Angiotensin-Converting Enzyme Inhibitor Associated Cough: Deceptive Information from the Physicians' Desk Reference



      Dry cough is a common, annoying adverse effect of all angiotensin-converting enzyme (ACE) inhibitors. The present study was designed to compare the rate of coughs reported in the literature with reported rates in the Physicians' Desk Reference (PDR)/drug label.


      We searched MEDLINE/EMBASE/CENTRAL for articles published from 1990 to the present about randomized clinical trials (RCTs) of ACE inhibitors with a sample size of at least 100 patients in the ACE inhibitors arm with follow-up for at least 3 months and reporting the incidence or withdrawal rates due to cough. Baseline characteristics, cohort enrolled, metrics used to assess cough, incidence, and withdrawal rates due to cough were abstracted.


      One hundred twenty-five studies that satisfied our inclusion criteria enrolled 198,130 patients. The pooled weighted incidence of cough for enalapril was 11.48% (95% confidence interval [CI], 9.54% to 13.41%), which was ninefold greater compared to the reported rate in the PDR/drug label (1.3%). The pooled weighted withdrawal rate due to cough for enalapril was 2.57% (95% CI, 2.40-2.74), which was 31-fold greater compared to the reported rate in the PDR/drug label (0.1%). The incidence of cough has increased progressively over the last 2 decades with accumulating data, but it has been reported consistently several-fold less in the PDR compared to the RCTs. The results were similar for most other ACE inhibitors.


      The incidence of ACE inhibitor-associated cough and the withdrawal rate (the more objective metric) due to cough is significantly greater in the literature than reported in the PDR/drug label and is likely to be even greater in the real world when compared with the data from RCTs. There exists a gap between the data available from the literature and that which is presented to the consumers (prescribing physicians and patients).


      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to The American Journal of Medicine
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


      1. 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 ([No authors listed]): 1429-1435
        • Hohneker J.
        • Ericson S.
        • Gruia G.
        FDA drug information that never reaches clinicians.
        N Engl J Med. 2010; 362 (author reply 563): 561
        • Tikkanen I.
        • Omvik P.
        • Jensen H.A.
        Comparison of the angiotensin II antagonist losartan with the angiotensin-converting enzyme inhibitor enalapril in patients with essential hypertension.
        J Hypertens. 1995; 13: 1343-1351
      2. Higgins J, Green S. Cochrane Handbook for Systematic Reviews of Interventions Version 5.0.0 ed: The Cochrane Collaboration 2008.

        • U.S. Food and Drug Administration
        (Accessed February 2010)
        • Moher D.
        • Cook D.J.
        • Eastwood S.
        • et al.
        Improving the quality of reports of meta-analyses of randomised controlled trials: the QUOROM statement.
        Lancet. 1999; 354: 1896-1900
        • Bradburn M.J.
        • Deeks J.J.
        • Altman D.G.
        Sbe24: metan – an alternative meta-analysis command.
        Stata Tech Bull. 1998; 44: 4-15
        • Galbraith R.F.
        A note on graphical presentation of estimated odds ratios from several clinical trials.
        Stat Med. 1988; 7: 889-894
        • DerSimonian R.
        • Laird N.
        Meta-analysis in clinical trials.
        Control Clin Trials. 1986; 7: 177-188
        • Bradburn M.J.
        • Deeks J.J.
        • Berlin J.A.
        • Russell Localio A.
        Much ado about nothing: a comparison of the performance of meta-analytical methods with rare events.
        Stat Med. 2007; 26: 53-77
        • Sweeting M.J.
        • Sutton A.J.
        • Lambert P.C.
        What to add to nothing?.
        Stat Med. 2004; 23: 1351-1375
        • Egger M.
        • Davey Smith G.
        • Schneider M.
        • Minder C.
        Bias in meta-analysis detected by a simple, graphical test.
        BMJ. 1997; 315: 629-634
        • Rumboldt Z.
        • Marinković M.
        • Drinovec J.
        Enalapril versus captopril: a double-blind multicentre comparison in essential hypertension.
        Int J Clin Pharmacol Res. 1988; 8: 181-188
        • Wright Jr, J.T.
        • Bakris G.
        • Greene T.
        • et al.
        Effect of blood pressure lowering and antihypertensive drug class on progression of hypertensive kidney disease: results from the AASK trial.
        JAMA. 2002; 288: 2421-2431
        • Messerli F.H.
        • Weber M.A.
        Long-term cardiovascular consequences of diuretics vs calcium channel blockers vs angiotensin-converting enzyme inhibitors.
        JAMA. 2003; 289 (author reply 2069-2070): 2067-2068
        • Vegter S.
        • de Jong-van den Berg L.T.
