Should All Patients Receive ACE inhibitors?
Overall Study Question
The effectiveness of angiotensin-converting enzyme (ACE) inhibitors in reversing and/or preventing progression of microalbuminuria in patients with type 1 diabetes mellitus (DM) is already well-established. (1,2,3) Using the rate of change of albumin excretion rate (AER) as the primary outcome measure, the main objective of this meta-analysis was to determine if there was a subgroup of patients with type 1 DM and microalbuminuria who were most likely to benefit from ACE inhibitor therapy. The subgroups identified included age, duration of diabetes, gender and glycemic control (hemoglobin A1c). The investigators also examined the impact of blood pressure (BP) and baseline AER as covariates on treatment effect. Finally, the risk for progression to macroalbuminuria and regression to normoalbuminuria was also examined.
Are the Results of the Study Valid?
1.Did the overview address a focused clinical question?
The authors could have been more explicit in phrasing their clinical questions, and could have expressed their objectives in a more concise form. They did not delineate a prior all covariates to be considered in their objectives.
2. Were the criteria used to select articles for inclusion appropriate?
Yes. Criteria for study selection included trials with at least 10 patients who had: 1) type 1 DM; 2) normotension, as defined by each individual trial); and 3) microalbuminuria, as defined as an AER of 20-200 mcg/min measured at baseline and one or more follow-up visits. All trials were required to have a placebo or non-intervention group, and a minimum follow up of 1 year. Of note, one-third of the patients who were classified as normotensive in earlier studies were actually considered hypertensive by current standards. This variance, however, allowed the authors to observe the efficacy of ACE inhibitors over a wider range of blood pressures. Other antihypertensive medication that patients may have been taking other than ACE inhibitors were never mentioned by the authors.
3. Is it unlikely that important, relevant studies were missed?
Probably. Only one database (Medline) was employed, thus studies not indexed in this database may have been missed. However, bibliographies of published studies were also reviewed by the authors, and experts in the field were also consulted. Manufacturers or trial registries did not appear to have been contacted by the authors, and no information was provided to suggest that abstracts from conference proceedings were reviewed. The authors also did not specify any restrictions on their searching (i.e. years considered or languages of publication).
4. Was the validity of the included studies appraised?
No. Information was not provided on how many reviewers were involved in retrieving the studies or assessing these studies for inclusion or exclusion from the meta-analysis. The reviewers did not comment on whether or not they were blind to study results when studies were selected for inclusion.
5. Were assessments of studies reproducible?
This meta-analysis assessed raw data obtained from all trials and pooled them to create one large database. Trial investigators were contacted to obtain individual patient data with respect to the objectives of this study. This method was employed as the authors claimed that individual studies were underpowered to analyze for subgroup effects or risk for progression to macroalbuminuria. As well, analysis of individual patient data allowed a consistent approach to assess renal outcome (ie. AER), covariates, and subgroup effects.
Both a trial-level and a patient-level analysis was performed. For the trial-level analysis, both fixed-effects and random-effects models were used to provide an estimate of the treatment effect, and estimates of between-trial variance were calculated. Treatment effect was expressed as a percentage difference of the relative change in AER between treatment and control groups compared to baseline. For the patient-level analysis, a random-effects regression model was used to determine the treatment effect for each patient. The authors do not state whether certain baseline risk factors (e.g. age, diabetes duration) were analyzed as continuous or categorical variables to determine a possible interaction.
Progression to macroalbuminuria or regression to normoalbuminuria may not have been as reproducible. Macroalbuminuria and normoalbuminuria were defined as AER greater than 200mcg/min or less than 20mcg/min, respectively, on two successive occasions at least 3 months apart, or at final visit. Since some patients may have met the criteria upon their final visit, the durability of the result over time could not be assessed.
6. Were the results similar from study to study?
All trials with at least a 2-year follow-up (n=10) showed a beneficial effect of ACE-inhibitors on rate of change in AER.
What were the Results?
1. What are the overall results of the review?
Initially, 12 trials and 698 patients were included in the meta-analysis. However, final analysis of treatment effects was limited to those studies with at least 2 years of follow-up, effectively excluding 2 trials and resulting in a total of 646 patients.
