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Effect of renin-angiotensin system inhibitors on mortality in heart failure with preserved ejection fraction: a meta-analysis of observational cohort and randomized controlled studies

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Abstract

Despite the high mortality rate, there is no therapy to improve survival in heart failure with preserved ejection fraction (HFpEF). Large randomized controlled trials (RCTs) did not show clear mortality benefit of renin-angiotensin system (RAS) inhibitors (angiotensin-converting enzyme inhibitors or angiotensin receptor blockers) in HFpEF. However, because of the strict enrollment criteria, the patients who participated in these trials might represent a selected group of patients that is poorly representative of patients treated in routine clinical practice. In contrast, clinical characteristics of real-world patients are similar to those of patients enrolled in observational cohort studies (OCSs). Although many OCSs have examined the prognostic effect of RAS inhibitors in HFpEF, the results are inconsistent due to limited power with small sample sizes and/or inadequate adjustment for known prognostic factors. We aimed to conduct a meta-analysis of OCSs with and those without propensity score (PS) analysis and RCTs on the effect of RAS inhibitors on mortality in HFpEF patients. The search of electronic databases identified 4 OCSs with PS analysis (10,164 patients), 8 OCSs without PS analysis (16,393 patients), and 3 RCTs (8001 patients). Use of RAS inhibitors was associated with reduced mortality in the pooled analysis of OCSs with PS analysis (RR [95% CI] = 0.90 [0.81–1.00]) and in that of OCSs without PS analysis (0.81 [0.68–0.96]) but not in that of RCTs (0.99 [0.87–1.12]). In conclusion, the present meta-analysis suggests the potential mortality benefit of RAS inhibitors in HFpEF, emphasizing the importance of conducting new well-designed RCTs.

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References

  1. Vasan RS, Larson MG, Benjamin EJ, Evans JC, Reiss CK, Levy D (1999) Congestive heart failure in subjects with normal versus reduced left ventricular ejection fraction: prevalence and mortality in a population-based cohort. J Am Coll Cardiol 33:1948–1955

    Article  CAS  PubMed  Google Scholar 

  2. Owan TE, Hodge DO, Herges RM, Jacobsen SJ, Roger VL, Redfield MM (2006) Trends in prevalence and outcome of heart failure with preserved ejection fraction. N Engl J Med 355:251–259

    Article  CAS  PubMed  Google Scholar 

  3. Tsuchihashi-Makaya M, Hamaguchi S, Kinugawa S et al (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  PubMed  Google Scholar 

  4. Yusuf S, Pfeffer MA, Swedberg K et al (2003) Effects of candesartan in patients with chronic heart failure and preserved left-ventricular ejection fraction: the CHARM-preserved trial. Lancet 362:777–781

    Article  CAS  PubMed  Google Scholar 

  5. Massie BM, Carson PE, McMurray JJ et al (2008) Irbesartan in patients with heart failure and preserved ejection fraction. N Engl J Med 359:2456–2467

    Article  CAS  PubMed  Google Scholar 

  6. Cleland JG, Tendera M, Adamus J, Freemantle N, Polonski L, Taylor J (2006) The perindopril in elderly people with chronic heart failure (PEP-CHF) study. Eur Heart J 27:2338–2345

    Article  CAS  PubMed  Google Scholar 

  7. Pitt B, Pfeffer MA, Assmann SF et al (2014) Spironolactone for heart failure with preserved ejection fraction. N Engl J Med 370:1383–1392

    Article  CAS  PubMed  Google Scholar 

  8. Yamamoto K, Origasa H, Hori M (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  PubMed  Google Scholar 

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

  10. The SOLVD investigators (1991) Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure. N Engl J Med 325:293–302

  11. Granger CB, McMurray JJ, Yusuf S et al (2003) Effects of candesartan in patients with chronic heart failure and reduced left-ventricular systolic function intolerant to angiotensin-converting-enzyme inhibitors: the CHARM-Alternative trial. Lancet 362:772–776

    Article  CAS  PubMed  Google Scholar 

  12. Hogg K, McMurray J (2005) Neurohumoral pathways in heart failure with preserved systolic function. Prog Cardiovasc Dis 47:357–366

    Article  CAS  PubMed  Google Scholar 

  13. Mentz RJ, Kelly JP, von Lueder TG et al (2014) Noncardiac comorbidities in heart failure with reduced versus preserved ejection fraction. J Am Coll Cardiol 64:2281–2293

    Article  PubMed  PubMed Central  Google Scholar 

  14. Philbin EF, Rocco TA Jr (1997) Use of angiotensin-converting enzyme inhibitors in heart failure with preserved left ventricular systolic function. Am Heart J 134:188–195

    Article  CAS  PubMed  Google Scholar 

  15. Philbin EF, Rocco TA Jr, Lindenmuth NW, Ulrich K, Jenkins PL (2000) Systolic versus diastolic heart failure in community practice: clinical features, outcomes, and the use of angiotensin-converting enzyme inhibitors. Am J Med 109:605–613

