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Effects of renin-angiotensin system blockade on mortality and hospitalization in heart failure with preserved ejection fraction

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Abstract

Heart failure with preserved ejection fraction (HF-PEF) is a well-recognized complication of long-standing hypertension. However, beyond the control of the traditional cardiovascular risk factors, there are few other recommendations for its management. To examine the potential benefit of renin-angiotensin system (RAS) inhibition in HF-PEF, we performed a systematic review of the published medical literature. MEDLINE, EMBASE, and COCHRANE databases were searched from 1966 to 2011 for longitudinal studies examining HF-PEF patients receiving treatment with RAS inhibitors, either ACE inhibitors (ACE-I) or angiotensin receptor blockers (ARB) in addition to their standard treatment compared to those receiving standard treatment alone. We examined the all-cause mortality, cardiovascular mortality, and hospitalizations for heart failure. A total of 12 studies with 11,259 participants were included in the analysis. Among the randomized clinical trials, with the use of RAS inhibitors over standard treatment, there was no improvement in all-cause mortality (RR: 0.99; 95 % CI: 0.88–1.12; p = 0.88), while there was a trend toward lowered rates of hospitalization (RR: 0.93; 95 % CI: 0.86–1.01; p = 0.08). There were no major differences in the outcomes between the ACE-I or ARB. However, among the observational studies with the use of RAS inhibitors, there was a significant benefit in all-cause mortality (RR: 0.76; 95 % CI: 0.62–0.93; p = 0.009), with no significant impact on the hospitalization rates. RAS inhibition in HF-PEF was not associated with significant reduction in all-cause or cardiovascular mortality, but randomized control trials appear to demonstrate a trend toward reduction in the risk for subsequent hospitalization. Further prospective randomized trials are warranted to confirm the effects of RAS inhibition on mortality and hospitalization.

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References

  1. 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(3):251–259. doi:10.1056/NEJMoa052256

    Article  PubMed  CAS  Google Scholar 

  2. 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(19):2338–2345. doi:10.1093/eurheartj/ehl250

    Article  PubMed  CAS  Google Scholar 

  3. Yusuf S, Pfeffer MA, Swedberg K, Granger CB, Held P, McMurray JJ, Michelson EL, Olofsson B, Ostergren J (2003) Effects of candesartan in patients with chronic heart failure and preserved left-ventricular ejection fraction: the CHARM-preserved trial. Lancet 362(9386):777–781. doi:10.1016/S0140-6736(03)14285-7

    Article  PubMed  CAS  Google Scholar 

  4. Massie BM, Carson PE, McMurray JJ, Komajda M, McKelvie R, Zile MR, Anderson S, Donovan M, Iverson E, Staiger C, Ptaszynska A (2008) Irbesartan in patients with heart failure and preserved ejection fraction. N Engl J Med 359(23):2456–2467. doi:10.1056/NEJMoa0805450

    Article  PubMed  CAS  Google Scholar 

  5. Yip GW, Wang M, Wang T, Chan S, Fung JW, Yeung L, Yip T, Lau ST, Lau CP, Tang MO, Yu CM, Sanderson JE (2008) The Hong Kong diastolic heart failure study: a randomised controlled trial of diuretics, irbesartan and ramipril on quality of life, exercise capacity, left ventricular global and regional function in heart failure with a normal ejection fraction. Heart 94(5):573–580. doi:10.1136/hrt.2007.117978

    Article  PubMed  CAS  Google Scholar 

  6. Zi M, Carmichael N, Lye M (2003) The effect of quinapril on functional status of elderly patients with diastolic heart failure. Cardiovasc Drugs Ther 17(2):133–139

    Article  PubMed  CAS  Google Scholar 

  7. Jadad AR, Moore RA, Carroll D, Jenkinson C, Reynolds DJ, Gavaghan DJ, McQuay HJ (1996) Assessing the quality of reports of randomized clinical trials: is blinding necessary? Control Clin Trials 17(1):1–12

    Article  PubMed  CAS  Google Scholar 

  8. Kjaergard LL, Villumsen J, Gluud C (2001) Reported methodologic quality and discrepancies between large and small randomized trials in meta-analyses. Ann Intern Med 135(11):982–989

    Article  PubMed  CAS  Google Scholar 

  9. DerSimonian R, Laird N (1986) Meta-analysis in clinical trials. Control Clin Trials 7(3):177–188

    Article  PubMed  CAS  Google Scholar 

  10. Demets DL (1987) Methods for combining randomized clinical trials: strengths and limitations. Stat Med 6(3):341–350

    Article  PubMed  CAS  Google Scholar 

  11. Higgins JP, Thompson SG (2002) Quantifying heterogeneity in a meta-analysis. Stat Med 21(11):1539–1558. doi:10.1002/sim.1186

    Article  PubMed  Google Scholar 

  12. Egger M, Davey Smith G, Schneider M, Minder C (1997) Bias in meta-analysis detected by a simple, graphical test. BMJ 315(7109):629–634

