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How Should Subgroup Analyses Affect Clinical Practice? Insights from the Metoprolol Succinate Controlled-Release/Extended-Release Randomized Intervention Trial in Heart Failure (MERIT-HF)

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Cardiac Electrophysiology Review

Abstract

Context: The Metoprolol CR/XL Randomized Intervention Trial in Chronic Heart Failure (MERIT-HF), the Cardiac Insufficiency Bisoprolol Study II (CIBIS-II), and the Carvedilol Prospective Randomized Cumulative Survival Study (COPERNICUS) have all demonstrated highly significant positive effects on total mortality as well as total mortality plus all-cause hospitalization in patients with heart failure. While none of these trials are large enough to provide definitive results in any particular subgroup, it is of interest for physicians to examine the consistency of results as regards efficacy and safety for various subgroups or risk groups.

Objective: To summarize results from both predefined as well as post-hoc subgroup analyses performed in the MERIT-HF trial, and to provide guidance as to whether any subgroup is at increased risk, despite an overall strongly positive effect, and to discuss the difficulties and limitations in conducting such subgroup analyses. For some subgroups we performed metaanalyses with data from the CIBIS II and COPERNICUS trials in order to obtain more robust data on mortality in subgroups with a small number of deaths (e.g. for women).

Setting: MERIT-HF was run in 14 countries, and randomized a total of 3,991 patients with symptomatic systolic heart failure (NYHA class II to IV with ejection fraction ≤0.40). Treatment was initiated with a very low dose with careful titration to a maximum target dose of 200 mg metoprolol succinate controlled release/extended release (CR/XL), or highest tolerated dose.

Main outcome measures: Total mortality (first primary endpoint), total mortality plus all-cause hospitalization (second primary endpoint), and total mortality plus hospitalization for heart failure (first secondary endpoint) analyzed on a time to first event basis.

Results: Overall, MERIT-HF demonstrated a 34% reduction in total mortality (p = 0.00009 nominal) and a 19% reduction for mortality plus all-cause hospitalization (p = 0.00012). The first secondary endpoint of mortality plus hospitalization for heart failure was reduced by 31% (p = 0.0000008). The results were remarkably consistent for both primary outcomes and the first secondary outcome across all predefined subgroups as well as nearly all post-hoc subgroups. Metoprolol CR/XL has been very well tolerated, overall as well as in all subgroups analyzed. Overall 87% of the patients reached a dose of 100 mg or more of metoprolol CR/XL once daily, and 64% reached the target dose of 200 mg once daily.

Conclusion: Our results show that when carefully titrated, metoprolol CR/XL can safely be instituted for the overwhelming majority of outpatients with clinically stable systolic heart failure, with minimal side effects or deterioration. The time has come to overcome the barriers that physicians perceive to beta-blocker treatment, and to provide it to the large number of patients with heart failure in need of this therapy, including also high risk patients like elderly patients, patients with severe heart failure, and patients with diabetes. Because of the increased risk, these are the patients in whom treatment will have the greatest impact as shown by number of lives saved and number of hospitalizations avoided. The target dose should be strived for in all patients who tolerate this dose. We should expect some variation of the treatment effect around the overall estimate as we examine a large number of subgroups due to small sample size in subgroups and due to chance. However, we believe that the best estimate of treatment effect for any particular subgroup should be the overall effect observed in the trial.

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References

  1. CIBIS II Investigators and Committees: The Cardiac Insufficiency Bisoprolol Study II (CIBIS II). Lancet 1999;353:9-13.

    Google Scholar 

  2. The International Steering Committee on behalf of the MERIT-HF Study Group. Rationale, design, and organization of the Metoprolol CR/XL Randomized Intervention Trial in Heart failure (MERIT-HF). Am J Cardiol 1997;80(Suppl 9B):54J-58J.

    Google Scholar 

  3. MERIT-HF Study Group. Effect of metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL randomized intervention trial in congestive heart failure (MERIT-HF). Lancet 1999;353:2001-2007.

    Google Scholar 

  4. Hjalmarson Å, Goldstein S, Fagerberg B, Wedel H, Waagstein F, Kjekshus J, Wikstrand J, El Allaf Di, Vítovec J, Aldershvile J, Halinen M, Dietz R, Neuhaus K-L, Jánosi A, Thorgeirsson G, Dunselman PHJM, Gullestad L, Kuch J, Herlitz J, Rickenbacher P, Ball S, Gottlieb S, Deedwania P for the MERIT-HF study Group. Effects of controlledrelease metoprolol on total mortality, hospitalizations, and well-being in patients with heart failure. The Metoprolol CR/XL Randomized Intervention Trial in Congestive Heart Failure (MERIT-HF). JAMA 2000;283:1295-1302.

