Diabetic kidney disease (DKD), defined as the presence of micro- or macroalbuminuria in patients with diabetes, occurs in 25% to 40% of type 1 and 2 diabetic patients within 20 to 25 years of the onset of diabetes (Ritz 1999). Both types of patients probably share the same pathogenetic and clinical stages of renal damage, including renal hypertrophy, incipient (microalbuminuria: urine albumin excretion 30-300 mg/d) nephropathy, overt (macroalbuminuria: > 300 mg/d) nephropathy and, finally, the presence of impairment of glomerular filtration rate (GFR) up to end-stage kidney disease (ESKD) (Mogensen 1995; Mogensen 1999) About one third of patients with DKD progress to ESKD (Ritz 1999).
Agents used to delay the progression of DKD include beta-blockers, calcium channel blockers, diuretics, angiotensin converting enzyme inhibitors (ACEi), and angiotensin II receptor antagonists (AIIRA). Since large scale randomised controlled trials (RCTs) have shown that ACEi and AIIRA slow the deterioration of renal function and reduce proteinuria, these have become the most broadly used agents in diabetic patients with nephropathy and major international guidelines (Arauz-Pacheo 2003; JNC 7 2003) advocate for their equivalent use as first line agents in these populations (CAPTOPRIL 1993; HOPE 2000; IDNT 2001; Kasiske 1993; RENAAL 2001).
If a patient has diabetes and nephropathy, mortality is reported to be 10% to 40% within 10 years of diagnosis, depending on cardiovascular comorbidities, with the primary cause of early death being fatal cardiovascular events. The presence of micro- or macroalbuminuria has been shown to be an independent risk factor for early death due to cardiovascular events in diabetic patients over and above the increased risk conferred by the diabetic status (Dinneen 1997). Microalbuminuria is associated with a two- to fourfold increase in the risk of death whereas macroalbuminuria/overt proteinuria and hypertension are associated with an even higher risk when present together.
In view of current guidelines recommendations on equivalent use of ACEi and AIIRA in these populations, we performed a systematic review of RCTs of ACEi and AIIRA used in patients with DKD to evaluate the evidence basis supporting these statements, with particular focus on their effects on renal and cardiovascular outcomes.
To evaluate the benefits and harms of ACEi and AIIRA in patients with DKD, with major focus on renal and cardiovascular outcomes.
Criteria for considering studies for this review
Types of studies
RCTs of at least six months duration in which ACEi or AIIRA were compared with placebo or no treatment or in which the relative effects of the agents were compared directly, head-to-head, in patients with DKD, were included in this systematic review.
Types of participants
RCTs of patients with DKD were included, independent of stage of nephropathy, either microalbuminuria (albumin excretion 30-300 mg/d) or macroalbuminuria (albumin excretion >300 mg/d).
Types of interventions
- ACEi versus placebo or no treatment
- AIIRA versus placebo or no treatment
- Head-to-head comparative RCTs of ACEi versus AIIRA
Types of outcome measures
- All-cause mortality
- Doubling of serum creatinine concentration
- Progression from micro- to macroalbuminuria
- Regression from micro- to normoalbuminuria
- Drug related toxicity, including cough, headache, hyperkalaemia, impotence and pedal oedema
Search methods for identification of studies
Search strategies were independently designed and performed by two separate investigators (GFMS, MC) in collaboration with the Cochrane Renal Group's Trial Search Coordinators at various stages from 2003 with a final update in December 2005.
The following electronic biomedical databases were searched
- Cochrane Renal Groups studies register and the Cochrane Central Register of Controlled Trials (CENTRAL, in The Cochrane Library issue 4 2005)
- MEDLINE(1966 - December 2005)
- EMBASE (1988 - December 2005)
We performed a combined search to identify studies for this review and the review Antihypertensive agents for preventing diabetic kidney disease (Strippoli 2005) and screened as described below.
CENTRAL and the Renal Group's specialised register contain the handsearched results of conference proceedings from general and speciality meetings. This is an ongoing activity across the Cochrane Collaboration and is both retrospective and prospective (http://www.cochrane.us/masterlist.asp). Therefore we did not specifically search conference proceedings. Please refer to The Cochrane Renal Review Group's Module in The Cochrane Library for the most up-to-date list of conference proceedings.
