Pharmacological treatments for heart failure with preserved ejection fraction—a systematic review and indirect comparison
- 429 Downloads
Abstract
Pharmacological interventions for heart failure with preserved ejection fraction (HFpEF) have failed to reduce mortality and hospitalization. Evidence for mineralocorticoid antagonists (MRAs), β-adrenoceptor blockers (β-blockers), and angiotensin-converting enzyme inhibitors/angiotensin receptor blockers (ACEIs/ARBs)–to reduce clinical outcomes in HFpEF remains unclear. We conducted a systematic search of MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, and Clinical Trials.gov for randomized controlled trials (RCTs) assessing pharmacological treatments in HFpEF diagnosed according the recommendations of the European Society of Cardiology (ESC) 2016 guidelines from inception to August, 2017. The study outcomes were mortality, hospitalization, changes in indexes of cardiac structure and function, biomarkers, and indexes of functional capacity—quality of life (QoL) assessment and 6-min walk distance test (6-MWD). The random-effects models were used to estimate pooled relative risks (RRs) for the binary outcomes and standardized mean differences for continuous outcomes, with 95% CI. A network meta-analysis using a random-effects model was employed to estimate the comparative efficacy of treatments. We included data from 15 RCTs comprising 5930 patients. There was no significant effect seen with all treatments compared with placebo and comparative efficacy of any two treatments on all outcomes assessed. However, mineralocorticoid antagonist spironolactone demonstrated a trend towards reducing mortality compared with placebo (RR 0.92; 95% CI 0.79–1.08), sildenafil (0.14; 0.01–2.78), perindopril (0.87; 0.59–1.28), and eplerenone (0.91; 0.25–3.33). Similar trends in treatment effect were observed with spironolactone on surrogate outcomes while eplerenone demonstrated a trend of superior effect in reduction of hospitalizations compared with all other drug treatment. No drug treatment demonstrated statistically significant improvement in clinical and surrogate outcomes in HFpEF diagnosed according to the ESC 2016 guideline. Spironolactone and eplerenone showed clinically relevant reduction in mortality and hospitalization respectively compared with other drug treatments. Further trials with MRAs are warranted to confirm treatment effects in HFpEF.
Keywords
Heart failure Preserved ejection fraction Pharmacological treatment Meta-analysisNotes
Author contributions
All authors conceived and designed the study. KOB and NC wrote the protocol. KOB and PA wrote the first draft. KOB and NC contributed substantially to the interpretation of the data and critical revision of the manuscript. KOB and PA screened, extracted the data and perform the quality assessment. KOB and NC have access to all the data in the study, analyzed the data and take responsibility for the integrity of the data and the accuracy of the analysis.
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest.
Ethical approval
Not required.
Supplementary material
References
- 1.Mozaffarian D, Benjamin EJ, Go AS, Arnett DK, Blaha MJ, Cushman M, Das SR, de Ferranti S, Despres JP, Fullerton HJ et al (2016) Heart disease and stroke Statistics-2016 update: a report from the American Heart Association. Circulation 133(4):e38–e360CrossRefPubMedGoogle Scholar
