The Art of Prescribing β-Blockers After Myocardial Infarction
2021; Lippincott Williams & Wilkins; Volume: 14; Issue: 4 Linguagem: Inglês
10.1161/circinterventions.121.010720
ISSN1941-7632
AutoresLiyew Desta, Sergio Raposeiras‐Roubín, Borja Ibáñez,
Tópico(s)Cardiac electrophysiology and arrhythmias
ResumoHomeCirculation: Cardiovascular InterventionsVol. 14, No. 4The Art of Prescribing β-Blockers After Myocardial Infarction Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyRedditDiggEmail Jump toFree AccessEditorialPDF/EPUBThe Art of Prescribing β-Blockers After Myocardial Infarction Liyew Desta, MD, PhD, Sergio Raposeiras-Roubin, MD, PhD and Borja Ibanez, MD, PhD Liyew DestaLiyew Desta Liyew Desta, MD, PhD, Karolinska University Hospital, Solna, Stockholm, Sweden, Email E-mail Address: [email protected] https://orcid.org/0000-0002-1950-4159 Department of Cardiology, Karolinska University Hospital, Solna, Stockholm, Sweden (L.D.). , Sergio Raposeiras-RoubinSergio Raposeiras-Roubin https://orcid.org/0000-0002-6462-4715 Clinical Research Department, Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain (S.R.-R., B.I.). Cardiology Department, University Hospital Álvaro Cunqueiro, Vigo, Spain (S.R.-R.). and Borja IbanezBorja Ibanez Correspondence to: Borja Ibanez, MD, PhD, Centro Nacional de Investigaciones Cardiovasculares Carlos III, c/Melchor Fernández Almagro 3, 28029 Madrid, Spain, Email E-mail Address: [email protected] https://orcid.org/0000-0002-5036-254X Clinical Research Department, Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain (S.R.-R., B.I.). Cardiology Department, IIS-Fundación Jiménez Díaz University Hospital, Madrid, Spain (B.I.). CIBER de Enfermedades Cardiovasculares, Madrid, Spain (B.I.). Originally published20 Apr 2021https://doi.org/10.1161/CIRCINTERVENTIONS.121.010720Circulation: Cardiovascular Interventions. 2021;14:e010720This article is a commentary on the followingLeft Ventricular Ejection Fraction 1 Year After Acute Myocardial Infarction Identifies the Benefits of the Long-Term Use of β-BlockersSee Article by Park et alMedicine is an example of the integration of science and art. Clinical science (mainly trials) allows to establish treatment algorithms (with categorical decisions) based on specific population sets. However, in daily practice, many times, patients have a clinical profile different from those included in trials who founded guidelines. Individualized treatment for specific patients based on the available evidence is a complex art that physicians practice every day. One clear example of the complex balance between science and art is the prescription of β-blockers for patients who experienced a myocardial infarction (MI) and do not have reduced left ventricular ejection fraction (LVEF). Most of the evidence leading to the general recommendation of prescribing β-blockers after an MI1 was generated at a time where reperfusion or revascularization was not implemented and where coadjuvant pharmacological therapy (antithrombotic, lipid lowering, etc) was very limited.2 Old prospective randomized trials demonstrated that long-term treatment with β-blockers after an MI improves outcome and lower mortality by about 20%. However, these trials, mostly from the 1980s, included many patients with large MIs in which left ventricular dysfunction was common and antedate modern reperfusion and medical therapy. Thanks to advances in invasive management and pharmacological therapy, prognosis of patients with MI has been significantly improved.3 While the benefits of β-blockers in patients with reduced LVEF (≤40%) is well founded on several trials executed in the 21st century,4 the question is whether β-blockers are still beneficial in the new scenario in the absence of heart failure or left ventricular dysfunction.There is scarce evidence of the value of maintenance β-blockers for patients with MI and preserved LVEF treated according to current standards, including reperfusion, complete revascularization, potent antithrombotics and aggressive lipid lowering therapies. In a meta-analysis, stratifying