Inspired by King’s word, the goal of optimal pharmacotherapy is optimizing patient outcomes in an appropriate and consistent fashion, integrating itself with other management strategies, when and as appropriate, but this goal cannot be achieved if such therapy is not implemented in a forceful and proactive fashion. Indeed, cardiovascular pharmacotherapy for ischemic heart disease due to coronary artery disease (CAD) represents a unique case study in this sense, given the complex interplay between societal and individual preventive strategies as well as clinical treatments aimed at secondary or tertiary prevention, which may apparently challenge immediate and thorough implementation

Biondi-Zoccai, Giuseppe

Chiariello, Giovanni A

Frati, Giacomo

Miraldi, Fabio

Versaci, Francesco

English

Archivio della ricerca- Università di Roma La Sapienza

Downloadedfromhttp://journals.lww.com/cardiovascularpharmbyBhDMf5ePHKav1zEoum1tQfN4a+kJLhEZgbsIHo4XMi0hCywCX1AWnYQp/IlQrHD3i3D0OdRyi7TvSFl4Cf3VC4/OAVpDDa8K2+Ya6H515kE=on01/09/2021Downloadedfromhttp://journals.lww.com/cardiovascularpharmbyBhDMf5ePHKav1zEoum1tQfN4a+kJLhEZgbsIHo4XMi0hCywCX1AWnYQp/IlQrHD3i3D0OdRyi7TvSFl4Cf3VC4/OAVpDDa8K2+Ya6H515kE=on01/09/2021COMMENTARYClinical Conundrum: Three Management Strategies forThree-Vessel Coronary Artery Disease?Giuseppe Biondi-Zoccai, MD, MStat,*† Giacomo Frati, MD, MSc,*‡ Fabio Miraldi, MD,§Giovanni A. Chiariello, MD,¶ and Francesco Versaci, MDkThis Commentary relates to the article by H. Zhao and D. Zhang on pages 527–532.Martin Luther King, Jr. once said “we are now faced with the fact that omorrow istoday. We are confronted with the fierce urgency of now. In this unfolding conun-drum of life and history, there “is” such a thing as being too late. This is no time for apathyor complacency. This is a time for vigorous and positive action. M are now faced with thefact that tomorrow is today. We are confronted with the fierce urgency of now. In thisunfolding conundrum of life and history, there “is” such a thing as being too late. This is notime for apathy or complacency. This is a time for vigorous and positive action.”Inspired by King’s word, the goal of optimal pharmacotherapy is optimizing patientoutcomes in an appropriate and consistent fashion, integrating itself with other managementstrategies, when and as appropriate, but this goal cannot be achieved if such therapy is notimplemented in a forceful and proactive fashion. Indeed, cardiovascular pharmacotherapyfor ischemic heart disease due to coronary artery disease (CAD) represents a unique casestudy in this sense, given the complex interplay between societal and individual preventivestrategies as well as clinical treatments aimed at secondary or tertiary prevention, whichmay apparently challenge immediate and thorough implementation.1,2This issue of the Journal offers a poignant synthesis of 2 competing treatments forCAD, which benefit, however, both from comprehensive and state-of-the-art pharmaco-logic therapy: percutaneous coronary intervention (PCI) and coronary artery bypassgrafting (CABG).3 In particular, Zhao and Zhang performed a comprehensive systematicreview and meta-analysis pooling randomized and nonrandomized studies comparing PCIversus CABG in patients with three-vessel CAD and highlighting consistent comparativebenefits for CABG (ie comparative hazards for PCI) when focusing on all-cause death,myocardial infarction, and repeat revascularization. Evidently, CABG is confirmed as thereal winner in the PCI versus CABG contest for complex CAD.4Irrespective of the results of this and similar meta-analysis comparing PCI versus CABG,a number of important issues should be borne in mind. First, any meta-analysis pooling smallrandomized trials or observational studies risks providing spuriously precise results if smallstudy effects are given excessive statistical weights (such as in the case of publication bias andselective reporting of extreme study results).5 Second, outcomes may differ in importance forpatients and also subjectively