    Google Scholar 

  5. Packer M, Coats AJS, Fowler MB, Katus HA, Krum H, Mohacsi P, Rouleau JL, Tendera M, Castaigne A, Roecker EB, Schultz MK, DeMets DL for the Carvedilol Prospective Randomized Cumulative Survival Study Group (COPERNICUS). Effect of Carvedilol on Survival in Severe Chronic Heart Failure. N Engl J Med 2001;344(22):1651-1658.

    Google Scholar 

  6. Packer M, Fowler MB, Roecker EB, Coats AJS, Katus HA, Krum H, Mohacsi P, Rouleau JL, Tendera M, Staiger C, Holcslaw TL, Amann-Zalan I, DeMets DL for the Carvedilol Prospective Randomized Cumulative Survival (COPERNICUS) Study Group. Effect of carvedilol on the morbidity of patients with severe chronic heart failure. Results of the Carvedilol Prospective Randomized Cumulative Survival (COPERNICUS) Study. Circulation 2002;106:2194-2199.

    Google Scholar 

  7. Wedel H, DeMets D, Deedwania P, Fagerberg B, Goldstein S, Gottlieb S, Hjalmarson Å, Kjekshus J, Waagstein F, Wikstrand J. Challenges of subgroup analyses in multinational clinical trials. Experiences from the MERIT-HF. Am Heart J 2001;142:502-511.

    Google Scholar 

  8. Julian D. Debate. A subversive view of subsets-A dissident clinician's opinion. Curr Control Trials Cardiovasc Med 2000; 1:28-30. http://cvm.controlled-trials.com/ content/1/1/028.

  9. Sleight P. Debate. Subgroup analyses in clinical trials: Fun to look at-But don't believe them! Curr Control Trials Cardiovasc Med 2000; 1:25-27. Available from: http://cvm. controlled-trials.com/content/1/1/025.

  10. ISIS-2 Collaborative Group. Randomised trial of intravenous streptokinase, oral aspirin, both, or neither among 17 187 cases of suspected acute myocardial infarction: ISIS-2. Lancet 1988;ii:349-360.

    Google Scholar 

  11. Fagerberg B. Screening, endpoint classification, and safety monitoring in the Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure. Eur J Heart Failure 2000;2:315-324.

    Google Scholar 

  12. Wikstrand J on behalf of the MERIT-HF Study Group. MERIT-HF-Description of the trial. Basic Res Cardiol 2000;95(Suppl 1):I/90-I/97.

    Google Scholar 

  13. Goldstein S, Fagerberg B, Hjalmarson Å, Kjekshus J, Waagstein F, Wedel H, Wikstrand J for the MERIT-HF Study Group. Metoprolol CR/XL in patients with severe heart failure. Analysis of the experience in MERIT-HF. J AmColl Cardiol 2001;38:932-938.

    Google Scholar 

  14. Ghali JK, Piña IL, Gottlieb SS, Deedwania PC, Wikstrand JC on behalf of the MERIT-HF Study Group. Metoprolol CR/XL in female patients with heart failure. Analysis of the experience in Metoprolol Extended-Release Randomized Intervention Trial in Heart Failure (MERITHF). Circulation 2002;105:1585-1591.

    Google Scholar 

  15. Deedwania PC, Giles T, Ghali K, Gottlieb S. Safety and efficacy of treatment with metoprolol CR/XL in diabetic patients with heart failure. Circulation 2000;102(Suppl II):II-779.

    Google Scholar 

  16. The Beta-Blocker Evaluation of Survival Trial Investigators. A trial of the beta-blocker bucindolol in patients with advanced chronic heart failure. N Engl J Med 2001;344:1659-1667.

    Google Scholar 

  17. Maack C, Cremers B, Flesch M, Höper A, Südkamp M, Böhm M. Different intrinsic activities of bucindolol, carvedilol and metoprolol in human failing myocardium. Br J Pharmacol 2000;130:1131-1139.

    Google Scholar 

  18. Simon, R. Patient subsets and variation in therapeutic efficacy. Br J Clin Pharm 1982;14:473-482.

    Google Scholar 

  19. Herlitz J, Wikstrand J, Denny M, Fenster P, Heywood Th, Masszi G, Rasmussen S, Thorgeirsson G, Wachtell K for the MERIT-HF Study Group. Effects of metoprolol CR/XL on mortality and hospitalizations in patients with heart failure and a history of hypertension. J Cardiac Failure 2002;8:8-14.

