Therapeutics
Review: In diabetes, ACE-Is, but not ARBs, reduce mortality and major CV events compared with placebo or active treatment
Cheng J, Zhang W, Zhang X, et al. 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. JAMA Intern Med. 2014;174:773-85.
Clinical impact ratings: F ★★★★★★✩ C ★★★★★★✩ e ★★★★★✩✩ n ★★★★★★✩ Question
Main results
In patients with diabetes, do angiotensin-converting enzyme inhibitors (ACE-Is) or angiotensin II–receptor blockers (ARBs) reduce mortality and cardiovascular (CV) events compared with placebo, no treatment, or other active treatments?
Meta-analysis showed that ACE-Is reduced all-cause and CV mortality, major CV events, MI, and CHF compared with control; ACE-Is and control did not differ for stroke (Table). ARBs reduced CHF compared with control; ARBs and control did not differ for any other outcome (Table).
Review scope Included studies compared ACE-Is or ARBs with placebo, no treatment, or other antihypertensive drugs in patients with diabetes mellitus; had mean or median follow-up ≥ 12 months; and reported all-cause or CV mortality. Crossover trials were excluded. Primary outcomes were all-cause and CV mortality. Other outcomes were major CV events (composite of CV mortality, nonfatal myocardial infarction [MI], stroke, congestive heart failure [CHF], coronary artery bypass graft, or percutaneous coronary intervention), MI, CHF, and stroke.
Review methods MEDLINE and EMBASE/Excerpta Medica to 2012; Cochrane Central Register of Controlled Trials; ClinicalTrials.gov; conference proceedings from American Diabetic Association meetings 2005 to 2012; and reference lists were searched for randomized controlled trials (RCTs) or subgroup analyses of RCTs. 35 RCTs (n = 56 444, mean age 29 to 76 y, 40% to 82% men) met the inclusion criteria: 22 evaluated ACE-Is, 12 evaluated ARBs, and 1 evaluated both drug classes. 10 of 23 ACE-I RCTs and 12 of 13 ARB RCTs had Jadad quality scores ≥ 4 out of 5. ACE-Is or ARBs vs control (placebo, no treatment, or other antihypertensive drug) in patients with diabetes* Outcomes
Number of trials (n)
Weighted RRR (95% CI) event rates ACE-Is Control
NNT (CI)
All-cause mortality
20 (25 544)
9.3%
11%
13% (2 to 22)
CV mortality
13 (24 334)
NR
NR
17% (1 to 30)
NR
Major CV events†
14 (34 352)
13%
15%
14% (5 to 23)
47 (29 to 131)
MI
11 (22 741)
7.3%
9.3%
21% (5 to 35)
52 (31 to 216)
CHF
8 (12 651)
5.5%
6.8%
19% (7 to 29)
Stroke
11 (33 508)
5.2%
5.4%
ARBs
Control
All-cause mortality
11 (17 334)
6.0%
6.4% 16%
73 (43 to 469)
78 (51 to 210)
5% (−4 to 14)
Not significant
6% (−8 to 18)
Not significant
Major CV events†
9 (18 743)‡ 15%
MI
6 (11 454)
3.6%
CHF
4 (4989)
9.3%
Stroke
8 (17 796)
6.0%
6.0%
0% (−12 to 11) Not significant
CV mortality
7 (10 801)
NR
NR
21% (−19 to 80) Not significant
4.0% 13%
6% (−1 to 13)
Not significant
11% (−7 to 26)
Not significant
30% (18 to 41)
26 (19 to 42)
RRI (CI)
NNH
*ACE-I = angiotensin-converting enzyme inhibitor; ARB = angiotensin II–receptor blocker; CHF = congestive heart failure; CV = cardiovascular; MI = myocardial infarction; NR = not reported; other abbreviations defined in Glossary. RRR, RRI, NNT, and CI calculated from risk ratios and control event rates in article using a random-effects model. †Composite of CV mortality, nonfatal MI, stroke, CHF, coronary artery bypass graft, or percutaneous coronary intervention. ‡579 patients in the ARB group were included twice, in both placebo and active control comparisons.