- 2.Ponikowski P, Voors AA, Anker SD, Bueno H, Cleland JGF, Coats AJS, Falk V, González-Juanatey JR, Harjola V-P, Jankowska EA et al (2016) 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failureThe 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(27):2129–2200CrossRefPubMedGoogle Scholar
- 3.Lam CSP, Donal E, Kraigher-Krainer E, Vasan RS (2011) Epidemiology and clinical course of heart failure with preserved ejection fraction. Eur J Heart Fail 13(1):18–28. https://doi.org/10.1093/eurjhf/hfq121 CrossRefPubMedGoogle Scholar
- 4.Santas E, Valero E, Mollar A, García-Blas S, Palau P, Miñana G, Núñez E, Sanchis J, Chorro FJ, Núñez J (2017) Burden of recurrent hospitalizations following an admission for acute heart failure: preserved versus reduced ejection fraction. Rev Esp Cardiol (English Edition) 70(04):239–246Google Scholar
- 5.Steinberg BA, Zhao X, Heidenreich PA, Peterson ED, Bhatt DL, Cannon CP, Hernandez AF, Fonarow GC (2012) Trends in patients hospitalized with heart failure and preserved left ventricular ejection fraction: prevalence, therapies, and outcomes. Circulation 126(1):65–75. https://doi.org/10.1161/CIRCULATIONAHA.111.080770 CrossRefPubMedGoogle Scholar
- 6.Lenzen MJ, Scholte op Reimer WJ, Boersma E, Vantrimpont PJ, Follath F, Swedberg K, Cleland J, Komajda M (2004) Differences between patients with a preserved and a depressed left ventricular function: a report from the EuroHeart Failure Survey. Eur Heart J 25(14):1214–1220. https://doi.org/10.1016/j.ehj.2004.06.006 CrossRefPubMedGoogle Scholar
- 7.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. https://doi.org/10.1056/NEJMoa052256 CrossRefPubMedGoogle Scholar
- 8.Borlaug BA, Paulus WJ (2011) Heart failure with preserved ejection fraction: pathophysiology, diagnosis, and treatment. Eur Heart J 32(6):670–679. https://doi.org/10.1093/eurheartj/ehq426 CrossRefPubMedGoogle Scholar
- 9.Japp AG, Gulati A, Cook SA, Cowie MR, Prasad SK (2016) The diagnosis and evaluation of dilated cardiomyopathy. J Am Coll Cardiol 67(25):2996–3010. https://doi.org/10.1016/j.jacc.2016.03.590 CrossRefPubMedGoogle Scholar
- 10.Kalogeropoulos AP, Fonarow GC, Georgiopoulou V, Burkman G, Siwamogsatham S, Patel A, Li S, Papadimitriou L, Butler J (2016) Characteristics and outcomes of adult outpatients with heart failure and improved or recovered ejection fraction. JAMA Cardiol 1(5):510–518. https://doi.org/10.1001/jamacardio.2016.1325 CrossRefPubMedGoogle Scholar
- 11.Shah AM, Claggett B, Sweitzer NK, Shah SJ, Anand IS, O'Meara E, Desai AS, Heitner JF, Li G, Fang J, Rouleau J, Zile MR, Markov V, Ryabov V, Reis G, Assmann SF, McKinlay SM, Pitt B, Pfeffer MA, Solomon SD (2014) Cardiac structure and function and prognosis in heart failure with preserved ejection fraction: findings from the echocardiographic study of the Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist (TOPCAT) Trial. Circ Heart Fail 7(5):740–751. https://doi.org/10.1161/CIRCHEARTFAILURE.114.001583 CrossRefPubMedPubMedCentralGoogle Scholar
- 12.Shah AM, Claggett B, Sweitzer NK, Shah SJ, Anand IS, Liu L, Pitt B, Pfeffer MA, Solomon SD (2015) Prognostic importance of impaired systolic function in heart failure with preserved ejection fraction and the impact of spironolactone. Circulation 132(5):402–414. https://doi.org/10.1161/CIRCULATIONAHA.115.015884 CrossRefPubMedPubMedCentralGoogle Scholar