        Misdiagnosis and mistreatment of a common side-effect–angiotensin-converting enzyme inhibitor-induced cough.
        Br J Clinical Pharmacol. 2010; 69: 200-203
        • Jamerson K.
        • Weber M.A.
        • Bakris G.L.
        • et al.
        Benazepril plus amlodipine or hydrochlorothiazide for hypertension in high-risk patients.
        N Engl J Med. 2008; 359: 2417-2428
        • Bakris G.L.
        • Toto R.D.
        • McCullough P.A.
        • et al.
        Effects of different ACE inhibitor combinations on albuminuria: results of the GUARD study.
        Kidney Int. 2008; 73: 1303-1309
        • Hou F.F.
        • Zhang X.
        • Zhang G.H.
        • et al.
        Efficacy and safety of benazepril for advanced chronic renal insufficiency.
        N Engl J Med. 2006; 354: 131-140
        • Malacco E.
        • Piazza S.
        • Carretta R.
        • et al.
        Comparison of benazepril-amlodipine and captopril-thiazide combinations in the management of mild-to-moderate hypertension.
        Int J Clin Pharmacol Ther. 2002; 40: 263-269
        • Maschio G.
        • Alberti D.
        • Janin G.
        • et al.
        Effect of the angiotensin-converting-enzyme inhibitor benazepril on the progression of chronic renal insufficiency.
        N Engl J Med. 1996; 334: 939-945
        • Hou F.F.
        • Xie D.
        • Zhang X.
        • et al.
        Renoprotection of Optimal Antiproteinuric Doses (ROAD) Study: a randomized controlled study of benazepril and losartan in chronic renal insufficiency.
        J Am Soc Nephrol. 2007; 18: 1889-1898
        • Jamerson K.A.
        • Nwose O.
        • Jean-Louis L.
        • et al.
        Initial angiotensin-converting enzyme inhibitor/calcium channel blocker combination therapy achieves superior blood pressure control compared with calcium channel blocker monotherapy in patients with stage 2 hypertension.
        Am J Hypertens. 2004; 17: 495-501
        • Clement D.L.
        • De Buyzere 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: 1-7
        • Cosin-Aguilar J.
        • Marrugat J.
        • Sanz G.
        • et al.
        Long-term results of the Spanish trial on treatment and survival of patients with predominantly mild heart failure.
        J Cardiovasc Pharmacol. 1999; 33: 733-740
        • Dohmen H.J.
        • Dunselman P.H.
        • Poole-Wilson P.A.
        Comparison of captopril and ibopamine in mild to moderate heart failure.
        Heart. 1997; 78: 285-290
        • Pitt B.
        • Segal R.
        • Martinez F.A.
        • et al.
        Randomised trial of losartan versus captopril in patients over 65 with heart failure (Evaluation of Losartan in the Elderly Study, ELITE).
        Lancet. 1997; 349: 747-752
        • Pitt B.
        • Poole-Wilson P.A.
        • Segal R.
        • et al.
        Effect of losartan compared with captopril on mortality in patients with symptomatic heart failure: randomised trial–the Losartan Heart Failure Survival Study ELITE II.
        Lancet. 2000; 355: 1582-1587
        • Lau C.P.
        • Tse H.F.
        • Ng W.
        • et al.
        Comparison of perindopril versus captopril for treatment of acute myocardial infarction.
        Am J Cardiol. 2002; 89: 150-154
        • Dickstein K.
        • Kjekshus J.
        • OPTIMAAL Steering Committee on the OPTIMAAL Study Group
        Effects of losartan and captopril on mortality and morbidity in high-risk patients after acute myocardial infarction: the OPTIMAAL randomised trial. Optimal Trial in Myocardial Infarction with Angiotensin II Antagonist Losartan.
        Lancet. 2002; 360: 752-760
        • Testa M.A.
        • Anderson R.B.
        • Nackley J.F.
        • Hollenberg N.K.
        Quality of life and antihypertensive therapy in men. A comparison of captopril with enalapri. The Quality-of-Life Hypertension Study Groupl.
        N Engl J Med. 1993; 328: 907-913
        • Roca-Cusachs A.
        • Oigman W.
        • Lepe L.
        • et al.
        A randomized, double-blind comparison of the antihypertensive efficacy and safety of once-daily losartan compared to twice-daily captopril in mild to moderate essential hypertension.
        Acta Cardiol. 1997; 52: 495-506
        • Pfeffer M.A.
        • Braunwald E.
        • Moyé L.A.
        • et al.
        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
        • Stimpel M.
        • Koch B.
        • Jansen T.
        • et al.
        Moexipril versus captopril in patients with mild to moderate hypertension.
