Dose response of ACE inhibitors: implications of the SECURE trial
© BioMed Central Ltd 2001
Published: 6 July 2001
The choice of the appropriate dosage of ACE inhibitor in clinical practice is an important one. The available evidence suggests that in chronic heart failure as well as in chronic coronary artery disease, high doses of angiotensin-converting enzyme (ACE) inhibitor are more effective than low ones. The current recommended clinical approach is to target ACE inhibitor dosing regimens to be similar to those used in the clinical trials, which demonstrated mortality and morbidity benefits. When titrated appropriately, ACE inhibitors are generally well tolerated and target doses can be achieved and maintained in the majority of patients with atherosclerotic vascular disease, with or without heart failure.
KeywordsACE inhibitors atherosclerosis coronary artery disease
Angiotensin-converting enzyme (ACE) inhibitors have been used extensively in the management of hypertension and heart failure. Recent trials, primarily the Heart Outcomes Prevention Evaluation (HOPE) study, also demonstrate a clear role for these agents in reducing the risk for adverse cardiovascular outcomes in patients without heart failure and with preserved left ventricular (LV) ejection fraction . Experimental research and recent clinical studies also show favorable effects of ACE inhibitor therapy on the arterial vascular wall. The Study to Evaluate Carotid Ultrasound changes in patients treated with Ramipril and vitamin E (SECURE), a substudy of the HOPE trial, thus demonstrated reduced progression of carotid atherosclerosis in patients treated with ramipril . Other investigations have revealed improved endothelial function in patients receiving ACE inhibitors [3,4].
What are 'optimal' doses of ACE inhibitors to be used in different clinical settings? This question is encountered frequently by clinicians and remains controversial. A number of surveys suggest that clinicians often prefer the use of low doses of ACE inhibitors, and the perception that low doses are as effective as high ones is quite prevalent. In addition, clinicians frequently titrate ACE inhibitor dose according to blood pressure and rely on 'adequate' blood pressure control as a marker of the effectiveness of this therapy, not only in patients treated for hypertension, but also in those treated for heart failure and for reduction of cardiovascular risk.
In this commentary, several lines of evidence have been extracted from clinical trials in chronic heart failure, coronary artery disease (CAD) and atherosclerosis to show that the size of the ACE inhibitor dose matters, higher doses are more effective than lower doses and the duration of therapy is important.
Clinical trials comparing high and low doses of ACE inhibitors in chronic heart failure
Trials exploring ACE inhibitor dosing regimens in heart failure
ACE-I regimens (daily doses)
NETWORK (n = 1532)
Enalapril 2.5 mg bid vs 5 mg bid vs 10 mg bid
No difference in hospitalizations for heart failure; trend
Follow-up: 5.5 months
towards fewer deaths with increasing dose
ATLAS (n = 3164)
Lisinopril 2.5-5 mg od vs 32.5-35 mg od
Trends towards reduced total and CV mortality and
significant reduction in mortality and all-cause
hospitalizations for high-dose lisinopril
CHIPS (n = 298)
Captopril 25 mg bid vs 50 mg bid
Trend towards reduced hospitalizations for heart failure and
Follow-up: 2 years
towards reduced fatal and nonfatal cardiac events for
HEDS (n = 248)
Enalapril 20 mg vs 60 mg
No significant differences in survival, clinical and
Follow-up: 12 months
A number of prospective observational studies have reported that heart failure patients discharged from hospital and maintained on 'high' ACE inhibitor doses had improved clinical outcomes compared to those receiving low dose therapy. The benefits included lower rates of death and re-hospitalization, thus incurring lower costs [10,11]. The ability to achieve adequate doses of ACE inhibitors for the treatment of chronic heart failure in general practice is also well documented. Studies such as the prospective evaluation by Messner Pellenc found that a daily dose of 20 mg of enalapril could be reached in a high proportion of heart-failure patients with good tolerability and improved outcomes .
Clinical practice guidelines, published by both the Agency for Health Care Policy and Research and the American College of Cardiology/American Heart Association, reflect the findings of these studies. These recommend that when managing chronic heart failure, every effort should be made to increase the dose of ACE inhibitors to the target doses shown in clinical trials to decrease mortality and morbidity, for example at least 150 mg daily of captopril or at least 20 mg daily of enalapril or lisinopril [13,14].
