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In Reply—The Different Effects of Angiotensin-Converting Enzyme Inhibitors and Angiotensin Receptor Blockers on Mortality

      Dr Mourad contends that the angiotensin-converting enzyme inhibitors (ACEis) are the only drug class to produce a major reduction in mortality even in contemporary practice and that angiotensin receptor blockers (ARBs) have no such effect. To support this position, he cites the data from his own meta-analysis
      • van Vark L.C.
      • Bertrand M.
      • Akkerhuis K.M.
      • et al.
      Angiotensin-converting enzyme inhibitors reduce mortality in hypertension: a meta-analysis of randomized clinical trials of renin-angiotensin-aldosterone system inhibitors involving 158,998 patients.
      and that of Savarese et al.
      • Savarese G.
      • Costanzo P.
      • Cleland J.G.
      • et al.
      A meta-analysis reporting effects of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers in patients without heart failure.
      This position is flawed for the simple but inescapable fact that no head-to-head trial of ACEis vs ARBs in patients without heart failure has documented a mortality advantage of ACEis. Head-to-head comparison trials are the only way to accurately test whether there is a mortality benefit of ACEis over ARBs. In fact, our analysis of 7 head-to-head randomized trials of ARBs vs ACEis with 22,422 participants revealed that no such mortality benefit exists (relative risk, 0.98; 95% CI, 0.90-1.07).
      • Bangalore S.
      • Fakheri R.
      • Toklu B.
      • Ogedegbe G.
      • Weintraub H.
      • Messerli F.H.
      Angiotensin-converting enzyme inhibitors or angiotensin receptor blockers in patients without heart failure? insights from 254,301 patients from randomized trials.
      Our analysis was very well powered (92%) to identify at least a 15% reduction in mortality with ACEis. The results of head-to-head comparison trials trump any indirect inference of ACEis and ARBs and confirms our conclusion that the effect of ACEis and ARBs are largely similar.
      • Bangalore S.
      • Fakheri R.
      • Toklu B.
      • Ogedegbe G.
      • Weintraub H.
      • Messerli F.H.
      Angiotensin-converting enzyme inhibitors or angiotensin receptor blockers in patients without heart failure? insights from 254,301 patients from randomized trials.
      Why are the results of the 3 meta-analyses for the end point of mortality different? The Table compares the 3 meta-analyses and the trials included in each. Savarese et al
      • Savarese G.
      • Costanzo P.
      • Cleland J.G.
      • et al.
      A meta-analysis reporting effects of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers in patients without heart failure.
      and van Vark et al
      • van Vark L.C.
      • Bertrand M.
      • Akkerhuis K.M.
      • et al.
      Angiotensin-converting enzyme inhibitors reduce mortality in hypertension: a meta-analysis of randomized clinical trials of renin-angiotensin-aldosterone system inhibitors involving 158,998 patients.
      combined both placebo-controlled trials and active-control trials (which is problematic), whereas we analyzed placebo-controlled trials separately from the active-control trials. Moreover, the number of placebo-controlled trials included in our analysis is far greater than that in either of the other 2 meta-analyses. The results of van Vark et al
      • van Vark L.C.
      • Bertrand M.
      • Akkerhuis K.M.
      • et al.
      Angiotensin-converting enzyme inhibitors reduce mortality in hypertension: a meta-analysis of randomized clinical trials of renin-angiotensin-aldosterone system inhibitors involving 158,998 patients.
      are driven by trials such as ASCOT-BPLA (Anglo-Scandinavian Cardiac Outcomes Trial–Blood Pressure Lowering Arm) and HYVET (Hypertension in the Very Elderly Trial), which are not ACEi trials. In both of these trials, ACEi was used as an add-on, if needed, and only a proportion of randomized patients received ACEis. Moreover, they included the ADVANCE (Action in Diabetes and Vascular Disease: PreterAx and Diamicron MR Controlled Evaluation) trial, which was a trial of a fixed-dose combination of perindopril and indapamide compared with placebo. It is therefore not acceptable to consider these trials as purely ACEi trials. Thus, a combination of the inclusion of trials that are inappropriate or conducted before 2000 and the exclusion of a large number of placebo-controlled trials in the 2 meta-analyses drives the difference in results among the 3 analyses. Finally, Supplemental Table 5 in our article provides the placebo death rate for the ACEi and ARB trials (2.65%/y vs 2.05%/y), and it is clear that the placebo death rate is higher in the ACEi trials. The discordance between this rate and the rate calculated by Mourad is due to a computational error. Dr Mourad used the average follow-up duration across all trials (placebo/active control) and not just the placebo-controlled trial follow-up period to calculate placebo event rates. In addition, he did not consider the weight of each of the trials. Each trial provides a certain weight for the overall analysis based on event rate and sample size.