trials into prereperfusion and reperfusion era, β-blockers did not reduce mortality in the reperfusion era.5 A recent study that examined the association between adherence or not to β-blocker therapy and long-term outcome in patients with MI in the SWEDEHEART registry (Swedish Web-System for Enhancement and Development of Evidence-Based Care in Heart Disease Evaluated According to Recommended Therapies) showed a significant benefit on survival and the risk of late-onset heart failure 4 years after the index event in patients with reduced LVEF while the association was less obvious albeit a positive trend in patients with preserved LVEF after adjusting for background factors.6Despite the widespread use and well overall tolerability of β-blockers, these drugs have some side effects. The most frequent is the asthenia and erectile dysfunction. In addition, in patients with hypertension (not after MI), β-blockers do not reduce coronary events,7 but their use is associated with an increased risk of stroke when compared with other treatments. β-blockers have also been shown to increase the risk of new-onset diabetes. When compared with nondiuretic antihypertensive drugs, β-blockers increase all-cause mortality and stroke in patients with new-onset diabetes.8,9In recent years, the only trials testing β-blockers in the MI context have been focused on the acute administration during ongoing ST-segment–elevation MI (STEMI). The METOCARD-CNIC trial (Metoprolol in Cardioprotection During an Acute Myocardial Infarction) demonstrated that the intravenous administration of metoprolol during ongoing anterior STEMI reduces the size of infarction,10 reduces the presence of microvascular obstruction and reperfusion injury,11 and improves long-term LVEF.12 Metoprolol exerts its beneficial effects specially when there is a delay between STEMI diagnosis and reperfusion,13 probably by delaying the progression of ischemic injury.14 Of note, a recent study has demonstrated that the benefits of acute intravenous administration of metoprolol during an ongoing STEMI are not shared by other β-blockers.15 The METOCARD-CNIC trial did not test the value of maintenance β-blockers since all patients received them from day 1 onward. Other trials performed in the era of reperfusion have focused only on the value of short-term β-blocker administration in STEMI.4,16Given the lack of trials testing the value of maintenance β-blockers for post-MI patients without reduced LVEF treated according to current standards, several observational studies have tried to address this highly relevant issue. Unfortunately, results from these observational studies have yielded opposite conclusions, with some suggesting that β-blockers are associated with a clinical benefit17–19 and others suggesting that they have no benefit.20,21 Due to the observational nature of these studies, and given that the indication for β-blocker is based on clinical guidelines, the risk of bias is very high. In particular, the existence of a confounding by indication factor is present when the prescription of the therapy is not random and is instead based on patients' clinical characteristics, especially when these characteristics are associated with the clinical outcome. Some randomness is needed to ensure that individuals with identical characteristics can be observed in both states, something that did not occur in any of these studies. The only chance for solving the question of the benefits of β-blockers is the execution of adequately sized clinical trials. Currently, 4 large trials are ongoing in Europe: REBOOT-CNIC trial (Treatment With Beta-Blockers After Myocardial Infarction Without Reduced Ejection Fraction; https://www.clinicaltrials.gov; unique identifier: NCT03596385), REDUCE-SWEDEHEART (https://www.clinicaltrials.gov; unique identifier: NCT03278509), BETAMI (Betablocker Treatment After Acute Myocardial Infarction in Patients Without Reduced Left Ventricular Systolic Function; https://www.clinicaltrials.gov; unique identifier: NCT03646357), and DANBLOCK (Danish Trial of Beta