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EDITORIAL

Intravenous beta-blockers in patients with ST-elevation myocardial infarction treated with primary PCI

Division of Cardiovascular Medicine, Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor, MI, USA

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The potential for acute beta-blocker administration to decrease myocardial infarct size, preserve left ventricular function, and improve survival in patients with ST-elevation myocardial infarction (STEMI) has been investigated for four decades11. Bates ER. Role of intravenous beta-blockers in the treatment of ST-elevation myocardial infarction: of mice (dogs, pigs) and men. Circulation. 2007;115:2904-6. . In the pre-fibrinolytic era, intravenous followed by oral beta-blockers administered to patients as monotherapy reduced myocardial infarct size and improved survival. In the fibrinolytic era, however, intravenous followed by oral beta-blockers administered as adjunctive therapy did not impact on myocardial infarct size, left ventricular ejection fraction (LVEF), or mortality; however, it did acutely increase the risk for bradycardia, hypotension, heart failure, and cardiogenic shock. Based on this evidence, the American and European STEMI guideline committees gave a Class IIa recommendation for the administration of intravenous beta-blockers at the time of presentation only for patients with hypertension or tachycardia and no signs of heart failure22. Task Force on the management of ST-segment elevation acute myocardial infarction of the European Society of Cardiology (ESC), Steg PG, James SK, Atar D, Badano LP, Blömstrom-Lundqvist C, Borger MA, Di Mario C, Dickstein K, Ducrocq G, Fernandez-Aviles F, Gershlick AH, Giannuzzi P, Halvorsen S, Huber K, Juni P, Kastrati A, Knuuti J, Lenzen MJ, Mahaffey KW, Valgimigli M, van ‘t Hof A, Widimsky P, Zahger D. ESC Guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation. Eur Heart J. 2012;33:2569-619. ,33. O’Gara PT, Kushner FG, Ascheim DD, Casey DE Jr, Chung MK, de Lemos JA, Ettinger SM, Fang JC, Fesmire FM, Franklin BA, Granger CB, Krumholz HM, Linderbaum JA, Morrow DA, Newby LK, Ornato JP, Ou N, Radford MJ, Tamis- Holland JE, Tommaso CL, Tracy CM, Woo YJ, Zhao DX, Anderson JL, Jacobs AK, Halperin JL, Albert NM, Brindis RG, Creager MA, DeMets D, Guyton RA, Hochman JS, Kovacs RJ, Kushner FG, Ohman EM, Stevenson WG, Yancy CW; American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. 2013 ACCF/AHA guideline for the management of ST-elevation myocardial infarction: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation. 2013;127:e362-425. .

Contraindications for beta-blocker administration include bradycardia, hypotension, atrioventricular block, bronchospasm, and heart failure. Clinical exclusions also include cardiac arrest and cardiogenic shock. The early risk with intravenous beta-blocker administration is the negative inotropic effect that can activate subclinical disease and precipitate heart failure or cardiogenic shock. Prudence, therefore, suggests that it is better to wait several hours for most patients with STEMI to stabilise after reperfusion therapy before starting a beta-blocker and to use oral, rather than intravenous, administration after the early risk for harm with acute administration has passed.