        J Cardiovasc Pharmacol. 1996; 28: 769-773
      3. Efficacy of atenololcaptopril in reducing risk of macrovascularmicrovascular complications in type 2 diabetes: UKPDS 39.
        BMJ. 1998; 317 ([No authors listed]): 713-720
        • Pfeffer M.A.
        • McMurray J.J.
        • Velazquez E.J.
        • et al.
        Valsartan, captopril, or both in myocardial infarction complicated by heart failure, left ventricular dysfunction, or both.
        N Engl J Med. 2003; 349: 1893-1906
        • Fletcher A.E.
        • Bulpitt C.J.
        • Chase D.M.
        • et al.
        Quality of life with three antihypertensive treatments.
        Hypertension. 1992; 19: 499-507
      4. Does the new angiotensin-converting enzyme inhibitor cilazapril prevent restenosis after percutaneous transluminal coronary angioplasty? Results of the MERCATOR study: a multicenter, randomized, double-blind placebo-controlled trial. Multicenter European Research Trial with Cilazapril after Angioplasty to Prevent Transluminal Coronary Obstruction and Restenosis (MERCATOR) Study Group.
        Circulation. 1992; 86 ([No authors listed]): 100-110
      5. A 12-month comparison of ACE inhibitor and CA antagonist therapy in mild to moderate essential hypertension–The GLANT Study.
        Hypertens Res. 1995; 18 ([No authors listed]): 235-244
        • Roca-Cusachs A.
        • Schmieder R.E.
        • Triposkiadis F.
        • et al.
        Efficacy of manidipine/delapril versus losartan/hydrochlorothiazide fixed combinations in patients with hypertension and diabetes.
        J Hypertens. 2008; 26: 813-818
        • Estacio R.O.
        • Jeffers B.W.
        • Hiatt W.R.
        • et al.
        The effect of nisoldipine as compared with enalapril on cardiovascular outcomes in patients with non-insulin-dependent diabetes and hypertension.
        N Engl J Med. 1998; 338: 645-652
        • Amerena J.
        • Pappas S.
        • Ouellet J.P.
        • et al.
        ABPM comparison of the anti-hypertensive profiles of telmisartan and enalapril in patients with mild-to-moderate essential hypertension.
        J Int Med Res. 2002; 30: 543-552
        • Esnault V.L.
        • Brown E.A.
        • Apetrei E.
        • et al.
        The effects of amlodipine and enalapril on renal function in adults with hypertension and nondiabetic nephropathies: a 3-year, randomized, multicenter, double-blind, placebo-controlled study.
        Clin Ther. 2008; 30: 482-498
        • Breeze E.
        • Rake E.C.
        • Donoghue M.D.
        • Fletcher A.E.
        Comparison of quality of life and cough on eprosartan and enalapril in people with moderate hypertension.
        J Hum Hypertens. 2001; 15: 857-862
        • Nissen S.E.
        • Tuzcu E.M.
        • Libby P.
        • et al.
        Effect of antihypertensive agents on cardiovascular events in patients with coronary disease and normal blood pressure: the CAMELOT study: a randomized controlled trial.
        JAMA. 2004; 292: 2217-2225
        • Komajda M.
        • Lutiger B.
        • Madeira H.
        • et al.
        Tolerability of carvedilol and ACE-inhibition in mild heart failure.
        Eur J Heart Fail. 2004; 6: 467-475
        • Cuspidi C.
        • Muiesan M.L.
        • Valagussa L.
        • et al.
        Comparative effects of candesartan and enalapril on left ventricular hypertrophy in patients with essential hypertension: the candesartan assessment in the treatment of cardiac hypertrophy (CATCH) study.
        J Hypertens. 2002; 20: 2293-2300
        • Swedberg K.
        • Held P.
        • Kjekshus J.
        • et al.
        Effects of the early administration of enalapril on mortality in patients with acute myocardial infarction.
        N Engl J Med. 1992; 327: 678-684
        • Cushman W.C.
        • Cohen J.D.
        • Jones R.P.
        • et al.
        Comparison of the fixed combination of enalapril/diltiazem ER and their monotherapies in stage 1 to 3 essential hypertension.
        Am J Hypertens. 1998; 11: 23-30
        • Elliott W.J.
        Double-blind comparison of eprosartan and enalapril on cough and blood pressure in unselected hypertensive patients.
        J Hum Hypertens. 1999; 13: 413-417
        • Zannad F.
        • Chati Z.
        • Guest M.
        • Plat F.
        Differential effects of fosinopril and enalapril in patients with mild to moderate chronic heart failure.
        Am Heart J. 1998; 136: 672-680
        • Philipp T.
        • Anlauf M.
        • Distler A.
        • et al.
        Randomised, double blind, multicentre comparison of hydrochlorothiazide, atenolol, nitrendipine, and enalapril in antihypertensive treatment: results of the HANE study. HANE Trial Research Group.
