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Long-term outcome of carvedilol therapy in Japanese patients with nonischemic heart failure

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Abstract

Nonischemic heart failure (HF) is common in Japan. We evaluated the long-term outcome of Japanese patients with nonischemic HF receiving carvedilol based on left ventricular ejection fraction (LVEF) category. We conducted a single-center observation study of 1550 patients with nonischemic HF who were initiated with carvedilol between 2005 and 2015. Of these patients, 38% had an LVEF < 40% (HFrEF, median age 57 years, 28% female) and 62% had an LVEF ≥ 40% (HFpEF, 64 years, 38% female). The primary outcome was all-cause.death The secondary outcomes were cardiac death and sudden cardiac death (SCD). After a median follow-up of 5.5 [interquartile range, 2.9–8.8] years, the median daily maintenance doses of carvedilol in patients with HFrEF and HFpEF were 7.5 [5–12.5] mg and 7.5 [5–10] mg, respectively. The cumulative survival rates of HFrEF patients at 1, 3 and 5 years were 96.1%, 90.2% and 85.5%, respectively, and the cumulative survival rates of HFpEF patients at 1, 3 and 5 years were 97.8%, 94.4% and 90.7%, respectively. The cumulative cardiac death-free rates at 5 years were 94.4% in HFrEF patients and 97.7% in HFpEF patients, and the cumulative SCD-free rates at 5 years were 96.7% in HFrEF patients and 97.9% in HFpEF patients. The adjusted survival rate showed that a higher dose (≥ 7.5 mg daily) was associated with more favourable outcomes than a lower dose (< 7.5 mg daily) in HFrEF patients, but not in HFpEF patients. The adjusted survival rate showed that a lower heart rate (< 75 bpm) was associated with favourable outcomes than a higher heart rate (≥ 75 bpm) in HFrEF patients, but not in HFpEF patients. Long-term survival was good in Japanese patients with nonischemic HF receiving carvedilol. Higher doses and lower heart rates were associated with favourable survival for HFrEF patients, but not in HFpEF patients.

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References

  1. Packer M, Bristow MR, Cohn JN, Colucci WS, Fowler MB, Gilbert EM, Shusterman NH, for the U.S. Carvedilol Heart Failure Study Group (1996) The effect of carvedilol on morbidity and mortality in patients with chronic heart failure. N Engl J Med 334:1349–1355

    Article  CAS  Google Scholar 

  2. Packer M, Coats AJ, 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 (COPERNICUS) Study Group (2001) Effect of carvedilol on survival in severe chronic heart failure. N Engl J Med 344:1651–1658

    Article  CAS  Google Scholar 

  3. CIBIS-II Investigators and Committees (1999) The cardiac insufficiency bisoprolol study II (CIBIS-II): a randomised trial. Lancet 353:9–13

    Article  Google Scholar 

  4. MERIT-HF Study Group (1999) Effect of metoprolol CR/XL in chronic heart failure: metoprolol CR/XL randomised intervention trial in congestive heart failure (MERIT-HF). Lancet 353:2001–2007

    Article  Google Scholar 

  5. Yancy CW, Jessup M, Bozkurt B, Butler J, Casey DE Jr, Drazner MH, Fonarow GC, Geraci SA, Horwich T, Januzzi JL, Johnson MR, Kasper EK, Levy WC, Masoudi FA, McBride PE, McMurray JJ, Mitchell JE, Peterson PN, Riegel B, Sam F, Stevenson LW, Tang WH, Tsai EJ, Wilkoff BL (2013) 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation 128:e240–e327

    PubMed  Google Scholar 

  6. Ponikowski P, Voors AA, Anker SD, Bueno H, Cleland JGF, Coats AJS, Falk V, González-Juanatey JR, Harjola VP, Jankowska EA, Jessup M, Linde C, Nihoyannopoulos P, Parissis JT, Pieske B, Riley JP, Rosano GMC, Ruilope LM, Ruschitzka F, Rutten FH, van der Meer P, ESC Scientific Document Group (2016) 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: the Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC) Developed with the special contribution of the Heart Failure Association (HFA) of the ESC. Eur Heart J 37:2129–2200

