Risk of Pneumonia and Use of ACE Inhibitors and ARBs
Risk of Pneumonia and Use of ACE Inhibitors and ARBs
The search of the electronic databases yielded 807 published studies. After applying the inclusion and exclusion criteria 29 studies were included for analysis (Figure 1). The results from eight additional studies were identified in the FDA regulatory documents. Overall, data were obtained from 37 studies.
(Enlarge Image)
Figure 1.
Flow of studies through review. ACE=angiotensin converting enzyme; ARBs=angiotensin receptor blockers
The 37 studies included 18 randomised controlled trials, 11 cohort studies, two nested case-control studies, and six case-control studies.
Among randomised controlled trials, eight were done worldwide, six in Europe, three in Asia,, and one in Europe and the United States. Most of the randomised controlled trials were multicentre (n=16). Seven randomised controlled trials compared ACE inhibitors with controls, nine compared ARBs with controls, and two compared ACE inhibitors with ARBs. Seven trials reported specific data for serious pneumonia, five for fatal pneumonia, and eight reported pneumonia without specifying the severity of disease. In only two trials was pneumonia a prespecified outcome.
Among observational studies, 10 were carried out in Asia, five in the United States, and four in Europe. Eleven studies were retrospective and eight were prospective. Seventeen evaluated ACE inhibitors, two ARBs, and two compared ACE inhibitors with ARBs.
Table 1 , Table 2 , and Table 3 summarise the main characteristics of the included studies.
The overall quality of the studies was considered to be good. All the randomised controlled trials, except one, met the criteria for random sequence generation and about half specifically reported adequate allocation concealment. Only two randomised controlled trials were considered to be at high risk of performance bias. Adequate blinding of outcome assessment and full description of study withdrawals were reported in 78% and 89% of randomised controlled trials, respectively. The highest risk of bias was found for potential reporting bias because only two randomised controlled trials presented results for pneumonia as a prespecified outcome.Supplementary Figure 1 and Supplementary Figure 2 show the results of the quality appraisal of the randomised controlled trials.
All observational studies were considered to have adequate inclusion and exclusion criteria and provided justification for the cohort. Five studies (26%) did not clearly stated how the drug use was assessed, and four studies (21%) did not provide details about outcome assessment. Eleven studies (58%) provided results after adjustment for at least one potential variable confounder. In one study it was unclear for which variables the results were adjusted. Few studies (26%) reported results adjusted for multiple confounders, and in seven studies (37%) no type of adjustment was mentioned. Supplementary Figure 3 and Supplementary Figure 4 show the results for the quality of the observational studies.
Primary outcome data were available from 19 studies comparing ACE inhibitors with controls (five randomised controlled trials, eight cohort or nested case-control studies, and six case-control studies), 11 studies comparing ARBs with controls (nine randomised controlled trials and two cohort or nested case-control studies), and two studies comparing ACE inhibitors with ARBs (one randomised controlled trial and one cohort study).
Use of ACE inhibitors was associated with a significant 34% reduction in risk of pneumonia compared with controls (odds ratio 0.66, 95% confidence interval 0.55 to 0.80; I=79%). The NNT for 2.0 years was 65 (48 to 112). The magnitude of the risk reduction was similar across all study designs (P=0.78 for subgroup differences). The odds ratios for randomised controlled trials, cohort or nested case-control studies, and case-control studies were 0.69 (0.56 to 0.85; I=0%), 0.58 (0.38 to 0.88; I=79%), and 0.67 (0.49 to 0.93; I=73%), respectively (Figure 2).
(Enlarge Image)
Figure 2.
Risk of pneumonia with use of angiotensin converting enzyme (ACE) inhibitors compared with control treatment
The risk of pneumonia was not, however, different between patients who did or did not use ARBs (0.95, 0.87 to 1.04; I=14%). Odds ratio estimates for randomised controlled trials (0.90, 0.79 to 1.01; I=7%) and cohort or nested case-control studies (1.01, 0.94 to 1.09; I=0%) did not differ significantly (P=0.10; Figure 3).
(Enlarge Image)
Figure 3.
Risk of pneumonia with use of angiotensin receptor blockers (ARBs) compared with control treatment
Pooled results from the two head to head studies showed a non-significant 37% reduction in risk of pneumonia associated with use of ACE inhibitors (0.63, 0.28 to 1.44; I=78%). In this case, estimates from the randomised controlled trial and cohort study differed significantly (P=0.03) (see Supplementary Figure 5 ).