      TableComparison of the Effect of ACEis on Mortality in 3 Contemporary Meta-analyses
      ACEi trialYear publishedComparisonBangalore et al
      • Bangalore S.
      • Fakheri R.
      • Toklu B.
      • Ogedegbe G.
      • Weintraub H.
      • Messerli F.H.
      Angiotensin-converting enzyme inhibitors or angiotensin receptor blockers in patients without heart failure? insights from 254,301 patients from randomized trials.
      (sensitivity analysis for placebo trials published after 2000)
      Saravese et al
      • Savarese G.
      • Costanzo P.
      • Cleland J.G.
      • et al.
      A meta-analysis reporting effects of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers in patients without heart failure.
      van Vark et al
      • van Vark L.C.
      • Bertrand M.
      • Akkerhuis K.M.
      • et al.
      Angiotensin-converting enzyme inhibitors reduce mortality in hypertension: a meta-analysis of randomized clinical trials of renin-angiotensin-aldosterone system inhibitors involving 158,998 patients.
      BENEDICT
      • Ruggenenti P.
      • Fassi A.
      • Ilieva A.P.
      • et al.
      Bergamo Nephrologic Diabetes Complications Trial (BENEDICT) Investigators
      Preventing microalbuminuria in type 2 diabetes.
      2004PlaceboX
      CAMELOT
      • Nissen S.E.
      • Tuzcu E.M.
      • Libby P.
      • et al.
      CAMELOT Investigators
      Effect of antihypertensive agents on cardiovascular events in patients with coronary disease and normal blood pressure: the CAMELOT study; a randomized controlled trial.
      2004PlaceboXX
      DEMAND
      • Ruggenenti P.
      • Lauria G.
      • Iliev I.P.
      • et al.
      DEMAND Study Investigators
      Effects of manidipine and delapril in hypertensive patients with type 2 diabetes mellitus: the Delapril and Manidipine for Nephroprotection in Diabetes (DEMAND) randomized clinical trial.
      2011PlaceboX
      DIABHYCAR
      • Marre M.
      • Lievre M.
      • Chatellier G.
      • Mann J.F.
      • Passa P.
      • Ménard J.
      DIABHYCAR Study Investigators
      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).
      2004PlaceboXX
      DREAM
      DREAM Trial Investigators
      Effect of ramipril on the incidence of diabetes.
      DREAM Trial Investigators
      Effects of ramipril and rosiglitazone on cardiovascular and renal outcomes in people with impaired glucose tolerance or impaired fasting glucose: results of the Diabetes REduction Assessment with ramipril and rosiglitazone Medication (DREAM) trial.
      2006PlaceboXX
      EUROPA
      European Trial on Reduction of Cardiac Events With Perindopril in Stable Coronary Artery Disease Investigators
      Efficacy of perindopril in reduction of cardiovascular events among patients with stable coronary artery disease: randomised, double-blind, placebo-controlled, multicentre trial (the EUROPA study).
      2003PlaceboXX
      Hou et al
      • Hou F.F.
      • Zhang X.
      • Zhang G.H.
      • et al.
      Efficacy and safety of benazepril for advanced chronic renal insufficiency.
      2006PlaceboX
      IMAGINE
      • Rouleau J.L.
      • Warnica W.J.
      • Baillot R.
      • et al.
      IMAGINE (Ischemia Management With Accupril Post-Bypass Graft via Inhibition of the Converting Enzyme) Investigators
      Effects of angiotensin-converting enzyme inhibition in low-risk patients early after coronary artery bypass surgery.
      2008PlaceboXX
      PEACE
      PEACE Trial Investigators
      Angiotensin-converting-enzyme inhibition in stable coronary artery disease.
      2004PlaceboXX
      PHARAO
      • Lüders S.
      • Schrader J.
      • Berger J.
      • et al.