    Article  Google Scholar 

  7. Tsutsui H, Isobe M, Ito H, Ito H, Okumura K, Ono M, Kitakaze M, Kinugawa K, Kihara Y, Goto Y, Komuro I, Saiki Y, Saito Y, Sakata Y, Sato N, Sawa Y, Shiose A, Shimizu W, Shimokawa H, Seino Y, Node K, Higo T, Hirayama A, Makaya M, Masuyama T, Murohara T, Momomura SI, Yano M, Yamazaki K, Yamamoto K, Yoshikawa T, Yoshimura M, Akiyama M, Anzai T, Ishihara S, Inomata T, Imamura T, Iwasaki YK, Ohtani T, Onishi K, Kasai T, Kato M, Kawai M, Kinugasa Y, Kinugawa S, Kuratani T, Kobayashi S, Sakata Y, Tanaka A, Toda K, Noda T, Nochioka K, Hatano M, Hidaka T, Fujino T, Makita S, Yamaguchi O, Ikeda U, Kimura T, Kohsaka S, Kosuge M, Yamagishi M, Yamashina A, Japanese Circulation Society and the Japanese Heart Failure Society Joint Working Group (2019) JCS 2017/JHFS 2017 guideline on diagnosis and treatment of acute and chronic heart failure—digest version. Circ J 83:2084–2184

    Article  Google Scholar 

  8. Roger VL (2013) Epidemiology of heart failure. Circ Res 113:646–659

    Article  CAS  Google Scholar 

  9. Sato T, Yoshihisa A, Kanno Y, Suzuki S, Yamaki T, Sugimoto K, Kunii H, Nakazato K, Suzuki H, Saitoh SI, Ishida T, Takeishi Y (2017) Cardiopulmonary exercise testing as prognostic indicators: comparisons among heart failure patients with reduced, mid-range and preserved ejection fraction. Eur J Prev Cardiol 24:1979–1987

    Article  Google Scholar 

  10. Hamatani Y, Nagai T, Shiraishi Y, Kohsaka S, Nakai M, Nishimura K, Kohno T, Nagatomo Y, Asaumi Y, Goda A, Mizuno A, Yasuda S, Ogawa H, Yoshikawa T, Anzai T, Investigators for the WET-NaDEF Collaboration Project (2018) Long-term prognostic significance of plasma B-type natriuretic peptide level in patients with acute heart failure with reduced, mid-range, and preserved ejection fractions. Am J Cardiol 121:731–738

    Article  CAS  Google Scholar 

  11. Shiga T, Suzuki A, Haruta S, Mori F, Ota Y, Yagi M, Oka T, Tanaka H, Murasaki S, Yamauchi T, Katoh J, Hattori H, Kikuchi N, Watanabe E, Yamada Y, Haruki S, Kogure T, Suzuki T, Uetsuka Y, Hagiwara N, HIJ-HF II Investigators (2019) Clinical characteristics of hospitalized heart failure patients with preserved, mid-range, and reduced ejection fractions in Japan. ESC Heart Fail 6:475–486

    Article  Google Scholar 

  12. Levey AS, Bosch JP, Lewis JB, Greene T, Rogers N, Roth D (1999) A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Modification of diet in renal disease study group. Ann Intern Med 130:461–470

    Article  CAS  Google Scholar 

  13. Waagstein F, Bristow MR, Swedberg K, Camerini F, Fowler MB, Silver MA, Gilbert EM, Johnson MR, Goss FG, Hjalmarson A, for the Metoprolol in Dilated Cardiomyopathy (MDC) Trial Study Group (1993) Beneficial effects of metoprolol in idiopathic dilated cardiomyopathy. Lancet 342:1441–1446

    Article  CAS  Google Scholar 

  14. Hori M, Sasayama S, Kitabatake A, Toyo-oka T, Handa S, Yokoyama M, Matsuzaki M, Takeshita A, Origasa H, Matsui K, Hosoda S, MUCHA Investigators (2004) Low-dose carvedilol improves left ventricular function and reduces cardiovascular hospitalization in Japanese patients with chronic heart failure: the multicenter carvedilol heart failure dose assessment (MUCHA) trial. Am Heart J 147:324–330

    Article  CAS  Google Scholar 

  15. Tsuchihashi-Makaya M, Kinugawa S, Yokoshiki H, Hamaguchi S, Yokota T, Goto D, Takeshita A, Tsutsui H, JCARE-CARD Investigators (2010) Beta-blocker use at discharge in patients hospitalized for heart failure is associated with improved survival. Circ J 74:1364–1371

    Article  Google Scholar 

  16. Matsumura Y, Takata J, Kitaoka H, Kubo T, Baba Y, Hoshikawa E, Hamada T, Okawa M, Hitomi N, Sato K, Yamasaki N, Yabe T, Furuno T, Nishinaga M, Doi Y (2006) Long-term prognosis of dilated cardiomyopathy revisited: an improvement in survival over the past 20 years. Circ J 70:376–383