Recently, there have been at least four small randomised trials evaluating the impact of early intravenous beta-blocker administration in patients with STEMI treated with primary percutaneous coronary intervention (PCI)44. Hanada K, Higuma T, Nishizaki F, Sukekawa T, Yokota T, Yamada M, Saito S, Kushibiki M, Oikawa K, Abe N, Tomita H, Osanai T, Okumura K. Randomized study on the efficacy and safety of landiolol, an ultra-short-acting β1-adrenergic blocker, in patients with acute myocardial infarction undergoing primary percutaneous coronary intervention. Circ J. 2012;76:439-45. ,55. Ibanez B, Macaya C, Sanchez-Brunete V, Pizarro G, Fernandez-Friera L, Mateos A, Fernandez-Ortiz A, Garcia-Ruiz JM, Garcia-Alvarez A, Iniguez A, Jiménez-Borreguero J, Lopez-Romero P, Fernandez-Jiménez R, Goicolea J, Ruiz-Mateos B, Bastante T, Arias M, Iglesias-Vazquez JA, Rodriguez MD, Escalera N, Acebal C, Cabrera JA, Valenciano J, Pérez de Prado A, Fernandez-Campos MJ, Casado I, Garcia-Rubira JC, Garcia-Prieto J, Sanz-Rosa D, Cuellas C, Hernandez-Antolin R, Albarran A, Fernandez-Vazquez F, de la Torre-Hernandez JM, Pocock S, Sanz G, Fuster V. 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;128:1495-503. ,66. Er F, Dahlem KM, Nia AM, Erdmann E, Waltenberger J, Hellmich M, Kuhr K, Le MT, Herrfurth T, Taghiyev Z, Biesenbach E, Yüksel D, Eran-Ergöknil A, Vanezi M, Caglayan E, Gassanov N. Randomized Control of Sympathetic Drive With Continuous Intravenous Esmolol in Patients With Acute ST-Segment Elevation Myocardial Infarction: The BEta-Blocker Therapy in Acute Myocardial Infarction (BEAT-AMI) Trial. JACC Cardiovasc Interv. 2016;9:231-40. ,77. Roolvink V, Ibanez B, Ottervanger JP, Pizarro G, van Royen N, Mateos A, Dambrink JE, Escalera N, Lipsic E, Albarran A, Fernandez-Ortiz A, Fernandez-Avilés F, Goicolea J, Botas J, Remkes W, Hernandez-Jaras V, Kedhi E, Zamorano JL, Navarro F, Alfonso F, Garcia-Lledo A, Alonso J, van Leeuwen M, Nijveldt R, Postma S, Kolkman E, Gosselink M, de Smet B, Rasoul S, Piek JJ, Fuster V, van ‘t Hof AW; 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;67:2705-15. . In contrast to the trials performed with fibrinolytic therapy, three trials suggested improvement in left ventricular function, but the largest trial found no benefit (Table 1). The trials were underpowered to evaluate clinical outcomes which were similar. Two older retrospective cohort analyses of patients undergoing primary PCI suggested that intravenous beta-blocker administration improved left ventricular function and reduced mortality, but there were many differences in baseline characteristics between cohorts suggesting selection bias88. Harjai KJ, Stone GW, Boura J, Grines L, Garcia E, Brodie B, Cox D, O’Neill WW, Grines C. Effects of prior beta-blocker therapy on clinical outcomes after primary coronary angioplasty for acute myocardial infarction. Am J Cardiol. 2003;91:655-60. ,99. Halkin A, Grines CL, Cox DA, Garcia E, Mehran R, Tcheng JE, Griffin JJ, Guagliumi G, Brodie B, Turco M, Rutherford BD, Aymong E, Lansky AJ, Stone GW. Impact of intravenous beta-blockade before primary angioplasty on survival in patients undergoing mechanical reperfusion therapy for acute myocardial infarction. J Am Coll Cardiol. 2004;43:1780-7. .

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In this issue of EuroIntervention, Mohammad and colleagues compared clinical outcomes with and without intravenous beta-blockers during primary PCI using the national SWEDEHEART registry1010. Mohammad MA, Andell P, Koul S, Desta L, Jernberg T, Omerovic E, Spaak J, Fröbert O, Jensen J, Engstrøm T, Hofman-Bang C, Persson H, Erlinge D. Intravenous beta-blocker therapy in ST-segment elevation myocardial infarction treated with primary percutaneous coronary intervention is not associated with benefit regarding short-term mortality: a Swedish nationwide observational study. EuroIntervention. 2017;13:210-8. .