in specific patients. For instance, considering a myocardial infarc-tion equivalent to a stroke may miss the point of the clearly different impact of each outcome onthe quality of life and independent lifestyle. Even definitions may matter, with definitions ofmyocardial infarction proving particularly challenging. Indeed, periprocedural myocardial infarc-tion may be defined differently after PCI versus CABG, and this may impact on comparativeanalysis. In addition, in some trials periprocedural myocardial infarction had been censored fromlong-term outcome comparisons, potentially favoring CABG. Symptom control may beFrom the *Department of Medical-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Latina, Italy; †Mediterranea Cardiocentro, Napoli, Italy;‡IRCCS NEUROMED, Pozzilli, Italy; §Department of Clinical, Internal Medicine, Anesthesiology and Cardiovascular Sciences, Sapienza University of Rome,Rome, Italy; ¶Dipartimento di Scienze Cardiovascolari, Università Cattolica del Sacro Cuore, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome,Italy; and kUnità Operativa Complessa di UTIC, Emodinamica e Cardiologia, Ospedale Santa Maria Goretti, Latina, Italy.G. Biondi-Zoccai has consulted for Replycare, Rome, Italy. The remaining authors report no conflicts of interest.Reprints: Giuseppe Biondi-Zoccai, MD, MStat, Department of Medical-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Corso dellaRepubblica 79, 04100 Latina, Italy (e-mail: giuseppe.biondizoccai@uniroma1.it).Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.J Cardiovasc Pharmacol  Volume 76, Number 5, November 2020 www.jcvp.org | 489Copyright © 2020 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.impacted by treatment strategy, and also symptom ascertainmentmay be difficult in studies lacking any form of actual blinding topatients or caring physicians. This holds even truer, given thatCABG may lead to reduced symptom burden simply because ofreduced cardiac innervation rather than because of more compre-hensive relief from ischemia. Finally, goals of treatment may bealtogether different, especially in light of time frames. Forinstance, PCI may, possibly, prevent myocardial infarction fromcomplex lesions but cannot protect from atherothrombosis pro-gression. This is at odds with CABG, in the sense that a leftinternal mammary artery to the mid left anterior descending mayprotect the patient from tightening of an already significant ste-nosis in the proximal left anterior descending and also fromdisease progression occurring, for instance, on the left main orthe mid left anterior descending.6,7 This is most likely the keyexplanation for the comparative superiority of CABG versus PCIin patients with multivessel or three-vessel disease, left maindisease, or left ventricular systolic dysfunction, given the sub-stantial atherosclerotic burden of these patient subsets.The main conundrum rests, however, not simply onchoosing PCI versus CABG or on referring a given patient toan interventional cardiologist versus a cardiac surgeon. Themain issue rests with optimizing noninvasive managementand adopting state-of-the-art PCI or CABG methods, whenchoosing one or the other, notwithstanding the possibility toundergo CABG after PCI or PCI after CABG (Fig. 1). First,aggregate-level risk factors such as climate and pollutionforce us to consider collective interventions to improve globalhealth, a choice which is even more important and potentiallybeneficial in the coronavirus disease 2019 (COVID-19)era.1,2,8 Second, lifestyle interventions ranging from regularaerobic exercise to a healthy (ie slightly hypocaloric) dietremain key baseline interventions. Third, systematic use ofmedications with proven prognostic and/or symptomatic ben-efits is crucial, especially in an era where inexpensivegenerics abound, ranging from antithrombotic agents, suchas aspirin or P2Y12 inhibitors, to statins, ezetimibe, propro-tein convertase subtilisin/kexin type 9 (PCSK9) inhibitors,angiotensin-converting enzyme inhibitors, angiotensin