Risk of pneumonia associated with use of angiotensinconverting enzyme inhibitors and angiotensin receptorblockers: systematic review and meta-analysis

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Daniel Caldeira cardiologist resident, assistant of clinical pharmacology 1, Joana Alarcão scientificconsultant, assistant of clinical pharmacology 2, António Vaz-Carneiro clinical professor of medicine,director of the Center for Evidence-BasedMedicine23, João Costa professor of clinical pharmacology,coordinator of the Portuguese Cochrane Centre 1 2 3

1Laboratory of Clinical Pharmacology and Therapeutics, Faculty of Medicine, University of Lisbon; 2Center for Evidence-Based Medicine, Facultyof Medicine, University of Lisbon, Avenue Professor Egas Moniz, 1649-028, Lisbon, Portugal; 3Cochrane Coordinating Center Portugal, Faculty ofMedicine, University of Lisbon

AbstractObjective To systematically review longitudinal studies evaluating useof angiotensin converting enzyme (ACE) inhibitors or angiotensin receptorblockers (ARBs) and risk of pneumonia.

Design Systematic review and meta-analysis.

Data sourcesMedline through PubMed,Web of Science with conferenceproceedings (inception to June 2011), and US Food and DrugAdministration website (June 2011). Systematic reviews and referencesof retrieved articles were also searched.

Study selection Two reviewers independently selected randomisedcontrolled trials and cohort and case-control studies evaluating the useof ACE inhibitors or ARBs and risk of pneumonia and retrievedcharacteristics of the studies and data estimates.

Data synthesis The primary outcome was incidence of pneumonia andthe secondary outcome was pneumonia related mortality. Subgroupanalyses were carried according to baseline morbidities (stroke, heartfailure, and chronic kidney disease) and patients’ characteristics (Asianand non-Asian). Pooled estimates of odds ratios and 95% confidenceintervals were derived by random effects meta-analysis. Adjustedfrequentist indirect comparisons between ACE inhibitors and ARBs wereestimated and combined with direct evidence whenever available.Heterogeneity was assessed using the I2 test.

Results 37 eligible studies were included. ACE inhibitors were associatedwith a significantly reduced risk of pneumonia compared with controltreatment (19 studies: odds ratio 0.66, 95% confidence interval 0.55 to0.80; I2=79%) and ARBs (combined direct and indirect odds ratio estimate

0.69, 0.56 to 0.85). In patients with stroke, the risk of pneumonia wasalso lower in those treated with ACE inhibitors compared with controltreatment (odds ratio 0.46, 0.34 to 0.62) and ARBs (0.42, 0.22 to 0.80).ACE inhibitors were associated with a significantly reduced risk ofpneumonia among Asian patients (0.43, 0.34 to 0.54) compared withnon-Asian patients (0.82, 0.67 to 1.00; P<0.001). Compared with controltreatments, both ACE inhibitors (seven studies: odds ratio 0.73, 0.58 to0.92; I2=51%) and ARBs (one randomised controlled trial: 0.63, 0.40 to1.00) were associated with a decrease in pneumonia related mortality,without differences between interventions.

Conclusions The best evidence available points towards a putativeprotective role of ACE inhibitors but not ARBs in risk of pneumonia.Patient populations that may benefit most are those with previous strokeand Asian patients. ACE inhibitors were also associated with a decreasein pneumonia related mortality, but the data lacked strength.

IntroductionPneumonia represents an important clinical condition becauseof its relatively high incidence (0.5% to 1.1% annually in theUnited Kingdom) and associated morbidity and mortality.1 2

Susceptibility is higher among elderly people (≥65 years), thosewith alcohol dependency, smokers, and patients with heartfailure, previous stroke, diabetes, chronic kidney disease, andchronic lung disease.3-6 Pneumonia is a common reason forhospital admission and a risk factor for prolonged hospital stay,carrying a considerable financial burden on healthcareresources.7 8

Correspondence to: J Costa jncosta@fm.ul.pt

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Search strategySupplementary figures 1-13

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Usage of some drugs has been shown to modulate the risk ofpneumonia. Acid suppressants can increase patients’susceptibility to pneumonia, whereas statins may have aprotective role.9 10 Angiotensin converting enzyme (ACE)inhibitors and angiotensin receptor blockers (ARBs) are oftenused in patients with cardiovascular disease. ACE inhibitors areknown to have adverse effects on the respiratory system, inparticular an increased incidence of cough. Basic investigationhas shown that bradykinin and substance P sensitise the sensorynerves of the airways and enhance the cough reflex,11-13 whichmay have a protective role on the tracheobronchial tree.14 15

