Clinical Research Study| Volume 133, ISSUE 2, e25-e31, February 2020

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Early Effects of Starting Doses of Enalapril in Patients with Chronic Heart Failure in the SOLVD Treatment Trial



      In the Studies of Left Ventricular Dysfunction (SOLVD) treatment trial, similar clinical benefits were observed between starting doses of enalapril and the target dose achieved by postrandomization up-titration. In our current analysis, protecting the randomization, we examined the early effects of starting doses of enalapril.


      There were 2569 patients with mild-to-moderate chronic heart failure with reduced ejection fraction (ejection fraction ≤35%) randomized to receive starting doses (5-10 mg/day) of placebo (n = 1284) or enalapril (n = 1285). At day 14, both study drugs were blindly up-titrated to the target dose (20 mg/day). Overall, 96% (2458/2569) of the patients returned for dose up-titration, which was achieved in 59% (1444/2458), 48% (696/1444) of whom were in the enalapril group. Hazard ratios (HRs) and 95% confidence intervals (CIs) for outcomes in the enalapril group were estimated.


      HRs (95% CIs) for all-cause mortality, heart failure hospitalization, and the combined endpoint of heart failure hospitalization or all-cause mortality at 14 days after randomization were 0.80 (0.32-2.03), 0.63 (0.35-1.12), and 0.65 (0.39-1.06), respectively. Corresponding HRs (95% CIs) at 30 days were 0.82 (0.41-1.67), 0.43 (0.27-0.68), and 0.43 (0.27-0.68), respectively. The magnitude of these early effects of starting doses of enalapril is similar to its previously reported long-term effects at the target dose.


      These data suggest that in stable ambulatory patients with heart failure with reduced ejection fraction, the magnitude of the early effect of starting doses of enalapril is similar to that observed during longer-term therapy with the target doses of the drug.


