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(Circulation. 1999;100:1056-1064.)
© 1999 American Heart Association, Inc.


Clinical Investigation and Reports

Comparison of Candesartan, Enalapril, and Their Combination in Congestive Heart Failure

Randomized Evaluation of Strategies for Left Ventricular Dysfunction (RESOLVD) Pilot Study: The RESOLVD Pilot Study Investigators

Writing Committee; R. S. McKelvie, MD, PhD; S. Yusuf, MBBS, DPhil; D. Pericak, MMath; A. Avezum, MD; R. J. Burns, MD; J. Probstfield, MD; R. T. Tsuyuki, PharmD, MSc; M. White, MD; J. Rouleau, MD; R. Latini, MD; A. Maggioni, MD; J. Young, MD; J. Pogue, MA, MSc

From Hamilton Health Sciences Corporation–General Division, and McMaster University, Hamilton, Ontario, Canada (R.S.M., S.Y., D.P., J. Pogue); Dante Pazzanese Cardiology Institute, Sao Paulo, Brazil (A.A.); Toronto Hospital–Western Division, Toronto, Ontario, Canada (R.J.B.); Fred Hutchinson Cancer Center, Seattle, Wash (J. Probstfield); University of Alberta Hospitals, Edmonton, Alberta, Canada (R.T.T.); Montreal Heart Institute, Montreal, Quebec, Canada (M.W., J.R.); Istituto di Ricerche Farmacologiche "Mario Negri," Milano, Italy (R.L., A.M.); and The Cleveland Clinic Foundation, Cleveland, Ohio (J.Y.)

Correspondence to Dr R.S. McKelvie, Canadian Cardiovascular Collaboration Project Office, Hamilton General Hospital, 237 Barton St E, Hamilton, Ontario L8L 2X2, Canada. E-mail mckelrob{at}hamcivhos.on.ca

Background—We investigated the effects of candesartan (an angiotensin II antagonist) alone, enalapril alone, and their combination on exercise tolerance, ventricular function, quality of life (QOL), neurohormone levels, and tolerability in congestive heart failure (CHF).

Methods and Results—Seven hundred sixty-eight patients in New York Heart Association functional class (NYHA-FC) II to IV with ejection fraction (EF) <0.40 and a 6-minute walk distance (6MWD) <500 m received either candesartan (4, 8, or 16 mg), candesartan (4 or 8 mg) plus 20 mg of enalapril, or 20 mg of enalapril for 43 weeks. There were no differences among groups with regard to 6MWD, NYHA-FC, or QOL. EF increased (P=NS) more with candesartan-plus-enalapril therapy (0.025±0.004) than with candesartan alone (0.015±0.004) or enalapril alone(0.015±0.005). End-diastolic (EDV) and end-systolic (ESV) volumes increased less with combination therapy (EDV 8±4 mL; ESV 1±4 mL; P<0.01) than with candesartan alone (EDV 27±4 mL; ESV 18±3 mL) or enalapril alone (EDV 23±7 mL; ESV 14±6 mL). Blood pressure decreased with combination therapy (6±1/4±1 mm Hg) compared with candesartan or enalapril alone (P<0.05). Aldosterone decreased (P<0.05) with combination therapy (23.2±5.3 pg/mL) at 17 but not 43 weeks compared with candesartan (0.7±7.8 pg/mL) or enalapril (-0.8±11.3 pg/mL). Brain natriuretic peptide decreased with combination therapy (5.8±2.7 pmol/L; P<0.01) compared with candesartan (4.4±3.8 pmol/L) and enalapril alone (4.0±5.0 pmol/L).

Conclusions—Candesartan alone was as effective, safe, and tolerable as enalapril. The combination of candesartan and enalapril was more beneficial for preventing left ventricular remodeling than either candesartan or enalapril alone.


