, HF, and resuscitatedcardiac arres	Over a median 3.2 y of follow-up,318 events occurred in theinvasive-strategy group and 352 inthe conservative-strategy group At 6 mo, the cumulative event ratewas 5.3% in the invasive-strategygroup and 3.4% in theconservative-strategy group(difference: 1.9 percentage points;95% CI: 0.8-3.0) At 5 y, the cumulative event rates were 16.4% and 18.2%, respectively (difference: -1.8 percentagepoints; 95% CI: -4.7 to 1.0)
Symptoms relief and quality of life
COURAGE	Weintraub²³(2008)	2,287 patients with ≥70% coronarystenosis and evidenceof myocardialischemia or ≥0% coronary stenosis withangina	Persistent CCS Class IV angina A markedly positive stress test Refractory HF or CS, LVEF <30% Recent revascularization (<6 mo) Coronary anatomy not suitablefor PCI	Randomization to eitherPCI with OMT (n = 1,149)or OMT alone (n = 1,138) Angina-specific healthstatus (SAQ scores) andoverall physical andmental function (RAND-36 scores) were assessedat baseline and 1, 3, 6,and 12 mo	At baseline, 22% of the patientswere free of angina At 3 months, 53% of the patients inthe PCI group and 42% in the OMT-alone group were angina free(P < 0.001) The benefit from PCI was incre-mental for 6 to 24 mo, and patientswith more severe angina had agreater benefit from PCI. Similarincremental bene?ts were seen insome but not all RAND-36 domains By 36 mo, there was no significant difference in health status betweenthe treatment groups
FAME 2	Xaplanteris¹⁸(2018)	888 patients with stableangina and at least1 coronarystenosis ≥50% eligible for PCI andwith FFR ≤0.80	CABG as the preferredtreatment LM coronary disease Recent ACS (<1 wk) Previous CABG Contraindication to DAPT,LVEF <30%, or planned needfor concomitant valvular oraortic surgery	Randomization to eitherFFR-guided PCI plusmedical therapy(n = 447) or to medicaltherapy alone (n = 441) Angina was classi?edaccording to the CCSfunctional classification	Lower percentage of patients withangina of CCS grade II, III, or IV inthe PCI group vs the medical-therapy group at all time pointsduring the first 3 y of follow-up This difference was no longer significant at 5 y
ISCHEMIA	Spertus²⁴(2020)	5,179 patients withmoderate/severeischemia on stressimaging or severeischemia onnonimaging exercisetolerance testing	eGFR <30 mL/min/1.73 m² Recent ACS (within theprevious 2 months) Unprotected LMstenosis ≥50% NYHA functional class III or IVHF or LVEF <35% Unacceptable angina despitethe use of medical therapy atmaximum acceptable doses	Randomization to aninitial invasive strategy(angiography and revas-cularization by PCI or CABG) and OMT or to aninitial conservative strategy of OMT alone andangiography if medicaltherapy failed Primary outcome: SAQsummary score	At baseline, 35% of the patientswere free of angina SAQ summary scores increased inboth treatment groups, with in-creases at 3, 12, and 36 mo thatwere, respectively, 4.1 points(95% CI: 3.2-5.0), 4.2 points(95% CI: 3.3-5.1), and 2.9 points(95% CI: 2.2-3.7) higher with theinvasive strategy than with theconservative strategy Differences were larger amongparticipants who had more frequentangina at baseline (8.5 vs 0.1 pointsat 3 mo and 5.3 vs 1.2 points at 36 mo among participants withdaily or weekly angina comparedwith no angina)
ORBITA	Al-Lamee²⁶(2018)	200 patients with anginaor equivalentsymptoms and atleast 1 coronarystenosis ≥70% suitable for PCI	Coronary stenosis ≥50% in anontarget vessel ACS Previous CABG LM coronary disease CTO Severe valvular disease orsevere LV systolic impairment Moderate to severe pulmonaryhypertension	After enrollment:6 wks of medicationoptimization Randomization 1:1 toundergo either PCI or aplacebo procedure Primary endpoint: difference in exercise timeincrement betweengroups at 6-wk follow-up	No significant difference in the pri-mary endpoint between the 2 groups (PCI minus placebo 16.6 s;95% CI: -8.9 to -42.0 s; P = 0.200)
ORBITA-2	Rajkumar²⁸(2023)	301 patients with anginaor angina equivalent,at least 1 severecoronary stenosis, andevidence of ischemia	Recent ACS (<6 mo) Previous CABG LM coronary disease CTO Severe valvular disease LVEF ≤35%	Stop all antianginalmedications, and 2-wksymptom assessmentphase beforerandomization Randomization 1:1 to un-dergo either PCI (n = 151)or a placebo procedure(n = 150) Primary endpoint: anginasymptom score (range 0-79, with higher scoresindicating worse healthstatus with respect to angina), at 12-wkfollow-up	The mean angina symptom scorewas 2.9 in the PCI group and 5.6 inthe placebo group (OR: 2.21;95% CI: 1.41-3.47; P < 0.001)

Inclusion criteria for Table 1: only RCTs directly comparing coronary revascularization plus OMT vs OMT alone, focusing on mortality, cardiovascular outcomes, and quality of life, published within the past 20 years.