They enrolled 16,909 patients with STEMI between 2006 and 2013: 2,876 (17.0%) were treated with intravenous beta-blockers. After multivariable adjustment for known confounders, the intravenous beta-blocker cohort had higher 30-day all-cause mortality (HR: 1.44, 95% CI: 1.14-1.83) and in-hospital mortality (HR: 1.23, 95% CI: 0.93-1.61), more in-hospital cardiogenic shock (OR: 1.53, 95% CI: 1.09-2.16), and were more often discharged with an LVEF <40% (OR: 1.70, 95% CI: 1.51-1.92). Propensity score matching and sensitivity analyses supported the results.

It is possible that the harm associated with early intravenous beta-blockers is overestimated in this analysis. The clinical indication for administration was not captured and use declined during the study period, so selection bias may have impacted on the results. For instance, the beta-blocker cohort had longer time to PCI, higher heart rate, higher blood pressure, more atrial fibrillation, more LAD culprit lesions, and larger enzymatic infarct size. Moreover, because this was a retrospective observational database study, residual confounding is another potential limitation. Nevertheless, the conclusion that early intravenous beta-blocker therapy was associated with risk and no benefit is consistent with the results from the fibrinolytic era and with the risk associated with acute beta-blocker administration in the perioperative setting. This study supports current guideline recommendations for very selective intravenous beta-blocker administration in patients with STEMI. The authors state that intravenous beta-blocker use ranges from 2% to 40% in Swedish hospitals, suggesting an opportunity for quality improvement by standardising therapeutic protocols across hospitals to be more consistent with guideline-directed medical therapy. This report should prompt hospitals and STEMI teams to review their use of intravenous beta-blockers in patients with STEMI. The best and only proven strategy to decrease infarct size and improve left ventricular function in patients with STEMI is decreasing time-to-treatment with reperfusion therapy and minimising the early risk for hypotension, heart failure, and cardiogenic shock. Starting oral beta-blocker therapy several hours after reperfusion therapy in stable patients without contraindications gives the patient the hospital benefit of decreasing the risk for recurrent ischaemia and ventricular arrhythmias without the risk of acute haemodynamic compromise. Oral beta-blockers should be continued for a few years in uncomplicated patients for secondary prevention and chronically in patients with heart failure.

Conflict of interest statement

The author has no conflicts of interest to declare.