    Article  PubMed  CAS  Google Scholar 

  13. Duval S, Tweedie R (2000) Trim and fill: a simple funnel-plot-based method of testing and adjusting for publication bias in meta-analysis. Biometrics 56(2):455–463

    Article  PubMed  CAS  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(2 Pt 1):188–195

    Article  PubMed  CAS  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(8):605–613

    Article  PubMed  CAS  Google Scholar 

  16. Grigorian Shamagian L, 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(2):128–133. doi:10.1016/j.cardfail.2005.09.001

    Article  PubMed  CAS  Google Scholar 

  17. 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(5):639–644. doi:10.1016/j.amjcard.2007.10.026

    Article  PubMed  CAS  Google Scholar 

  18. 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(3):221–228. doi:10.1054/jcaf.2001.26896

    Article  PubMed  CAS  Google Scholar 

  19. 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(2):365–372

    Article  PubMed  Google Scholar 

  20. 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(3):363–365

    Article  PubMed  CAS  Google Scholar 

  21. Solomon SD, Dobson J, Pocock S, Skali H, McMurray JJ, Granger CB, Yusuf S, Swedberg K, Young JB, Michelson EL, Pfeffer MA (2007) Influence of nonfatal hospitalization for heart failure on subsequent mortality in patients with chronic heart failure. Circulation 116(13):1482–1487. doi:10.1161/CIRCULATIONAHA.107.696906

    Article  PubMed  Google Scholar 

  22. Melenovsky V, Borlaug BA, Rosen B, Hay I, Ferruci L, Morell CH, Lakatta EG, Najjar SS, Kass DA (2007) Cardiovascular features of heart failure with preserved ejection fraction versus nonfailing hypertensive left ventricular hypertrophy in the urban Baltimore community: the role of atrial remodeling/dysfunction. J Am Coll Cardiol 49(2):198–207. doi:10.1016/j.jacc.2006.08.050

    Article  PubMed  Google Scholar 

  23. Tartiere-Kesri L, Tartiere JM, Logeart D, Beauvais F, Cohen Solal A (2012) Increased proximal arterial stiffness and cardiac response with moderate exercise in patients with heart failure and preserved ejection fraction. J Am Coll Cardiol 59(5):455–461. doi:10.1016/j.jacc.2011.10.873

    Article  PubMed  Google Scholar 

  24. Yamamoto K, Masuyama T, Sakata Y, Mano T, Nishikawa N, Kondo H, Akehi N, Kuzuya T, Miwa T, Hori M (2000) Roles of renin-angiotensin and endothelin systems in development of diastolic heart failure in hypertensive hearts. Cardiovasc Res 47(2):274–283

    Article  PubMed  CAS  Google Scholar 

  25. Tropeano AI, Boutouyrie P, Pannier B, Joannides R, Balkestein E, Katsahian S, Laloux B, Thuillez C, Struijker-Boudier H, Laurent S (2006) Brachial pressure-independent reduction in carotid stiffness after long-term angiotensin-converting enzyme inhibition in diabetic hypertensives. Hypertension 48(1):80–86. doi:10.1161/01.HYP.0000224283.76347.8c

    Article  PubMed  CAS  Google Scholar 

  26. Packer M (2011) Can brain natriuretic peptide be used to guide the management of patients with heart failure and a preserved ejection fraction? The wrong way to identify new treatments for a nonexistent disease. Circ Heart Fail 4(5):538–540. doi:10.1161/CIRCHEARTFAILURE.111.963710

    Article  PubMed  Google Scholar 

  27. Paulus WJ, Tschope C, Sanderson JE, Rusconi C, Flachskampf FA, Rademakers FE, Marino P, Smiseth OA, De Keulenaer G, Leite-Moreira AF, Borbely A, Edes I, Handoko ML, Heymans S, Pezzali N, Pieske B, Dickstein K, Fraser AG, Brutsaert DL (2007) How to diagnose diastolic heart failure: a consensus statement on the diagnosis of heart failure with normal left ventricular ejection fraction by the heart failure and echocardiography associations of the european society of cardiology. Eur Heart J 28(20):2539–2550. doi:10.1093/eurheartj/ehm037

    Article  PubMed  Google Scholar 

  28. Nagueh SF, Appleton CP, Gillebert TC, Marino PN, Oh JK, Smiseth OA, Waggoner AD, Flachskampf FA, Pellikka PA, Evangelista A (2009) Recommendations for the evaluation of left ventricular diastolic function by echocardiography. J Am Soc Echocardiogr 22(2):107–133. doi:10.1016/j.echo.2008.11.023

