Toleration of high doses of angiotensin-converting enzyme inhibitors in patients with chronic heart failure: Results from the ATLAS trial

Barry M. Massie, Paul W. Armstrong, John G F Cleland, John D. Horowitz, Milton Packer, Philip A. Poole-Wilson, Lars Rydén

Research output: Contribution to journalArticle

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Abstract

Background: Treatment with angiotensin-converting enzyme (ACE) inhibitors reduces mortality and morbidity in patients with chronic heart failure (CHF), but most affected patients are not receiving these agents or are being treated with doses lower than those found to be efficacious in trials, primarily because of concerns about the safety and tolerability of these agents, especially at the recommended doses. The present study examines the safety and tolerability of high-compared with low-dose lisinopril in CHF. Methods: The Assessment of Lisinopril and Survival study was a multicenter, randomized, double-blind trial in which patients with or without previous ACE inhibitor treatment were stabilized receiving medium-dose lisinopril (12.5 or 15.0 mg once daily [OD]) for 2 to 4 weeks and then randomized to high- (35.0 or 32.5 mg OD) or low-dose (5.0 or 2.5 mg OD) groups. Patients with New York Heart Association classes II to IV CHF and left ventricular ejection fractions of no greater than 0.30 (n = 3164) were randomized and followed up for a median of 46 months. We examined the occurrence of adverse events and the need for discontinuation and dose reduction during treatment, with a focus on hypotension and renal dysfunction. Results: Of 405 patients not previously receiving an ACE inhibitor, doses in only 4.2% could not be titrated to the medium doses required for randomization because of symptoms possibly related to hypotension (2.0%) or because of renal dysfunction or hyperkalemia (2.3%). Doses in more than 90% of randomized patients in the high- and low-dose groups were titrated to their assigned target, and the mean doses of blinded medication in both groups remained similar throughout the study. Withdrawals occurred in 27.1% of the high- and 30.7% of the low-dose groups. Subgroups presumed to be at higher risk for ACE inhibitor intolerance (blood pressure, <120 mm Hg; creatinine, ≥132.6 μmol/L [≥1.5 mg/dL]; age, ≥70 years; and patients with diabetes) generally tolerated the high-dose strategy. Conclusions: These findings demonstrate that ACE inhibitor therapy in most patients with CHF can be successfully titrated to and maintained at high doses, and that more aggressive use of these agents is warranted.

Original languageEnglish (US)
Pages (from-to)165-171
Number of pages7
JournalArchives of Internal Medicine
Volume161
Issue number2
StatePublished - Jan 22 2001

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Angiotensin-Converting Enzyme Inhibitors
Heart Failure
Lisinopril
Hypotension
Enzyme Therapy
Kidney
Safety
Hyperkalemia
Random Allocation
Stroke Volume
Creatinine
Therapeutics
Blood Pressure
Morbidity
Survival
Mortality

ASJC Scopus subject areas

  • Internal Medicine

Cite this

Massie, B. M., Armstrong, P. W., Cleland, J. G. F., Horowitz, J. D., Packer, M., Poole-Wilson, P. A., & Rydén, L. (2001). Toleration of high doses of angiotensin-converting enzyme inhibitors in patients with chronic heart failure: Results from the ATLAS trial. Archives of Internal Medicine, 161(2), 165-171.

Toleration of high doses of angiotensin-converting enzyme inhibitors in patients with chronic heart failure : Results from the ATLAS trial. / Massie, Barry M.; Armstrong, Paul W.; Cleland, John G F; Horowitz, John D.; Packer, Milton; Poole-Wilson, Philip A.; Rydén, Lars.

In: Archives of Internal Medicine, Vol. 161, No. 2, 22.01.2001, p. 165-171.

Research output: Contribution to journalArticle

Massie, BM, Armstrong, PW, Cleland, JGF, Horowitz, JD, Packer, M, Poole-Wilson, PA & Rydén, L 2001, 'Toleration of high doses of angiotensin-converting enzyme inhibitors in patients with chronic heart failure: Results from the ATLAS trial', Archives of Internal Medicine, vol. 161, no. 2, pp. 165-171.
Massie BM, Armstrong PW, Cleland JGF, Horowitz JD, Packer M, Poole-Wilson PA et al. Toleration of high doses of angiotensin-converting enzyme inhibitors in patients with chronic heart failure: Results from the ATLAS trial. Archives of Internal Medicine. 2001 Jan 22;161(2):165-171.
Massie, Barry M. ; Armstrong, Paul W. ; Cleland, John G F ; Horowitz, John D. ; Packer, Milton ; Poole-Wilson, Philip A. ; Rydén, Lars. / Toleration of high doses of angiotensin-converting enzyme inhibitors in patients with chronic heart failure : Results from the ATLAS trial. In: Archives of Internal Medicine. 2001 ; Vol. 161, No. 2. pp. 165-171.
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abstract = "Background: Treatment with angiotensin-converting enzyme (ACE) inhibitors reduces mortality and morbidity in patients with chronic heart failure (CHF), but most affected patients are not receiving these agents or are being treated with doses lower than those found to be efficacious in trials, primarily because of concerns about the safety and tolerability of these agents, especially at the recommended doses. The present study examines the safety and tolerability of high-compared with low-dose lisinopril in CHF. Methods: The Assessment of Lisinopril and Survival study was a multicenter, randomized, double-blind trial in which patients with or without previous ACE inhibitor treatment were stabilized receiving medium-dose lisinopril (12.5 or 15.0 mg once daily [OD]) for 2 to 4 weeks and then randomized to high- (35.0 or 32.5 mg OD) or low-dose (5.0 or 2.5 mg OD) groups. Patients with New York Heart Association classes II to IV CHF and left ventricular ejection fractions of no greater than 0.30 (n = 3164) were randomized and followed up for a median of 46 months. We examined the occurrence of adverse events and the need for discontinuation and dose reduction during treatment, with a focus on hypotension and renal dysfunction. Results: Of 405 patients not previously receiving an ACE inhibitor, doses in only 4.2{\%} could not be titrated to the medium doses required for randomization because of symptoms possibly related to hypotension (2.0{\%}) or because of renal dysfunction or hyperkalemia (2.3{\%}). Doses in more than 90{\%} of randomized patients in the high- and low-dose groups were titrated to their assigned target, and the mean doses of blinded medication in both groups remained similar throughout the study. Withdrawals occurred in 27.1{\%} of the high- and 30.7{\%} of the low-dose groups. Subgroups presumed to be at higher risk for ACE inhibitor intolerance (blood pressure, <120 mm Hg; creatinine, ≥132.6 μmol/L [≥1.5 mg/dL]; age, ≥70 years; and patients with diabetes) generally tolerated the high-dose strategy. Conclusions: These findings demonstrate that ACE inhibitor therapy in most patients with CHF can be successfully titrated to and maintained at high doses, and that more aggressive use of these agents is warranted.",
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