ACE inhibitors used in the trials were captopril (3 trials), lisinopril (3 trials), ramipril (2 trials), enalapril (1 trial) and perindopril (1 trial). Overall, at two years and using a random-effects model, AER was 50.2% (95% CI, 30.0%-64.6%, p<0.001) lower in patients receiving ACE inhibitors as compared to placebo. When the impact of a reduction in blood pressure on AER was accounted for, the treatment effect was attenuated slightly to 45.1% (p<0.001). A more pronounced reduction in AER was noted among subjects who had a baseline AER at the upper end of microalbuminuria (200 mcg/min) compared to those at the lower end (20 mcg/min) (74.1% vs. 17.8%, respectively, p=0.04). Other covariates (age, diabetes duration, sex, glycemic control) had no apparent impact on treatment effect.
Progression to macroalbuminuria decreased by one-third as compared to placebo, with an odds ratio (OR) of 0.38 (95% CI, 0.25-0.57, p<0.001) in favour of the ACE inhibitor. As well, there was a threefold increase in regression to normoalbuminuria with an OR of 3.07 (95% CI, 2.15-4.44, p<0.001). All trials demonstrated beneficial effects of ACE inhibitors with respect to regression to normoalbuminuria, and all were favourable except for one regarding risk for progression to macroalbuminuria.
2. How precise were the results?
Both fixed-effects and random-effects models showed similar results on rate of change of AER. A marginal attenuation in treatment effect was observed using the estimates derived from the patient-level rather than trial-level regression models. The confidence intervals around the treatment estimate for the progression to macroalbuminuria and the regression to normoalbuminuria were fairly narrow. The lower boundary of both confidence intervals (0.25 and 2.15, respectively) provide odds ratios that are consistent with a clinically important effect. The confidence intervals that contain the treatment effect of different covariates on AER are almost identical to the effect of ACE inhibitors alone. Thus, it is not a surprise that these covariates had little effect on the beneficial outcome of ACE inhibitors.
3. How much does allowance for uncertainty change the results?
Although it is possible that the authors did not identify all relevant studies, including some smaller or unpublished studies, it is unlikely that these studies would overwhelm the consistent effect of ACE inhibitors on microalbuminuria in the subgroups studied.
Will the Results Help Me in Caring for My Patients?
- 1. Can the results be applied to my patient care?
- Yes. The results indicate that ACE inhibitors have a significant effect on reversing and/or preventing the worsening of albuminuria associated with type 1 diabetic renal disease. These effects occurred across a broad range of patients, regardless of age, glycemic control, gender, baseline BP or diabetes duration. The results were strongly influenced by baseline AER with the greatest reduction in AER observed in patients with the highest baseline levels. Although AER is a surrogate marker, it is a useful predictor for development and progression of nephropathy. Since approximately 80% of untreated patients with type 1 DM and microalbuminuria increase their AER at a rate of 10-20% per year to the stage of overt nephropathy over a period of 10-15 years, the results of this meta-analysis will have a definite impact on patient care.
2. Were all clinically important outcomes considered?
- The maximum age included in the meta-analysis was 68 years; thus results would need to be extrapolated for older populations. Since AER is only a surrogate marker for underlying renal dysfunction, the results could have been strengthened by correlating the effects of ACE inhibitors with other indicators of renal function, such as a measure of glomerular filtration rate.
3. Are the likely treatment benefits worth the potential harms and costs?
- Yes. Since many patients require ACE inhibitors for other indications (e.g. hypertension, congestive heart failure), these patients enjoy added benefit at no additional cost. For the patients to whom this meta-analysis most directly applies (i.e. normotensive patients with microalbuminuria), the cost and minimal side effects of an ACE inhibitor would be good value for a reduction or delay in end-stage renal disease, need for dialysis and the associated reduction in quality of life.
This meta-analysis provides justification for initiating an ACE inhibitor in any patient with type 1 DM and microalbuminuria, even if the patient is normotensive. The appearance of clinically detectable microalbuminuria usually occurs after a period of 5-10 years following the onset of type 1 DM. Since the duration of diabetes was not found to be significant, the use of ACE inhibitors either early (at the onset of microalbuminuria) or later on in the disease process would be beneficial. The meta-analysis did show, however, that patients with greater baseline microalbuminuria have a larger proportional benefit than those with less. As well, since treatment effect was only slightly attenuated when BP reduction was taken into account, this analysis supports the results of previous studies that have also suggested that ACE-inhibitors can provide benefit independent of BP reduction.
The 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;134:370-379.