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References

  • 1. Bates ER. Role of intravenous beta-blockers in the treatment of ST-elevation myocardial infarction: of mice (dogs, pigs) and men. Circulation. 2007;115:2904-6.
  • 2. Task Force on the management of ST-segment elevation acute myocardial infarction of the European Society of Cardiology (ESC), Steg PG, James SK, Atar D, Badano LP, Blömstrom-Lundqvist C, Borger MA, Di Mario C, Dickstein K, Ducrocq G, Fernandez-Aviles F, Gershlick AH, Giannuzzi P, Halvorsen S, Huber K, Juni P, Kastrati A, Knuuti J, Lenzen MJ, Mahaffey KW, Valgimigli M, van ‘t Hof A, Widimsky P, Zahger D. ESC Guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation. Eur Heart J. 2012;33:2569-619.
  • 3. O’Gara PT, Kushner FG, Ascheim DD, Casey DE Jr, Chung MK, de Lemos JA, Ettinger SM, Fang JC, Fesmire FM, Franklin BA, Granger CB, Krumholz HM, Linderbaum JA, Morrow DA, Newby LK, Ornato JP, Ou N, Radford MJ, Tamis- Holland JE, Tommaso CL, Tracy CM, Woo YJ, Zhao DX, Anderson JL, Jacobs AK, Halperin JL, Albert NM, Brindis RG, Creager MA, DeMets D, Guyton RA, Hochman JS, Kovacs RJ, Kushner FG, Ohman EM, Stevenson WG, Yancy CW; American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. 2013 ACCF/AHA guideline for the management of ST-elevation myocardial infarction: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation. 2013;127:e362-425.
  • 4. Hanada K, Higuma T, Nishizaki F, Sukekawa T, Yokota T, Yamada M, Saito S, Kushibiki M, Oikawa K, Abe N, Tomita H, Osanai T, Okumura K. Randomized study on the efficacy and safety of landiolol, an ultra-short-acting β1-adrenergic blocker, in patients with acute myocardial infarction undergoing primary percutaneous coronary intervention. Circ J. 2012;76:439-45.
  • 5. Ibanez B, Macaya C, Sanchez-Brunete V, Pizarro G, Fernandez-Friera L, Mateos A, Fernandez-Ortiz A, Garcia-Ruiz JM, Garcia-Alvarez A, Iniguez A, Jiménez-Borreguero J, Lopez-Romero P, Fernandez-Jiménez R, Goicolea J, Ruiz-Mateos B, Bastante T, Arias M, Iglesias-Vazquez JA, Rodriguez MD, Escalera N, Acebal C, Cabrera JA, Valenciano J, Pérez de Prado A, Fernandez-Campos MJ, Casado I, Garcia-Rubira JC, Garcia-Prieto J, Sanz-Rosa D, Cuellas C, Hernandez-Antolin R, Albarran A, Fernandez-Vazquez F, de la Torre-Hernandez JM, Pocock S, Sanz G, Fuster V. 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;128:1495-503.
  • 6. Er F, Dahlem KM, Nia AM, Erdmann E, Waltenberger J, Hellmich M, Kuhr K, Le MT, Herrfurth T, Taghiyev Z, Biesenbach E, Yüksel D, Eran-Ergöknil A, Vanezi M, Caglayan E, Gassanov N. Randomized Control of Sympathetic Drive With Continuous Intravenous Esmolol in Patients With Acute ST-Segment Elevation Myocardial Infarction: The BEta-Blocker Therapy in Acute Myocardial Infarction (BEAT-AMI) Trial. JACC Cardiovasc Interv. 2016;9:231-40.
  • 7. Roolvink V, Ibanez B, Ottervanger JP, Pizarro G, van Royen N, Mateos A, Dambrink JE, Escalera N, Lipsic E, Albarran A, Fernandez-Ortiz A, Fernandez-Avilés F, Goicolea J, Botas J, Remkes W, Hernandez-Jaras V, Kedhi E, Zamorano JL, Navarro F, Alfonso F, Garcia-Lledo A, Alonso J, van Leeuwen M, Nijveldt R, Postma S, Kolkman E, Gosselink M, de Smet B, Rasoul S, Piek JJ, Fuster V, van ‘t Hof AW; 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;67:2705-15.
  • 8. Harjai KJ, Stone GW, Boura J, Grines L, Garcia E, Brodie B, Cox D, O’Neill WW, Grines C. Effects of prior beta-blocker therapy on clinical outcomes after primary coronary angioplasty for acute myocardial infarction. Am J Cardiol. 2003;91:655-60.
  • 9. Halkin A, Grines CL, Cox DA, Garcia E, Mehran R, Tcheng JE, Griffin JJ, Guagliumi G, Brodie B, Turco M, Rutherford BD, Aymong E, Lansky AJ, Stone GW. Impact of intravenous beta-blockade before primary angioplasty on survival in patients undergoing mechanical reperfusion therapy for acute myocardial infarction. J Am Coll Cardiol. 2004;43:1780-7.
  • 10. Mohammad MA, Andell P, Koul S, Desta L, Jernberg T, Omerovic E, Spaak J, Fröbert O, Jensen J, Engstrøm T, Hofman-Bang C, Persson H, Erlinge D. Intravenous beta-blocker therapy in ST-segment elevation myocardial infarction treated with primary percutaneous coronary intervention is not associated with benefit regarding short-term mortality: a Swedish nationwide observational study. EuroIntervention. 2017;13:210-8.