Data collection and analysis
This review was undertaken by six authors (GFMS, MC, JD, CB, SDN, JCC). The search strategies described were used to obtain titles and abstracts of studies that might be relevant to the review. The titles and abstracts were screened independently by (GS, MC, SDN and CB), who discarded studies that were not applicable based on the inclusion criteria for this review, however studies and reviews that might include relevant data or information on studies were retained initially and their full-text version was analysed. Authors GS, MC, SDN and CB independently assessed abstracts of all citations retrieved by the searches and, if necessary, the full text of these studies to determine study eligibility. Data extraction was carried out independently by the same reviewers using standard data extraction forms. Where more than one publication of one trial existed, only the publication with the most complete data was used. Any further information or clarification required from the authors was requested by written or electronic correspondence and relevant information obtained in this manner was included in the review. Disagreements in data extraction were resolved by discussion among authors.
The methodological quality of included studies was assessed independently by GFMS, MC, SDN and CB without blinding to authorship or journal using the checklist developed by the Cochrane Renal Group. Discrepancies were resolved by discussion among authors. The quality items assessed were allocation concealment, blinding of investigators, participants outcome assessors, data assessors, intention-to-treat analysis, and the completeness to follow-up.
- Adequate (A): Randomisation method described that would not allow investigator/participant to know or influence intervention group before eligible participant entered in the study
- Unclear (B): Randomisation stated but no information on method used is available
- Inadequate (C): Method of randomisation used such as alternate medical record numbers or unsealed envelopes; any information in the study that indicated that investigators or participants could influence intervention group
- Blinding of investigators: Yes/no/not stated
- Blinding of participants: Yes/no/not stated
- Blinding of outcome assessor: Yes/no/not stated
- Blinding of data analysis: Yes/no/not stated
- Yes: Specifically reported by authors that intention-to-treat analysis was undertaken and this was confirmed on study assessment.
- Yes: Not specifically stated but confirmed upon study assessment
- No: Not reported and lack of intention-to-treat analysis confirmed on study assessment (patients who were randomised were not included in the analysis because they did not receive the study intervention, they withdrew from the study or were not included because of protocol violation).
- No: Stated, but not confirmed upon study assessment
- Not stated
Completeness to follow-up
Per cent of participants excluded or lost to follow-up.
The effect of ACEi or AIIRA in individual studies were summarised using risk ratio (RR) with 95% confidence intervals (CI). Data of all studies comparing the same interventions (ACEi versus placebo, AIIRA versus placebo, ACEi versus AIIRA) were pooled in meta-analyses using the random effects model. Heterogeneity of treatment effects between studies was examined using the Cochran Q and I² statistic (Higgins 2003). Subgroup analysis and random effects meta-regression were performed as applicable to explore the influence of the following sources of heterogeneity on treatment effect: duration of follow up, type of diabetes (type 1, type 2 or studies including mixed populations of type 1 and type 2 diabetic patients), type of drug (different agents of the same class), presence or absence of hypertension at baseline, stage of DKD (studies enrolling patients with microalbuminuria, macroalbuminuria or mixed populations of patients with micro- and macroalbuminuria), and specific quality items (allocation concealment, blinding, use of intention -to-treat analysis). meta-regression analyses were undertaken in STATA version 8.0.
Description of studies
The combined search identified a total of 5701 citations, of which 5376 were excluded after title and abstract review. The major reasons for exclusion were a non-randomised design, non-antihypertensive interventions, study populations with non-DKD, and duplicate publications. Full text analysis of 325 articles lead to the final inclusion of 49 studies (73 publications) which met the inclusion criteria (Figure 1- Flow chart of study identification) (ABCD 1996; Ahmad 1997; Ahmad 2003; AIPRI 1996; ATLANTIS SG 2000; Bakris 1994; Bauer 1992; Bojestig 2001; Capek 1994; CAPTOPRIL 1993; Carella 1999; Chase 1993; Cordonnier 1999; Crepaldi 1998; DETAIL 2004; DIABHYCAR 2004; ESPRIT 2001; EUCLID 1997; Garg 1998; Hansen 1994; HOPE 2000; IDNT 2001; IRMA-2 2001; JAPAN-IDDM 2002; Jerums 2001; Jerums 2004; Ko 2005; Lacourciere 2000; Laffel 1995; Lebovitz 1994; Marre 1987; Mathiesen 1999; Muirhead 1999; Nankervis 1998; O'Donnell 1993; Parving 1989; Parving 2001a; Phillips 1993; Poulsen 2001; Ravid 1993; RENAAL 2001; Rizzoni 2005; Romero 1993; Sano 1994; Sato 2003; Stornello 1992; Tan 2002; Trevisan 1995; Tutuncu 2001). Data on characteristics of the populations, interventions and outcomes were extracted from all studies and supplemental data on design features and outcomes were obtained from the authors of ten studies or from duplicate publications relating to the primary trial.
