Effects of angiotensin converting enzyme inhibitors and angiotensin II receptor antagonists on mortality and renal outcomes in diabetic neph
http://www.100md.com
《英国医生杂志》
1 NHMRC Centre for Clinical Research Excellence in Renal Medicine, Cochrane Renal Group, Children's Hospital at Westmead, Westmead, NSW 2145, Australia, 2 Department of Emergency and Organ Transplantation, Section of Nephrology, University of Bari, Italy
Correspondence to: G F M Strippoli gfmstrippoli@katamail.com
Abstract
Diabetic nephropathy occurs in 25-40% of patients with type 1 or type 2 diabetes within 20-25 years of the onset of disease.1 Both types of patients probably share the same pathogenetic and clinical stages of renal damage, including renal hypertrophy, incipient (microalbuminuric) nephropathy, overt (macroalbuminuric) nephropathy and, finally, end stage renal disease.2 3 About one third of patients with diabetic nephropathy progress to end stage renal disease.1
Agents used to delay the progression of diabetic nephropathy include blockers, calcium channel blockers, diuretics, angiotensin converting enzyme (ACE) inhibitors, and angiotensin II receptor antagonists (AIIRAs). Large scale randomised controlled trials have shown that ACE inhibitors and AIIRAs slow the deterioration of renal function and reduce proteinuria, and for this reason they are the most widely used agents in diabetic patients.4-8
Mortality is reported to be 10-40% within 10 years of diabetes being diagnosed, depending on cardiovascular comorbidities. The primary cause of early death is cardiovascular. Nephropathy has been shown to be an independent risk factor for early death due to cardiovascular diseases in diabetic patients.9 Microalbuminuria is associated with a twofold to fourfold increase in the risk of death, and overt proteinuria and hypertension are associated with an even higher risk when present together.
The Joint National Committee on Prevention, Diagnosis and Management of Hypertension and the American Diabetes Association recommend that hypertensive and normotensive patients with diabetic nephropathy should receive ACE inhibitors or AIIRAs as first line treatment.10 11 We searched for evidence from randomised controlled trials of the effects of ACE inhibitors and AIIRAs on renal outcomes and mortality in patients with diabetic nephropathy.
Methods
Of the 4723 articles we identified, 4425 were excluded after review of the title and abstract (fig 1). The major reasons for exclusion were a non-randomised design, non-antihypertensive interventions, study populations with non-diabetic nephropathy, and duplicate publications. After assessing the full text of 298 studies, we identified 43 eligible randomised controlled trials (59 publications), which enrolled 7545 patients.w1-w59
Fig 1 Flow chart showing number of citations retrieved by individual searches and number of trials included in review
We obtained supplemental data on design features and outcomes from the authors of nine trials, or from publications relating to the primary trial.
Study characteristics
Of the 43 trials, 36 (4008 patients) compared ACE inhibitors with placebo, four (3331 patients) compared AIIRAs with placebo, and three (206 patients) compared ACE inhibitors with AIIRAs (table 1).
Table 1 Characteristics of populations and interventions of included studies
ACE inhibitors compared with placebo
Of the trials comparing ACE inhibitors with placebo, 20 enrolled patients with type 1 diabetes, 11 enrolled patients with type 2 diabetes, and five enrolled mixed populations. Sixteen trials included patients with hypertension at baseline. In 18 trials, other antihypertensive agents were given to equalise blood pressure in both groups and to minimise the confounding effect of blood pressure. Twenty three trials enrolled patients with microalbuminuria, eight enrolled patients with macroalbuminuria, and five enrolled mixed populations. Three trials also enrolled a few patients with normoalbuminuria.w2 w16 w53
AIIRAs compared with placebo
The four trials that compared AIIRAs with placebo enrolled hypertensive patients with type 2 diabetes. Antihypertensive cointerventions were given in all four trials. Two trials enrolled patients with microalbuminuria and the other two trials enrolled patients with macroalbuminuria.
ACE inhibitors compared with AIIRAs
The three trials that compared ACE inhibitors with AIIRAs enrolled microalbuminuric patients with type 2 diabetes. Two trials enrolled hypertensive patients and one trial enrolled normotensive participants. Antihypertensive cointerventions were given in two trials.