        BMJ. 1997; 315: 154-159
        • Baba S.
        • J-MIND Study Group
        Nifedipine and enalapril equally reduce the progression of nephropathy in hypertensive type 2 diabetics.
        Diabetes Res Clin Pract. 2001; 54: 191-201
        • Yui Y.
        • Sumiyoshi T.
        • Kodama K.
        • et al.
        Comparison of nifedipine retard with angiotensin-converting enzyme inhibitors in Japanese hypertensive patients with coronary artery disease: the Japan Multicenter Investigation for Cardiovascular Diseases-B (JMIC-B) randomized trial.
        Hypertens Res. 2004; 27: 181-191
        • Keane W.F.
        • Polis A.
        • Wolf D.
        • et al.
        The long-term tolerability of enalapril in hypertensive patients with renal impairment.
        Nephrol Dial Transplant. 1997; 12: 75-81
        • Leon A.S.
        Efficacy and safety of enalapril versus extended-release nifedipine for the treatment of mild-to-moderate essential hypertension: a multicenter 22-week study. Multicenter Cooperative Study Group.
        Clin Ther. 1993; 15: 1094-1107
        • Malmqvist K.
        • Kahan T.
        • Dahl M.
        Angiotensin II type 1 (AT1) receptor blockade in hypertensive women: benefits of candesartan cilexetil versus enalapril or hydrochlorothiazide.
        Am J Hypertens. 2000; 13: 504-511
        • Coca A.
        • Calvo C.
        • García-Puig J.
        • et al.
        A multicenter, randomized, double-blind comparison of the efficacy and safety of irbesartan and enalapril in adults with mild to moderate essential hypertension, as assessed by ambulatory blood pressure monitoring: the MAPAVEL Study (Monitorización Ambulatoria Presión Arterial APROVEL).
        Clin Ther. 2002; 24: 126-138
        • Mimran A.
        • Ruilope L.
        • Kerwin L.
        • et al.
        A randomised, double-blind comparison of the angiotensin II receptor antagonist, irbesartan, with the full dose range of enalapril for the treatment of mild-to-moderate hypertension.
        J Hum Hypertens. 1998; 12: 203-208
        • Marre M.
        • Puig J.G.
        • Kokot F.
        • et al.
        Equivalence of indapamide SR and enalapril on microalbuminuria reduction in hypertensive patients with type 2 diabetes: the NESTOR Study.
        J Hypertens. 2004; 22: 1613-1622
      6. Clinical outcome with enalapril in symptomatic chronic heart failure; a dose comparison.
        Eur Heart J. 1998; 19 ([No authors listed]): 481-489
        • Omvik P.
        • Herland O.B.
        • Thaulow E.
        • et al.
        Evaluation and quality-of-life assessment of amlodipine and enalapril in patients with hypertension.
        J Hum Hypertens. 1995; 9: S17-24
        • Ostergren J.
        • Storstein L.
        • Karlberg B.E.
        • Tibblin G.
        Quality of life in hypertensive patients treated with either carvedilol or enalapril.
        Blood Press. 1996; 5: 41-49
        • Packer M.
        • Califf R.M.
        • Konstam M.A.
        • et al.
        Comparison of omapatrilat and enalapril in patients with chronic heart failure: the Omapatrilat Versus Enalapril Randomized Trial of Utility in Reducing Events (OVERTURE).
        Circulation. 2002; 106: 920-926
        • Perry Jr, H.M.
        • Hall W.D.
        • Benz J.R.
        • et al.
        Efficacy and safety of atenolol, enalapril, and isradipine in elderly hypertensive women.
        Am J Med. 1994; 96: 77-86
        • Dahlöf B.
        • Gosse P.
        • Guéret P.
        • et al.
        Perindopril/indapamide combination more effective than enalapril in reducing blood pressure and left ventricular mass: the PICXEL study.
        J Hypertens. 2005; 23: 2063-2070
        • Mogensen C.E.
        • Viberti G.
        • Halimi S.
        • et al.
        Effect of low-dose perindopril/indapamide on albuminuria in diabetes: preterax in albuminuria regression: PREMIER.
        Hypertension. 2003; 41: 1063-1071
        • Remme W.J.
        • Krayenbühl H.P.
        • Baumann G.
        • et al.
        Long-term efficacy and safety of pimobendan in moderate heart failure. A double-blind parallel 6-month comparison with enalapril. The Pimobendan-Enalapril Study Group.
        Eur Heart J. 1994; 15: 947-956
        • Agabiti Rosei E.
        • Morelli P.
        • Rizzoni D.
        Effects of nifedipine GITS 20 mg or enalapril 20 mg on blood pressure and inflammatory markers in patients with mild-moderate hypertension.