JC2
© 2014 American College of Physicians
Conclusion In diabetes, angiotensin-converting enzyme inhibitors, but not angiotensin II–receptor blockers, reduce all-cause mortality, cadiovascular (CV) mortality, and major CV events compared with placebo, no treatment, or active control. Sources of funding: National Basic Research Program of China and Zhejiang Provincial Education Department. For correspondence: Dr. J. Chen, Medical School of Zhejiang University, Zhejiang Province, People’s Republic of China. E-mail chenjianghua@ zju.edu.cn. ■
Commentary The meta-analysis by Cheng and colleagues evaluated the relative CV benefits of ACE-Is and ARBs in diabetes. Although ACE-Is seemed to be superior to both placebo and other antihypertensive drugs in reducing all-cause mortality, CV mortality, and major CV events, ARBs did not differ from placebo or other drugs in reducing the risk for any outcome except heart failure. The positive results of ACE-I therapy for all-cause mortality were driven primarily by 2 placebo-controlled trials, ADVANCE and HOPE, and moderate or higher heterogeneity between trials for most outcomes limited the validity of the pooled analysis. Only the DETAIL study directly compared ACE-Is to ARBs (1); other studies provided only indirect evidence, which is susceptible to bias, for ACE-I superiority. However, DETAIL assessed ACEI and ARB effects on glomerular filtration rate and was underpowered to detect differences in secondary CV endpoints (1). Cheng and colleagues excluded the only other RCT that directly compared ACE-I and ARB therapy (2). The ONTARGET trial found no difference between an ARB and ACE-I for CV events and mortality in the subgroup of patients with diabetes but did not provide specific data (2). Although it is plausible that ACE-Is and ARBs have different CV outcomes based on different targets along the renin–angiotensin system, the meta-analysis by Cheng and colleagues reinforces the need for head-to-head comparative effectiveness studies, as well as evaluation of the drugs in clinically important subgroups, such as racial minorities, patients with chronic kidney disease, and the elderly, who often respond differently to antihypertensive therapy. Rozalina McCoy, MD Steven Smith, MD Mayo Clinic Rochester, Minnesota, USA References 1. Barnett AH, Bain SC, Bouter P, et al; Diabetics Exposed to Telmisartan and Enalapril Study Group. N Engl J Med. 2004;351:1952-61. 2. Yusuf S, Teo KK, Pogue J, et al; ONTARGET Investigators. N Engl J Med. 2008;358:1547-59. 19 August 2014 | ACP Journal Club | Volume 161 • Number 4
Downloaded From: https://annals.org/pdfaccess.ashx?url=/data/journals/aim/930674/ by a Duke Medical Library User on 07/09/2017
Review: In diabetes, ACE-Is, but not ARBs, reduce mortality and major CV events compared with placebo or active treatment
Cheng J, Zhang W, Zhang X, et al. 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. JAMA Intern Med. 2014;174:773-85.
Clinical impact ratings: F ★★★★★★✩ C ★★★★★★✩ e ★★★★★✩✩ n ★★★★★★✩ Question
Main results
In patients with diabetes, do angiotensin-converting enzyme inhibitors (ACE-Is) or angiotensin II–receptor blockers (ARBs) reduce mortality and cardiovascular (CV) events compared with placebo, no treatment, or other active treatments?
Meta-analysis showed that ACE-Is reduced all-cause and CV mortality, major CV events, MI, and CHF compared with control; ACE-Is and control did not differ for stroke (Table). ARBs reduced CHF compared with control; ARBs and control did not differ for any other outcome (Table).
Review scope Included studies compared ACE-Is or ARBs with placebo, no treatment, or other antihypertensive drugs in patients with diabetes mellitus; had mean or median follow-up ≥ 12 months; and reported all-cause or CV mortality. Crossover trials were excluded. Primary outcomes were all-cause and CV mortality. Other outcomes were major CV events (composite of CV mortality, nonfatal myocardial infarction [MI], stroke, congestive heart failure [CHF], coronary artery bypass graft, or percutaneous coronary intervention), MI, CHF, and stroke.