recep-tor blockers, beta-blockers, ivabradine, ranolazine, and,possibly, colchicine compounded as appropriate by medica-tions with proven benefits in ischemic heart failure, such asmineralocorticoid receptor antagonists, angiotensin receptor-neprilysin inhibitors, sodium/glucose cotransporter 2 inhibi-tors, and glucagon-like peptide-1 receptor agonists.9Before invasive assessment and management is consid-ered, it is imperative to weigh pros and cons and explicitlydefine goals (eg symptom control or systolic functionimprovement). To optimize such decision making, recentresults from the pivotal International Study of ComparativeHealth Effectiveness With Medical and Invasive Approach(ISCHEMIA) trial should be well considered, including, forinstance, the increased risk of periprocedural myocardialinfarction, the reduced risk of spontaneous myocardialinfarction, and the overall greater symptomatic benefit inpatients managed invasively.10 After coronary angiography,joint decision making is best sought by multidisciplinaryevaluation with a noninvasive cardiologist, an interventionalcardiologist, and a cardiac surgeon. Fit patients with extensiveCAD are typically better served by CABG, in terms of prog-nosis and symptoms, whereas less fit patients or those withmore focal lesions may equally benefit from PCI. In any case,FIGURE 1. Multidimensional man-agement of CAD, beginning withaggressive medical therapy. Patientsfailing medical management orthose with specific clinical featuresmay benefit from PCI (orange arrow)or CABG (blue arrow), choosingrevascularization strategy accordingto a comprehensive appraisal ofpatient, cardiac, and coronary fea-tures. PCI may be followed by CABGin case of restenosis or disease pro-gression, and minimally invasiveCABG may be combined with PCI ofnon-LAD lesions. ACEi, angiotensinconverting enzyme inhibitor; ARB,angiotensin receptor blocker; DEB,drug-eluting balloon; DES, drug-eluting stent; FFR, fractional flowreserve; IVUS, intravascular ultra-sound; LAD, left anterior descend-ing; LIMA, left internal mammaryartery; LVEF, left ventricular ejectionfraction; MCS mechanical cardiacsupport; OCT, optical coherence tomography; OPCABG, off-pump coronary artery bypass grafting; PCSK9, Proprotein convertasesubtilisin/kexin type 9; RIMA, right internal mammary artery; TA-CABG, totally arterial coronary artery bypass grafting. Thescheme was created using royalty-free images downloaded from shutterstock.com.Commentary J Cardiovasc Pharmacol  Volume 76, Number 5, November 2020490 | www.jcvp.org Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.Copyright © 2020 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.it is paramount to continue to offer optimal medical therapy tothese patients because both PCI and CABG are simply defacto palliative therapies for coronary atherosclerosis. Forinstance, fractional flow reserve, instantaneous wave-freeratio, intravascular ultrasound, and optical coherence tomog-raphy should be used whenever appropriate to improve deci-sion making and enable PCI optimization, which should bebased on thin-strut new-generation drug-eluting stents (with apotential niche role for drug-eluting balloons), exploitingmechanical cardiac support whenever necessary in complexor hemodynamically unstable patients.11 Similarly, CABG-related benefits are clearly greater if a totally arterial revascu-larization strategy is sought, for instance, with use of bothright and left internal mammary arteries and reliance on radialartery grafts for the remaining needs.6,7,12Notwithstanding the distance between PCI andCABG, in selected cases off-pump CABG with left internalmammary artery grafting to the left anterior descending canbe combined with PCI on the other diseased vessels duringthe same hospitalization. Similarly, PCI can be performed inan emergency for ST-elevation myocardial infarction andfollowed during the same hospitalization by CABG forresidual multivessel disease.13,14 Finally, CABG remains areasonable alternative for patients with disease