Blocker Treatment After Myocardial Infarction Without Reduced Ejection Fraction; https://www.clinicaltrials.gov; unique identifier: NCT03778554). These trials are expected to end in 2024.In the current issue of the journal, an analysis from the well regarded KAMIR-NIH registry, which included 13 104 MI patients between 2011 and 2015, presents data regarding the long-term (ie, beyond 1 year) benefits of β-blockers in post-MI patients according to 1-year LVEF.22 From the 13 104 patients in the registry, 1659 were dead or lost in follow-up at 1 year and thus excluded from this analysis. An additional 7437 patients were excluded because data regarding β-blocker use or 1-year LVEF were not available. Thus, a total of 4008 patients comprise the study population. Eighty-six percent of the population was discharged from index event on β-blockers, and 79% were still on β-blockers at 1 year. At 1 year, 1001 patients had LVEF <50% (83% on β-blockers at discharge and 80% still on β-blockers at 1 year), and 3007 had an LVEF ≥50% (87% on β-blockers at discharge and 79% still on β-blockers at 1 year). The study shows that β-blockers at discharge improve 3-year mortality regardless of baseline LVEF. In survivors at 1 year, mortality 2 years later was improved by β-blocker therapy only when LVEF at 1 year is <50%. In patients with LVEF <50%, cumulative incidence of events at 3 years in those who were withdrawn from β-blockers anytime during the year after MI was significantly higher than those who were kept on β-blockers. These results are in line with current evidence showing that post-MI patients with low LVEF should be kept on β-blockers in the long term. Conversely, in patients with LVEF ≥50%, cumulative incidence of events at 3 years in those who were withdrawn from β-blockers anytime during the year after MI was not different from those who were kept on β-blockers. The fact that the study only included patients alive at 1 year precludes a definite answer on whether β-blockers can be safely withdrawn in patients with preserved LVEF at 1 year. In fact, we do not know if β-blockers were beneficial during the first year and not beyond 1 year or by contrast they were not beneficial at all. Another interesting finding from the study is the significant interaction between 1-year LVEF (not baseline LVEF) and benefits of β-blockers. This result should be interpreted with caution since the categorization of LVEF (<50% or ≥50%) based on echocardiography can be troublesome in values close to 50%. The variability of the technique (especially in a registry environment) can result in variable categorization of a patient. There were 743 patients with LVEF 6 months before to withdraw β-blockers or maintain them. Indeed, the strength of evidence in favor or against long-term β-blocker treatment after MI with preserved LVEF remains uncertain underlining the need for robust and reliable data from the ongoing trials and beyond.Sources of FundingDr Ibanez is supported by the European Commission (ERC-CoG grant No. 819775), and by the Spanish Ministry of Science and Innovation (MCN; 'RETOS 2019' grant No. PID2019-107332RB-I00). The CNIC is supported by the ISCIII, the Ministerio de Ciencia e Innovación, and the Pro CNIC Foundation.Disclosures None.FootnotesThe opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.For Sources of Funding and Disclosures, see page 401.Correspondence to: Borja Ibanez, MD, PhD, Centro Nacional de Investigaciones Cardiovasculares Carlos III, c/Melchor Fernández Almagro 3, 28029 Madrid, Spain, Email [email protected]esLiyew Desta, MD, PhD, Karolinska University Hospital, Solna, Stockholm, Sweden, Email liyew.[email protected]seReferences1. Ibanez B, James S, Agewall S, Antunes MJ, Bucciarelli-Ducci C, Bueno H, Caforio ALP, Crea F, Goudevenos JA, Halvorsen S, et al.; ESC Scientific Document Group. 