    Article  Google Scholar 

  17. Edelmann F, Musial-Bright L, Gelbrich G, Trippel T, Radenovic S, Wachter R, Inkrot S, Loncar G, Tahirovic E, Celic V, Veskovic J, Zdravkovic M, Lainscak M, Apostolović S, Neskovic AN, Pieske B, Düngen HD, CIBIS-ELD Investigators and Project Multicenter Trials in the Competence Network Heart Failure (2016) Tolerability and feasibility of beta-blocker titration in HFpEF versus HFrEF: insights from the CIBIS-ELD trial. JACC Heart Fail 4:140–149

    Article  Google Scholar 

  18. Tsuchihashi-Makaya M, Hamaguchi S, Kinugawa S, Yokota T, Goto D, Yokoshiki H, Kato N, Takeshita A, Tsutsui H, JCARE-CARD Investigators (2009) Characteristics and outcomes of hospitalized patients with heart failure and reduced vs preserved ejection fraction. Report from the Japanese cardiac registry of heart failure in cardiology (JCARE-CARD). Circ J 73:1893–1900

    Article  Google Scholar 

  19. Nagai T, Yoshikawa T, Saito Y, Takeishi Y, Yamamoto K, Ogawa H, Anzai T, JASPER Investigators (2018) Clinical characteristics, management, and outcomes of Japanese patients hospitalized for heart failure with preserved ejection fraction—a report from the japanese heart failure syndrome with preserved ejection fraction (JASPER) registry. Circ J 82:1534–1545

    Article  Google Scholar 

  20. Chioncel O, Lainscak M, Seferovic PM, Anker SD, Crespo-Leiro MG, Harjola VP, Parissis J, Laroche C, Piepoli MF, Fonseca C, Mebazaa A, Lund L, Ambrosio GA, Coats AJ, Ferrari R, Ruschitzka F, Maggioni AP, Filippatos G (2017) Epidemiology and one-year outcomes in patients with chronic heart failure and preserved, mid-range and reduced ejection fraction: an analysis of the ESC heart failure long-term registry. Eur J Heart Fail 19:1574–1585

    Article  CAS  Google Scholar 

  21. Hoshikawa E, Matsumura Y, Kubo T, Okawa M, Yamasaki N, Kitaoka H, Furuno T, Takata J, Doi YL (2011) Effect of left ventricular reverse remodeling on long-term prognosis after therapy with angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers and β blockers in patients with idiopathic dilated cardiomyopathy. Am J Cardiol 107:1065–1070

    Article  CAS  Google Scholar 

  22. Konishi M, Haraguchi G, Kimura S, Inagaki H, Kawabata M, Hachiya H, Hirao K, Isobe M (2010) Comparative effects of carvedilol vs bisoprolol for severe congestive heart failure. Circ J 74:1127–1134

    Article  CAS  Google Scholar 

  23. Teng TK, Tromp J, Tay WT, Anand I, Ouwerkerk W, Chopra V, Wander GS, Yap JJ, MacDonald MR, Xu CF, Chia YM, Shimizu W, ASIAN-HF investigators, Richards AM, Voors A, Lam CS (2018) Prescribing patterns of evidence-based heart failure pharmacotherapy and outcomes in the ASIAN-HF registry: a cohort study. Lancet Glob Health 6:e1008–e1018

    Article  Google Scholar 

  24. Zhou HH, Koshakji RP, Silberstein DJ, Wilkinson GR, Wood AJ (1989) Racial differences in drug response. Altered sensitivity to and clearance of propranolol in men of Chinese descent as compared with American whites. N Engl J Med 320:565–570

    Article  CAS  Google Scholar 

  25. Yamamoto K, Origasa H, Hori M, J-DHF Investigators (2013) Effects of carvedilol on heart failure with preserved ejection fraction: the Japanese diastolic heart failure study (J-DHF). Eur J Heart Fail 15:110–118

    Article  CAS  Google Scholar 

  26. Bristow MR, Gilbert EM, Abraham WT, Adams KF, Fowler MB, Hershberger RE, Kubo SH, Narahara KA, Ingersoll H, Krueger S, Young S, Shusterman N (1996) Carvedilol produces dose-related improvements in left ventricular function and survival in subjects with chronic heart failure. MOCHA Investigators. Circulation 94:2807–2816