      PHARAO Study Group
      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.
      2008PlaceboX
      PREAMI
      PREAMI 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.
      2006PlaceboX
      PREVEND IT
      • Asselbergs F.W.
      • Diercks G.F.
      • Hillege H.L.
      • et al.
      Prevention of Renal and Vascular Endstage Disease Intervention Trial (PREVEND IT) Investigators
      Effects of fosinopril and pravastatin on cardiovascular events in subjects with microalbuminuria.
      2004PlaceboX
      PROGRESS
      PROGRESS Collaborative Group
      Randomised trial of a perindopril-based blood-pressure-lowering regimen among 6,105 individuals with previous stroke or transient ischaemic attack.
      2001PlaceboXX
      QUIET
      • Pitt B.
      • O'Neill B.
      • Feldman R.
      • et al.
      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.
      2001PlaceboXX
      QUINS
      • 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.
      2007PlaceboX
      QUO VADIS
      • Oosterga M.
      • Voors A.A.
      • Pinto Y.M.
      • et al.
      Effects of quinapril on clinical outcome after coronary artery bypass grafting (the QUO VADIS Study).
      2001PlaceboX
      RASS
      • Mauer M.
      • Zinman B.
      • Gardiner R.
      • et al.
      Renal and retinal effects of enalapril and losartan in type 1 diabetes.
      2009PlaceboX
      Wang et al
      • Wang N.
      • Zheng Z.
      • Jin H.Y.
      • Xu X.
      Treatment effects of captopril on non-proliferative diabetic retinopathy.
      2012PlaceboX
      ADVANCE
      • Patel A.
      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.
      2007PlaceboX
      HYVET
      • Beckett N.S.
      • Peters R.
      • Fletcher A.E.
      • et al.
      HYVET Study Group
      Treatment of hypertension in patients 80 years of age or older.
      2008PlaceboX
      AIPRI
      • Maschio G.
      • Alberti D.
      • Janin G.
      • et al.
      Angiotensin-Converting-Enzyme Inhibition in Progressive Renal Insufficiency Study Group
      Effect of the angiotensin-converting-enzyme inhibitor benazepril on the progression of chronic renal insufficiency.
      1996PlaceboX
      Lewis et al
      • Lewis E.J.
      • Hunsicker L.G.
      • Bain R.P.
      • Rohde R.D.
      Collaborative Study Group
      The effect of angiotensin-converting-enzyme inhibition on diabetic nephropathy.
      1993PlaceboX
      PART-2
      • MacMahon S.
      • Sharpe N.
      • Gamble G.
      • et al.
      PART-2 Collaborative Research Group
      Randomized, placebo-controlled trial of the angiotensin-converting enzyme inhibitor, ramipril, in patients with coronary or other occlusive arterial disease.
      2000PlaceboX
      SCAT
      • Teo K.K.
      • Burton J.R.
      • Buller C.E.
      • et al.
      Long-term effects of cholesterol lowering and angiotensin-converting enzyme inhibition on coronary atherosclerosis: the Simvastatin/Enalapril Coronary Atherosclerosis Trial (SCAT).
      2000PlaceboX
      ALLHAT
      • Barzilay J.I.
      • Davis B.R.
      • Cutler J.A.
      • et al.
      ALLHAT Collaborative Research Group
      Fasting glucose levels and incident diabetes mellitus in older nondiabetic adults randomized to receive 3 different classes of antihypertensive treatment: a report from the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT).
      ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group
      Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic: the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT).
      2002Chlorthalidone or amlodipineX
      ANBP2
      • Chowdhury E.K.
      • Owen A.
      • Ademi Z.
      • et al.
      Second Australian National Blood Pressure Study Management Committee
      Short- and long-term survival in treated elderly hypertensive patients with or without diabetes: findings from the Second Australian National Blood Pressure study.
      • Wing L.M.
      • Reid C.M.
      • Ryan P.
      • et al.
      Second Australian National Blood Pressure Study Group
      A comparison of outcomes with angiotensin-converting–enzyme inhibitors and diuretics for hypertension in the elderly.
      2003HCTZX
      ASCOT-BPLA
      • Dahlöf B.
      • Sever P.S.
      • Poulter N.R.
      • et al.