ACS = acute coronary syndrome; BARI 2D = Second Bypass Angioplasty Revascularization Intervention in Diabetics; CABG = coronary artery bypass grafting; CAD = coronary artery disease; CCS = CanadianCardiovascular Society; COURAGE = Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation; CS = cardiogenic shock; CTO = chronic total occlusion; CV = cardiovascular; DAPT = dualantiplatelet therapy; eGFR = estimated glomerular filtration rate; FAME 2 = Fractional Flow Reserve Versus Angiography for Multivessel Evaluation; FFR = fractional flow reserve; HF = heart failure; ISCHEMIA = International Study of Comparative Health Effectiveness With Medical and Invasive Approaches; LM = left main; LVEF = left ventricular ejection fraction; MACE = major adverse cardiovascular events; MI = myocardial infarction; OMT = optimal medical therapy; ORBITA = Objective Randomized Blinded Investigation With Optimal Medical Therapy of Angioplasty in Stable Angina; PCI = percutaneous coronaryintervention; RCT = randomized controlled trial; SAQ = Seattle Angina Questionnaire; T2DM = type 2 diabetes mellitus; UA = unstable angina. JACC VOL.84,NO.8,2024 Montone et al AUGUST 20, 2024: 744 – 760 Optimizing Management of Stable Angina

Table 2. Summary of Drugs, Dosages, and Indications for Managing Angina in Chronic Coronary Syndrome Patients
Class of Drugs	Dosage	Indications for Use
β-blockers	Atenolol (50-200 mg once daily) Bisoprolol (5-10 mg once daily) Carvedilol (3.125-25 mg twice daily) Metoprolol tartrate (25-100 mg twice daily) Nebivolol (5-10 mg once daily)	They should be preferred in patients with elevated BP and/or HR, historyof AF, HCM, HF (especially HFrEF), or history of ACS In patients with diabetes mellitus, vasodilating β-blockers, such as car-vedilol and nebivolol, should be preferred as they could improve insulinsensitivity They should not be combined with nondihydropyridine CCBs (risk ofbradycardia, AV block, and hypotension) They should not be abruptly discontinued because up-regulation of β-adrenoceptors could lead to severe tachycardia and vasoconstriction They are contraindicated in VSA because they can precipitate α-mediatedvasospasm
CCBs	Dihydropyridine: Amlodipine (5-10 mg orally once daily)Nondihydropyridine: Diltiazem (30-90 mg 4 times daily forimmediate-release formulations; 120-480 mgonce daily for extended-release formulations) Verapamil (40-160 mg 3 times daily forimmediate-release formulations; 120-480 mgonce daily for extended-release formulations)	Nondihydropyridine CCBs should be preferred in patients with elevatedHR, BP, or history of AF, whereas they should be avoided in those withlow HR Dihydropyridine CCBs should be preferred in patients with low HR orelevated BP and avoided in those with elevated HR, AF or low BP, and incombination with ivabradine First choice for VSA
Ivabradine	5-7.5 mg orally twice daily	It should be used only in patients in sinus rhythm with HR ≥70 beats/min It provides additional benefits when used in combination with otherantianginal drugs, especially β-blockers, owing to synergistic effects
Nitrates	Nitroglycerine (5-20 mg daily for transdermalpatch; 6.5-15 mg twice daily for prolonged-release tablets) Isosorbide mononitrate (5-10 mg once daily) Isosorbide dinitrate (10-40 mg twice daily)	They should be titrated at the lowest possible dose to control symptoms They should be avoided in patients with elevated HR and are contra-indicated in patients with obstructive HCM, severe aortic or mitral ste-nosis, or constrictive pericarditis, and in combination with PDE-5inhibitor
Ranolazine	375 mg up to 750 mg twice daily	It should be preferred in patients with low BP or HR because of itsneutral hemodynamic profile It should be the preferred in patients with diabetes mellitus Its use is contraindicated in patients with severe hepatic or renalimpairment because of the risk of QT interval prolongation
Nicorandil	10-30 mg twice daily	Its concomitant use with aspirin might increase the risk of gastrointes-tinal ulcers, perforations, and hemorrhage
Trimetazidine	20 mg twice daily (35 mg once daily formodi?ed-release formulations)	It should be preferred in patients with low BP or HR because it does notexert hemodynamic effects (it does not affect oxygen demand but im-proves the metabolic ef?ciency of the ischemic myocytes) Its use is not recommended in patients with Parkinson disease, parkin-sonism, and other related movement disorders, or in patients with severerenal impairment