        Blood Press Suppl. 2005; 1: 14-22
        • Ruilope L.
        • Jäger B.
        • Prichard B.
        Eprosartan versus enalapril in elderly patients with hypertension: a double-blind, randomized trial.
        Blood Press. 2001; 10: 223-229
        • Saruta T.
        • Arakawa K.
        • Iimura O.
        • et al.
        Difference in the incidence of cough induced by angiotensin-converting enzyme inhibitors: a comparative study using imidapril hydrochloride and enalapril maleate.
        Hypertens Res. 1999; 22: 197-202
        • Saruta T.
        • Omae T.
        • Kuramochi M.
        • et al.
        Imidapril hydrochloride in essential hypertension: a double-blind comparative study using enalapril maleate as a control.
        J Hypertens Suppl. 1995; 13: 523-530
        • Os I.
        • Hotnes T.
        • Dollerup J.
        • Mogensen C.E.
        Comparison of the combination of enalapril and a very low dose of hydrochlorothiazide with atenolol in patients with mild-to-moderate hypertension.
        Am J Hypertens. 1997; 10: 899-904
        • Libretti A.
        • Catalano M.
        Lipid profile during antihypertensive treatment.
        Drugs. 1993; 46: 16-23
        • Kostis J.B.
        • Shelton B.
        • Gosselin G.
        • et al.
        Adverse effects of enalapril in the Studies of Left Ventricular Dysfunction (SOLVD).
        Am Heart J. 1996; 131: 350-355
        • Hansson L.
        • Lindholm L.H.
        • Ekbom T.
        • et al.
        Randomised trial of old and new antihypertensive drugs in elderly patients: cardiovascular mortality and morbidity the Swedish Trial in Old Patients with Hypertension-2 study.
        Lancet. 1999; 354: 1751-1756
        • Suzuki H.
        • Geshi E.
        • Nanjyo S.
        • et al.
        Inhibitory effect of valsartan against progression of left ventricular dysfunction after myocardial infarction: T-VENTURE study.
        Circ J. 2009; 73: 918-924
        • Karlberg B.E.
        • Lins L.E.
        • Hermansson K.
        Efficacy and safety of telmisartan, a selective AT1 receptor antagonist, compared with enalapril in elderly patients with primary hypertension.
        J Hypertens. 1999; 17: 293-302
        • Townsend R.
        • Haggert B.
        • Liss C.
        • Edelman J.M.
        Efficacy and tolerability of losartan versus enalapril alone or in combination with hydrochlorothiazide in patients with essential hypertension.
        Clin Ther. 1995; 17: 911-923
        • Koylan N.
        • Acarturk E.
        • Canberk A.
        • et al.
        Effect of irbesartan monotherapy compared with ACE inhibitors and calcium-channel blockers on patient compliance in essential hypertension patients: a multicenter, open-labeled, three-armed study.
        Blood Press Suppl. 2005; 1: 23-31
        • Cohn J.N.
        • Johnson G.
        • Ziesche S.
        • et al.
        A comparison of enalapril with hydralazine-isosorbide dinitrate in the treatment of chronic congestive heart failure.
        N Engl J Med. 1991; 325: 303-310
        • Van Nueten L.
        • Schelling A.
        • Vertommen C.
        • et al.
        Nebivolol vs enalapril in the treatment of essential hypertension: a double-blind randomised trial.
        J Hum Hypertens. 1997; 11: 813-819
        • Waeber B.
        • Detry J.M.
        • Dahlöf B.
        • et al.
        Felodipine-metoprolol combination tablet: a valuable option to initiate antihypertensive therapy?.
        Am J Hypertens. 1999; 12: 915-920
        • Williams G.H.
        • Burgess E.
        • Kolloch R.E.
        • et al.
        Efficacy of eplerenone versus enalapril as monotherapy in systemic hypertension.
        Am J Cardiol. 2004; 93: 990-996
        • Wu N.
        • Fan Z.
        Secondary prevention of cardiac events following myocardial infarction: effects of atenolol and enalapril. Beijing Collaborative Study Group.
        Chin Med J (Engl). 1997; 110: 602-606
        • Marin R.
        • Ruilope L.M.
        • Aljama P.
        • et al.
        A random comparison of fosinopril and nifedipine GITS in patients with primary renal disease.
        J Hypertens. 2001; 19: 1871-1876
        • Borghi C.
        • Marino P.
        • Zardini P.
        • et al.
        Short- and long-term effects of early fosinopril administration in patients with acute anterior myocardial infarction undergoing intravenous thrombolysis: results from the Fosinopril in Acute Myocardial Infarction Study. FAMIS Working Party.
        Am Heart J. 1998; 136: 213-225
        • Erhardt L.