Study quality
Trial quality was variable. Allocation concealment was unclear in 36 (84%) trials, inadequate in one (2%) trial, and adequate in six (14%) trials. Participants were blinded in 33 (77%) trials, investigators in 29 (66%) trials, and outcome assessors in four (9%) trials. Thirteen (30%) trials used an intention to treat analysis. Between 0% and 20% of patients were lost to follow up in 40 (93%) trials and between 21% and 40% were lost to follow up in three (7%) trials.
All cause mortality and renal outcomes
In 20 trials (2838 patients), all cause mortality was lower with ACE inhibitors than with placebo or no treatment (relative risk 0.79, 95% confidence interval 0.63 to 0.99; fig 2). This analysis was dominated by two trials, which contributed 88.4% and 7.5% of the weight to the summary estimate.w25 w33
Fig 2 Effect of angiotensin converting enzyme inhibitors or angiotensin II receptor antagonists compared with placebo or no treatment on overall mortality
No statistically significant reduction in all cause mortality was found in the four trials (3329 patients) of AIIRAs compared with placebo or no treatment (relative risk 0.99, 0.85 to 1.17; fig 2). This analysis was dominated by two trials, which contributed 64.6% and 34.9% of the weight to the summary estimate.w56 w57
Nine of the trials (1907 patients) comparing ACE inhibitors with placebo showed weak evidence for a reduced risk of end stage renal disease (relative risk 0.64, 0.40 to 1.03) and eight of the trials (1868 patients) showed weak evidence for a doubling of serum creatinine concentration (0.60, 0.34 to 1.05; fig 3). In 16 trials (2010 patients), ACE inhibitors significantly reduced the risk of progression from microalbuminuria to macroalbuminuria (0.45, 0.28 to 0.71; fig 4), and in 15 trials (1888 patients) ACE inhibitors significantly increased the rate of regression from microalbuminuria to normoalbuminuria (3.42, 1.95 to .99; fig 5).
Fig 3 Effect of angiotensin converting enzyme inhibitors compared with placebo or no treatment on renal function (doubling of serum creatinine concentration and end stage renal disease)
Fig 4 Effect of angiotensin converting enzyme inhibitors compared with placebo or no treatment on risk of progression from microalbuminuria to macroalbuminuria
Fig 5 Effect of angiotensin converting enzyme inhibitors compared with placebo or no treatment on rate of progression from microalbuminuria to normoalbuminuria
Three trials (3251 patients) comparing AIIRAs with placebo or no treatment showed a significantly reduced risk of end stage renal disease (relative risk 0.78, 0.67 to 0.91) and doubling of serum creatinine concentration (0.79, 0.67 to 0.93; fig 6). AIIRAs also significantly decreased the risk of progression from microalbuminuria to macroalbuminuria (three trials, 761 patients; 0.49, 0.32 to 0.75; fig 7) and increased the rate of regression from microalbuminuria to normoalbuminuria (two trials, 670 patients; 1.42, 1.05 to 1.93; fig 8).
Fig 6 Effect of angiotensin II receptor antagonists compared with placebo or no treatment on renal function (doubling of serum creatinine concentration and end stage renal disease)
Fig 7 Effect of angiotensin II receptor antagonists compared with placebo or no treatment on albuminuria, showing agent reduces risk of progression from microalbuminuria to macroalbuminuria
Fig 8 Effect of angiotensin II receptor antagonists compared with placebo or no treatment on rate of regression from microalbuminuria to normoalbuminuria
ACE inhibitors compared with AIIRAs
The three trials that compared ACE inhibitors with AIIRAs did not report on all cause mortality, end stage renal disease, and doubling of serum creatinine concentration, and we were unable to obtain these data from the authors. Progression from microalbuminuria to macroalbuminuria was reported in one trial (92 patients) and there was no significant difference in risk, with the point estimate favouring ACE inhibitors (relative risk 0.16, 0.02 to 1.44).w53 Regression from microalbuminuria to normoalbuminuria in one trial showed a non-significant difference in the risk.w54
Indirect comparison of treatment effects
Regression analysis of treatment effects of ACE inhibitors compared with AIIRAs, using active treatment as the explanatory variable showed no significant difference between these two agents for the risk of any outcome (death: relative risk 0.79, 0.60 to 1.05; end stage renal disease: 0.82, 0.50 to 1.36; doubling of serum creatinine concentration: 0.83, 0.58 to 1.20; progression from microalbuminuria to macroalbuminuria: 1.14, 0.31 to 4.22; regression from microalbuminuria to normoalbuminuria: 0.76, 0.56 to 1.05).