    Google Scholar 

  20. Jánosi A, Ghali JK, Herlitz J, Czuriga I, Klibaner M, Wikstrand J, Hjalmarson Å on behalf of the MERIT-HF Study Group. Metoprolol CR/XL in postmyocardial infarction patients with chronic heart failure: Experiences from MERIT-HF. Am Heart J 2003;146:721-728.

    Google Scholar 

  21. The CAPRICORN Investigators. Effect of carvedilol on outcome after myocardial infarction in patients with leftventricular dysfunction: The CAPRICORN randomized trial. Lancet 2001;257:1385-1390.

    Google Scholar 

  22. Goldstein S, Deedwania P, Gottlieb S, Wikstrand J for the MERIT-HF Study Group. Metoprolol CR/XL in black patients with heart failure (from the Metoprolol CR/XL Randomized Intervention Trial in Chronic Heart Failure). Am J Cardiol 2003;92:478-480.

    Google Scholar 

  23. Yancy CW, Fowler MB, Colucci WS, Gilbert EM, Bristow MR, Cohn JN, Lukas MA, Young ST, Packer M, for the US Carvedilol Heart Failure Study Group. Race and the response to adrenergic blockade with carvedilol in patients with chronic heart failure. N Engl J Med 2001;344:1358-1365.

    Google Scholar 

  24. Carson P, Fowler MB, Mohacsi P, Krum H, Tendera M, Coats AJS, Rouleau JL, Holsclaw T, Staiger C, Roecker EB, Amann-Zalan I, Packer M. Effect of carvedilol in black patients with severe chronic heart failure: Results of the COPERNICUS Study. Circulation 2001;104(Suppl II):II-754.

    Google Scholar 

  25. Ghali JK, Dunselman P, Waagstein F, Wikstrand JC. Consistency of the beneficial effect of metoprolol extended release across a wide range dose of ACE inhibitors. Circulation 2002;106 (Suppl):3022.

    Google Scholar 

  26. Erdmann E, Lechat P, Verkenne P, Wiemann H. Results from post-hoc analyses of the CIBIS II trial: Effect of bisoprolol in high-risk patient groups with chronic heart failure. Eur J Heart Fail 2001;3:469-479.

    Google Scholar 

  27. Mohacsi P, Fowler MB, Krum H, et al. Should physicians avoid the use of beta-blockers in patients with heart failure who have diabetes? Results of the COPERNICUS Study. Am Heart Ass Meeting 2001, Abstract 3551.

  28. Deedwania PC, Wikstrand J, Gottlieb S, Wedel H, Klibaner M. Efficacy and tolerability of with metoprolol CR/XL in elderly patients with heart failure. Circulation 2001;104(Suppl II):II-753.

    Google Scholar 

  29. Gottlieb S, Fisher ML, Kjekshus J, Deedwania P, Gullestad L, Vitovec J, Wikstrand J on behalf of theMERIT-HF Investigators. Tolerability of β-blocker initiation and titration in the Circulation 2002;105:1182-1188.

    Google Scholar 

  30. Wikstrand J, Hjalmarson Å, Waagstein F, Wedel H, Fagerberg B, Fagerberg B, Goldstein S, Kjekshus J, Wedel H for the MERIT-HF Study Group. Dose of metoprolol CR/XL and clinical outcomes in patients with heart failure. Analysis of the experience in Metoprolol CR/XL Randomized Intervention Trial in Chronic Heart Failure (MERIT-HF). J AmColl Cardiol 2002;40:491-498.

    Google Scholar 

  31. Hill AB. Principles on Medical Statistics, 9th ed. London: Lancet, 1971.

    Google Scholar 

  32. The Norwegian Multicenter Study Group. Influence of heart size on mortality and reinfarction in patients treated with timolol after myocardial infarction. Br Heart J 1983;50(2):135-139.

    Google Scholar 

  33. Herlitz J, Waagstein F, Lindqvist J, Swedberg K, Hjalmarson A. Effect of metoprolol on the prognosis for patients with suspected acute myocardial infarction and indirect signs of congestive heart failure (a subgroup analysis of the Goteborg Metoprolol Trial). Am J Cardiol 1997;80(9B):40J-44J.

    Google Scholar 

  34. Chadda K, Goldstein S, Byington R, Curb JD. Effect of propranolol after acute myocardial infarction in patients with congestive heart failure. Circulation 1986;73:503-510.