    Article  CAS  PubMed  Google Scholar 

  16. Dauterman KW, Go AS, Rowell R, Gebretsadik T, Gettner S, Massie BM (2001) Congestive heart failure with preserved systolic function in a statewide sample of community hospitals. J Card Fail 7:221–228

    Article  CAS  PubMed  Google Scholar 

  17. Ahmed A, Roseman JM, Duxbury AS, Allman RM, DeLong JF (2002) Correlates and outcomes of preserved left ventricular systolic function among older adults hospitalized with heart failure. Am Heart J 144:365–372

    Article  PubMed  Google Scholar 

  18. Sueta CA, Russo A, Schenck A, Brown DW, Simpson RJ (2003) Effect of angiotensin-converting inhibitor or angiotensin receptor blocker on one-year survival in patients > or =65 years hospitalized with a left ventricular ejection fraction > or =50%. Am J Cardiol 91:363–365

    Article  CAS  PubMed  Google Scholar 

  19. Fukuta H, Sane DC, Brucks S, Little WC (2005) Statin therapy may be associated with lower mortality in patients with diastolic heart failure: a preliminary report. Circulation 112:357–363

    Article  CAS  PubMed  Google Scholar 

  20. Chan JD, Rea TD, Smith NL et al (2005) Association of beta-blocker use with mortality among patients with congestive heart failure in the Cardiovascular Health Study (CHS). Am Heart J 150:464–470

    Article  CAS  PubMed  Google Scholar 

  21. Shah R, Wang Y, Foody JM (2008) Effect of statins, angiotensin-converting enzyme inhibitors, and beta blockers on survival in patients > or =65 years of age with heart failure and preserved left ventricular systolic function. Am J Cardiol 101:217–222

    Article  CAS  PubMed  Google Scholar 

  22. D’Agostino RB Jr (2007) Propensity scores in cardiovascular research. Circulation 115:2340–2343

    Article  PubMed  Google Scholar 

  23. Martens EP, Pestman WR, De, BA, Belitser SV, Klungel OH. Systematic differences in treatment effect estimates between propensity score methods and logistic regression. Int J Epidemiol 2008;37:1142–1147

  24. Moher D, Liberati A, Tetzlaff J, Altman DG (2009) Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. Ann Intern Med 151:264–269 W64

    Article  PubMed  Google Scholar 

  25. Stroup DF, Berlin JA, Morton SC et al (2000) Meta-analysis of observational studies in epidemiology: a proposal for reporting. Meta-analysis Of Observational Studies in Epidemiology (MOOSE) group. JAMA 283:2008–2012

    Article  CAS  PubMed  Google Scholar 

  26. Jadad AR, Moore RA, Carroll D et al (1996) Assessing the quality of reports of randomized clinical trials: is blinding necessary? Control Clin Trials 17:1–12

    Article  CAS  PubMed  Google Scholar 

  27. Higgins JP, Thompson SG, Deeks JJ, Altman DG (2003) Measuring inconsistency in meta-analyses. BMJ 327:557–560

    Article  PubMed  PubMed Central  Google Scholar 

  28. Tribouilloy C, Rusinaru D, Leborgne L, Peltier M, Massy Z, Slama M (2008) Prognostic impact of angiotensin-converting enzyme inhibitor therapy in diastolic heart failure. Am J Cardiol 101:639–644

    Article  CAS  PubMed  Google Scholar 

  29. Patel K, Fonarow GC, Kitzman DW et al (2012) Angiotensin receptor blockers and outcomes in real-world older patients with heart failure and preserved ejection fraction: a propensity-matched inception cohort clinical effectiveness study. Eur J Heart Fail 14:1179–1188

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Lund LH, Benson L, Dahlstrom U, Edner M (2012) Association between use of renin-angiotensin system antagonists and mortality in patients with heart failure and preserved ejection fraction. JAMA 308:2108–2117

    Article  CAS  PubMed  Google Scholar 

  31. Mujib M, Patel K, Fonarow GC et al (2013) Angiotensin-converting enzyme inhibitors and outcomes in heart failure and preserved ejection fraction. Am J Med 126:401–410

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Grigorian SL, Roman AV, Ramos PM, Veloso PR, Bandin Dieguez MA, Gonzalez-Juanatey JR (2006) Angiotensin-converting enzyme inhibitors prescription is associated with longer survival among patients hospitalized for congestive heart failure who have preserved systolic function: a long-term follow-up study. J Card Fail 12:128–133

    Article  Google Scholar 

  33. Agarwal V, Briasoulis A, Messerli FH (2013) Effects of renin-angiotensin system blockade on mortality and hospitalization in heart failure with preserved ejection fraction. Heart Fail Rev 18:429–437

    Article  CAS  PubMed  Google Scholar 

  34. Sakata Y, Yamamoto K, Mano T et al (2003) Angiotensin II type 1 receptor blockade prevents diastolic heart failure through modulation of Ca(2+) regulatory proteins and extracellular matrix. J Hypertens 21:1737–1745