|Figure 1. Flow chart showing number of citations retrieved by individual searches, number of trials included in the systematic review and number of trials reporting each outcome.|
Of the 49 studies, 38 (8970 patients) compared ACEi with placebo (ABCD 1996; Ahmad 1997; Ahmad 2003; AIPRI 1996; ATLANTIS SG 2000; Bakris 1994; Bauer 1992; Bojestig 2001; Capek 1994; CAPTOPRIL 1993; Carella 1999; Chase 1993; Cordonnier 1999; Crepaldi 1998; DIABHYCAR 2004; ESPRIT 2001; EUCLID 1997; Garg 1998; Hansen 1994; HOPE 2000; JAPAN-IDDM 2002; Jerums 2001; Jerums 2004; Laffel 1995; Lebovitz 1994; Marre 1987; Mathiesen 1999; Nankervis 1998; O'Donnell 1993; Parving 1989; Parving 2001a; Phillips 1993; Poulsen 2001; Ravid 1993; Romero 1993; Sano 1994; Stornello 1992; Trevisan 1995), four (2540 patients) compared AIIRA with placebo (Lacourciere 2000; Muirhead 1999; RENAAL 2001; Tutuncu 2001), and seven (557 patients) compared ACEi with AIIRA (DETAIL 2004; IDNT 2001; IRMA-2 2001; Ko 2005; Rizzoni 2005; Sato 2003; Tan 2002).
Of studies comparing ACEi with placebo, 20 enrolled patients with type 1 diabetes, 13 enrolled patients with type 2 diabetes, and five enrolled mixed populations of type 1 and type 2 diabetic patients. Seventeen studies enrolled patients with hypertension at baseline, the remaining enrolled normotensive patients. In 20 studies, other antihypertensive agents were administered beyond the randomised interventions (ACEi or AIIRA) in a non-randomised fashion to equalise blood pressure in both groups, minimise the confounding effect of blood pressure. Twenty five studies enrolled patients with microalbuminuria, eight enrolled patients with macroalbuminuria, and five enrolled mixed populations of micro- and macroalbuminuric patients. Three studies also enrolled minimal proportions of patients with normoalbuminuria and were therefore included.
The four studies that compared AIIRA with placebo all enrolled hypertensive patients with type 2 diabetes. Antihypertensive co-interventions were given in all four studies. Two studies enrolled patients with microalbuminuria and the other two studies enrolled patients with macroalbuminuria.
Of the seven studies comparing ACEi with AIIRA directly, six enrolled microalbuminuric patients and one enrolled mixed populations of micro- and macroalbuminuric patients. Six studies enrolled patients with type 2 diabetes and one study enrolled patients with both type 1 and type 2 diabetes. Six studies enrolled hypertensive patients and one trial enrolled normotensive participants. Antihypertensive co-interventions were given in two studies.
Risk of bias in included studies
By current standards, trial methodological quality was suboptimal.
Allocation concealment was unclear in 40/49 (82%) studies, inadequate in 1/49 (2%) trial, and adequate in 8/49 (16%) studies.
Blinding occurred in the participants in 36/49 (73%) studies, investigators in 32/49 (65%) studies, and outcome assessors in 4/49 (8%) studies.
Reported intention-to-treat analysis
An intention-to-treat analysis was used in 15/49 (31%) studies.
Completeness of follow-up
Between 0% and 20% of patients were lost to follow-up in 45/49 (92%) studies and between 21% and 41% were lost to follow-up in 4/49 (8%) studies.