ACE inhibitor dose in chronic coronary artery disease
Notably, the Quinapril Ischemic Event Trial (QUIET) , used an intermediate dose of quinapril (20 mg daily) and failed to demonstrate a clear benefit for ACE inhibitor therapy in patients with preserved LV systolic function. By contra-distinction, the Trial on Reversing Endothelial Dysfunction(TREND) substudy of QUIET, which used a higher ACE inhibitor daily dose of 40 mg of quinapril, did show significant improvement in coronary endothelial function in actively treated patients. The failure to demonstrate a statistically significant advantage for quinapril in the QUIET trial may be related to multiple factors, such as the low event rates, the inadequate sample size, the duration of the study and the suboptimal compliance. It remains possible, however, that the chosen ACE inhibitor dose may have also contributed to the overall disappointing results of this study.
In the absence of clinical trials that compare high-dose versus low-dose ACE inhibitor regimens in chronic CAD, the most prudent approach is to aim for the relatively high target doses used in the large randomized clinical trials.
Studies of ACE inhibitors in atherosclerosis
A large body of experimental evidence suggests that prolonged ACE inhibitor therapy may have beneficial effects on atherogenesis, both by inhibiting the formation of tissue and circulating angiotensin II and by bradykinin potentiation. These ACE inhibitor actions result in decreased proliferation and migration of smooth muscle cells, decreased accumulation and activation of inflammatory cells, decreased oxidative stress, and increased endothelial nitric oxide formation, leading to improved endothelial function . Increased ACE activity has been demonstrated in human coronary artery lesions , and long-term ACE inhibitor therapy has been shown to reduce the area of atherosclerotic lesions in normotensive animal models of atherosclerosis. Interestingly, in all the experimental animal model studies of atherosclerosis that demonstrated beneficial effects of ACE inhibitors, high drug doses were used (e.g. captopril 3-25 mg/kg/day, cilazapril 10 mg/kg/day, quinapril 10 mg/kg/day) [23,24,25,26].
Effect of ramipril on echocardiographic measurements of left ventricular mass and function in a substudy of HOPE
Ramipril 2.5 mg/day
Ramipril 10 mg/day
Δ LVMI (g/m2)
3.98 ± 25.23
4.15 ± 22.77
-2.02 ± 27.12*
Δ LVEF (%)
-2.02 ± 1.54
-1.54 ± 8.94
-0.17 ± 8.62†
Δ LVEDV (ml)
4.16 ± 30.89
-0.43 ± 33.3
-5.90 ± 35.17††
Δ LVESV (ml)
5.31 ± 20.49
2.90 ± 17.68
-1.90 ± 18.71††
New wall motion abnormalities
Higher doses of ACE inhibitors are better than lower doses in chronic heart failure and in coronary artery disease.
Duration of therapy is important. In patients with atherosclerotic vascular disease (with or without LV systolic function and with or without clinical manifestations of heart failure) prolonged therapy is associated with improved outcomes.
The safest and most logical clinical approach needs to be based on principles of evidence-based medicine. The currently available evidence supports the use of those specific ACE inhibitors shown to reduce mortality and morbidity in clinical trials. The target doses used in these clinical trials were 10 mg ramipril/day, 20-40 mg enalapril/day, 150 mg captopril/day, 10-35 mg lisino-pril/day or 4 mg trandolapril/day. The use of other ACE inhibitors that have not been tested in large-scale clinical trials with mortality and/or morbidity endpoints, and the use of lower target ACE inhibitor doses cannot be endorsed .
There are no adequate surrogate markers to aid clinicians in the choice of the most effective ACE inhibitor dose. The use of blood pressure and even the use of clinical symptoms appear to be inadequate in determining optimal ACE inhibitor dose level.
High ACE inhibitor doses, when titrated appropriately, are generally well tolerated and can be achieved and maintained in the majority of patients with atheroscle-rotic vascular disease and/or chronic heart failure. In those who cannot tolerate target doses, the highest tolerated dose should be used.
CAD remains the main killer of men and women in our society. An aggressive approach to therapy with comprehensive risk factor modification and use of multiple drugs as well as non-pharmaceutical approaches can improve significantly both quality of life and survival in most patients. Maximizing doses of drugs that are shown to be effective is an important component of this aggressive treatment strategy and should be applied rigorously.
Assessment of Treatment with Lisinopril and Survival trial
coronary artery disease
Heart Outcomes Prevention Evaluation study
Ney York Heart Association
- NETWORK trial:
Network of general practitioners and hospital physicians involved in the study of low versus high doses of enalapril in patients with heart failure trial
Study to Evaluate Carotid Ultrasound changes in patients treated with Ramipril and Vitamin E
Quinapril Ischemic Event Trial.