The ACE inhibitor and AIIRA trials had potentially important differences in study design, particularly the two pairs of trials that dominate the summary estimates of effects (table 2).
Table 2 Characteristics of study populations and trial designs of four influential trials of angiotensin converting enzyme inhibitors and angiotensin II receptor antagonists in patients with diabetic nephropathy. Values are means (standard deviations) unless stated otherwise
Side effects and investigations for sources of heterogeneity
Reports of side effects were few in the smaller trials. Table 3 shows the summary estimates of the effects of ACE inhibitors and AIIRAs on cough, hyperkalaemia, headache, and impotence. We found no significant heterogeneity across all trials.
Table 3 Comparative risk of developing drug related side effects with angiotensin converting enzyme inhibitors or angiotensin II receptor antagonists
Metaregression and subgroup analyses were possible only in trials comparing ACE inhibitors with placebo or no treatment, given the small number of trials evaluating AIIRAs (table 4). We found no evidence that the effect of ACE inhibitors on all cause mortality varied according to type of diabetes, presence or absence of hypertension, or microalbuminuria compared with macroalbuminuria at baseline. Differences in the risk of other outcomes according to type of diabetes, hypertension, and study design are all explained by the results of the micro-HOPE trial.4 When we excluded this trial from our analyses, results were homogeneous for all outcomes.
Table 4 Metaregression and subgroup analysis of sources of variability for major outcomes analysed in review (in respect of categorical and continuous study factors) in studies of angiotensin converting enzyme inhibitors compared with placebo
Discussion
w1-w59 are on bmj.com
We thank Denise Campbell (medical editor) for editing the manuscript; Narelle Willis, Sharn G?kalp, and Sandra Puckeridge for editorial and administrative support; Ruth Mitchell, Linda Heslop, Gail Higgins (trial search coordinators with the Cochrane Renal Group) for search strategies for this review; and Janice Pogue and the HOPE trialists, M Ravid, PJ Phillips, HH Parving, R Romero, S Katayama, ER Mathiesen, BM Brenner, and KC Tan who provided data on the trials on request.
Contributors: GFMS was responsible for the conception and design of the study; extraction, analysis, and interpretation of data; and writing the article. He is guarantor. MC was responsible for the conception and design of the study and data extraction. JJD was responsible for analysis and interpretation of the data and critical revision of the manuscript for intellectual content. FPS was responsible for clinical revision for intellectual content. JCC was responsible for the conception and design of the study; analysis and interpretation of the data; and writing the article. He approved the final manuscript.
Funding: Australia-Europe Scholarship 2003 (Department of Education, Science and Training of Australia), an NHMRC Centre for Clinical Research Excellence Grant (2003), and the Italian Society of Nephrology (Young Investigator Scholarship 2003).
Competing interests: None declared.
Ethical approval: Not required.
References
Ritz E, Orth SR. Nephropathy in patients with type 2 diabetes mellitus. N Engl J Med 1999;341: 1127-33.
Mogensen CE. Drug treatment for hypertensive patients in special situations: diabetes and hypertension. Clin Exp Hypertens 1999;21: 895-906.
Mogensen CE. Microalbuminuria in prediction and prevention of diabetic nephropathy in insulin-dependent diabetes mellitus patients. J Diabetes Complications 1995;9: 337-49.
Heart Outcomes Prevention Evaluation (HOPE) Study Investigators. Effects of ramipril on cardiovascular and microvascular outcomes in people with diabetes mellitus: results of the HOPE study and MICRO-HOPE substudy. Lancet 2000;355: 253-9.