    Article  PubMed  Google Scholar 

  29. Rosendorff C, Black HR, Cannon CP, Gersh BJ, Gore J, Izzo JL Jr, Kaplan NM, O’Connor CM, O’Gara PT, Oparil S (2007) Treatment of hypertension in the prevention and management of ischemic heart disease: a scientific statement from the American Heart Association Council for High Blood Pressure Research and the councils on clinical cardiology and epidemiology and prevention. Circulation 115(21):2761–2788. doi:10.1161/CIRCULATIONAHA.107.183885

    Article  PubMed  Google Scholar 

  30. Lee TT, Chen J, Cohen DJ, Tsao L (2006) The association between blood pressure and mortality in patients with heart failure. Am Heart J 151(1):76–83. doi:10.1016/j.ahj.2005.03.009

    Article  PubMed  Google Scholar 

  31. Ather S, Chan W, Chillar A, Aguilar D, Pritchett AM, Ramasubbu K, Wehrens XH, Deswal A, Bozkurt B (2011) Association of systolic blood pressure with mortality in patients with heart failure with reduced ejection fraction: a complex relationship. Am Heart J 161(3):567–573. doi:10.1016/j.ahj.2010.12.009

    Article  PubMed  Google Scholar 

  32. Lee DS, Ghosh N, Floras JS, Newton GE, Austin PC, Wang X, Liu PP, Stukel TA, Tu JV (2009) Association of blood pressure at hospital discharge with mortality in patients diagnosed with heart failure. Circ Heart Fail 2(6):616–623. doi:10.1161/CIRCHEARTFAILURE.109.869743

    Article  PubMed  Google Scholar 

  33. Nunez J, Nunez E, Fonarow GC, Sanchis J, Bodi V, Bertomeu-Gonzalez V, Minana G, Merlos P, Bertomeu-Martinez V, Redon J, Chorro FJ, Llacer A (2010) Differential prognostic effect of systolic blood pressure on mortality according to left-ventricular function in patients with acute heart failure. Eur J Heart Fail 12(1):38–44. doi:10.1093/eurjhf/hfp176

    Article  PubMed  Google Scholar 

  34. Schwartzenberg S, Redfield MM, From AM, Sorajja P, Nishimura RA, Borlaug BA (2012) Effects of vasodilation in heart failure with preserved or reduced ejection fraction implications of distinct pathophysiologies on response to therapy. J Am Coll Cardiol 59(5):442–451. doi:10.1016/j.jacc.2011.09.062

    Article  PubMed  Google Scholar 

  35. Desai AS, Lewis EF, Li R, Solomon SD, Assmann SF, Boineau R, Clausell N, Diaz R, Fleg JL, Gordeev I, McKinlay S, O’Meara E, Shaburishvili T, Pitt B, Pfeffer MA (2011) Rationale and design of the treatment of preserved cardiac function heart failure with an aldosterone antagonist trial: a randomized, controlled study of spironolactone in patients with symptomatic heart failure and preserved ejection fraction. Am Heart J 162(6):966–972 e910. doi:10.1016/j.ahj.2011.09.007

    Google Scholar 

  36. Edelmann F, Schmidt AG, Gelbrich G, Binder L, Herrmann-Lingen C, Halle M, Hasenfuss G, Wachter R, Pieske B (2010) Rationale and design of the ‘aldosterone receptor blockade in diastolic heart failure’ trial: a double-blind, randomized, placebo-controlled, parallel group study to determine the effects of spironolactone on exercise capacity and diastolic function in patients with symptomatic diastolic heart failure (Aldo-DHF). Eur J Heart Fail 12(8):874–882. doi:10.1093/eurjhf/hfq087

    Article  PubMed  CAS  Google Scholar 

  37. Schulz KF, Chalmers I, Hayes RJ, Altman DG (1995) Empirical evidence of bias. Dimensions of methodological quality associated with estimates of treatment effects in controlled trials. JAMA 273(5):408–412

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

Franz Messerli has served as an ad hoc consultant for Novartis, Boehringer Ingelheim, Daiichi Sankyo, Sanofi, and Takeda and has received research funding and grants from Novartis, Boehringer Ingelheim, and Forest.

Conflict of interest

Vikram Agarwal: no relationships to disclose. Alexandros Briasoulis: no relationships to disclose

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Authors and Affiliations

  1. Department of Medicine, St Luke’s Roosevelt Hospital Center, Columbia University College of Physicians and Surgeons, New York, NY, USA

    Vikram Agarwal & Alexandros Briasoulis

  2. Hypertension Program, Department of Cardiology, St Luke’s Roosevelt Hospital Center, Columbia University College of Physicians and Surgeons, 1000 10th Avenue, Suite 3B-30, New York, NY, 10019, USA

    Franz H. Messerli

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  1. Vikram Agarwal
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Correspondence to Franz H. Messerli.

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Agarwal, V., Briasoulis, A. & Messerli, F.H. Effects of renin-angiotensin system blockade on mortality and hospitalization in heart failure with preserved ejection fraction. Heart Fail Rev 18, 429–437 (2013). https://doi.org/10.1007/s10741-012-9329-8

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