2017 ESC guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation: the task force for the management of acute myocardial infarction in patients presenting with ST-segment elevation of the European Society of Cardiology (ESC).Eur Heart J. 2018; 39:119–177. doi: 10.1093/eurheartj/ehx393CrossrefMedlineGoogle Scholar2. Freemantle N, Cleland J, Young P, Mason J, Harrison J. Beta Blockade after myocardial infarction: systematic review and meta regression analysis.BMJ. 1999; 318:1730–1737. doi: 10.1136/bmj.318.7200.1730CrossrefMedlineGoogle Scholar3. Desta L, Jernberg T, Löfman I, Hofman-Bang C, Hagerman I, Spaak J, Persson H. Incidence, temporal trends, and prognostic impact of heart failure complicating acute myocardial infarction. The SWEDEHEART Registry (Swedish Web-System for Enhancement and Development of Evidence-Based Care in Heart Disease Evaluated According to Recommended Therapies): a study of 199,851 patients admitted with index acute myocardial infarctions, 1996 to 2008.JACC Heart Fail. 2015; 3:234–242. doi: 10.1016/j.jchf.2014.10.007MedlineGoogle Scholar4. Martínez-Milla J, Raposeiras-Roubín S, Pascual-Figal DA, Ibáñez B. Role of beta-blockers in cardiovascular disease in 2019.Rev Esp Cardiol (Engl Ed). 2019; 72:844–852. doi: 10.1016/j.rec.2019.04.014MedlineGoogle Scholar5. Bangalore S, Makani H, Radford M, Thakur K, Toklu B, Katz SD, DiNicolantonio JJ, Devereaux PJ, Alexander KP, Wetterslev J, et al.. Clinical outcomes with β-blockers for myocardial infarction: a meta-analysis of randomized trials.Am J Med. 2014; 127:939–953. doi: 10.1016/j.amjmed.2014.05.032CrossrefMedlineGoogle Scholar6. Desta L, Khedri M, Jernberg T, Andell P, Mohammad MA, Hofman-Bang C, Erlinge D, Spaak J, Persson H. Adherence to beta-blockers and long-term risk of heart failure and mortality after a myocardial infarction.ESC Heart Fail. 2021; 8:344–355. doi: 10.1002/ehf2.13079CrossrefMedlineGoogle Scholar7. Wiysonge CS, Bradley HA, Volmink J, Mayosi BM, Opie LH. Beta-blockers for hypertension.Cochrane Database Syst Rev. 2017; 1:CD002003. doi: 10.1002/14651858.CD002003.pub5MedlineGoogle Scholar8. Bangalore S, Messerli FH, Kostis JB, Pepine CJ. Cardiovascular protection using beta-blockers: a critical review of the evidence.J Am Coll Cardiol. 2007; 50:563–572. doi: 10.1016/j.jacc.2007.04.060CrossrefMedlineGoogle Scholar9. Bangalore S, Steg G, Deedwania P, Crowley K, Eagle KA, Goto S, Ohman EM, Cannon CP, Smith SC, Zeymer U, et al.; REACH Registry Investigators. β-Blocker use and clinical outcomes in stable outpatients with and without coronary artery disease.JAMA. 2012; 308:1340–1349. doi: 10.1001/jama.2012.12559CrossrefMedlineGoogle Scholar10. Ibanez B, Macaya C, Sánchez-Brunete V, Pizarro G, Fernández-Friera L, Mateos A, Fernández-Ortiz A, García-Ruiz JM, García-Álvarez A, Iñiguez A, et al.. Effect of early metoprolol on infarct size in ST-segment-elevation myocardial infarction patients undergoing primary percutaneous coronary intervention: the Effect of Metoprolol in Cardioprotection During an Acute Myocardial Infarction (METOCARD-CNIC) trial.Circulation. 2013; 128:1495–1503. doi: 10.1161/CIRCULATIONAHA.113.003653LinkGoogle Scholar11. García-Prieto J, Villena-Gutiérrez R, Gómez M, Bernardo E, Pun-García A, García-Lunar I, Crainiciuc G, Fernández-Jiménez R, Sreeramkumar V, Bourio-Martínez R, et al.. Neutrophil stunning by metoprolol reduces infarct size.Nat Commun. 2017; 8:14780. doi: 10.1038/ncomms14780CrossrefMedlineGoogle Scholar12. Pizarro G, Fernández-Friera L, Fuster V, Fernández-Jiménez R, García-Ruiz JM, García-Álvarez A, Mateos A, Barreiro MV, Escalera N, Rodriguez MD, et al.. Long-term benefit of early pre-reperfusion metoprolol administration in patients with acute myocardial infarction: results from the METOCARD-CNIC trial (Effect of Metoprolol in Cardioprotection During an Acute Myocardial Infarction).J Am Coll Cardiol. 2014; 63:2356–2362. doi: 10.1016/j.jacc.2014.03.014CrossrefMedlineGoogle Scholar13. García-Ruiz JM, Fernández-Jiménez R, García-Alvarez A, Pizarro G, Galán-Arriola C, Fernández-Friera L, Mateos A, Nuno-Ayala M, Aguero J, Sánchez-González J, et al.. Impact of the timing of metoprolol administration during STEMI on infarct size and ventricular function.J Am Coll Cardiol. 