progressionor multivessel restenosis after PCI, whereas PCI is optimallysuited to manage disease progression or graft failure afterCABG or in case of contraindications to surgery, such asvery advanced age.15In conclusion, modern management of CAD requires acomprehensive integration of several lifestyle, pharmaco-logic, and invasive strategies, to maximize prognostic andsymptomatic benefits while appropriately using resources.Indeed, quoting a pioneering cardiologist such as AntonioColombo, “birds fly because they have wings and they flapthem”. Similarly, optimal clinical results can only be achievedby using optimal cardiovascular medications in combinationwith PCI or CABG when each one is appropriate (typically insimpler and more complex cases, respectively).REFERENCES1. Versaci F, Biondi-Zoccai G, Giudici AD, et al. Climate changes and ST-elevation myocardial infarction treated with primary percutaneous coro-nary angioplasty. Int J Cardiol. 2019;294:1–5.2. Biondi-Zoccai G, Frati G, Gaspardone A, et al. Impact of environmentalpollution and weather changes on the incidence of ST-elevation myocar-dial infarction. Eur J Prev Cardiol. 2020:2047487320928450. doi: 10.1177/2047487320928450.3. Zhao H, Zhang D. Percutaneous coronary intervention compared to coronaryartery bypass graft surgery for patients with three-vessel disease: a PRISMA-compliant systematic review and meta-analysis. J Cardiovasc Pharmacol.2020:0000000000000888. doi: 10.1097/FJC.0000000000000888.4. Ruel M, Farkouh ME. Why NOBLE and EXCEL are consistent witheach other and with previous trials. Circulation. 2017;135:822–824.5. Hu D, O’Connor AM, Wang C, et al. How to conduct a bayesian networkmeta-analysis. Front Vet Sci. 2020;7:271.6. Gaudino M, Benedetto U, Fremes S, et al. Radial-artery or saphenous-vein grafts in coronary-artery bypass surgery. N Engl J Med. 2018;378:2069–2077.7. Benedetto U, Raja SG, Albanese A, et al. Searching for the second bestgraft for coronary artery bypass surgery: a network meta-analysis ofrandomized controlled trials. Eur J Cardiothorac Surg. 2015;47:59–65.8. Benmarhnia T. Linkages between air pollution and the health burdenfrom COVID-19: methodological challenges and opportunities. Am JEpidemiol. 2020:kwaa148. doi: 10.1093/aje/kwaa148.9. Vaduganathan M, Claggett BL, Jhund PS, et al. Estimating lifetime ben-efits of comprehensive disease-modifying pharmacological therapies inpatients with heart failure with reduced ejection fraction: a comparativeanalysis of three randomised controlled trials. Lancet. 2020;396e:121–128.10. Biondi Zoccai G, Frati G, Romagnoli E, et al. Final results of theISCHEMIA trial: distinguishing mass media coverage from clinical inter-pretation. Minerva Cardioangiol. 2020;68:9–14.11. Combes A, Price S, Slutsky AS, et al. Temporary circulatory support forcardiogenic shock. Lancet. 2020;396:199–212.12. Moreno PR, Stone GW, Gonzalez-Lengua CA, et al. The hybrid coronaryApproach for optimal revascularization: JACC review topic of the week.J Am Coll Cardiol. 2020;76:321–333.13. Genuardi L, Burzotta F, Russo G, et al. Novel ultra-long (48 mm)everolimus-eluting stent for diffusely coronary vessels disease. MinervaCardioangiol. 2019;67:87–93.14. Stepien K, Nowak K, Skorek P, et al. Baseline indicators of coronaryartery disease burden in patients with non-ST-segment elevation acutecoronary syndrome. Minerva Cardioangiol. 2019;67:181–190.15. Biondi Zoccai G, Abbate A, D’Ascenzo F, et al. Percutaneous coronaryintervention in nonagenarians: pros and cons. J Geriatr Cardiol. 2013;10:82–90.CommentaryJ Cardiovasc Pharmacol  Volume 76, Number 5, November 2020Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved. www.jcvp.org | 491Copyright © 2020 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.

Clinical conundrum. Three management strategies for three-vessel coronary artery disease?

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Clinical conundrum. Three management strategies for three-vessel coronary artery disease?

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