      ASCOT Investigators
      Prevention of cardiovascular events with an antihypertensive regimen of amlodipine adding perindopril as required versus atenolol adding bendroflumethiazide as required, in the Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure Lowering Arm (ASCOT-BPLA): a multicentre randomised controlled trial.
      2005Atenolol +/− bendroflumethiazideX
      HYVET-pilot
      • Bulpitt C.J.
      • Beckett N.S.
      • Cooke J.
      • et al.
      Hypertension in the Very Elderly Trial Working Group
      Results of the pilot study for the Hypertension in the Very Elderly Trial.
      2003ThiazidesX
      JMIC-B
      • Yui Y.
      • Sumiyoshi T.
      • Kodama K.
      • et al.
      JMIC-B Study Group
      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.
      2004NifedipineX
      HOPE
      • Bosch J.
      • Yusuf S.
      • Pogue J.
      • et al.
      HOPE Investigators
      Use of ramipril in preventing stroke: double blind randomised trial.
      • Dagenais G.R.
      • Yusuf S.
      • Bourassa M.G.
      • et al.
      HOPE Investigators
      Effects of ramipril on coronary events in high-risk persons: results of the Heart Outcomes Prevention Evaluation Study.
      Heart Outcomes Prevention Evaluation Study Investigators
      Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients.
      2000AtenololX
      ACEi vs controls (as reported in the publication)0.89 (0.76-1.05)0.91 (0.85-0.98)0.90 (0.84-0.97)
      ACEis = angiotensin-converting enzyme inhibitors; ADVANCE = Action in Diabetes and Vascular Disease: PreterAx and Diamicron MR Controlled Evaluation; AIPRI = Angiotensin-Converting-Enzyme Inhibition in Progressive Renal Insufficiency; ALLHAT = Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial; ANBP2 = Second Australian National Blood Pressure Study; ASCOT-BPLA = Anglo-Scandinavian Cardiac Outcomes Trial–Blood Pressure Lowering Arm; BENEDICT = Bergamo Nephrologic Diabetes Complications Trial; CAMELOT = Comparison of Amlodipine vs Enalapril to Limit Occurrences of Thrombosis; DEMAND = Delapril and Manidipine for Nephroprotection in Diabetes; DIABHYCAR = Non-Insulin-Dependent Diabetes, Hypertension, Microalbuminuria or Proteinuria, Cardiovascular Events, and Ramipril; DREAM = Diabetes Reduction Assessment With Ramipril and Rosiglitazone Medication; EUROPA = European Trial on Reduction of Cardiac Events With Perindopril in Stable Coronary Artery Disease; HCTZ = hydrochlorothiazide; HOPE = Heart Outcomes Prevention Evaluation; HYVET = Hypertension in the Very Elderly Trial; IMAGINE = Ischemia Management With Accupril Post-Bypass Graft via Inhibition of the Converting Enzyme; JMIC-B = Japan Multicenter Investigation for Cardiovascular Diseases-B; PART-2 = Prevention of Atherosclerosis with Ramipril Trial; PEACE = Prevention of Events With Angiotensin Converting Enzyme Inhibition; PHARAO = Prevention of Hypertension in Patients With High-Normal Blood Pressure With the Angiotensin-Converting-Enzyme-Inhibitor Ramipril; PREAMI = Perindopril and Remodeling in Elderly with Acute Myocardial Infarction; PREVEND IT = Prevention of Renal and Vascular Endstage Disease Intervention Trial; PROGRESS = Perindopril Protection Against Recurrent Stroke Study; QUIET = Quinapril Ischemic Event Trial; QUINS = Quinapril in Scleroderma; QUO VADIS = Quinapril on Vascular ACE and Determinants of Ischemia; RASS = Renin-Angiotensin System Study; SCAT = Simvastatin/Enalapril Coronary Atherosclerosis Trial.
      Similarly, the results of van Vark et al
      • van Vark L.C.
      • Bertrand M.
      • Akkerhuis K.M.
      • et al.
      Angiotensin-converting enzyme inhibitors reduce mortality in hypertension: a meta-analysis of randomized clinical trials of renin-angiotensin-aldosterone system inhibitors involving 158,998 patients.
      and Savarese et al
      • Savarese G.
      • Costanzo P.
      • Cleland J.G.
      • et al.