Indirect comparison of ACE inhibitors with ARBs showed a significant 30% reduction in risk of pneumonia associated with use of ACE inhibitors (0.70, 0.56 to 0.86). Similar results were obtained from pooled direct and indirect estimates (0.69, 0.56 to 0.85) without discrepancy (P=0.82) or heterogeneity (I=0%) between both estimates (figure 4). The NNT for 2.2 years based on this estimate was 72 (51 to 147).
(Enlarge Image)
Figure 4.
Summary of meta-analysis estimates and subgroup analyses. ACE=angiotensin converting enzyme; ARBs=angiotensin receptor blockers
Patients With Previous Stroke. In patients with previous stroke, use of ACE inhibitors was associated with a 54% reduction in risk of pneumonia compared with controls (0.46, 0.34 to 0.62, I=0%; seven studies pooled) (see Supplementary Figure 6 ). In the same population, however, use of ARBs was not associated with a significant reduction in risk (0.86, 0.67 to 1.09; I=0%; two studies pooled) (see Supplementary Figure 7 ).
The pooled estimate from indirect (odds ratio 0.53, 95% confidence interval 0.16 to 1.79) and direct (0.38, 0.17 to 0.81) evidence of ACE inhibitors compared with ARBs showed a significant 58% reduction in risk of pneumonia (0.42, 0.22 to 0.80; figure 4), without discrepancy (P=0.44) or heterogeneity (I=0%) between indirect and direct estimates.
Patients With Heart Failure. In patients with heart failure, two studies evaluated the risk of pneumonia in those treated with ACE inhibitors and two other studies reported data for those treated with ARBs. ACE inhibitors were associated with a significant 37% reduction in risk of pneumonia (0.63, 0.47 to 0.84; I=0%), whereas ARBs showed no significant effect (0.85, 0.49 to 1.47; I=15%) (see Supplementary Figure 8 ).
Patients With Chronic Kidney Disease. In patients with chronic kidney disease, the results from one randomised controlled trial of ACE inhibitors (odds ratio 0.15, 95% confidence interval 0.00 to 7.70) and two randomised controlled trials of ARBs (1.21, 0.32 to 4.52; I=77%) did not differ significantly when compared with controls (see Supplementary Figure 9 ).
Asian and Non-Asian Patients. Eleven studies were carried out in Asian countries and 11 were done outside of Asia. The PROGRESS study was the only multicentre study carried out worldwide that supplied separate data for Asian and non-Asian patients. To lower analysis bias, the other studies carried out worldwide that did not provide separate data for both groups were excluded.
The reduction in risk of pneumonia associated with ACE inhibitors was significantly higher among Asian patients (0.43, 0.34 to 0.54; I=0%) compared with non-Asian patients (0.82, 0.67 to 1.00, I=80%, P<0.001 for subgroup differences) (see Supplementary Figure 10 ). ARBs, however, were not associated with a reduction in risk of pneumonia in Asian patients (1.04, 0.59 to 1.84; one randomised controlled trial HIJ-CREATE) or non-Asian patients (0.97, 0.84 to 1.12; I=27%; five studies pooled; Figure 4 and Supplementary Figure 11 ).
Data for secondary outcomes were extracted from seven studies comparing ACE inhibitors with controls (three randomised controlled trials and four cohort studies), one randomised controlled trial comparing ARBs with control, and one head to head randomised controlled trial. Five studies comparing ACE inhibitors with controls were carried out on an enriched population—that is, enrolled patients with pneumonia.
Treatment with ACE inhibitors was associated with a significant 27% reduction in risk of pneumonia related mortality compared with controls (0.73, 0.58 to 0.92; I=51%), without significant differences between estimates from randomised controlled trials and observational studies (P=0.76). The pooled result from randomised controlled trials, however, failed to reach statistical significance (0.61, 0.20 to 1.90; I=61%) (Figure 5).
(Enlarge Image)
Figure 5.
Pneumonia related mortality in studies comparing angiotensin converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) with control treatment
Only one randomised controlled trial reported the effect of treatment with ARBs on pneumonia related mortality (odds ratio 0.63, 95% confidence interval 0.40 to 1.00) (figure 5).
The risk of pneumonia related mortality in indirect (1.16, 0.69 to 1.94), direct (HEAVEN randomised controlled trial 7.29, 0.14 to 367.24), and pooled comparisons (1.19, 0.71 to 1.98) did not differ between ACE inhibitors and ARBs (figure 4). There was no discrepancy (P=0.36) or heterogeneity (I=0%) between indirect and direct estimates.
Visual inspection of funnel plots did not reveal any obvious asymmetrical tail (see Supplementary Figure 12 ). Publication bias was not suggested by sensitivity analysis taking into account published and unpublished trials (see Supplementary Figure 13 ).