Effects of interventions
ACEi versus placebo/no treatment
There was no significant reduction in the risk of all-cause mortality with ACEi compared with placebo/no treatment ( Analysis 1.1 (21 studies, 7295 patients): RR 0.91, 95% CI 0.71 to 1.17). This analysis was dominated by two studies, which contributed 49.68% and 37.78% of the weight to the summary estimate (DIABHYCAR 2004; HOPE 2000) but there was no significant heterogeneity between the studies (heterogeneity χ² = 11.04, I² = 27.6 %). A subgroup analysis of studies which used ACEi at the maximum tolerable dose compared with placebo/no treatment, there was a significant reduction in the risk of all-cause mortality (Analysis 1.02 (5 studies, 2034 patients): RR 0.78, 95% CI 0.61 to 0.98) while this was not found in studies using half or less than half the maximum tolerable dose of these agents ( Analysis 1.1.1 (4 studies, 5261 patients): RR 1.18, 95% CI 0.41 to 3.44). There was no significant heterogeneity in any of these analyses.
AIIRA versus placebo/no treatment
No statistically significant reduction in the risk of all-cause mortality was found in the five studies (3409 patients) of AIIRA versus placebo/no treatment ( Analysis 2.1: RR 0.99, 95% CI 0.85 to 1.17). This analysis was dominated by two studies, which contributed 64.6% and 34.9% of the weight to the summary estimate (IDNT 2001; RENAAL 2001). There was no significant heterogeneity between the studies (χ² = 0.63 , I² = 0%).
ACEi versus AIIRA
No statistically significant reduction in the risk of all-cause mortality was found in the only three studies (307 patients) that compared ACEi with AIIRA ( Analysis 3.1: RR 0.92, 95% CI 0.31 to 2.78).
ESKD and doubling of serum creatinine
ACEi versus placebo/no treatment
There was a significant reduction in the risk of ESRD with ACEi compared to placebo/no treatment ( Analysis 1.4 (10 studies, 6819 patients): RR 0.60, 95% CI 0.39 to 0.93) with no significant heterogeneity between the studies (χ² = 1.71, I² = 0%).
There was some evidence of reduction of the risk of doubling of serum creatinine concentration with ACEi compared to placebo/no treatment ( Analysis 1.3 (9 studies, 6780 patients): RR 0.68, 95% CI 0.47 to 1.00). There was no significant heterogeneity between the studies (χ² = 9.52, I² = 37.0%).
AIIRA versus placebo/no treatment
There was a significant reduction in the risk of ESKD with AIIRA compared to placebo/no treatment ( Analysis 2.4 (3 studies, 3251 patients): RR 0.78, 95% CI 0.67 to 0.91) with no significant heterogeneity between the studies (χ² = 0.05, I² = 0%).
There was also a significant reduction in the risk of doubling of serum creatinine concentration with AIIRA compared to placebo/no treatment ( Analysis 2.3 (3 studies, 3251 patients), RR 0.79, 95% CI 0.67 to 0.93), with no significant heterogeneity between the studies (χ² = 1.22, I² = 18.2%).
ACEi versus AIIRA
The seven studies that compared ACEi with AIIRA did not report the outcome of ESKD or doubling of serum creatinine, and we were unable to obtain these data from the authors.
Progression from micro- to macroalbuminuria
ACEi versus placebo/no treatment
ACEi significantly reduced the risk of progression from micro- to macroalbuminuria ( Analysis 1.5 (17 studies, 2036 patients): RR 0.45, 95% CI 0.29 to 0.69).There was no significant heterogeneity between the studies (χ² = 26.48, I² = 47.1%).
AIIRA versus placebo/no treatment
The use of AIIRA versus placebo/no treatment was also associated with a significant reduction in the risk of progression from micro- to macroalbuminuria ( Analysis 2.5 (3 studies, 761 patients): RR 0.49, 95% CI 0.32 to 0.75), with no significant heterogeneity between the studies (χ² = 1.10, I² = 0%).
ACEi versus AIIRA
Progression from micro to macroalbuminuria was reported in one trial (41 patients) only, which showed no significant difference in risk (Ko 2005).
Regression for micro- to normoalbuminuria
ACEi versus placebo/no treatment
There was a significant increase in regression from micro- to normoalbuminuria with ACEi versus placebo/no treatment ( Analysis 1.6 (16 studies, 1910 patients): RR 3.06, 95% CI 1.76 to 5.35), with no significant heterogeneity between the studies (χ² = 23.91, I² = 45.6%).
AIIRA versus placebo/no treatment
There was a significant increase in regression from micro- to normoalbuminuria with AIIRA versus placebo/no treatment ( Analysis 2.6 (2 studies, 670 patients): RR 1.42, 95% CI 1.05 to 1.93) with no significant heterogeneity between the studies (χ² = 0.51, I² = 0%).