AF - atrial fibrillation; AV - atrioventricular; BP - blood pressure; CCB - calcium channel blocker; CCS - chronic coronary syndromes; HCM - hypertrophic cardiomyopathy; HF - heart failure; HFrEF - heartfailure with reduced ejection fraction; HR - heart rate; PDE-5 - phosphodiesterase-5; VSA - vasospastic angina.JACC VOL. 84,NO.8,2024 Montone et al AUGUST 20, 2024:744 – 760 Optimizing Management of Stable Angina751

Authors and Disclosures

Rocco A. Montone, MD, PHD,^a,b Riccardo Rinaldi, MD,^a,c Giampaolo Niccoli, MD, PHD,^d Giuseppe Andò, MD, PHD,^e Felice Gragnano, MD, PHD,^f,g Raffaele Piccolo, MD, PHD,^h Francesco Pelliccia, MD, PHD,ⁱ Elisabetta Moscarella, MD, PHD,^f,g Marco Zimarino, MD, PHD,^j,k Enrico Fabris, MD, PHD,^l Salvatore de Rosa, MD, PHD,^m Paolo Calabrò, MD, PHD,^f,g Italo Porto, MD, PHD,ⁿ Francesco Burzotta, MD, PHD,^a,b Francesco Grigioni, MD, PHD,^o Emanuele Barbato, MD, PHD,^p Alaide Chieffo, MD, PHD,^q,r Davide Capodanno, MD, PHD,^s Rasha Al-Lamee, MD, PHD,^t Tom J. Ford, MD, PHD,^u Salvatore Brugaletta, MD, PHD,^c Ciro Indolfi, MD, PHD,^m Gianfranco Sinagra, MD,^l Pasquale Perrone Filardi, MD, PHD,^h Filippo Crea, MD, PHD,^a,v the Interventional Cardiology Working Group of the Italian Society of Cardiology

From the ^aDepartment of Cardiovascular and Pulmonary Sciences, Catholic University of the Sacred Heart, Rome, Italy; ^bDepartment of Cardiovascular Sciences, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy; ^cHospital Clínic, Cardiovascular Clinic Institute, Institut d’Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain; ^dDepartment of Medicine, University of Parma, Parma, Italy; ^eDepartment of Clinical and Experimental Medicine, University of Messina, AOU Policlinico “Gaetano Martino,” Messina, Italy; ^fDepartment of Translational Medical Sciences, University of Campania “Luigi Vanvitelli,” Caserta, Italy; ^gDivision of Clinical Cardiology, AORN “Sant’Anna e San Sebastiano,” Caserta, Italy; ^hDepartment of Advanced Biomedical Sciences, Federico II University of Naples, Naples, Italy; ⁱDepartment of Cardiovascular Sciences, “La Sapienza” University, Rome, Italy; ^jDepartment of Neuroscience, Imaging and Clinical Sciences, “Gabriele d’Annunzio” University of Chieti-Pescara, Chieti, Italy; ^kDepartment of Cardiology, “SS. Annunziata Hospital,” Abruzzo, Chieti, Italy; ^lCardio-thoracovascular Department, Azienda Sanitaria Universitaria Giuliano Isontina, University of Trieste, Trieste, Italy; ^mDivision of Cardiology, Department of Medical and Surgical Sciences, Magna Graecia University of Catanzaro, Catanzaro, Italy; ⁿCardiovascular Disease Unit, IRCCS Ospedale Policlinico San Martino, Genoa, Italy; ^oFondazione Policlinico Universitario Campus Bio-Medico, Rome, Italy; ^pDepartment of Clinical and Molecular Medicine, Sapienza University of Rome, Rome, Italy; ^qInterventional Cardiology Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy; ^rUniversity Vita-Salute San Raffaele, Milan, Italy; ^sDivision of Cardiology, A.O.U. Policlinico “G. Rodolico—San Marco,” University of Catania, Catania, Italy; ^tNational Heart and Lung Institute, Imperial College London, London, United Kingdom; ^uFaculty of Medicine, University of Newcastle, Newcastle, New South Wales, Australia; and the vCenter of Excellence of Cardiovascular Sciences, Ospedale Isola Tiberina–Gemelli Isola, Rome, Italy.

Funding Support and Author Disclosures: The authors have reported that they have no relationships relevant to the contents of this paper to disclose.

Address for Correspondence: Dr Rocco A. Montone, Department of Cardiovascular Sciences, Fondazione Policlinico A. Gemelli IRCCS, L.go A. Gemelli, 1, 00168 Rome, Italy. E-mail: roccoantonio. montone@unicatt.it.

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Optimizing Management of Stable Angina

A Patient-Centered Approach Integrating Revascularization, Medical Therapy, and Lifestyle Interventions

Abstract and Introduction

Abstract

Introduction

Tables

Tables

References

Authors and Disclosures

Authors and Disclosures

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