Results
The search of the electronic databases yielded 807 published studies. After applying the inclusion and exclusion criteria 29 studies were included for analysis (Figure 1). The results from eight additional studies were identified in the FDA regulatory documents. Overall, data were obtained from 37 studies.
(Enlarge Image)
Figure 1.
Flow of studies through review. ACE=angiotensin converting enzyme; ARBs=angiotensin receptor blockers
Description of Studies
The 37 studies included 18 randomised controlled trials, 11 cohort studies, two nested case-control studies, and six case-control studies.
Among randomised controlled trials, eight were done worldwide, six in Europe, three in Asia,, and one in Europe and the United States. Most of the randomised controlled trials were multicentre (n=16). Seven randomised controlled trials compared ACE inhibitors with controls, nine compared ARBs with controls, and two compared ACE inhibitors with ARBs. Seven trials reported specific data for serious pneumonia, five for fatal pneumonia, and eight reported pneumonia without specifying the severity of disease. In only two trials was pneumonia a prespecified outcome.
Among observational studies, 10 were carried out in Asia, five in the United States, and four in Europe. Eleven studies were retrospective and eight were prospective. Seventeen evaluated ACE inhibitors, two ARBs, and two compared ACE inhibitors with ARBs.
Table 1 , Table 2 , and Table 3 summarise the main characteristics of the included studies.
The overall quality of the studies was considered to be good. All the randomised controlled trials, except one, met the criteria for random sequence generation and about half specifically reported adequate allocation concealment. Only two randomised controlled trials were considered to be at high risk of performance bias. Adequate blinding of outcome assessment and full description of study withdrawals were reported in 78% and 89% of randomised controlled trials, respectively. The highest risk of bias was found for potential reporting bias because only two randomised controlled trials presented results for pneumonia as a prespecified outcome.Supplementary Figure 1 and Supplementary Figure 2 show the results of the quality appraisal of the randomised controlled trials.
All observational studies were considered to have adequate inclusion and exclusion criteria and provided justification for the cohort. Five studies (26%) did not clearly stated how the drug use was assessed, and four studies (21%) did not provide details about outcome assessment. Eleven studies (58%) provided results after adjustment for at least one potential variable confounder. In one study it was unclear for which variables the results were adjusted. Few studies (26%) reported results adjusted for multiple confounders, and in seven studies (37%) no type of adjustment was mentioned. Supplementary Figure 3 and Supplementary Figure 4 show the results for the quality of the observational studies.
Primary Outcome: Incidence of Pneumonia
Primary outcome data were available from 19 studies comparing ACE inhibitors with controls (five randomised controlled trials, eight cohort or nested case-control studies, and six case-control studies), 11 studies comparing ARBs with controls (nine randomised controlled trials and two cohort or nested case-control studies), and two studies comparing ACE inhibitors with ARBs (one randomised controlled trial and one cohort study).
Use of ACE inhibitors was associated with a significant 34% reduction in risk of pneumonia compared with controls (odds ratio 0.66, 95% confidence interval 0.55 to 0.80; I=79%). The NNT for 2.0 years was 65 (48 to 112). The magnitude of the risk reduction was similar across all study designs (P=0.78 for subgroup differences). The odds ratios for randomised controlled trials, cohort or nested case-control studies, and case-control studies were 0.69 (0.56 to 0.85; I=0%), 0.58 (0.38 to 0.88; I=79%), and 0.67 (0.49 to 0.93; I=73%), respectively (Figure 2).
(Enlarge Image)
Figure 2.
Risk of pneumonia with use of angiotensin converting enzyme (ACE) inhibitors compared with control treatment
The risk of pneumonia was not, however, different between patients who did or did not use ARBs (0.95, 0.87 to 1.04; I=14%). Odds ratio estimates for randomised controlled trials (0.90, 0.79 to 1.01; I=7%) and cohort or nested case-control studies (1.01, 0.94 to 1.09; I=0%) did not differ significantly (P=0.10; Figure 3).
(Enlarge Image)
Figure 3.
Risk of pneumonia with use of angiotensin receptor blockers (ARBs) compared with control treatment
Pooled results from the two head to head studies showed a non-significant 37% reduction in risk of pneumonia associated with use of ACE inhibitors (0.63, 0.28 to 1.44; I=78%). In this case, estimates from the randomised controlled trial and cohort study differed significantly (P=0.03) (see Supplementary Figure 5 ).
Indirect comparison of ACE inhibitors with ARBs showed a significant 30% reduction in risk of pneumonia associated with use of ACE inhibitors (0.70, 0.56 to 0.86). Similar results were obtained from pooled direct and indirect estimates (0.69, 0.56 to 0.85) without discrepancy (P=0.82) or heterogeneity (I=0%) between both estimates (figure 4). The NNT for 2.2 years based on this estimate was 72 (51 to 147).