        • MacLean A.
        • Ilgenfritz J.
        • et al.
        Fosinopril attenuates clinical deterioration and improves exercise tolerance in patients with heart failure.
        Eur Heart J. 1995; 16: 1892-1899
        • Fogari R.
        • Preti P.
        • Zoppi A.
        • et al.
        Effects of amlodipine fosinopril combination on microalbuminuria in hypertensive type 2 diabetic patients.
        Am J Hypertens. 2002; 15: 1042-1049
        • Cesari M.
        • Kritchevsky S.B.
        • Atkinson H.H.
        • et al.
        Angiotensin-converting enzyme inhibition and novel cardiovascular risk biomarkers: results from the Trial of Angiotensin-converting Enzyme Inhibition and Novel Cardiovascular Risk Factors (TRAIN) study.
        Am Heart J. 2009; 157: 334.e1-334.e8
        • Dews I.
        • VandenBurg M.
        A 24-week dose-titration study of the angiotensin-converting enzyme inhibitor imidapril in the treatment of mild-to-moderate essential hypertension in the elderly.
        J Int Med Res. 2001; 29: 100-107
        • van der Does R.
        • Euler R.
        A randomized, double-blind, parallel-group study to compare the anti-hypertensive effects of imidapril and nifedipine in the treatment of mild-to-moderate essential hypertension.
        J Int Med Res. 2001; 29: 154-162
        • 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.
        Circulation. 1999; 100: 2312-2318
        • Black H.R.
        • Graff A.
        • Shute D.
        • et al.
        Valsartan, a new angiotensin II antagonist for the treatment of essential hypertension: efficacy, tolerability and safety compared to an angiotensin-converting enzyme inhibitor, lisinopril.
        J Hum Hypertens. 1997; 11: 483-489
        • Bremner A.D.
        • Baur M.
        • Oddou-Stock P.
        • Bodin F.
        Valsartan: long-term efficacy and tolerability compared to lisinopril in elderly patients with essential hypertension.
        Clin Exp Hypertens. 1997; 19: 1263-1285
        • Chrysant S.G.
        Antihypertensive effectiveness of low-dose lisinopril-hydrochlorothiazide combination. A large multicenter study. Lisinopril-Hydrochlorothiazide Group.
        Arch Intern Med. 1994; 154: 737-743
      7. Randomised placebo-controlled trial of lisinopril in normotensive patients with insulin-dependent diabetes and normoalbuminuria or microalbuminuria.
        Lancet. 1997; 349 ([No authors listed]): 1787-1792
        • Rouleau J.L.
        • Pfeffer M.A.
        • Stewart D.J.
        • et al.
        Comparison of vasopeptidase inhibitor, omapatrilat, and lisinopril on exercise tolerance and morbidity in patients with heart failure: IMPRESS randomised trial.
        Lancet. 2000; 356: 615-620
        • Herlitz J.
        Comparison of lisinopril versus digoxin for congestive heart failure during maintenance diuretic therapy.
        Am J Cardiol. 1992; 70: 84C-90C
        • McInnes G.T.
        • O'Kane K.P.
        • Istad H.
        • et al.
        Comparison of the AT1-receptor blocker, candesartan cilexetil, and the ACE inhibitor, lisinopril, in fixed combination with low dose hydrochlorothiazide in hypertensive patients.
        J Hum Hypertens. 2000; 14: 263-269
        • Neutel J.M.
        • Frishman W.H.
        • Oparil S.
        • et al.
        Comparison of telmisartan with lisinopril in patients with mild-to-moderate hypertension.
        Am J Ther. 1999; 6: 161-166
        • Pannier B.E.
        • Garabedian V.G.
        • Madonna O.
        • et al.
        Lisinopril versus atenolol: decrease in systolic versus diastolic blood pressure with converting enzyme inhibition.
        Cardiovasc Drugs Ther. 1991; 5: 775-781
        • Malacco E.
        • Santonastaso M.
        • Vari N.A.
        • et al.
        Comparison of valsartan 160 mg with lisinopril 20 mg, given as monotherapy or in combination with a diuretic, for the treatment of hypertension: the Blood Pressure Reduction and Tolerability of Valsartan in Comparison with Lisinopril (PREVAIL) study.
        Clin Ther. 2004; 26: 855-865
        • Chrysant S.G.
        • Stimpel M.
        Antihypertensive effectiveness of a very low fixed-dose combination of moexipril and hydrochlorothiazide.
        J Cardiovasc Pharmacol. 1998; 31: 384-390
        • Patel A.
        • MacMahon S.
        • et al.
        • ADVANCE Collaborative Group
        Effects of a fixed combination of perindopril and indapamide on macrovascular and microvascular outcomes in patients with type 2 diabetes mellitus (the ADVANCE trial): a randomised controlled trial.