- The HOPE Investigators: Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. N Engl J Med. 2000, 342: 145-153. 10.1056/NEJM200001203420301.View ArticleGoogle Scholar
- Lonn E, Yusuf S, Dzavik V, Doris I, Yi Q, Smith S, Moore-Cox A, Bosch J, Riley WA, Teo KK, for the SECURE Investigators: Effects of ramipril and of vitamin E on atheroslerosis: results of the prospective randomized Study to Evaluate Carotid Ultrasound changes in patients treated with Ramipril and vitamin E (SECURE). Circulation. 2001, 103: 919-925.View ArticlePubMedGoogle Scholar
- Mancini GBJ, Henry GC, Macaya C, O'Neill BJ, Pucillo AL, Carere RG, Wargovich TJ, Mudra H, Luscher TF, Klibaner MI, Haber HE, Uprichard AC, Pepine CJ, Pitt B: Angiotensin-converting enzyme inhibition with quinapril improves endothelial vasomotor dysfunction in patients with coronary artery disease. The TREND (Trial on Reversing Endothelial Dysfunction) Study. Circulation. 1996, 94: 258-265.View ArticlePubMedGoogle Scholar
- Anderson TJ, Elstein E, Haber H, Charbonneau F: Comparative study of ACE inhibition, angiotensin II antagonism and calcium channel blockade on flow-mediated vasodilation in patients with coronary disease (BANFF study). J Am Coll Cardiol. 2000, 35: 60-66. 10.1016/S0735-1097(99)00537-9.View ArticlePubMedGoogle Scholar
- The NETWORK Investigators: Clinical outcome with enalapril in symptomatic chronic heart failure: a dose comparison. Eur Heart J. 1998, 19: 481-489. 10.1053/euhj.1997.0839.View ArticleGoogle Scholar
- Packer M, Poole-Wilson A, Armstrong PW, Cleland JGF, Horowitz JD, Massie BM, Ryden L, Thygesen K, Uretsky BF, on behalf of the ATLAS Study Group: Comparative effects of low and high doses of the angiotensin-converting enzyme inhibitor, lisinopril, on morbidity and mortality in chronic heart failure. Circulation. 1999, 100: 2312-2318.View ArticlePubMedGoogle Scholar
- Clement DL, DeBuyzere M, Tomas M, Vanavermaete G: Long-term effects of clinical outcome with low and high dose in the Captopril in Heart Insufficient Patients Study (CHIPS). Acta Cardiol. 2000, 55(1): 1-7.View ArticleGoogle Scholar
- Nanas JN, Alexopoulos G, Anastasiou-Nana MI, Karidis K, Tirol-ogos A, Zobolos S, Pirgakis V, Anthopoulos L, Sideris D, Stamatelopoulos SF, Moulopoulos SD, for the High Enalapril Dose Study Group: Outcome of patients with congestive heart failure treated with standard versus high doses of enalapril: a multicenter study. J Am Coll Cardiol. 2000, 36: 2090-2095. 10.1016/S0735-1097(00)01025-1.View ArticlePubMedGoogle Scholar
- Ryden L, Armstrong PW, Cleland JGF, Horowitz JD, Massie BM, Packer M, Poole-Wilson PA, on behalf of the ATLAS Study Group: Efficacy and safety of high-dose lisinopril in chronic heart failure patients at high cardiovascular risk, including those with diabetes mellitus. Results from the ATLAS trial. Eur Heart J. 2000, 21: 1967-1978. 10.1053/euhj.2000.2311.View ArticlePubMedGoogle Scholar
- Luzier AB, Forrest A, Feuerstein SG, Schemtag JJ, Izzo JL: Containment of heart failure hospitalizations and cost by angiotensin-converting enzyme inhibitor dosage optimization. Am J Cardiol. 2000, 86: 519-523. 10.1016/S0002-9149(00)01005-5.View ArticlePubMedGoogle Scholar
- Chen Y-T, Wang Y, Radford MJ, Krumholz HM: Angiotensin-converting enzyme inhibitor dosages in elderly patients with heart failure. Am Heart J. 2001, 141: 410-417. 10.1067/mhj.2001.113227.View ArticlePubMedGoogle Scholar
- Messner Pellenc P, Rudnicki A, Leclercq F, Grolleau R: Enalapril in the treatment of mild-to-moderate heart failure in general medical practice: a prospective and multicentre study concerning 17,546 patients. Acta Cardiol. 1995, 50(3): 187-201.Google Scholar
- Konstam MA, Dracup K, Baker DW, Bottorff MB, Brooks NH, Darcey RA, Dunbar SB, Jackson AB, Jessup M, Johnson JC, Jones RH, Luichi RJ: Heart failure: evaluation and care of patients with left ventricular systolic dysfunction. Clinical Practice Guidelines 11 (AHCPR publication no. 94-0612). Rockville, MD: Agency for Healthcare Policy and Research. 1994Google Scholar