      A meta-analysis reporting effects of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers in patients without heart failure.
      fail to explain why the mortality benefit of ACEis (if there truly is one) is not seen in head-to-head comparison trials of ACEis vs ARBs. Ours is the only meta-analysis that ties together the results of placebo-controlled trials, active-control trials, and head-to-head comparison trials, all of which reveal that the outcomes between ACEis and ARBs in patients without heart failure are largely similar.

      References

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        • Bertrand M.
        • Akkerhuis K.M.
        • et al.
        Angiotensin-converting enzyme inhibitors reduce mortality in hypertension: a meta-analysis of randomized clinical trials of renin-angiotensin-aldosterone system inhibitors involving 158,998 patients.
        Eur Heart J. 2012; 33: 2088-2097
        • Savarese G.
        • Costanzo P.
        • Cleland J.G.
        • et al.
        A meta-analysis reporting effects of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers in patients without heart failure.
        J Am Coll Cardiol. 2013; 61: 131-142
        • Bangalore S.
        • Fakheri R.
        • Toklu B.
        • Ogedegbe G.
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        • Messerli F.H.
        Angiotensin-converting enzyme inhibitors or angiotensin receptor blockers in patients without heart failure? insights from 254,301 patients from randomized trials.
        Mayo Clin Proc. 2016; 91: 51-60
        • Ruggenenti P.
        • Fassi A.
        • Ilieva A.P.
        • et al.
        • Bergamo Nephrologic Diabetes Complications Trial (BENEDICT) Investigators
        Preventing microalbuminuria in type 2 diabetes.
        N Engl J Med. 2004; 351: 1941-1951
        • Nissen S.E.
        • Tuzcu E.M.
        • Libby P.
        • et al.
        • CAMELOT Investigators
        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
        • Ruggenenti P.
        • Lauria G.
        • Iliev I.P.
        • et al.
        • DEMAND Study Investigators
        Effects of manidipine and delapril in hypertensive patients with type 2 diabetes mellitus: the Delapril and Manidipine for Nephroprotection in Diabetes (DEMAND) randomized clinical trial.
        Hypertension. 2011; 58: 776-783
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        • Lievre M.
        • Chatellier G.
        • Mann J.F.
        • Passa P.
        • Ménard J.
        • DIABHYCAR Study Investigators
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        BMJ. 2004; 328 ([published correction appears in BMJ. 2004;328(7441):686]): 495
        • DREAM Trial Investigators
        Effect of ramipril on the incidence of diabetes.
        N Engl J Med. 2006; 355: 1551-1562
        • DREAM Trial Investigators
        Effects of ramipril and rosiglitazone on cardiovascular and renal outcomes in people with impaired glucose tolerance or impaired fasting glucose: results of the Diabetes REduction Assessment with ramipril and rosiglitazone Medication (DREAM) trial.
        Diabetes Care. 2008; 31: 1007-1014
        • European Trial on Reduction of Cardiac Events With Perindopril in Stable Coronary Artery Disease Investigators
        Efficacy of perindopril in reduction of cardiovascular events among patients with stable coronary artery disease: randomised, double-blind, placebo-controlled, multicentre trial (the EUROPA study).
        Lancet. 2003; 362: 782-788
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        • 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
        • Rouleau J.L.
        • Warnica W.J.
        • Baillot R.
        • et al.
        • IMAGINE (Ischemia Management With Accupril Post-Bypass Graft via Inhibition of the Converting Enzyme) Investigators
        Effects of angiotensin-converting enzyme inhibition in low-risk patients early after coronary artery bypass surgery.
        Circulation. 2008; 117: 24-31
        • PEACE Trial Investigators
        Angiotensin-converting-enzyme inhibition in stable coronary artery disease.
        N Engl J Med. 2004; 351: 2058-2068
        • Lüders S.
        • Schrader J.
        • Berger J.
        • et al.
        • PHARAO Study Group
        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
        • PREAMI 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
        • Asselbergs F.W.
        • Diercks G.F.
        • Hillege H.L.
        • et al.
        • Prevention of Renal and Vascular Endstage Disease Intervention Trial (PREVEND IT) Investigators
        Effects of fosinopril and pravastatin on cardiovascular events in subjects with microalbuminuria.
        Circulation. 2004; 110: 2809-2816
        • PROGRESS Collaborative Group
        Randomised trial of a perindopril-based blood-pressure-lowering regimen among 6,105 individuals with previous stroke or transient ischaemic attack.