These mechanisms also improve swallowing by avoiding theexposure of the respiratory tree to oropharynx secretions.11 14 16

Taken together, the pleiotropic effects of ACE inhibitors weresuggested to reduce the incidence of pneumonia, but availableclinical evidence lacks strength17-19 and published results havebeen contradictory.20-22

We systematically reviewed and meta-analysed all studies(experimental and observational) evaluating the use of ACEinhibitors and incidence of pneumonia. Because the clinicalcharacteristics and risk factors of populations using ARBs aresimilar to those of patients using ACE inhibitors, and thereforestudies evaluating these interventions share identical potentialclinical confounders, we also estimated the incidence ofpneumonia in studies evaluating ARBs. Moreover, patientstreated with ARBs are less likely to experience respiratoryadverse events,23 24 and therefore ARBs may have a protectiverole.

MethodsThe systematic review was carried out in accordance with themeta-analysis of observational studies in epidemiology andpreferred reporting items for systematic reviews andmeta-analyses statements.25 26

Our primary outcome was the incidence of pneumonia. Weconsidered cases of pneumonia, lower respiratory tractinfections, and admissions to hospital due to lower respiratorytract infections. Data were extracted irrespective of whetherthey had been reported as predefined outcomes or as adverseeffects. If studies reported data for death from pneumonia only,to avoid duplication we did not consider these cases for theprimary outcome. The secondary outcome was pneumoniarelated mortality, defined as death directly related to thiscondition or in-hospital death or mortality within 30 days afteronset of pneumonia.27 For both outcomes, we did not considerundefined data or data on upper respiratory tract infections.We considered randomised controlled parallel trials, cohortstudies, and case-control studies with ACE inhibitors or ARBsas interventions and with predefined outcomes. Treatment armscould compare ACE inhibitors and ARBs with each other orwith placebo or any other active drug. Cohort studies could bebased on populations in the community or those in institutionsor hospital and had to follow patients to determine pneumoniaoutcomes.In case-control studies, cases had to be defined as patients withnew onset pneumonia identified through clinical examination,radiological methods, or database codes. Controls had to bematched to cases, but without new onset pneumonia. Forpneumonia related mortality, we allowed case-control studieswith both cases and controls having pneumonia.We allowed all participants, irrespective of baseline diseasesand risk factors.

Information sources and search methodWe identified potentially eligible studies through an electronicsearch of bibliographic databases from inception to June 2011(Medline through PubMed andWeb of Science with conferenceproceedings). See the supplementary file for details of the searchstrategy. No language restrictions were applied. We screenedand cross checked identified systematic reviews andmeta-analyses evaluating ACE inhibitors or ARBs, as well asreference lists of papers for potential additional studies. We alsosearched the Food and Drug Administration website (10 June2011) for regulatory documents with unpublished data fromclinical trials.

Study selection and data collection processThe titles and abstracts of obtained records were screened.Doubts and disagreements were resolved by consensus. Weassessed the selected studies in full text to determineappropriateness for inclusion. Two authors independentlyextracted data on study design, location, period of study,patients’ characteristics, drug use and how it was assessed,primary outcomes, data of required outcomes, and adjustmentsof estimates.When studies presented different estimates on primary outcomesaccording to the severity of pneumonia, we extracted for analysisonly those reporting the most severe cases. For the primaryoutcome we considered drug withdrawals due to pneumoniaonly when no other estimates were available. When more thanone risk estimate was available from several sources, we usedonly the most precise or adjusted measures of association fromeach report. Otherwise we used the crude odds ratio or derivedit from the raw data.Two authors (DC and JA) independently analysed the qualityof reporting by using a qualitative classification according torisk of bias (high, unclear, or low). For observational studieswe used a six item classification based on the meta-analysis ofobservational studies in epidemiology,25 the quality assessmenttool for systematic reviews of observational studies,28 andstrengthening the reporting of observational studies inepidemiology.29 This system was adapted from a previouslypublished systematic review30 31 and took into consideration theparticipants (if any justification was given for the cohort andthe study reported appropriate inclusion and exclusion criteria),intervention (if drug use was adequately assessed and not basedon self report), outcome (if pneumonia was assessed by clinicalexamination, radiological methods, or database codes and notbased on self report), and outcome adjustments (for both ageand at least one of the following: smoker or pulmonary disease,cardiovascular diseases or drug use or chronic kidney disease;other adjustments). For randomised controlled trials we adaptedthe Cochrane Collaboration’s tool for assessing risk of bias toevaluate the quality of reporting: randomisation method,allocation concealment, blinding of participants and staff,blinding of outcome assessment, selective reporting (ifpneumonia was a prespecified outcome), and description ofwithdrawals.32 From these tools we derived risk of bias graphs.