Lewis EJ, Hunsicker LG, Bain RP, Rohde RD. The effects of angiotension converting enzyme inhibition to diabetic nephropathy. N Engl J Med 1993;329: 1456-62.
Kasiske BL, Kalil RS, Ma JZ, Liao M, Keane WF. Effect of antihypertensive therapy on the kidney in patients with diabetes: a meta-regression analysis. Ann Intern Med 1993;118: 129-38.
Brenner BM, Cooper ME, de Zeeuw D, Keane WF, Mitch WE, Parving HH, et al. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med 2001;345: 861-9.
Lewis E, Hunsicker LG, Clarke WR, Berl T, Pohl MA, Lewis JB, et al. Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N Engl J Med 2001;345: 851-60.
Dinneen SF, Gerstein HC. The association of microalbuminuria and mortality in non-insulin-dependent diabetes mellitus. A systematic overview of the literature. Arch Intern Med 1997;157: 1413-8.
Chobanian AV, Bakris GL, Black HR, Cushman WC, Green LA, Izzo JL Jr, et al. Seventh report of the joint national committee on prevention, detection, evaluation, and treatment of high blood pressure: the JNC-7 report. JAMA 2003;289: 2560-72.
Arauz-Pacheo C, Parrott MA, Raskin P. Treatment of hypertension in adults with diabetes. Diabetes Care 2003;26: S80-2.
Dickersin K, Scherer R, Lefebvre C. Identifying relevant studies for systematic reviews. BMJ 1994;309: 1286-91.
DerSimonian R, Laird N. Meta-analysis in clinical trials. Contr Clin Trials 1986;7: 177-88.
Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. BMJ 2003;327: 557-60.
Grossman E, Messerli FH, Goldbourt U. Intensive blood pressure control and drugs reduce morbidity and mortality in hypertension and diabetes mellitus. Evidence Based Med 2001;6: 44.
Wachtell K, Ibsen H, Olsen MH, Borch-Johnsen K, Lindholm LH, Mogensen CE, et al. Albuminuria and cardiovascular risk in hypertensive patients with left ventricular hypertrophy: the LIFE study. Ann Intern Med 2003;139: 901-6.
Zuanetti G. Prognosis of diabetic patients post-MI: the role of ACE inhibitor treatment. GISSI-3 Investigators. J Diabetes Complications 1996;10: 139-40.
Garg R, Yusuf S. Overview of randomized trials of angiotensin-converting enzyme inhibitors on mortality and morbidity in patients with heart failure. Collaborative Group on ACE Inhibitor Trials. JAMA 1995;273: 1450-6.
Cohn JN, Tognoni G, Valsartan Heart Failure Trial Investigators. A randomized trial of the angiotensin-receptor blocker valsartan in chronic heart failure. N Engl J Med 2001;345: 1667-75.
ACE-Inhibitors in Diabetic Nephropathy Trialist Group. Should all patients with type 1 diabetes mellitus and microalbuminuria receive angiotensin-converting-enzyme inhibitors? A meta-analysis of individual patient data. Ann Intern Med 2001;134: 370-9.
Song F, Altman DG, Glenny AM, Deeks JJ. Validity of indirect comparison for estimating efficacy of competing interventions: empirical evidence from published meta-analyses. BMJ 2003;326: 472.
Watanabe K, Juan W, Narasimman G, Ma M, Inoue M, Saito Y, et al. Comparative effects of angiotensin II receptor blockade (candesartan) with angiotensin-converting-enzyme inhibitor (quinapril) in rats with dilated cardiomyopathy. J Cardiovasc Pharmacol 2003;41: S93-7.
Ozer MK, Sahna E, Birincioglu M, Acet A. Effects of captopril and losartan on myocardial ischemia-reperfusion induced arrhythmias and necrosis in rats. Pharmacol Res 2002;45: 257-63.
Klahr S, Morrissey J. Comparative effects of ACE inhibition and angiotensin II receptor blockade in the prevention of renal damage. Kidney Int 2002;62(Suppl 82): S23-6.