Key Words: cardiac volume • heart failure • natriuretic peptides




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A. D Struthers
Aldosterone blockade in heart failure
Journal of Renin-Angiotensin-Aldosterone System, March 1, 2004; 5(1_suppl): S23 - S27.
[Abstract] [PDF]


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HypertensionHome page
J. D. Imig
ACE Inhibition and Bradykinin-Mediated Renal Vascular Responses: EDHF Involvement
Hypertension, March 1, 2004; 43(3): 533 - 535.
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ChestHome page
S. de Denus, C. Pharand, and D. R. Williamson
Brain Natriuretic Peptide in the Management of Heart Failure: The Versatile Neurohormone
Chest, February 1, 2004; 125(2): 652 - 668.
[Abstract] [Full Text] [PDF]


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J. Am. Soc. Nephrol.Home page
T. Berl
Angiotensin-Converting Enzyme Inhibitors versus AT1 Receptor Antagonist in Cardiovascular and Renal Protection: The case for AT1 Receptor Antagonist
J. Am. Soc. Nephrol., January 1, 2004; 15(90010): S71 - 76.
[Abstract] [Full Text]


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J Clin PharmacolHome page
L. M. Prisant, H. Krum, B. Roniker, S. L. Krause, K. Fakouhi, and W. He
Can Renin Status Predict the Antihypertensive Efficacy of Eplerenone Add-On Therapy?
J. Clin. Pharmacol., November 1, 2003; 43(11): 1203 - 1210.
[Abstract] [Full Text] [PDF]


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Eur Heart JHome page
R. S. McKelvie, J.-L. Rouleau, M. White, R. Afzal, J. B. Young, A. P. Maggioni, P. Held, and S. Yusuf
Comparative impact of enalapril, candesartan or metoprolol alone or in combination on ventricular remodelling in patients with congestive heart failure
Eur. Heart J., October 1, 2003; 24(19): 1727 - 1734.
[Abstract] [Full Text] [PDF]


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Eur J Heart FailHome page
A. Matsumori and on behalf of the assessment of response to candesa
Efficacy and safety of oral candesartan cilexetil in patients with congestive heart failure
Eur J Heart Fail, October 1, 2003; 5(5): 669 - 677.
[Abstract] [Full Text] [PDF]


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Eur J Heart FailHome page
A. P. Coletta, J. G.F. Cleland, N. Freemantle, H. Loh, A. Memon, and A. L. Clark
Clinical trials update from the European Society of Cardiology: CHARM, BASEL, EUROPA and ESTEEM
Eur J Heart Fail, October 1, 2003; 5(5): 697 - 704.
[Abstract] [Full Text] [PDF]


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CirculationHome page
J. N. Cohn, I. S. Anand, R. Latini, S. Masson, Y.-T. Chiang, and R. Glazer
Sustained Reduction of Aldosterone in Response to the Angiotensin Receptor Blocker Valsartan in Patients With Chronic Heart Failure: Results From the Valsartan Heart Failure Trial
Circulation, September 16, 2003; 108(11): 1306 - 1309.
[Abstract] [Full Text] [PDF]


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J CARDIOVASC PHARMACOL THERHome page
B. I. Jugdutt and V. Menon
Upregulation of Angiotensin II Type 2 Receptor and Limitation of Myocardial Stunning by Angiotensin II Type 1 Receptor Blockers during Reperfused Myocardial Infarction in the Rat
Journal of Cardiovascular Pharmacology and Therapeutics, September 1, 2003; 8(3): 217 - 226.
[Abstract] [PDF]


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Journal of Renin-Angiotensin-Aldosterone SystemHome page
B. Pitt, C. T Stier Jr, and S. Rajagopalan
Mineralocorticoid receptor blockade: new insights into the mechanism of action in patients with cardiovascular disease
Journal of Renin-Angiotensin-Aldosterone System, September 1, 2003; 4(3): 164 - 168.
[Abstract] [PDF]


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Journal of Renin-Angiotensin-Aldosterone SystemHome page
J. Ostergren and J. J. McMurray
Angiotensin receptor blockers in heart failure
Journal of Renin-Angiotensin-Aldosterone System, September 1, 2003; 4(3): 171 - 175.
[Abstract] [PDF]