ACEi versus AIIRA
Regression from micro- to normoalbuminuria was reported in only one head-to-head study and showed a non-significant difference in the risk (Tutuncu 2001).
ACEi versus placebo/no treatment
The use of ACEi was associated with a significant increase in the risk of cough ( Analysis 1.7 (10 studies, 7087 patients): RR 3.17, 95% CI 2.29 to 4.38), with no significant heterogeneity between the studies (χ² = 4.30, I² = 0%).
The use of ACEi was not found to be associated with a significant increase in the risk of hyperkalaemia ( Analysis 1.10 (2 studies, 1219 patients): RR 0.85, 95% CI 0.32 to 2.21), with no significant heterogeneity between the studies (χ² = 0.05, I² = 0%).
Four studies (6186 patients) reported headaches and there was no significant increase in the risk of headache with ACEi compared to placebo/no treatment ( Analysis 1.8: RR 0.92, 95% CI 0.33 to 2.53). Also in this analysis, there was no significant heterogeneity between the studies (χ² = 3.20, I² = 6.2%).
Five studies (1528 patients) reported on impotence, and there was no evidence of a significant difference in the risk with ACEi compared to placebo/no treatment ( Analysis 1.9: RR 1.02, 95% CI 0.26 to 3.91), and there was no significant heterogeneity between the studies (χ² = 0.61, I² = 0%).
AIIRA versus placebo/no treatment
AIIRA were not found to be associated with an increased risk of cough compared to placebo/no treatment (Analysis 2.07 (2 studies, 194 patients): RR 4.93, 95% CI 1.00 to 24.35). There was no significant heterogeneity between the studies (χ² = 1.43, I² = 30.0%).
There was a significant increase in the risk of hyperkalaemia with AIIRA compared to placebo/no treatment ( Analysis 2.10 (1study, 1148 patients): RR 5.41, 95% CI 1.20 to 24.28).
One trial (91 patients) of AIIRA versus placebo/no treatment reported the outcome of headache and found no significant increase in risk with AIIRA ( Analysis 2.8: RR 0.70, 95% CI 0.03 to 16.68).
There were no studies of AIIRA versus placebo/no treatment reporting the outcome of impotence.
Investigation of sources of heterogeneity
Metaregression and subgroup analyses for sources of heterogeneity were only possible in studies of ACEi versus placebo/no treatment given the small number of studies evaluating AIIRA versus placebo/no treatment or ACEi versus AIIRA directly. There was no evidence that the effect of ACEi on all-cause mortality (interaction P value = 0.84), doubling of serum creatinine (interaction P value = 0.56), ESKD (interaction P value = 0.05) and progression from micro- to macroalbuminuria (interaction P value = 0.12) varied according to type of diabetes. On the contrary, the rate of regression from micro- to normoalbuminuria was significantly higher in patients with type 2 diabetes (interaction P value < 0.001).
The presence (versus absence) of hypertension in the enrolled populations did not significantly impact on the effect of ACEi compared to placebo/no treatment on all-cause mortality (interaction P value = 0.45), doubling of serum creatinine (interaction P value = 0.22), ESKD (interaction P value = 0.34), but normotensive patients had a significantly higher rate of progression from micro- to macroalbuminuria (interaction P value = 0.001) and significantly higher rate of regression from micro- to normoalbuminuria (interaction P value = 0.01).
The stage of nephropathy in enrolled populations (microalbuminuria versus macroalbuminuria or mixed populations with micro- or macroalbuminuria) did not significantly affect any of these outcomes in patients treated with ACEi compared to placebo/no treatment (all-cause mortality, interaction P value = 0.92; doubling of serum creatinine, interaction P value = 0.88, ESKD, interaction P value = 0.55, progression from micro- to macroalbuminuria, interaction P value = 0.86, regression from micro- to normoalbuminuria, interaction P value = 0.80). There were also no significant variations in the effect of ACEi versus placebo/no treatment on any of these outcomes by any trial quality indicators (allocation concealment, blinding, use of intention-to-treat analysis and proportions of patients lost to follow-up). The few significant differences observed in these analyses were all explained by the results of the large HOPE 2000 study. When we excluded this study from our analyses, results were homogeneous for all outcomes.