Nakao N, Yoshimura A, Morita H, Takada M, Kayano T, Ideura T. Combination treatment of angiotensin-II receptor blocker and angiotensin-converting enzyme inhibitor in non-diabetic renal disease (COOPERATE): a randomised controlled trial. Lancet 2003;361: 117-24.(Giovanni F M Strippoli, e)
Correspondence to: G F M Strippoli gfmstrippoli@katamail.com
Abstract
Diabetic nephropathy occurs in 25-40% of patients with type 1 or type 2 diabetes within 20-25 years of the onset of disease.1 Both types of patients probably share the same pathogenetic and clinical stages of renal damage, including renal hypertrophy, incipient (microalbuminuric) nephropathy, overt (macroalbuminuric) nephropathy and, finally, end stage renal disease.2 3 About one third of patients with diabetic nephropathy progress to end stage renal disease.1
Agents used to delay the progression of diabetic nephropathy include blockers, calcium channel blockers, diuretics, angiotensin converting enzyme (ACE) inhibitors, and angiotensin II receptor antagonists (AIIRAs). Large scale randomised controlled trials have shown that ACE inhibitors and AIIRAs slow the deterioration of renal function and reduce proteinuria, and for this reason they are the most widely used agents in diabetic patients.4-8
Mortality is reported to be 10-40% within 10 years of diabetes being diagnosed, depending on cardiovascular comorbidities. The primary cause of early death is cardiovascular. Nephropathy has been shown to be an independent risk factor for early death due to cardiovascular diseases in diabetic patients.9 Microalbuminuria is associated with a twofold to fourfold increase in the risk of death, and overt proteinuria and hypertension are associated with an even higher risk when present together.
The Joint National Committee on Prevention, Diagnosis and Management of Hypertension and the American Diabetes Association recommend that hypertensive and normotensive patients with diabetic nephropathy should receive ACE inhibitors or AIIRAs as first line treatment.10 11 We searched for evidence from randomised controlled trials of the effects of ACE inhibitors and AIIRAs on renal outcomes and mortality in patients with diabetic nephropathy.
Methods
Of the 4723 articles we identified, 4425 were excluded after review of the title and abstract (fig 1). The major reasons for exclusion were a non-randomised design, non-antihypertensive interventions, study populations with non-diabetic nephropathy, and duplicate publications. After assessing the full text of 298 studies, we identified 43 eligible randomised controlled trials (59 publications), which enrolled 7545 patients.w1-w59
Fig 1 Flow chart showing number of citations retrieved by individual searches and number of trials included in review
We obtained supplemental data on design features and outcomes from the authors of nine trials, or from publications relating to the primary trial.
Study characteristics
Of the 43 trials, 36 (4008 patients) compared ACE inhibitors with placebo, four (3331 patients) compared AIIRAs with placebo, and three (206 patients) compared ACE inhibitors with AIIRAs (table 1).
Table 1 Characteristics of populations and interventions of included studies
ACE inhibitors compared with placebo
Of the trials comparing ACE inhibitors with placebo, 20 enrolled patients with type 1 diabetes, 11 enrolled patients with type 2 diabetes, and five enrolled mixed populations. Sixteen trials included patients with hypertension at baseline. In 18 trials, other antihypertensive agents were given to equalise blood pressure in both groups and to minimise the confounding effect of blood pressure. Twenty three trials enrolled patients with microalbuminuria, eight enrolled patients with macroalbuminuria, and five enrolled mixed populations. Three trials also enrolled a few patients with normoalbuminuria.w2 w16 w53
AIIRAs compared with placebo
The four trials that compared AIIRAs with placebo enrolled hypertensive patients with type 2 diabetes. Antihypertensive cointerventions were given in all four trials. Two trials enrolled patients with microalbuminuria and the other two trials enrolled patients with macroalbuminuria.
ACE inhibitors compared with AIIRAs
The three trials that compared ACE inhibitors with AIIRAs enrolled microalbuminuric patients with type 2 diabetes. Two trials enrolled hypertensive patients and one trial enrolled normotensive participants. Antihypertensive cointerventions were given in two trials.