- 13.Gheorghiade M, Vaduganathan M, Greene SJ, Mentz RJ, Adams KF, Anker SD, Arnold M, Baschiera F, Cleland JGF, Cotter G, Fonarow GC, Giordano C, Metra M, Misselwitz F, Mühlhofer E, Nodari S, Frank Peacock W, Pieske BM, Sabbah HN, Sato N, Shah MR, Stockbridge NL, Teerlink JR, van Veldhuisen DJ, Zalewski A, Zannad F, Butler J (2014) Site selection in global clinical trials in patients hospitalized for heart failure: perceived problems and potential solutions. Heart Fail Rev 19(2):135–152. https://doi.org/10.1007/s10741-012-9361-8 CrossRefPubMedPubMedCentralGoogle Scholar
- 14.Oktay AA, Sanjiv JS (2015) Diagnosis and management of heart failure with preserved ejection fraction: 10 key lessons. Curr Cardiol Rev 11(1):42–52CrossRefPubMedGoogle Scholar
- 15.Mills EJ, Thorlund K, Ioannidis JPA (2013) Demystifying trial networks and network meta-analysis. BMJ 346:f2194CrossRefGoogle Scholar
- 16.Li T, Puhan MA, Vedula SS, Singh S, Dickersin K (2011) Network meta-analysis-highly attractive but more methodological research is needed. BMC Med 9(1):1–5CrossRefGoogle Scholar
- 17.Whiting P, Savović J, Higgins JPT, Caldwell DM, Reeves BC, Shea B, Davies P, Kleijnen J, Churchill R (2016) ROBIS: a new tool to assess risk of bias in systematic reviews was developed. J Clin Epidemiol 69:225–234CrossRefPubMedPubMedCentralGoogle Scholar
- 18.Chaimani A, Higgins JP, Mavridis D, Spyridonos P, Salanti G (2013) Graphical tools for network meta-analysis in STATA. PLoS One 8(10):e76654. https://doi.org/10.1371/journal.pone.0076654 CrossRefPubMedPubMedCentralGoogle Scholar
- 19.Salanti G, Ades AE, Ioannidis JP (2011) Graphical methods and numerical summaries for presenting results from multiple-treatment meta-analysis: an overview and tutorial. J Clin Epidemiol 64(2):163–171. https://doi.org/10.1016/j.jclinepi.2010.03.016 CrossRefPubMedGoogle Scholar
- 20.Higgins JP, Jackson D, Barrett JK, Lu G, Ades AE, White IR (2012) Consistency and inconsistency in network meta-analysis: concepts and models for multi-arm studies. Res Synth Methods 3(2):98–110. https://doi.org/10.1002/jrsm.1044 CrossRefPubMedPubMedCentralGoogle Scholar
- 21.Donegan S, Williamson P, D'Alessandro U, Tudur Smith C (2013) Assessing key assumptions of network meta-analysis: a review of methods. Res Synth Methods 4(4):291–323. https://doi.org/10.1002/jrsm.1085 CrossRefPubMedGoogle Scholar
- 22.Egger M, Davey Smith G, Schneider M, Minder C (1997) Bias in meta-analysis detected by a simple, graphical test. BMJ (Clin Res ed) 315(7109):629–634CrossRefGoogle Scholar
- 23.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 (London, England) 362(9386):777–781. https://doi.org/10.1016/S0140-6736(03)14285-7 CrossRefGoogle Scholar
- 24.Mottram PM, Haluska B, Leano R, Cowley D, Stowasser M, Marwick TH (2004) Effect of aldosterone antagonism on myocardial dysfunction in hypertensive patients with diastolic heart failure. Circulation 110(5):558–565. https://doi.org/10.1161/01.CIR.0000138680.89536.A9 CrossRefPubMedGoogle Scholar
- 25.Deswal A, Richardson P, Bozkurt B, Mann DL (2011) Results of the Randomized Aldosterone Antagonism in Heart Failure with Preserved Ejection Fraction trial (RAAM-PEF). J Card Fail 17(8):634–642. https://doi.org/10.1016/j.cardfail.2011.04.007 CrossRefPubMedGoogle Scholar