        Lancet. 2007; 370: 829-840
        • Castaigne A.
        • Chalmers J.
        • Morgan T.
        • et al.
        Efficacy and safety of an oral fixed low-dose perindopril 2 MG/indapamide 0.625 MG combination: a randomized, double-blind, placebo-controlled study in elderly patients with mild to moderate hypertension.
        Clin Exp Hypertens. 1999; 21: 1097-1110
        • Chanudet X.
        • De Champvallins M.
        Antihypertensive efficacy and tolerability of low-dose perindopril/indapamide combination compared with losartan in the treatment of essential hypertension.
        Int J Clin Pract. 2001; 55: 233-239
        • Fox K.M.
        EURopean trial On reduction of cardiac events with Perindopril in stable coronary Artery disease Investigators.
        Lancet. 2003; 362: 782-788
        • Mallion J.M.
        • Chastang C.
        • Unger P.
        Efficacy and safety of a fixed low-dose perindopril/indapamide combination in essential hypertension.
        Clin Exp Hypertens. 2000; 22: 23-32
        • Chrysant S.G.
        • McDonald R.H.
        • Wright J.T.
        • et al.
        Perindopril as monotherapy in hypertension: a multicenter comparison of two dosing regimens. The Perindopril Study Group.
        Clin Pharmacol Ther. 1993; 53: 479-484
        • Ferrari R.
        • Perindopril and Remodeling in Elderly with Acute Myocardial Infarction Investigators
        Effects of angiotensin-converting enzyme inhibition with perindopril on left ventricular remodeling and clinical outcome: results of the randomized Perindopril and Remodeling in Elderly with Acute Myocardial Infarction (PREAMI) Study.
        Arch Intern Med. 2006; 166: 659-666
        • Mallion J.M.
        • Chamontin B.
        • Asmar R.
        • et al.
        Twenty-four-hour ambulatory blood pressure monitoring efficacy of perindopril/indapamide first-line combination in hypertensive patients: the REASON study.
        Am J Hypertens. 2004; 17: 245-251
        • Mourad J.J.
        • Waeber B.
        • Zannad F.
        • et al.
        Comparison of different therapeutic strategies in hypertension: a low-dose combination of perindopril/indapamide versus a sequential monotherapy or a stepped-care approach.
        J Hypertens. 2004; 22: 2379-2386
        • Gliddon A.E.
        • Doré C.J.
        • Black C.M.
        • et al.
        Prevention of vascular damage in scleroderma and autoimmune Raynaud's phenomenon: a multicenter, randomized, double-blind, placebo-controlled trial of the angiotensin-converting enzyme inhibitor quinapril.
        Arthritis Rheum. 2007; 56: 3837-3846
        • Rouleau J.L.
        • Warnica W.J.
        • Baillot R.
        • et al.
        Effects of angiotensin-converting enzyme inhibition in low-risk patients early after coronary artery bypass surgery.
        Circulation. 2008; 117: 24-31
        • Okimoto T.
        • Imazu M.
        • Hayashi Y.
        • et al.
        Quinapril with high affinity to tissue angiotensin-converting enzyme reduces restenosis after percutaneous transcatheter coronary intervention.
        Cardiovasc Drugs Ther. 2001; 15: 323-329
        • Pitt B.
        • O'Neill B.
        • Feldman R.
        • et al.
        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
        • Riegger G.A.
        Effects of quinapril on exercise tolerance in patients with mild to moderate heart failure.
        Eur Heart J. 1991; 12: 705-711
        • Rosenthal J.
        • Bahrmann H.
        • Benkert K.
        • et al.
        Analysis of adverse effects among patients with essential hypertension receiving an ACE inhibitor or a beta-blocker.
        Cardiology. 1996; 87: 409-414
      8. Effect of ramipril on mortality and morbidity of survivors of acute myocardial infarction with clinical evidence of heart failure.
        Lancet. 1993; 342 ([No authors listed]): 821-828
        • Andersen K.
        • Weinberger M.H.
        • Egan B.
        • et al.
        Comparative efficacy and safety of aliskiren, an oral direct renin inhibitor, and ramipril in hypertension: a 6-month, randomized, double-blind trial.
        J Hypertens. 2008; 26: 589-599
        • Miranda R.D.
        • Mion Jr, D.
        • Rocha J.C.
        • et al.
        An 18-week, prospective, randomized, double-blind, multicenter study of amlodipine/ramipril combination versus amlodipine monotherapy in the treatment of hypertension: the assessment of combination therapy of amlodipine/ramipril (ATAR) study.
        Clin Ther. 2008; 30: 1618-1628
        • Marre M.
        • Lievre M.
        • Chatellier G.
        • et al.