Study quality
Trial quality was variable. Allocation concealment was unclear in 36 (84%) trials, inadequate in one (2%) trial, and adequate in six (14%) trials. Participants were blinded in 33 (77%) trials, investigators in 29 (66%) trials, and outcome assessors in four (9%) trials. Thirteen (30%) trials used an intention to treat analysis. Between 0% and 20% of patients were lost to follow up in 40 (93%) trials and between 21% and 40% were lost to follow up in three (7%) trials.
All cause mortality and renal outcomes
In 20 trials (2838 patients), all cause mortality was lower with ACE inhibitors than with placebo or no treatment (relative risk 0.79, 95% confidence interval 0.63 to 0.99; fig 2). This analysis was dominated by two trials, which contributed 88.4% and 7.5% of the weight to the summary estimate.w25 w33
Fig 2 Effect of angiotensin converting enzyme inhibitors or angiotensin II receptor antagonists compared with placebo or no treatment on overall mortality
No statistically significant reduction in all cause mortality was found in the four trials (3329 patients) of AIIRAs compared with placebo or no treatment (relative risk 0.99, 0.85 to 1.17; fig 2). This analysis was dominated by two trials, which contributed 64.6% and 34.9% of the weight to the summary estimate.w56 w57
Nine of the trials (1907 patients) comparing ACE inhibitors with placebo showed weak evidence for a reduced risk of end stage renal disease (relative risk 0.64, 0.40 to 1.03) and eight of the trials (1868 patients) showed weak evidence for a doubling of serum creatinine concentration (0.60, 0.34 to 1.05; fig 3). In 16 trials (2010 patients), ACE inhibitors significantly reduced the risk of progression from microalbuminuria to macroalbuminuria (0.45, 0.28 to 0.71; fig 4), and in 15 trials (1888 patients) ACE inhibitors significantly increased the rate of regression from microalbuminuria to normoalbuminuria (3.42, 1.95 to .99; fig 5).
Fig 3 Effect of angiotensin converting enzyme inhibitors compared with placebo or no treatment on renal function (doubling of serum creatinine concentration and end stage renal disease)
Fig 4 Effect of angiotensin converting enzyme inhibitors compared with placebo or no treatment on risk of progression from microalbuminuria to macroalbuminuria
Fig 5 Effect of angiotensin converting enzyme inhibitors compared with placebo or no treatment on rate of progression from microalbuminuria to normoalbuminuria
Three trials (3251 patients) comparing AIIRAs with placebo or no treatment showed a significantly reduced risk of end stage renal disease (relative risk 0.78, 0.67 to 0.91) and doubling of serum creatinine concentration (0.79, 0.67 to 0.93; fig 6). AIIRAs also significantly decreased the risk of progression from microalbuminuria to macroalbuminuria (three trials, 761 patients; 0.49, 0.32 to 0.75; fig 7) and increased the rate of regression from microalbuminuria to normoalbuminuria (two trials, 670 patients; 1.42, 1.05 to 1.93; fig 8).
Fig 6 Effect of angiotensin II receptor antagonists compared with placebo or no treatment on renal function (doubling of serum creatinine concentration and end stage renal disease)
Fig 7 Effect of angiotensin II receptor antagonists compared with placebo or no treatment on albuminuria, showing agent reduces risk of progression from microalbuminuria to macroalbuminuria
Fig 8 Effect of angiotensin II receptor antagonists compared with placebo or no treatment on rate of regression from microalbuminuria to normoalbuminuria
ACE inhibitors compared with AIIRAs
The three trials that compared ACE inhibitors with AIIRAs did not report on all cause mortality, end stage renal disease, and doubling of serum creatinine concentration, and we were unable to obtain these data from the authors. Progression from microalbuminuria to macroalbuminuria was reported in one trial (92 patients) and there was no significant difference in risk, with the point estimate favouring ACE inhibitors (relative risk 0.16, 0.02 to 1.44).w53 Regression from microalbuminuria to normoalbuminuria in one trial showed a non-significant difference in the risk.w54
Indirect comparison of treatment effects
Regression analysis of treatment effects of ACE inhibitors compared with AIIRAs, using active treatment as the explanatory variable showed no significant difference between these two agents for the risk of any outcome (death: relative risk 0.79, 0.60 to 1.05; end stage renal disease: 0.82, 0.50 to 1.36; doubling of serum creatinine concentration: 0.83, 0.58 to 1.20; progression from microalbuminuria to macroalbuminuria: 1.14, 0.31 to 4.22; regression from microalbuminuria to normoalbuminuria: 0.76, 0.56 to 1.05).
