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Original Investigation |

Effect of Angiotensin-Converting Enzyme Inhibitors and Angiotensin II Receptor Blockers on All-Cause Mortality, Cardiovascular Deaths, and Cardiovascular Events in Patients With Diabetes Mellitus:  A Meta-analysis

Jun Cheng, MD1; Wen Zhang, MMed2; Xiaohui Zhang, MMed1; Fei Han, MD1; Xiayu Li, MD1; Xuelin He, MD1; Qun Li, MMed1; Jianghua Chen, MMed1
[+] Author Affiliations
1Kidney Disease Center, The First Affiliated Hospital, Medical School of Zhejiang University, Hangzhou, China
2Department of Nephrology, Hangzhou Red Cross Hospital, Hangzhou, China
JAMA Intern Med. 2014;174(5):773-785. doi:10.1001/jamainternmed.2014.348.
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Published online

Importance  Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs) may have different effects on cardiovascular (CV) events in patients with diabetes mellitus (DM).

Objective  To conduct a meta-analysis to separately evaluate the effects of ACEIs and ARBs on all-cause mortality, CV deaths, and major CV events in patients with DM.

Data Sources  Data sources included MEDLINE (1966-2012), EMBASE (1988-2012), the Cochrane Central Register of Controlled Trials, conference proceedings, and article reference lists.

Study Selection  We included randomized clinical trials reporting the effects of ACEI and ARB regimens for DM on all-cause mortality, CV deaths, and major CV events with an observation period of at least 12 months. Studies were excluded if they were crossover trials.

Data Extraction and Synthesis  Dichotomous outcome data from individual trials were analyzed using the risk ratio (RR) measure and its 95% CI with random-effects models. We estimated the difference between the estimates of the subgroups according to tests for interaction. We performed meta-regression analyses to identify sources of heterogeneity.

Main Outcomes and Measures  Primary end points were all-cause mortality and death from CV causes. Secondary end points were the effects of ACEIs and ARBs on major CV events.

Results  Twenty-three of 35 identified trials compared ACEIs with placebo or active drugs (32 827 patients) and 13 compared ARBs with no therapy (controls) (23 867 patients). When compared with controls (placebo/active treatment), ACEIs significantly reduced the risk of all-cause mortality by 13% (RR, 0.87; 95% CI, 0.78-0.98), CV deaths by 17% (0.83; 0.70-0.99), and major CV events by 14% (0.86; 0.77-0.95), including myocardial infarction by 21% (0.79; 0.65-0.95) and heart failure by 19% (0.81; 0.71-0.93). Treatment with ARBs did not significantly affect all-cause mortality (RR, 0.94; 95% CI, 0.82-1.08), CV death rate (1.21; 0.81-1.80), and major CV events (0.94; 0.85-1.01) with the exception of heart failure (0.70; 0.59-0.82). Both ACEIs and ARBs were not associated with a decrease in the risk for stroke in patients with DM. Meta-regression analysis showed that the ACEI treatment effect on all-cause mortality and CV death did not vary significantly with the starting baseline blood pressure and proteinuria of the trial participants and the type of ACEI and DM.

Conclusions and Relevance  Angiotensin-converting enzyme inhibitors reduced all-cause mortality, CV mortality, and major CV events in patients with DM, whereas ARBs had no benefits on these outcomes. Thus, ACEIs should be considered as first-line therapy to limit excess mortality and morbidity in this population.

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Figure 1.
Flowchart of Article Selection for Meta-analysis

Potentially relevant reports identified and screened for retrieval. ACEIs indicates angiotensin-converting enzyme inhibitors; ARBs, angiotensin II receptor blockers.

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Figure 2.
Angiotensin-Converting Enzyme Inhibitors (ACEIs) and All-Cause Mortality Stratified by Comparison Group (Placebo vs Active)

Diamond indicates the overall summary estimate for the analysis (width of the diamond represents the 95% CI); boxes, the weight of individual studies in the pooled analysis. Trials to the left of the vertical line showed a reduction in risk with the experimental intervention; those to the right showed an increase in risk with the experimental intervention. M-H indicates Mantel-Haenszel. See Table 1 footnote for expansion of clinical trial acronyms.

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Figure 3.
Angiotensin II Receptor Blockers (ARBs) and All-Cause Mortality Stratified by Comparison Group (Placebo vs Active)

Diamond indicates the overall summary estimate for the analysis (width of the diamond represents the 95% CI); boxes, the weight of individual studies in the pooled analysis. Trials to the left of the vertical line showed a reduction in risk with the experimental intervention; those to the right showed an increase in risk with the experimental intervention. M-H indicates Mantel-Haenszel. See Table 1 footnote for expansion of clinical trial acronyms.

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Figure 4.
Angiotensin-Converting Enzyme Inhibitors (ACEIs) and Cause-Specific Cardiovascular Outcomes

Diamond indicates the overall summary estimate for the analysis (width of the diamond represents the 95% CI); boxes, the weight of individual studies in the pooled analysis. Trials to the left of the vertical line showed a reduction in risk with the experimental intervention; those to the right showed an increase in risk with the experimental intervention. M-H indicates Mantel-Haenszel. See Table 1 footnote for expansion of clinical trial acronyms.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 5.
Angiotensin II Receptor Blockers (ARBs) and Cause-Specific Cardiovascular (CV) Outcomes

Diamond indicates the overall summary estimate for the analysis (width of the diamond represents the 95% CI); boxes, the weight of individual studies in the pooled analysis. Trials to the left of that line showed a reduction in risk with the experimental intervention; those to the right showed an increase in risk with the experimental intervention. M-H indicates Mantel-Haenszel. See Table 1 footnote for expansion of clinical trial acronyms.

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