Review methods MEDLINE and EMBASE/Excerpta Medica to 2012; Cochrane Central Register of Controlled Trials; ClinicalTrials.gov; conference proceedings from American Diabetic Association meetings 2005 to 2012; and reference lists were searched for randomized controlled trials (RCTs) or subgroup analyses of RCTs. 35 RCTs (n = 56 444, mean age 29 to 76 y, 40% to 82% men) met the inclusion criteria: 22 evaluated ACE-Is, 12 evaluated ARBs, and 1 evaluated both drug classes. 10 of 23 ACE-I RCTs and 12 of 13 ARB RCTs had Jadad quality scores ≥ 4 out of 5. ACE-Is or ARBs vs control (placebo, no treatment, or other antihypertensive drug) in patients with diabetes* Outcomes
Number of trials (n)
Weighted RRR (95% CI) event rates ACE-Is Control
NNT (CI)
All-cause mortality
20 (25 544)
9.3%
11%
13% (2 to 22)
CV mortality
13 (24 334)
NR
NR
17% (1 to 30)
NR
Major CV events†
14 (34 352)
13%
15%
14% (5 to 23)
47 (29 to 131)
MI
11 (22 741)
7.3%
9.3%
21% (5 to 35)
52 (31 to 216)
CHF
8 (12 651)
5.5%
6.8%
19% (7 to 29)
Stroke
11 (33 508)
5.2%
5.4%
ARBs
Control
All-cause mortality
11 (17 334)
6.0%
6.4% 16%
73 (43 to 469)
78 (51 to 210)
5% (−4 to 14)
Not significant
6% (−8 to 18)
Not significant
Major CV events†
9 (18 743)‡ 15%
MI
6 (11 454)
3.6%
CHF
4 (4989)
9.3%
Stroke
8 (17 796)
6.0%
6.0%
0% (−12 to 11) Not significant
CV mortality
7 (10 801)
NR
NR
21% (−19 to 80) Not significant
4.0% 13%
6% (−1 to 13)
Not significant
11% (−7 to 26)
Not significant
30% (18 to 41)
26 (19 to 42)
RRI (CI)
NNH
*ACE-I = angiotensin-converting enzyme inhibitor; ARB = angiotensin II–receptor blocker; CHF = congestive heart failure; CV = cardiovascular; MI = myocardial infarction; NR = not reported; other abbreviations defined in Glossary. RRR, RRI, NNT, and CI calculated from risk ratios and control event rates in article using a random-effects model. †Composite of CV mortality, nonfatal MI, stroke, CHF, coronary artery bypass graft, or percutaneous coronary intervention. ‡579 patients in the ARB group were included twice, in both placebo and active control comparisons.
JC2
© 2014 American College of Physicians
Conclusion In diabetes, angiotensin-converting enzyme inhibitors, but not angiotensin II–receptor blockers, reduce all-cause mortality, cadiovascular (CV) mortality, and major CV events compared with placebo, no treatment, or active control. Sources of funding: National Basic Research Program of China and Zhejiang Provincial Education Department. For correspondence: Dr. J. Chen, Medical School of Zhejiang University, Zhejiang Province, People’s Republic of China. E-mail chenjianghua@ zju.edu.cn. ■
Commentary The meta-analysis by Cheng and colleagues evaluated the relative CV benefits of ACE-Is and ARBs in diabetes. Although ACE-Is seemed to be superior to both placebo and other antihypertensive drugs in reducing all-cause mortality, CV mortality, and major CV events, ARBs did not differ from placebo or other drugs in reducing the risk for any outcome except heart failure. The positive results of ACE-I therapy for all-cause mortality were driven primarily by 2 placebo-controlled trials, ADVANCE and HOPE, and moderate or higher heterogeneity between trials for most outcomes limited the validity of the pooled analysis. Only the DETAIL study directly compared ACE-Is to ARBs (1); other studies provided only indirect evidence, which is susceptible to bias, for ACE-I superiority. However, DETAIL assessed ACEI and ARB effects on glomerular filtration rate and was underpowered to detect differences in secondary CV endpoints (1). Cheng and colleagues excluded the only other RCT that directly compared ACE-I and ARB therapy (2). The ONTARGET trial found no difference between an ARB and ACE-I for CV events and mortality in the subgroup of patients with diabetes but did not provide specific data (2). Although it is plausible that ACE-Is and ARBs have different CV outcomes based on different targets along the renin–angiotensin system, the meta-analysis by Cheng and colleagues reinforces the need for head-to-head comparative effectiveness studies, as well as evaluation of the drugs in clinically important subgroups, such as racial minorities, patients with chronic kidney disease, and the elderly, who often respond differently to antihypertensive therapy. Rozalina McCoy, MD Steven Smith, MD Mayo Clinic Rochester, Minnesota, USA References 1. Barnett AH, Bain SC, Bouter P, et al; Diabetics Exposed to Telmisartan and Enalapril Study Group. N Engl J Med. 2004;351:1952-61. 2. Yusuf S, Teo KK, Pogue J, et al; ONTARGET Investigators. N Engl J Med. 2008;358:1547-59. 19 August 2014 | ACP Journal Club | Volume 161 • Number 4
Downloaded From: https://annals.org/pdfaccess.ashx?url=/data/journals/aim/930674/ by a Duke Medical Library User on 07/09/2017