The ACE inhibitor and AIIRA trials had potentially important differences in study design, particularly the two pairs of trials that dominate the summary estimates of effects (table 2).
Table 2 Characteristics of study populations and trial designs of four influential trials of angiotensin converting enzyme inhibitors and angiotensin II receptor antagonists in patients with diabetic nephropathy. Values are means (standard deviations) unless stated otherwise
Side effects and investigations for sources of heterogeneity
Reports of side effects were few in the smaller trials. Table 3 shows the summary estimates of the effects of ACE inhibitors and AIIRAs on cough, hyperkalaemia, headache, and impotence. We found no significant heterogeneity across all trials.
Table 3 Comparative risk of developing drug related side effects with angiotensin converting enzyme inhibitors or angiotensin II receptor antagonists
Metaregression and subgroup analyses were possible only in trials comparing ACE inhibitors with placebo or no treatment, given the small number of trials evaluating AIIRAs (table 4). We found no evidence that the effect of ACE inhibitors on all cause mortality varied according to type of diabetes, presence or absence of hypertension, or microalbuminuria compared with macroalbuminuria at baseline. Differences in the risk of other outcomes according to type of diabetes, hypertension, and study design are all explained by the results of the micro-HOPE trial.4 When we excluded this trial from our analyses, results were homogeneous for all outcomes.
Table 4 Metaregression and subgroup analysis of sources of variability for major outcomes analysed in review (in respect of categorical and continuous study factors) in studies of angiotensin converting enzyme inhibitors compared with placebo
Discussion
w1-w59 are on bmj.com
We thank Denise Campbell (medical editor) for editing the manuscript; Narelle Willis, Sharn G?kalp, and Sandra Puckeridge for editorial and administrative support; Ruth Mitchell, Linda Heslop, Gail Higgins (trial search coordinators with the Cochrane Renal Group) for search strategies for this review; and Janice Pogue and the HOPE trialists, M Ravid, PJ Phillips, HH Parving, R Romero, S Katayama, ER Mathiesen, BM Brenner, and KC Tan who provided data on the trials on request.
Contributors: GFMS was responsible for the conception and design of the study; extraction, analysis, and interpretation of data; and writing the article. He is guarantor. MC was responsible for the conception and design of the study and data extraction. JJD was responsible for analysis and interpretation of the data and critical revision of the manuscript for intellectual content. FPS was responsible for clinical revision for intellectual content. JCC was responsible for the conception and design of the study; analysis and interpretation of the data; and writing the article. He approved the final manuscript.
Funding: Australia-Europe Scholarship 2003 (Department of Education, Science and Training of Australia), an NHMRC Centre for Clinical Research Excellence Grant (2003), and the Italian Society of Nephrology (Young Investigator Scholarship 2003).
Competing interests: None declared.
Ethical approval: Not required.
References
Ritz E, Orth SR. Nephropathy in patients with type 2 diabetes mellitus. N Engl J Med 1999;341: 1127-33.
Mogensen CE. Drug treatment for hypertensive patients in special situations: diabetes and hypertension. Clin Exp Hypertens 1999;21: 895-906.
Mogensen CE. Microalbuminuria in prediction and prevention of diabetic nephropathy in insulin-dependent diabetes mellitus patients. J Diabetes Complications 1995;9: 337-49.
Heart Outcomes Prevention Evaluation (HOPE) Study Investigators. Effects of ramipril on cardiovascular and microvascular outcomes in people with diabetes mellitus: results of the HOPE study and MICRO-HOPE substudy. Lancet 2000;355: 253-9.
Lewis EJ, Hunsicker LG, Bain RP, Rohde RD. The effects of angiotension converting enzyme inhibition to diabetic nephropathy. N Engl J Med 1993;329: 1456-62.