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Am. J. Physiol. Heart Circ. Physiol.Home page
H. Sato, H. Yaoita, K. Maehara, and Y. Maruyama
Attenuation of heart failure due to coronary stenosis by ACE inhibitor and angiotensin receptor blocker
Am J Physiol Heart Circ Physiol, June 5, 2003; 285(1): H359 - H368.
[Abstract] [Full Text] [PDF]


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Journal of Renin-Angiotensin-Aldosterone SystemHome page
M. A Weber
Review: Angiotensin II receptor blockers and cardiovascular outcomes: what does the future hold?
Journal of Renin-Angiotensin-Aldosterone System, June 1, 2003; 4(2): 62 - 73.
[Abstract] [PDF]


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Cardiovasc ResHome page
A. Schafer, D. Fraccarollo, S. K Hildemann, P. Tas, G. Ertl, and J. Bauersachs
Addition of the selective aldosterone receptor antagonist eplerenone to ACE inhibition in heart failure: effect on endothelial dysfunction
Cardiovasc Res, June 1, 2003; 58(3): 655 - 662.
[Abstract] [Full Text] [PDF]


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CirculationHome page
N. J. Brown
Eplerenone: Cardiovascular Protection
Circulation, May 20, 2003; 107(19): 2512 - 2518.
[Abstract] [Full Text] [PDF]


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CirculationHome page
B. Bozkurt and D. L. Mann
Use of Biomarkers in the Management of Heart Failure: Are We There Yet?
Circulation, March 11, 2003; 107(9): 1231 - 1233.
[Full Text] [PDF]


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CirculationHome page
J. V. Linseman and M. R. Bristow
Drug Therapy and Heart Failure Prevention
Circulation, March 11, 2003; 107(9): 1234 - 1236.
[Full Text] [PDF]


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Mayo Clin Proc.Home page
P. Manohar and I. L. Pina
Therapeutic Role of Angiotensin II Receptor Blockers in the Treatment of Heart Failure
Mayo Clin. Proc., March 1, 2003; 78(3): 334 - 338.
[Abstract] [PDF]


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Card Surg AdultHome page
J. M. Bailey, K. A. Tanaka, and J. H. Levy
Cardiac Surgical Pharmacology
Card. Surg. Adult, January 1, 2003; 2(2003): 85 - 118.
[Full Text]


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Eur Heart J SupplHome page
M. Bartnik, K. Malmberg, and L. Ryden
Diabetes and the heart: compromised myocardial function -- a common challenge
Eur. Heart J. Suppl., January 1, 2003; 5(suppl_B): B33 - B41.
[Abstract] [PDF]


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CirculationHome page
R. Latini, S. Masson, I. Anand, D. Judd, A. P. Maggioni, Y.-T. Chiang, M. Bevilacqua, M. Salio, P. Cardano, P. H.J.M. Dunselman, et al.
Effects of Valsartan on Circulating Brain Natriuretic Peptide and Norepinephrine in Symptomatic Chronic Heart Failure: The Valsartan Heart Failure Trial (Val-HeFT)
Circulation, November 5, 2002; 106(19): 2454 - 2458.
[Abstract] [Full Text] [PDF]


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Am. J. Physiol. Heart Circ. Physiol.Home page
J. R. R. Heyen, E. R. Blasi, K. Nikula, R. Rocha, H. A. Daust, G. Frierdich, J. F. Van Vleet, P. De Ciechi, E. G. McMahon, and A. E. Rudolph
Structural, functional, and molecular characterization of the SHHF model of heart failure
Am J Physiol Heart Circ Physiol, November 1, 2002; 283(5): H1775 - H1784.
[Abstract] [Full Text] [PDF]


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Journal of Pharmacy PracticeHome page
J. M. Fink
The Use of Angiotensin-II Receptor Blockers in Heart Failure
Journal of Pharmacy Practice, August 1, 2002; 15(4): 318 - 325.
[Abstract] [PDF]