    Google Scholar 

  35. Haywood LJ. Coronary heart disease mortality/morbidity and risk in blacks. I: Clinical manifestations and diagnostic criteria: The experience with the Beta Blocker Heart Attack Trial. Am Heart J 1984;108:787-793.

    Google Scholar 

  36. Poole-Wilson PA, Swedberg K, Cleland JGF, Di Lenarda A, Hanrath P, Komajda M, Lubsen J, Lutiger B, Metra M, Remme WJ, Torp-Pedersen C, Scherhag A, Skene A, for the COMET investigators. Comparison of carvedilol and metoprolol on clinical outcomes in patients with chronic heart failure in the Carvedilol Or Metoprolol European Trial (COMET): Randomised controlled trial. Lancet 2003;362:7-13.

    Google Scholar 

  37. Hjalmarson Å, Olsson G, Bondjers G, Dahlöf C, Sandberg A, Åblad B, Wiklund I, Wikstrand J. Cardioselective β-adrenoreceptor blockers. Metoprolol. In: Messerli FH, ed. Cardiovascular Drug Therapy, 2nd ed. Philadelphia, USA: W.B. Saunders Co. 1996:522-540.

    Google Scholar 

  38. Carlson WD, Gilbert EM. Carvedilol. In: Messerli FH, ed. Cardiovascular Drug Therapy, 2nd ed. Philadelphia, USA: W.B. Saunders Co. 1996:583-599.

    Google Scholar 

  39. Eichhorn EJ. β-Blocker withdrawal: The song of Orpheus. Editorial. Am Heart J 1999;138:387-389.

    Google Scholar 

  40. Wikstrand J, Andersson B, Kendall MJ, Stanbrook H, Klibaner M. Pharmacokinetic considerations of formulation: Extended-release metoprolol succinate in the treatment of heart failure. J Cardiovasc Pharmacol 2003;41:151-157.

    Google Scholar 

  41. Hjalmarson Å, Waagstein F. COMET: A proposed mechanism of action to explain the results and concerns about dose. Letter to the editor. Lancet 2003;3562:1077.

    Google Scholar 

  42. Wikstrand J, Fagerberg B, Goldstein S, Kjekshus J, Wedel H. COMET: A proposed mechanism of action to explain the results and concerns about dose. Letter to the editor. Lancet 2003;3562:1076-1077.

    Google Scholar 

  43. Bristow MR, Feldman AM, Adams KF, Goldstein S. Selective versus nonselective β-blockade for heart failure therapy: Are there lessons to be learned from theCOMETtrial? J Cardiac Failure 2003;9:444-453.

    Google Scholar 

  44. Scandinavian simvastatin survival study group. Randomized trial of cholesterol lowering in 4444 patients with coronary heart disease: The Scandinavian simvastatin survival study (4S). Lancet 1994;344:1383-1389.

    Google Scholar 

  45. The CONSENSUS Trial study Group. Effects of enalapril on mortality in severe congestive heart failure. Results of the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS). N Engl J Med 1987;316:1429-1435.

    Google Scholar 

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Authors and Affiliations

  1. Wallenberg Laboratory for Cardiovascular Research, Sahlgrenska University Hospital, Göteborg, Sweden (John Wikstrand also senior medical advisor, Clinical science, AstraZeneca, Mölndal, Sweden)

    John Wikstrand

  2. Nordic School of Public Health, Göteborg, Sweden

    Hans Wedel

  3. Cardiac Centers of Louisiana, Shreveport, Louisiana

    Jalal Ghali

  4. University of California, San Francisco, California

    Prakash Deedwania

  5. Wallenberg Laboratory for Cardiovascular Research, Sahlgrenska University Hospital, Göteborg, Sweden; Institute of Internal Medicine, Sahlgrenska University Hospital, Göteborg, Sweden

    Björn Fagerberg

  6. Henry Ford Hospital, Detroit, Michigan

    Sidney Goldstein

  7. University of Maryland, Baltimore, Maryland

    Stephen Gottlieb

  8. The Cardiovascular Institute, Sahlgrenska University Hospital, Göteborg, Sweden

    Åke Hjalmarson & Finn Waagstein

  9. Rikshospitalet, Oslo, Norway

    John Kjekshus

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Wikstrand, J., Wedel, H., Ghali, J. et al. How Should Subgroup Analyses Affect Clinical Practice? Insights from the Metoprolol Succinate Controlled-Release/Extended-Release Randomized Intervention Trial in Heart Failure (MERIT-HF). Card Electrophysiol Rev 7, 264–275 (2003). https://doi.org/10.1023/B:CEPR.0000012438.04416.00

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