- Packer M, Cohn JN, Abraham WT, Colucci WS, Fowler MB, Greenberg BH, Leier CV, Massie BM, Young JB: Consensus recommendations for the management of chronic heart failure. Am J Cardiol. 1999, 83: 27A-35A. 10.1016/S0002-9149(98)00777-2.View ArticleGoogle Scholar
- Pfeffer MA, Braunwald E, Moye LA, Basta L, Brown EJ, Cuddy TE, Davis BR, Geltman EM, Goldman S, Flaker GC: Effect of captopril on mortality and morbidity in patients with left ventricular dysfunction after myocardial infarction: results of the survival and ventricular enlargement trial. The SAVE Investigators. N Engl J Med. 1992, 327: 669-677.View ArticlePubMedGoogle Scholar
- 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.View ArticleGoogle Scholar
- The SOLVD Investigators: Effect of enalapril on mortality and the development of heart failure in asymptomatic patients with reduced left ventricular ejection fractions. N Engl J Med. 1992, 327: 685-691.View ArticleGoogle Scholar
- Kober L, Torp-Pedersen C, Carlsen JE, Bagger H, Eliasen P, Lyngborg K, Videbaek J, Cole DS, Auclert L, Pauly NC: A clinical trial of the angiotensin-converting-enzyme inhibitor tran-dolapril in patients with left ventricular dysfunction after myocardial infarction. Trandolapril Cardiac Evaluation (TRACE) Study Group. N Engl J Med. 1995, 333: 1670-1676. 10.1056/NEJM199512213332503.View ArticlePubMedGoogle Scholar
- Acute Infarction Ramipril Efficacy (AIRE) Study Investigators: Effect of ramipril on mortality and morbidity of survivors of acute myocardial infarction with clinical evidence of heart failure. Lancet. 1993, 342: 821-828. 10.1016/0140-6736(93)92693-N.Google Scholar
- Pitt B, O'Neil B, Feldman R, Ferrari R, Schwartz L, Mudra H, Bass T, Pepine C, Texter M, haber H, Uprichard A, Cashin-Hemphill L, Lees RS, for the QUIET Study Group: The Quinapril Ischemic Event Trial (QUIET): Evaluation of chronic ACE inhibitor therapy in patients with ischemic heart disease and preserved left ventricular function. Am J Cardiol. 2001, 87: 1058-1063. 10.1016/S0002-9149(01)01461-8.View ArticlePubMedGoogle Scholar
- Dzau VJ: Mechanism of protective effects of ACE inhibition on coronary artery disease. Eur Heart J. 1998, 19 (Suppl): J2-J6.Google Scholar
- Diet F, Pratt RE, Berry GJ, Momose N, Gibbons GH, Dzau VJ: Increased accumulation of tissue ACE in human atherosclerotic coronary artery disease. Circulation. 1996, 94: 2756-2767.View ArticlePubMedGoogle Scholar
- Chobanian AV, Haudenschild CC, Nickerson C, Drago R: Antiatherogenic effect of captopril in the Watanabe Heritable Hyperlipidemic Rabbit. Hypertension. 1990, 15: 327-332.View ArticlePubMedGoogle Scholar
- Aberg G, Ferrer P: Effects of captopril on atherosclerosis in cynomolgus monkeys. J Cardiovascular Pharmacol. 1990, 15(Suppl): S65-S72.View ArticleGoogle Scholar
- Powell JS, Clozel JP, Muller RKM, Kuhn H, Hefti F, Hosang M, Baumgartner HR: Inhibitors of angiotensin-converting enzyme prevent myointimal proliferation after vascular injury. Science. 1989, 245: 186-188.View ArticlePubMedGoogle Scholar
- Hoshida S, Yamashita N, Kiminori K, Kuzuya T, Hori M: Amelioration by quinapril of myocardial infarction induced by coronary occlusion/reperfusion in a rabbit model of atherosclerosis: possible mechanisms. Circulation. 1999, 99: 434-440.View ArticlePubMedGoogle Scholar
- Lonn E, Shaikholeslami R, Yi Q, Bosch J, Magi A, Yusuf S: Effects of ramipril on left ventricular mass and function in normotensive patients with preserved left ventricular function. A substudy of HOPE. J Am Coll Cardiol. 2001, 37(Suppl): 165A-Google Scholar
- Furberg CD, Pitt B: Are all angiotensin-converting enzyme inhibitors interchangeable?. J Am Coll Cardiol. 2001, 37: 1456-1460. 10.1016/S0735-1097(01)01161-5.View ArticlePubMedGoogle Scholar