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Arterioscler. Thromb. Vasc. Bio.Home page
S. Kim, Y. Izumi, Y. Izumiya, Y. Zhan, M. Taniguchi, and H. Iwao
Beneficial Effects of Combined Blockade of ACE and AT1 Receptor on Intimal Hyperplasia in Balloon-Injured Rat Artery
Arterioscler Thromb Vasc Biol, August 1, 2002; 22(8): 1299 - 1304.
[Abstract] [Full Text] [PDF]


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HypertensionHome page
H. Krum, H. Nolly, D. Workman, W. He, B. Roniker, S. Krause, and K. Fakouhi
Efficacy of Eplerenone Added to Renin-Angiotensin Blockade in Hypertensive Patients
Hypertension, August 1, 2002; 40(2): 117 - 123.
[Abstract] [Full Text] [PDF]


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HypertensionHome page
A. S. Mihailidou, M. Mardini, J. W. Funder, and M. Raison
Mineralocorticoid and Angiotensin Receptor Antagonism During Hyperaldosteronemia
Hypertension, August 1, 2002; 40(2): 124 - 129.
[Abstract] [Full Text] [PDF]


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HypertensionHome page
M. Naruse, A. Tanabe, A. Sato, S. Takagi, K. Tsuchiya, T. Imaki, and K. Takano
Aldosterone Breakthrough During Angiotensin II Receptor Antagonist Therapy in Stroke-Prone Spontaneously Hypertensive Rats
Hypertension, July 1, 2002; 40(1): 28 - 33.
[Abstract] [Full Text] [PDF]


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CirculationHome page
L. A. Nikolaidis, A. Doverspike, R. Huerbin, T. Hentosz, and R. P. Shannon
Angiotensin-Converting Enzyme Inhibitors Improve Coronary Flow Reserve in Dilated Cardiomyopathy by a Bradykinin-Mediated, Nitric Oxide-Dependent Mechanism
Circulation, June 11, 2002; 105(23): 2785 - 2790.
[Abstract] [Full Text] [PDF]


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Journal of Renin-Angiotensin-Aldosterone SystemHome page
D. A Sica
Review: The practical aspects of combination therapy with angiotensin receptor blockers and angiotensin-converting enzyme inhibitors
Journal of Renin-Angiotensin-Aldosterone System, June 1, 2002; 3(2): 66 - 71.
[Abstract] [PDF]


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J Am Coll CardiolHome page
W. Johnson, T. Omland, C. Hall, C. Lucas, O. L. Myking, C. Collins, M. Pfeffer, J.-L. Rouleau, and L. W. Stevenson
Neurohormonal activation rapidly decreases after intravenous therapy withdiuretics and vasodilators for class IV heart failure
J. Am. Coll. Cardiol., May 15, 2002; 39(10): 1623 - 1629.
[Abstract] [Full Text] [PDF]


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J Am Coll CardiolHome page
N. Lapointe and J.-L. Rouleau
Activation of vascular tissue angiotensin-converting enzyme (ACE) in heart failure: Effects of ACE inhibitors
J. Am. Coll. Cardiol., March 6, 2002; 39(5): 776 - 779.
[Full Text] [PDF]


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Eur J Heart FailHome page
G. R. Ellis, A. K. Nightingale, D. J. Blackman, R. A. Anderson, C. Mumford, G. Timmins, D. Lang, S. K. Jackson, M. D. Penney, M. J. Lewis, et al.
Addition of candesartan to angiotensin converting enzyme inhibitor therapy in patients with chronic heart failure does not reduce levels of oxidative stress
Eur J Heart Fail, March 1, 2002; 4(2): 193 - 199.
[Abstract] [Full Text] [PDF]


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J Am Coll CardiolHome page
P. Jong, C. Demers, R. S. McKelvie, and P. P. Liu
Angiotensin receptor blockers in heart failure: meta-analysis of randomized controlled trials
J. Am. Coll. Cardiol., February 6, 2002; 39(3): 463 - 470.
[Abstract] [Full Text] [PDF]