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        • 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
        • The SOLVD Investigators
        Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure.
        N Engl J Med. 1991; 325: 293-302
        • Yancy C.W.
        • Jessup M.
        • Bozkurt B.
        • et al.
        2017 ACC/AHA/HFSA Focused Update of the 2013 ACCF/AHA Guideline for the Management of Heart Failure: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Failure Society of America.
        J Am Coll Cardiol. 2017; 70: 776-803
        • Yancy C.W.
        • Jessup M.
        • Bozkurt B.
        • et al.
        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.
        J Am Coll Cardiol. 2013; 62: e147-e239
        • Lam P.H.
        • Dooley D.J.
        • Fonarow G.C.
        • et al.
        Similar clinical benefits from below-target and target dose enalapril in patients with heart failure in the SOLVD Treatment trial.
        Eur J Heart Fail. 2018; 20: 359-369
        • Packer M.
        Inferential characterization of the dose-response relationships of neurohormonal antagonists in chronic heart failure: a novel approach based on large-scale trials with active comparators.
        Int J Cardiol. 2018; 261: 130-133
        • Krum H.
        • Roecker E.B.
        • Mohacsi P.
        • et al.
        Effects of initiating carvedilol in patients with severe chronic heart failure: results from the COPERNICUS Study.
        JAMA. 2003; 289: 712-718
        • Pitt B.
        • White H.
        • Nicolau J.
        • et al.
        Eplerenone reduces mortality 30 days after randomization following acute myocardial infarction in patients with left ventricular systolic dysfunction and heart failure.
        J Am Coll Cardiol. 2005; 46: 425-431
        • Fonarow G.C.
        • Lukas M.A.
        • Robertson M.
        • Colucci W.S.
        • Dargie H.J.
        Effects of carvedilol early after myocardial infarction: analysis of the first 30 days in Carvedilol Post-Infarct Survival Control in Left Ventricular Dysfunction (CAPRICORN).
        Am Heart J. 2007; 154: 637-644
        • Reams G.P.
        • Lal S.M.
        • Whalen J.J.
        • Bauer J.H.
        Enalaprilat: an intravenous substitute for oral enalapril therapy. Humoral and pharmacokinetic effects.
        J Clin Hypertens. 1986; 2: 245-253
        • Remme W.J.
        Effect of ACE inhibition on neurohormones.
        Eur Heart J. 1998; 19: J16-J23
        • Sigurdsson A.
        • Held P.
        • Swedberg K.
        • Wall B.
        Neurohormonal effects of early treatment with enalapril after acute myocardial infarction and the impact on left ventricular remodelling.
        Eur Heart J. 1993; 14: 1110-1117
        • Schulman S.P.
        • Weiss J.L.
        • Becker L.C.
        • et al.
        Effect of early enalapril therapy on left ventricular function and structure in acute myocardial infarction.
        Am J Cardiol. 1995; 76: 764-770
        • Foster R.E.
        • Johnson D.B.
        • Barilla F.
        • et al.
        Changes in left ventricular mass and volumes in patients receiving angiotensin-converting enzyme inhibitor therapy for left ventricular dysfunction after Q-wave myocardial infarction.
        Am Heart J. 1998; 136: 269-275
        • Bazzino O.
        • Navarro Estrada J.L.
        • Sosa Liprandi A.
        • et al.
        Early treatment with low-dose enalapril after acute myocardial infarction: an equilibrium radionuclide angiographic study. Enalapril despues del Infarto (EDI) Trial Investigators.
        J Nucl Cardiol. 1997; 4: 133-139
        • Sanam K.
        • Bhatia V.
        • Bajaj N.S.
        • et al.
        Renin-angiotensin system inhibition and lower 30-day all-cause readmission in Medicare beneficiaries with heart failure.
        Am J Med. 2016; 129: 1067-1073
        • Gheorghiade M.
        • Albert N.M.
        • Curtis A.B.
        • et al.
        Medication dosing in outpatients with heart failure after implementation of a practice-based performance improvement intervention: findings from IMPROVE HF.
        Congest Heart Fail. 2012; 18: 9-17
        • Barywani S.B.
        • Ergatoudes C.
        • Schaufelberger M.
        • Petzold M.
        • Fu M.L.
        Does the target dose of neurohormonal blockade matter for outcome in Systolic heart failure in octogenarians?.
        Int J Cardiol. 2015; 187: 666-672
        • de Groote P.
        • Isnard R.
        • Assyag P.
        • et al.
        Is the gap between guidelines and clinical practice in heart failure treatment being filled? Insights from the IMPACT RECO survey.
        Eur J Heart Fail. 2007; 9: 1205-1211
        • Packer M.
        • Coats A.J.
        • Fowler M.B.
        • et al.
        Effect of carvedilol on survival in severe chronic heart failure.
        N Engl J Med. 2001; 344: 1651-1658
        • Pitt B.
        • Remme W.
        • Zannad F.
        • et al.
        Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction.
        N Engl J Med. 2003; 348: 1309-1321
        • McMurray J.J.
        • Packer M.
        • Desai A.S.
        • et al.
        Angiotensin-neprilysin inhibition versus enalapril in heart failure.
        N Engl J Med. 2014; 371: 993-1004
        • Vardeny O.
        • Claggett B.
        • Packer M.
        • et al.
        Efficacy of sacubitril/valsartan vs. enalapril at lower than target doses in heart failure with reduced ejection fraction: the PARADIGM-HF trial.
        Eur J Heart Fail. 2016; 18: 1228-1234
        • Packer M.
        • Poole-Wilson P.A.
        • Armstrong P.W.
        • et al.
        Comparative effects of low and high doses of the angiotensin-converting enzyme inhibitor, lisinopril, on morbidity and mortality in chronic heart failure. ATLAS Study Group.
        Circulation. 1999; 100: 2312-2318
        • Konstam M.A.
        • Neaton J.D.
        • Dickstein K.
        • et al.
        Effects of high-dose versus low-dose losartan on clinical outcomes in patients with heart failure (HEAAL study): a randomised, double-blind trial.
        Lancet. 2009; 374: 1840-1848
        • Packer M.
        Love of angiotensin-converting enzyme jnhibitors in the time of cholera.
        JACC Heart Fail. 2016; 4: 403-408
        • Packer M.
        Kicking the tyres of a heart failure trial: physician response to the approval of sacubitril/valsartan in the USA.
        Eur J Heart Fail. 2016; 18: 1211-1219