Kasiske BL, Kalil RS, Ma JZ, Liao M, Keane WF. Effect of antihypertensive therapy on the kidney in patients with diabetes: a meta-regression analysis. Ann Intern Med 1993;118: 129-38.
Brenner BM, Cooper ME, de Zeeuw D, Keane WF, Mitch WE, Parving HH, et al. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med 2001;345: 861-9.
Lewis E, Hunsicker LG, Clarke WR, Berl T, Pohl MA, Lewis JB, et al. Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N Engl J Med 2001;345: 851-60.
Dinneen SF, Gerstein HC. The association of microalbuminuria and mortality in non-insulin-dependent diabetes mellitus. A systematic overview of the literature. Arch Intern Med 1997;157: 1413-8.
Chobanian AV, Bakris GL, Black HR, Cushman WC, Green LA, Izzo JL Jr, et al. Seventh report of the joint national committee on prevention, detection, evaluation, and treatment of high blood pressure: the JNC-7 report. JAMA 2003;289: 2560-72.
Arauz-Pacheo C, Parrott MA, Raskin P. Treatment of hypertension in adults with diabetes. Diabetes Care 2003;26: S80-2.
Dickersin K, Scherer R, Lefebvre C. Identifying relevant studies for systematic reviews. BMJ 1994;309: 1286-91.
DerSimonian R, Laird N. Meta-analysis in clinical trials. Contr Clin Trials 1986;7: 177-88.
Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. BMJ 2003;327: 557-60.
Grossman E, Messerli FH, Goldbourt U. Intensive blood pressure control and drugs reduce morbidity and mortality in hypertension and diabetes mellitus. Evidence Based Med 2001;6: 44.
Wachtell K, Ibsen H, Olsen MH, Borch-Johnsen K, Lindholm LH, Mogensen CE, et al. Albuminuria and cardiovascular risk in hypertensive patients with left ventricular hypertrophy: the LIFE study. Ann Intern Med 2003;139: 901-6.
Zuanetti G. Prognosis of diabetic patients post-MI: the role of ACE inhibitor treatment. GISSI-3 Investigators. J Diabetes Complications 1996;10: 139-40.
Garg R, Yusuf S. Overview of randomized trials of angiotensin-converting enzyme inhibitors on mortality and morbidity in patients with heart failure. Collaborative Group on ACE Inhibitor Trials. JAMA 1995;273: 1450-6.
Cohn JN, Tognoni G, Valsartan Heart Failure Trial Investigators. A randomized trial of the angiotensin-receptor blocker valsartan in chronic heart failure. N Engl J Med 2001;345: 1667-75.
ACE-Inhibitors in Diabetic Nephropathy Trialist Group. Should all patients with type 1 diabetes mellitus and microalbuminuria receive angiotensin-converting-enzyme inhibitors? A meta-analysis of individual patient data. Ann Intern Med 2001;134: 370-9.
Song F, Altman DG, Glenny AM, Deeks JJ. Validity of indirect comparison for estimating efficacy of competing interventions: empirical evidence from published meta-analyses. BMJ 2003;326: 472.
Watanabe K, Juan W, Narasimman G, Ma M, Inoue M, Saito Y, et al. Comparative effects of angiotensin II receptor blockade (candesartan) with angiotensin-converting-enzyme inhibitor (quinapril) in rats with dilated cardiomyopathy. J Cardiovasc Pharmacol 2003;41: S93-7.
Ozer MK, Sahna E, Birincioglu M, Acet A. Effects of captopril and losartan on myocardial ischemia-reperfusion induced arrhythmias and necrosis in rats. Pharmacol Res 2002;45: 257-63.
Klahr S, Morrissey J. Comparative effects of ACE inhibition and angiotensin II receptor blockade in the prevention of renal damage. Kidney Int 2002;62(Suppl 82): S23-6.
Nakao N, Yoshimura A, Morita H, Takada M, Kayano T, Ideura T. Combination treatment of angiotensin-II receptor blocker and angiotensin-converting enzyme inhibitor in non-diabetic renal disease (COOPERATE): a randomised controlled trial. Lancet 2003;361: 117-24.(Giovanni F M Strippoli, e)