(Enlarge Image)
Figure 4.
Summary of meta-analysis estimates and subgroup analyses. ACE=angiotensin converting enzyme; ARBs=angiotensin receptor blockers
Subgroup Analyses for Primary Outcome
Patients With Previous Stroke. In patients with previous stroke, use of ACE inhibitors was associated with a 54% reduction in risk of pneumonia compared with controls (0.46, 0.34 to 0.62, I=0%; seven studies pooled) (see Supplementary Figure 6 ). In the same population, however, use of ARBs was not associated with a significant reduction in risk (0.86, 0.67 to 1.09; I=0%; two studies pooled) (see Supplementary Figure 7 ).
The pooled estimate from indirect (odds ratio 0.53, 95% confidence interval 0.16 to 1.79) and direct (0.38, 0.17 to 0.81) evidence of ACE inhibitors compared with ARBs showed a significant 58% reduction in risk of pneumonia (0.42, 0.22 to 0.80; figure 4), without discrepancy (P=0.44) or heterogeneity (I=0%) between indirect and direct estimates.
Patients With Heart Failure. In patients with heart failure, two studies evaluated the risk of pneumonia in those treated with ACE inhibitors and two other studies reported data for those treated with ARBs. ACE inhibitors were associated with a significant 37% reduction in risk of pneumonia (0.63, 0.47 to 0.84; I=0%), whereas ARBs showed no significant effect (0.85, 0.49 to 1.47; I=15%) (see Supplementary Figure 8 ).
Patients With Chronic Kidney Disease. In patients with chronic kidney disease, the results from one randomised controlled trial of ACE inhibitors (odds ratio 0.15, 95% confidence interval 0.00 to 7.70) and two randomised controlled trials of ARBs (1.21, 0.32 to 4.52; I=77%) did not differ significantly when compared with controls (see Supplementary Figure 9 ).
Asian and Non-Asian Patients. Eleven studies were carried out in Asian countries and 11 were done outside of Asia. The PROGRESS study was the only multicentre study carried out worldwide that supplied separate data for Asian and non-Asian patients. To lower analysis bias, the other studies carried out worldwide that did not provide separate data for both groups were excluded.
The reduction in risk of pneumonia associated with ACE inhibitors was significantly higher among Asian patients (0.43, 0.34 to 0.54; I=0%) compared with non-Asian patients (0.82, 0.67 to 1.00, I=80%, P<0.001 for subgroup differences) (see Supplementary Figure 10 ). ARBs, however, were not associated with a reduction in risk of pneumonia in Asian patients (1.04, 0.59 to 1.84; one randomised controlled trial HIJ-CREATE) or non-Asian patients (0.97, 0.84 to 1.12; I=27%; five studies pooled; Figure 4 and Supplementary Figure 11 ).
Secondary Outcome: Pneumonia Related Mortality
Data for secondary outcomes were extracted from seven studies comparing ACE inhibitors with controls (three randomised controlled trials and four cohort studies), one randomised controlled trial comparing ARBs with control, and one head to head randomised controlled trial. Five studies comparing ACE inhibitors with controls were carried out on an enriched population—that is, enrolled patients with pneumonia.
Treatment with ACE inhibitors was associated with a significant 27% reduction in risk of pneumonia related mortality compared with controls (0.73, 0.58 to 0.92; I=51%), without significant differences between estimates from randomised controlled trials and observational studies (P=0.76). The pooled result from randomised controlled trials, however, failed to reach statistical significance (0.61, 0.20 to 1.90; I=61%) (Figure 5).
(Enlarge Image)
Figure 5.
Pneumonia related mortality in studies comparing angiotensin converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) with control treatment
Only one randomised controlled trial reported the effect of treatment with ARBs on pneumonia related mortality (odds ratio 0.63, 95% confidence interval 0.40 to 1.00) (figure 5).
The risk of pneumonia related mortality in indirect (1.16, 0.69 to 1.94), direct (HEAVEN randomised controlled trial 7.29, 0.14 to 367.24), and pooled comparisons (1.19, 0.71 to 1.98) did not differ between ACE inhibitors and ARBs (figure 4). There was no discrepancy (P=0.36) or heterogeneity (I=0%) between indirect and direct estimates.
Publication Bias
Visual inspection of funnel plots did not reveal any obvious asymmetrical tail (see Supplementary Figure 12 ). Publication bias was not suggested by sensitivity analysis taking into account published and unpublished trials (see Supplementary Figure 13 ).