        Lancet. 2001; 358 ([published corrections appear in Lancet. 2001;358(9292):1556 and Lancet. 2002;359(9323):2120]): 1033-1041
        • Pitt B.
        • O'Neill B.
        • Feldman R.
        • et al.
        • 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
        • 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
        • Oosterga M.
        • Voors A.A.
        • Pinto Y.M.
        • et al.
        Effects of quinapril on clinical outcome after coronary artery bypass grafting (the QUO VADIS Study).
        Am J Cardiol. 2001; 87: 542-546
        • Mauer M.
        • Zinman B.
        • Gardiner R.
        • et al.
        Renal and retinal effects of enalapril and losartan in type 1 diabetes.
        N Engl J Med. 2009; 361: 40-51
        • Wang N.
        • Zheng Z.
        • Jin H.Y.
        • Xu X.
        Treatment effects of captopril on non-proliferative diabetic retinopathy.
        Chin Med J (Engl). 2012; 125: 287-292
        • Patel A.
        • 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
        • Beckett N.S.
        • Peters R.
        • Fletcher A.E.
        • et al.
        • HYVET Study Group
        Treatment of hypertension in patients 80 years of age or older.
        N Engl J Med. 2008; 358: 1887-1898
        • Maschio G.
        • Alberti D.
        • Janin G.
        • et al.
        • Angiotensin-Converting-Enzyme Inhibition in Progressive Renal Insufficiency Study Group
        Effect of the angiotensin-converting-enzyme inhibitor benazepril on the progression of chronic renal insufficiency.
        N Engl J Med. 1996; 334: 939-945
        • Lewis E.J.
        • Hunsicker L.G.
        • Bain R.P.
        • Rohde R.D.
        • Collaborative Study Group
        The effect of angiotensin-converting-enzyme inhibition on diabetic nephropathy.
        N Engl J Med. 1993; 329: 1456-1462
        • MacMahon S.
        • Sharpe N.
        • Gamble G.
        • et al.
        • PART-2 Collaborative Research Group
        Randomized, placebo-controlled trial of the angiotensin-converting enzyme inhibitor, ramipril, in patients with coronary or other occlusive arterial disease.
        J Am Coll Cardiol. 2000; 36: 438-443
        • Teo K.K.
        • Burton J.R.
        • Buller C.E.
        • et al.
        Long-term effects of cholesterol lowering and angiotensin-converting enzyme inhibition on coronary atherosclerosis: the Simvastatin/Enalapril Coronary Atherosclerosis Trial (SCAT).
        Circulation. 2000; 102: 1748-1754
        • Barzilay J.I.
        • Davis B.R.
        • Cutler J.A.
        • et al.
        • ALLHAT Collaborative Research Group
        Fasting glucose levels and incident diabetes mellitus in older nondiabetic adults randomized to receive 3 different classes of antihypertensive treatment: a report from the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT).
        Arch Intern Med. 2006; 166: 2191-2201
        • ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group
        Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic: the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT).
        JAMA. 2002; 288 ([published corrections appear in JAMA. 2003;289(2):178 and JAMA. 2004;291(18):2196]): 2981-2997
        • Chowdhury E.K.
        • Owen A.
        • Ademi Z.
        • et al.
        • Second Australian National Blood Pressure Study Management Committee
        Short- and long-term survival in treated elderly hypertensive patients with or without diabetes: findings from the Second Australian National Blood Pressure study.
        Am J Hypertens. 2014; 27: 199-206
        • Wing L.M.
        • Reid C.M.
        • Ryan P.
        • et al.
        • Second Australian National Blood Pressure Study Group
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      Linked Article

      • The Different Effects of Angiotensin-Converting Enzyme Inhibitors and Angiotensin Receptor Blockers on Mortality
        Mayo Clinic ProceedingsVol. 91Issue 7
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          The article by Bangalore et al1 published in the January 2016 issue of Mayo Clinic Proceedings deals with the important topic of cardiovascular protection. In this regard, several recent studies have compared the 2 classes of cardioprotective drugs, angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs). As highlighted by Bangalore et al, these studies have often reported mortality reduction with ACE inhibitors vs placebo or comparators, while ARBs were not associated with significant effect.
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