    Article  CAS  PubMed  Google Scholar 

  35. Yamamoto K, Mano T, Yoshida J et al (2005) ACE inhibitor and angiotensin II type 1 receptor blocker differently regulate ventricular fibrosis in hypertensive diastolic heart failure. J Hypertens 23:393–400

    Article  CAS  PubMed  Google Scholar 

  36. Klingbeil AU, Schneider M, Martus P, Messerli FH, Schmieder RE (2003) A meta-analysis of the effects of treatment on left ventricular mass in essential hypertension. Am J Med 115:41–46

    Article  PubMed  Google Scholar 

  37. Zile MR, Brutsaert DL (2002) New concepts in diastolic dysfunction and diastolic heart failure: part II: causal mechanisms and treatment. Circulation 105:1503–1508

    Article  PubMed  Google Scholar 

  38. Aurigemma GP, Gaasch WH (2004) Clinical practice. Diastolic heart failure. N Engl J Med 351:1097–1105

    Article  CAS  PubMed  Google Scholar 

  39. Redfield MM (2004) Understanding “diastolic” heart failure. N Engl J Med 350:1930–1931

    Article  CAS  PubMed  Google Scholar 

  40. Zieman SJ, Melenovsky V, Kass DA (2005) Mechanisms, pathophysiology, and therapy of arterial stiffness. Arterioscler Thromb Vasc Biol 25:932–943

    Article  CAS  PubMed  Google Scholar 

  41. O’Rourke MF. Diastolic heart failure, diastolic left ventricular dysfunction and exercise intolerance. J Am Coll Cardiol 2001;38:803–805

  42. Kass DA, Bronzwaer JG, Paulus WJ (2004) What mechanisms underlie diastolic dysfunction in heart failure? Circ Res 94:1533–1542

    Article  CAS  PubMed  Google Scholar 

  43. Sutton MG, Sharpe N (2000) Left ventricular remodeling after myocardial infarction: pathophysiology and therapy. Circulation 101:2981–2988

    Article  CAS  PubMed  Google Scholar 

  44. Chaugai S, Sherpa LY, Sepehry AA, Arima H, Wang DW (2016) Effect of RAAS blockers on adverse clinical outcomes in high CVD risk subjects with atrial fibrillation: a meta-analysis and systematic review of randomized controlled trials. Medicine (Baltimore) 95:e4059

    Article  CAS  Google Scholar 

  45. Olsson LG, Swedberg K, Ducharme A et al (2006) Atrial fibrillation and risk of clinical events in chronic heart failure with and without left ventricular systolic dysfunction: results from the Candesartan in Heart failure-Assessment of Reduction in Mortality and morbidity (CHARM) program. J Am Coll Cardiol 47:1997–2004

    Article  PubMed  Google Scholar 

  46. Schneider MP, Hua TA, Bohm M, Wachtell K, Kjeldsen SE, Schmieder RE (2010) Prevention of atrial fibrillation by renin-angiotensin system inhibition a meta-analysis. J Am Coll Cardiol 55:2299–2307

    Article  PubMed  Google Scholar 

  47. Jones WS, Roe MT, Antman EM et al (2016) The changing landscape of randomized clinical trials in cardiovascular disease. J Am Coll Cardiol 68:1898–1907

    Article  PubMed  Google Scholar 

  48. Solomon SD, Wang D, Finn P et al (2004) Effect of candesartan on cause-specific mortality in heart failure patients: the Candesartan in Heart failure Assessment of Reduction in Mortality and morbidity (CHARM) program. Circulation 110:2180–2183

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Cardio-Renal Medicine and Hypertension, Nagoya City University Graduate School of Medical Sciences, 1 Kawasumi Mizuho-cho Mizuho-ku, Nagoya, 467-8601, Japan

    Hidekatsu Fukuta, Toshihiko Goto, Kazuaki Wakami & Nobuyuki Ohte

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  1. Hidekatsu Fukuta
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  2. Toshihiko Goto
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  3. Kazuaki Wakami
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  4. Nobuyuki Ohte
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Correspondence to Hidekatsu Fukuta.

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This paper is not funded by any external source.

Conflict of interest

Dr. Ohte has received lecture fees from Takeda Pharmaceutical Co., Ltd., Daiichi Sankyo Co., Ltd., and Boehringer Ingelheim and grant support from Takeda Pharmaceutical Co., Ltd., Daiichi Sankyo Co., Ltd., MSD, Astellas Pharma Inc., and Otsuka Pharmaceutical Co., Ltd. No other disclosures were reported.

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This article does not contain any studies with human participants performed by any of the authors.

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Fukuta, H., Goto, T., Wakami, K. et al. Effect of renin-angiotensin system inhibitors on mortality in heart failure with preserved ejection fraction: a meta-analysis of observational cohort and randomized controlled studies. Heart Fail Rev 22, 775–782 (2017). https://doi.org/10.1007/s10741-017-9637-0

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