Placebo controlled studies have shown a survival advantage for ACEi when used at the maximum tolerable dose but not at "renal doses" (half or less than half the maximum tolerable dose) in patients with DKD. On the other hand, there has been no data showing a survival advantage with AIIRA versus placebo/no treatment, in patients with DKD. The relative survival advantage of one class of antihypertensives over the other in this population is, however, still unknown because only indirect comparisons based on small studies are available. ACEi, used at the maximum tolerable dose, significantly reduced the risk of all-cause mortality (mainly cardiovascular) by about 20% and progression from micro- to macroalbuminuria by about 55%. They also increased the rate of regression from micro- to normoalbuminuria by about threefold. We found no evidence that these effects are related to baseline hypertension, type of diabetes, stage of DKD, and duration of treatment. In comparison, current studies of AIIRA in patients with DKD have not shown a reduction in all-cause mortality, with a RR of 0.99 and narrow 95% CI (0.85 to 1.17), which is unlikely to be explained by chance alone. There is strong evidence that AIIRA are beneficial for renal outcomes, with a reduction in risk of ESKD and doubling of serum creatinine of about 22%, a reduction in progression rates from micro- to macroalbuminuria by around 51%, and an increase in the regression from micro- to normoalbuminuria of about 42%. Three potential explanations for these apparent different effects between the two classes of antihypertensives are chance, confounding, and true differences. The usual 5% level for statistical significance was reached for all renal outcomes for AIIRA versus ACEi,and this threshold was reached for ESKD, the prevention of progression from micro- to macroalbuminuria, and regression of micro- to normoalbuminuria, but not doubling of serum creatinine. The point estimates of effect for all renal outcomes favoured ACEi versus AIIRA, but there was some imprecision surrounding these summary point estimates for ACEi due to lower event rates and because of the heterogeneity in study results due to one large study (HOPE 2000). For all cause mortality, the absence of benefit shown by AIIRA is unlikely to be due to chance alone because the summary point estimate is close to unity (0.99) and the 95% CIs are relatively narrow. We did not formally test differences in ACEi and AIIRA through indirect comparison since there are clear differences in the design and conduct of the ACEi and AIIRA studies, which may explain apparent differences in results if such non randomised comparison was performed. In particular, micro-HOPE primarily included high cardiac risk patients with relatively low renal risk, and although end of treatment blood pressure was not different between the two groups (possibly due to survival bias), equalisation of blood pressure was not targeted and so may have confounded the observed benefit of ramipril. True differences in the relative effects of ACEi and AIIRA can only be established by adequately powered studies that directly compare the two agents, which unfortunately are currently not available.
Comparison with existing knowledge
In studies that enrolled patients with diabetes without nephropathy (which have not been included in this review), it has been shown that intensive control of blood pressure with any agent reduced cardiovascular morbidity and mortality, independent of type of agent used (Grossman 2001). In addition, in one study in which losartan was compared to atenolol in hypertensive patients with diabetes, losartan significantly reduced the risk of all-cause mortality (Wachtell 2003). Following myocardial infarction, ACEi have been shown to reduce all-cause mortality (Zunetti 1996), whereas no relevant information with AIIRA are available. Our findings are consistent with other large meta-analyses in patients with congestive heart failure, which showed a significant reduction in the risk of all cause mortality with ACEi versus placebo/no treatment but not for AIIRA (Cohn 2001; Garg 1995). Previous studies have already analysed the role of various antihypertensive agents, including ACEi and AIIRA, in patients affected by DKD. Particular focus was on the effect of ACEi in specific categories of patients (e.g. only type 1 diabetics). A recent meta-analysis of individual patient data from the ACEi in DKD Triallist Group concluded that in normotensive patients with type 1 diabetes and microalbuminuria, ACEi significantly reduced progression to macroalbuminuria and increased the chances of regression to normoalbuminuria (ACEIDN 2001). An earlier metaregression analysis indicated that ACEi reduced proteinuria and preserved GFR in patients with diabetes, independent of changes in systemic blood pressure (Kasiske 1993). The main difference with our study is that we included both ACEi and AIIRA studies, obtained additional data from the authors when possible, and evaluated all outcomes of interest, including all-cause mortality, and not simply the traditional renal outcomes. Another meta-analysis on the effects of inhibitors of the renin-angiotensin system and other antihypertensive agents on renal outcomes has been recently published (Casas 2005). This analysis, which included small studies conducted in high-risk patients with diabetic and non-diabetic chronic nephropathies, concluded that there are no superior effects of renin-angiotensin-system blockers over other antihypertensive agents in chronic nephropathies. Comparison between these data and ours is difficult because of different inclusion criteria and research questions.