- 26.Kurrelmeyer KM, Ashton Y, Xu J, Nagueh SF, Torre-Amione G, Deswal A (2014) Effects of spironolactone treatment in elderly women with heart failure and preserved left ventricular ejection fraction. J Card Fail 20(8):560–568. https://doi.org/10.1016/j.cardfail.2014.05.010 CrossRefPubMedGoogle Scholar
- 27.Pitt B, Pfeffer MA, Assmann SF, Boineau R, Anand IS, Claggett B, Clausell N, Desai AS, Diaz R, Fleg JL et al (2014) Spironolactone for heart failure with preserved ejection fraction. N Engl J Med 370(15):1383–1392. https://doi.org/10.1056/NEJMoa1313731 CrossRefPubMedGoogle Scholar
- 28.Edelmann F, Wachter R, Schmidt AG, Kraigher-Krainer E, Colantonio C, Kamke W, Duvinage A, Stahrenberg R, Durstewitz K, Loffler M et al (2013) Effect of spironolactone on diastolic function and exercise capacity in patients with heart failure with preserved ejection fraction: the Aldo-DHF randomized controlled trial. JAMA 309(8):781–791. https://doi.org/10.1001/jama.2013.905 CrossRefPubMedGoogle Scholar
- 29.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. https://doi.org/10.1093/eurheartj/ehl250 CrossRefPubMedGoogle Scholar
- 30.Kitzman DW, Hundley WG, Brubaker PH, Morgan TM, Moore JB, Stewart KP, Little WC (2010) A randomized double-blind trial of enalapril in older patients with heart failure and preserved ejection fraction: effects on exercise tolerance and arterial distensibility. Circ Heart Fail 3(4):477–485. https://doi.org/10.1161/CIRCHEARTFAILURE.109.898916 CrossRefPubMedPubMedCentralGoogle Scholar
- 31.Aronow WS, Kronzon I (1993) Effect of enalapril on congestive heart failure treated with diuretics in elderly patients with prior myocardial infarction and normal left ventricular ejection fraction. Am J Cardiol 71(7):602–604. https://doi.org/10.1016/0002-9149(93)90520-M CrossRefPubMedGoogle Scholar
- 32.Liu Gang JZ, Shen LK (2006) Spironolactone in the treatment of elderly patients with hypertension and diastolic heart failure. Chin J New Drugs Clin Remedies 25(8):567–570Google Scholar
- 33.Hung MJ, Cherng WJ, Kuo LT, Wang CH (2002) Effect of verapamil in elderly patients with left ventricular diastolic dysfunction as a cause of congestive heart failure. Int J Clin Pract 56(1):57–62PubMedGoogle Scholar
- 34.Kampourides N, Tziakas D, Chalikias G, Papazoglou D, Maltezos E, Symeonides D, Konstantinides S (2012) Usefulness of matrix metalloproteinase-9 plasma levels to identify patients with preserved left ventricular systolic function after acute myocardial infarction who could benefit from eplerenone. Am J Cardiol 110(8):1085–1091CrossRefPubMedGoogle Scholar
- 35.Redfield MM, Chen HH, Borlaug BA, Semigran MJ, Lee KL, Lewis G, MM LW, Rouleau JL, Bull DA, Mann DL et al (2013) Effect of phosphodiesterase-5 inhibition on exercise capacity and clinical status in heart failure with preserved ejection fraction: a randomized clinical trial. JAMA 309(12):1268–1277. https://doi.org/10.1001/jama.2013.2024 CrossRefPubMedGoogle Scholar
- 36.Zile MR, Bourge RC, Redfield MM, Zhou D, Baicu CF, Little WC (2014) Randomized, double-blind, placebo-controlled study of sitaxsentan to improve impaired exercise tolerance in patients with heart failure and a preserved ejection fraction. JACC Heart Fail 2(2):123–130. https://doi.org/10.1016/j.jchf.2013.12.002 CrossRefPubMedGoogle Scholar
- 37.Kosmala W, Rojek A, Przewlocka-Kosmala M, Wright L, Mysiak A, Marwick TH (2016) Effect of aldosterone antagonism on exercise tolerance in heart failure with preserved ejection fraction. J Am Coll Cardiol 68(17):1823–1834. https://doi.org/10.1016/j.jacc.2016.07.763 CrossRefPubMedGoogle Scholar