    Article  CAS  Google Scholar 

  27. Fiuzat M, Wojdyla D, Kitzman D, Fleg J, Keteyian SJ, Kraus WE, Piña IL, Whellan D, O’Connor CM (2012) Relationship of beta-blocker dose with outcomes in ambulatory heart failure patients with systolic dysfunction. J Am Coll Cardiol 60:208–215

    Article  CAS  Google Scholar 

  28. Paolillo S, Mapelli M, Bonomi A, Corrà U, Piepoli M, Veglia F, Salvioni E, Gentile P, Lagioia R, Metra M, Limongelli G, Sinagra G, Cattadori G, Scardovi AB, Carubelli V, Scrutino D, Badagliacca R, Raimondo R, Emdin M, Magrì D, Correale M, Parati G, Caravita S, Spadafora E, Re F, Cicoira M, Frigerio M, Bussotti M, Minà C, Oliva F, Battaia E, Belardinelli R, Mezzani A, Pastormerlo L, Di Lenarda A, Passino C, Sciomer S, Iorio A, Zambon E, Guazzi M, Pacileo G, Ricci R, Contini M, Apostolo A, Palermo P, Clemenza F, Marchese G, Binno S, Lombardi C, Passantino A, Perrone Filardi P, Agostoni P (2017) Prognostic role of β-blocker selectivity and dosage regimens in heart failure patients. Insights from the MECKI score database. Eur J Heart Fail 19:904–914

    Article  CAS  Google Scholar 

  29. Okamoto H, Hori M, Matsuzaki M, Tsutsui H, Yamazaki T, Nagai R, Yoshikawa T, Fujio Y, Nonen S, Azuma J, Izumi T, Ohashi Y, Kitabatake A, J-CHF Investigators (2013) Minimal dose for effective clinical outcome and predictive factors for responsiveness to carvedilol: Japanese chronic heart failure (J-CHF) study. Int J Cardiol 164:238–244

    Article  Google Scholar 

  30. Pocock SJ, Wang D, Pfeffer MA, Yusuf S, McMurray JJ, Swedberg KB, Ostergren J, Michelson EL, Pieper KS, Granger CB (2006) Predictors of mortality and morbidity in patients with chronic heart failure. Eur Heart J 27:65–75

    Article  Google Scholar 

  31. McAlister FA, Wiebe N, Ezekowitz JA, Leung AA, Armstrong PW (2009) Meta-analysis: beta-blocker dose, heart rate reduction, and death in patients with heart failure. Ann Intern Med 150:784–794

    Article  Google Scholar 

  32. Cleland JG, Swedberg K, Follath F, Komajda M, Cohen-Solal A, Aguilar JC, Dietz R, Gavazzi A, Hobbs R, Korewicki J, Madeira HC, Moiseyev VS, Preda I, van Gilst WH, Widimsky J, Freemantle N, Eastaugh J, Mason J, Study Group on Diagnosis of the Working Group on Heart Failure of the European Society of Cardiology (2003) The EuroHeart failure survey programme—a survey on the quality of care among patients with heart failure in Europe. Part 1: patient characteristics and diagnosis. Eur Heart J 24:442–463

    Article  CAS  Google Scholar 

  33. Böhm M, Borer J, Ford I, Gonzalez-Juanatey JR, Komajda M, Lopez-Sendon J, Reil JC, Swedberg K, Tavazzi L (2013) Heart rate at baseline influences the effect of ivabradine on cardiovascular outcomes in chronic heart failure: analysis from the SHIFT study. Clin Res Cardiol 102:11–22

    Article  Google Scholar 

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Acknowledgements

We thank Ms. Emi Sawada for her assistance and project management.

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This research received no grant from any funding agency in the public, commercial or not-for-profit sectors.

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Authors and Affiliations

  1. Department of Cardiology, Tokyo Women’s Medical University, Tokyo, Japan

    Kimiko Nagara, Atsushi Suzuki, Tsuyoshi Shiga & Nobuhisa Hagiwara

  2. Department of Clinical Pharmacology and Therapeutics, The Jikei University School of Medicine, 3-25-8 Nishi-shinbashi, Minato-ku, Tokyo, 105-8461, Japan

    Tsuyoshi Shiga

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  1. Kimiko Nagara
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Correspondence to Tsuyoshi Shiga.

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Dr Shiga and Dr Hagiwara received research funding and lecture fees from Daiichi-Sankyo. The other authors have nothing to disclose.

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Nagara, K., Suzuki, A., Shiga, T. et al. Long-term outcome of carvedilol therapy in Japanese patients with nonischemic heart failure. Heart Vessels 35, 957–966 (2020). https://doi.org/10.1007/s00380-020-01560-w

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