        Effects of low dose ramipril on cardiovascular and renal outcomes in patients with type 2 diabetes and raised excretion of urinary albumin: randomised, double blind, placebo controlled trial (the DIABHYCAR study).
        BMJ. 2004; 328: 495
        • Bosch J.
        • Yusuf S.
        • et al.
        • DREAM Trial Investigators
        Effect of ramipril on the incidence of diabetes.
        N Engl J Med. 2006; 355: 1551-1562
        • Yusuf S.
        • Sleight P.
        • Pogue J.
        • et al.
        Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients.
        N Engl J Med. 2000; 342: 145-153
        • Bakris G.L.
        • Ruilope L.
        • Locatelli F.
        • et al.
        Treatment of microalbuminuria in hypertensive subjects with elevated cardiovascular risk: results of the IMPROVE trial.
        Kidney Int. 2007; 72: 879-885
        • Yusuf S.
        • Teo K.K.
        • et al.
        • ONTARGET Investigators
        Telmisartan, ramipril, or both in patients at high risk for vascular events.
        N Engl J Med. 2008; 358: 1547-1559
        • Luders S.
        • Schrader J.
        • Berger J.
        • et al.
        The PHARAO study: prevention of hypertension with the angiotensin-converting enzyme inhibitor ramipril in patients with high-normal blood pressure: a prospective, randomized, controlled prevention trial of the German Hypertension League.
        J Hypertens. 2008; 26: 1487-1496
        • Williams B.
        • Gosse P.
        • Lowe L.
        • Harper R.
        • PRISMA I Study Group
        The prospective, randomized investigation of the safety and efficacy of telmisartan versus ramipril using ambulatory blood pressure monitoring (PRISMA I).
        J Hypertens. 2006; 24: 193-200
        • Lacourcière Y.
        • Neutel J.M.
        • Davidai G.
        • Koval S.
        A multicenter, 14-week study of telmisartan and ramipril in patients with mild-to-moderate hypertension using ambulatory blood pressure monitoring.
        Am J Hypertens. 2006; 19: 104-112
        • Pittrow D.B.
        • Antlsperger A.
        • Welzel D.
        • et al.
        Evaluation of the efficacy and tolerability of a low-dose combination of isradipine and spirapril in the first-line treatment of mild to moderate essential hypertension.
        Cardiovasc Drugs Ther. 1997; 11: 619-627
        • Sierakowski B.
        • Püchler K.
        • Witte P.U.
        • et al.
        Comparison of temocapril and atenolol in the long-term treatment of mild to moderate essential hypertension.
        Blood Press. 1997; 6: 229-234
        • Ruggenenti P.
        • Fassi A.
        • Ilieva A.P.
        • et al.
        Preventing microalbuminuria in type 2 diabetes.
        N Engl J Med. 2004; 351: 1941-1951
        • Braunwald E.
        • Domanski M.J.
        • Fowler S.E.
        • et al.
        Angiotensin-converting-enzyme inhibition in stable coronary artery disease.
        N Engl J Med. 2004; 351: 2058-2068
        • Ruilope L.M.
        • Usan L.
        • Segura J.
        • Bakris G.L.
        Intervention at lower blood pressure levels to achieve target goals in type 2 diabetes: PRADID (PResión Arterial en DIabéticos tipo Dos) study.
        J Hypertens. 2004; 22: 217-222
        • Toto R.D.
        • Tian M.
        • Fakouhi K.
        • et al.
        Effects of calcium channel blockers on proteinuria in patients with diabetic nephropathy.
        J Clin Hypertens (Greenwich). 2008; 10: 761-769
        • Kober L.
        • Torp-Pedersen C.
        • Carlsen J.E.
        • et al.
        A clinical trial of the angiotensin-converting-enzyme inhibitor trandolapril in patients with left ventricular dysfunction after myocardial infarction.
        N Engl J Med. 1995; 333: 1670-1676
        • Farsang C.
        Blood pressure control and response rates with zofenopril compared with amlodipine in hypertensive patients.
        Blood Press Suppl. 2007; 2: 19-24

      Linked Article

      • Robust, Reliable Drug Safety Information
        The American Journal of MedicineVol. 124Issue 4
        • Preview
          In their recent meta-analysis, “Angiotensin-Converting Enzyme Inhibitor Associated Cough: Deceptive Information from the Physicians' Desk Reference,” Bangalore et al1 describe underreporting of angiotensin-converting enzyme inhibitor-associated cough in commercial product information, compared with medical literature, and the persistence of underreporting over decades. Robust, reliable, and accurate information regarding drug safety is essential to inform risk/benefit therapeutic decisions. This is especially important for drugs that are widely used and when the consequences of an adverse event may be catastrophic.
        • Full-Text
        • PDF