2016; 67:2093–2104. doi: 10.1016/j.jacc.2016.02.050CrossrefMedlineGoogle Scholar14. Lobo-Gonzalez M, Galán-Arriola C, Rossello X, González-Del-Hoyo M, Vilchez JP, Higuero-Verdejo MI, García-Ruiz JM, López-Martín GJ, Sánchez-González J, Oliver E, et al.. Metoprolol blunts the time-dependent progression of infarct size.Basic Res Cardiol. 2020; 115:55. doi: 10.1007/s00395-020-0812-4CrossrefMedlineGoogle Scholar15. Clemente-Moragón A, Gómez M, Villena-Gutiérrez R, Lalama DV, García-Prieto J, Martínez F, Sánchez-Cabo F, Fuster V, Oliver E, Ibáñez B. Metoprolol exerts a non-class effect against ischaemia-reperfusion injury by abrogating exacerbated inflammation.Eur Heart J. 2020; 41:4425–4440. doi: 10.1093/eurheartj/ehaa733CrossrefMedlineGoogle Scholar16. Roolvink V, Ibáñez B, Ottervanger JP, Pizarro G, van Royen N, Mateos A, Dambrink JE, Escalera N, Lipsic E, Albarran A, et al.; EARLY-BAMI Investigators. Early intravenous beta-blockers in patients with ST-segment elevation myocardial infarction before primary percutaneous coronary intervention.J Am Coll Cardiol. 2016; 67:2705–2715. doi: 10.1016/j.jacc.2016.03.522CrossrefMedlineGoogle Scholar17. Goldberger JJ, Bonow RO, Cuffe M, Liu L, Rosenberg Y, Shah PK, Smith SC, Subačius H; OBTAIN Investigators. Effect of beta-blocker dose on survival after acute myocardial infarction.J Am Coll Cardiol. 2015; 66:1431–1441. doi: 10.1016/j.jacc.2015.07.047CrossrefMedlineGoogle Scholar18. Kim J, Kang D, Park H, Kang M, Park TK, Lee JM, Yang JH, Song YB, Choi JH, Choi SH, et al.. Long-term β-blocker therapy and clinical outcomes after acute myocardial infarction in patients without heart failure: nationwide cohort study.Eur Heart J. 2020; 41:3521–3529. doi: 10.1093/eurheartj/ehaa376CrossrefMedlineGoogle Scholar19. Raposeiras-Roubín S, Abu-Assi E, Redondo-Diéguez A, González-Ferreiro R, López-López A, Bouzas-Cruz N, Castiñeira-Busto M, Peña Gil C, García-Acuña JM, González-Juanatey JR. Prognostic benefit of beta-blockers after acute coronary syndrome with preserved systolic function. Still relevant today?Rev Esp Cardiol (Engl Ed). 2015; 68:585–591. doi: 10.1016/j.rec.2014.07.028MedlineGoogle Scholar20. Dondo TB, Hall M, West RM, Jernberg T, Lindahl B, Bueno H, Danchin N, Deanfield JE, Hemingway H, Fox KAA, et al.. β-blockers and mortality after acute myocardial infarction in patients without heart failure or ventricular dysfunction.J Am Coll Cardiol. 2017; 69:2710–2720. doi: 10.1016/j.jacc.2017.03.578CrossrefMedlineGoogle Scholar21. Holt A, Blanche P, Zareini B, Rajan D, El-Sheikh M, Schjerning AM, Schou M, Torp-Pedersen C, McGettigan P, Gislason GH, et al.. Effect of long-term beta-blocker treatment following myocardial infarction among stable, optimally treated patients without heart failure in the reperfusion era: a Danish, nationwide cohort study.Eur Heart J. 2021; 42:907–914. doi: 10.1093/eurheartj/ehaa1058CrossrefMedlineGoogle Scholar22. Park CS, Yang HM, Ki YJ, Kang J, Han JK, Park KW, Kang HJ, Koo BK, Kim CJ, Cho MC, et al.. Left ventricular ejection fraction 1-year after acute myocardial infarction identifies the benefits of the long-term use of β-blockers: analysis of data from the KAMIR-NIH registry.Circ Cardiovasc Interv. 2021; 14:e010159. doi: 10.1161/CIRCINTERVENTIONS.120.010159LinkGoogle Scholar23. Zeitouni M, Kerneis M, Lattuca B, Guedeney P, Cayla G, Collet JP, Montalescot G, Silvain J. Do patients need lifelong β-blockers after an uncomplicated myocardial infarction?Am J Cardiovasc Drugs. 2019; 19:431–438. doi: 10.1007/s40256-019-00338-4CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsRelated articlesLeft Ventricular Ejection Fraction 1 Year After Acute Myocardial Infarction Identifies the Benefits of the Long-Term Use of β-BlockersChan Soon Park, et al. Circulation: Cardiovascular Interventions. 2021;14 April 2021Vol 14, Issue 4Article InformationMetrics Download: 407 © 2021 American Heart Association, Inc.https://doi.org/10.1161/CIRCINTERVENTIONS.121.010720PMID: 33877861 Originally publishedApril 20, 2021 Keywordsmyocardial infarctionmedicineprognosisheart failureEditorialsPDF download SubjectsMyocardial Infarction
Referência(s)