Strengths and limitations
The strength of this investigation is that it represents a comprehensive systematic review with rigid inclusion criteria for RCTs only; and a comprehensive search strategy. Data extraction, data analysis, and methodological quality assessments were performed by two or more independent investigators, and consistency was checked with all six authors. The major limitation of our study is the lack of direct comparative data of ACEi and AIIRA. Studies directly comparing the two agents were only few and small and did not report outcomes relevant to patients, therefore they were largely uninformative. Other limitations include the small number and suboptimal quality of included studies and the potential for publication bias. These issues are unlikely to be influential as the review is dominated by a few larger studies.
Implications for practice
The role of ACEi in the management of patients with DKD is well established. Recently, equivalence of the newer and more expensive class of antihypertensive agents, AIIRA, has been widely advocated and is accepted in current practice. For example, the Joint National Committee on Prevention, Diagnosis and Management of Hypertension (JNC 7 2003) and the guidelines of the American Diabetes Association (ADA, Arauz-Pacheo 2003), suggest that ACEi and AIIRA can be used interchangeably. Our study shows that there is randomised trial evidence that ACEi versus placebo/no treatment used at their maximum tolerable dose prevent death in patients with DKD, but not that AIIRA versus placebo/no treatment do. Both agents prevent progression of nephropathy and promote regression to a more favourable clinical pattern of normoalbuminuria. The relative effects of ACEi and AIIRA are uncertain. These data suggest that outside of a comparative RCT, ACEi, the cheaper class of agent with proven survival benefit, should be used as first line treatment.
Implications for research
The findings of this study mandate an adequately powered comparative trial of ACEi versus AIIRA with renal and all-cause mortality as measured outcomes. In general studies of the newer pharmacological agents (AIIRA) have been designed as placebo-controlled rather than direct comparisons with existing agents (ACEi). This clearly makes it easier to prove that there is a benefit with the new agent, but harder to prove differential advantage compared to existing ones, as this may be only done by indirect comparison. It should be therefore recommended that future studies compare these agents directly. Given the recent promising results of combination therapy, a factorial trial may be the preferred design. Meanwhile, undertaking an individual patient data meta-analysis may allow the effects of baseline cardiac and renal disease to be better understood and accounted for through subgroup analysis.
We are indebted to Narelle Willis for editorial support and Sandra Puckeridge for administrative support. Ruth Mitchell, Linda Heslop and Gail Higgins provided search strategies for this review. We are also indebted to Janice Pogue and the HOPE triallists, Drs M Ravid, PJ Phillips, HH Parving, R Romero, S Katayama, EM Mathiesen, BR Brenner, and KC Tan who provided data of their studies upon request. This study was partly funded by a "2002 Young Investigator Scholarship" awarded to Giovanni FM Strippoli by the Italian Society of Nephrology, and by a University of Sydney School of Public Health non-established PhD scholarship.
Data and analyses
- Top of page
- Authors' conclusions
- Data and analyses
- What's new
- Contributions of authors
- Declarations of interest
- Sources of support
- Index terms
Last assessed as up-to-date: 15 August 2006.
Protocol first published: Issue 4, 2006
Review first published: Issue 4, 2006
Contributions of authors
- Strippoli GFM: Design, conduct, data-extraction, data-analysis, data interpretation, writing the review
- Bonifati C: Data-extraction, data entry and interpretation, writing the review
- Craig M: Data-extraction, writing the review
- Navaneethan S: Data-extraction, data entry and interpretation, writing of review
- Craig JC: Design, conduct, data-analysis, data interpretation, writing the review.
Declarations of interest
Sources of support
- University of Sydney School of Public Health, non-established PhD scholarship, Australia.
- 2002-03 Young Investigator Scholarship, Italian Society of Nephrology, Italy.
Medical Subject Headings (MeSH)
Angiotensin II Type 1 Receptor Blockers [adverse effects; *therapeutic use]; Angiotensin-Converting Enzyme Inhibitors [adverse effects; *therapeutic use]; Cause of Death; Diabetic Nephropathies [*drug therapy; mortality]; Disease Progression; Randomized Controlled Trials as Topic
MeSH check words
* Indicates the major publication for the study