- 38.Takeda Y, Fukutomi T, Suzuki S, Yamamoto K, Ogata M, Kondo H, Sugiura M, Shigeyama J, Itoh M (2004) Effects of carvedilol on plasma B-type natriuretic peptide concentration and symptoms in patients with heart failure and preserved ejection fraction. Am J Cardiol 94(4):448–453CrossRefPubMedGoogle Scholar
- 39.Dharmarajan K, Hsieh AF, Lin Z, Bueno H, Ross JS, Horwitz LI, Barreto-Filho JA, Kim N, Bernheim SM, Suter LG, Drye EE, Krumholz HM (2013) Diagnoses and timing of 30-day readmissions after hospitalization for heart failure, acute myocardial infarction, or pneumonia. JAMA 309(4):355–363. https://doi.org/10.1001/jama.2012.216476 CrossRefPubMedPubMedCentralGoogle Scholar
- 40.Fu M, Zhou J, Sun A, Zhang S, Zhang C, Zou Y, Fu M, Ge J (2012) Efficacy of ACE inhibitors in chronic heart failure with preserved ejection fraction--a meta analysis of 7 prospective clinical studies. Int J Cardiol 155(1):33–38. https://doi.org/10.1016/j.ijcard.2011.01.081 CrossRefPubMedGoogle Scholar
- 41.Massie BM, Carson PE, McMurray JJ, Komajda M, McKelvie R, Zile MR, Anderson S, Donovan M, Iverson E, Staiger C et al (2008) Irbesartan in patients with heart failure and preserved ejection fraction. N Engl J Med 359(23):2456–2467. https://doi.org/10.1056/NEJMoa0805450 CrossRefPubMedGoogle Scholar
- 42.Liu F, Chen Y, Feng X, Teng Z, Yuan Y, Bin J (2014) Effects of beta-blockers on heart failure with preserved ejection fraction: a meta-analysis. PLoS One 9(3):e90555. https://doi.org/10.1371/journal.pone.0090555 CrossRefPubMedPubMedCentralGoogle Scholar
- 43.Pfeffer MA, Claggett B, Assmann SF, Boineau R, Anand IS, Clausell N, Desai AS, Diaz R, Fleg JL, Gordeev I, Heitner JF, Lewis EF, O'Meara E, Rouleau JL, Probstfield JL, Shaburishvili T, Shah SJ, Solomon SD, Sweitzer NK, McKinlay SM, Pitt B (2015) Regional variation in patients and outcomes in the Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist (TOPCAT) trial. Circulation 131(1):34–42. https://doi.org/10.1161/CIRCULATIONAHA.114.013255 CrossRefPubMedGoogle Scholar
- 44.Chen Y, Wang H, Lu Y, Huang X, Liao Y, Bin J (2015) Effects of mineralocorticoid receptor antagonists in patients with preserved ejection fraction: a meta-analysis of randomized clinical trials. BMC Med 13(1):10. https://doi.org/10.1186/s12916-014-0261-8 CrossRefPubMedPubMedCentralGoogle Scholar
- 45.van Heerebeek L, Paulus WJ (2016) Understanding heart failure with preserved ejection fraction: where are we today? Neth Hear J 24(4):227–236. https://doi.org/10.1007/s12471-016-0810-1 CrossRefGoogle Scholar
- 46.Zheng SL, Chan FT, Nabeebaccus AA, Shah AM, McDonagh T, Okonko DO, Ayis S (2017) Drug treatment effects on outcomes in heart failure with preserved ejection fraction: a systematic review and meta-analysis. Heart 0:1–9. https://doi.org/10.1136/heartjnl-2017-311652 Google Scholar
- 47.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 JJV, Mitchell JE, Peterson PN, Riegel B, Sam F, Stevenson LW, Tang WHW, Tsai EJ, Wilkoff BL (2013) 2013 ACCF/AHA guideline for the management of heart failure: executive summary: a report of the American College of Cardiology Foundation/American Heart Association Task Force on practice guidelines. Circulation 128(16):1810–1852. https://doi.org/10.1161/CIR.0b013e31829e8807 CrossRefPubMedGoogle Scholar