Statistical analysisWe used RevMan 5.1.4 software for statistical analysis (NordicCochrane Centre, Cochrane Collaboration, 2011) and to deriveforest plots showing the results of individual studies and pooledanalysis.We carried out three analyses. Firstly, we compared ACEinhibitors and ARBs with each control group using randomeffects meta-analysis weighted by the inverse variance method

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to estimate pooled odds ratios and 95% confidence intervals.Heterogeneity was assessed with the I2 test, which measures thepercentage of total variation between studies due toheterogeneity.33 We used the random effects modelindependently of the existence (I2≥50%) of substantialheterogeneity between the results of trials, as we pooled theresults of studies with different designs and patients’characteristics. We chose the odds ratio as the measurementestimate for effect because relative estimates are more similarthan absolute effects across studies with different designs,populations, and lengths of follow-up.34 Raw data were firstconverted to odds ratios through classic methods, or throughPeto’s method if one arm had a zero count cell. When raw dataor odds ratios were not available we took the hazard ratio orrisk ratio for analysis. To explore differences in estimates foroutcomes we presented the results stratified according to studydesign. For the purpose of the analysis we treated nestedcase-control studies as cohort studies. We carried out subgroupanalyses for patients with previous stroke, heart failure, andchronic kidney disease because such patients are known to beparticularly susceptible to pneumonia and all indications areclinically approved for treatment with ACE inhibitors andARBs.5 6 35 36 In view of the suggestion that ACE inhibitors maybe more efficient in reducing the risk of pneumonia in Asianpatients we also calculated estimates for Asian and non-Asianpopulations.37 We evaluated differences between subgroupswith the method described by Deeks et al, based on the inversevariance method.33

In the second analysis we carried out adjusted indirectcomparisons between the pooled estimate of ACE inhibitors(versus control) and ARBs (versus control) using the Bucherfrequentist method, which compares different treatmentsadjusted to the results of their direct comparison with a commoncontrol.38 This method partially overcomes the problem ofdifferent prognostic characteristics between participants amongstudies, and it is believed to be valid assuming that the relativeeffect of interventions is consistent across different studies, asverified in our case.39 By default we used the random effectsmodel because adjusted indirect comparisons that used the fixedeffects model tend to underestimate the standard errors of pooledestimates.39

Thirdly, we combined evidence generated by indirectcomparisons with evidence from head to head studies comparingACE inhibitors with ARBs using the random effects model forquantitative pooling,40 41 and we determined the discrepancyand heterogeneity between direct and indirect estimates.42

We also calculated the number needed to treat (NNT) and 95%confidence intervals, taking into account the baseline risk(weighted proportion of event rate in control group) because ofthe differences in the predicted absolute benefit of treatmentaccording to variation in baseline risk between groups.34 43 Inour case, the weighted risk of pneumonia in the control groupswas 4.6% (95% confidence interval 3.1% to 6.7%). Publicationbias was assessed through visual inspection of the asymmetryin funnel plots.

ResultsThe search of the electronic databases yielded 807 publishedstudies. After applying the inclusion and exclusion criteria 29studies were included for analysis (fig 1⇓). The results fromeight additional studies were identified in the FDA regulatorydocuments. Overall, data were obtained from 37 studies.20-22 44-79

Description of studiesThe 37 studies included 18 randomised controlled trials,20 44-61

11 cohort studies,62-73 two nested case-control studies,21 74 andsix case-control studies.22 75-79

Among randomised controlled trials, eight were doneworldwide,47 48 51 52 55 57 58 61 six in Europe,44-46 53 56 60 three inAsia,49 50 59, and one in Europe and the United States.54 Most ofthe randomised controlled trials were multicentre (n=16). Sevenrandomised controlled trials compared ACE inhibitors withcontrols,44-50 nine compared ARBs with controls,51-59 and twocompared ACE inhibitors with ARBs.60 61 Seven trials reportedspecific data for serious pneumonia, five for fatal pneumonia,and eight reported pneumonia without specifying the severityof disease. In only two trials was pneumonia a prespecifiedoutcome.49 59

Among observational studies, 10 were carried out in Asia, fivein the United States, and four in Europe. Eleven studies wereretrospective and eight were prospective. Seventeen evaluatedACE inhibitors, two ARBs, and two compared ACE inhibitorswith ARBs.Tables 1 to 3⇓⇓⇓ summarise the main characteristics of theincluded studies.The overall quality of the studies was considered to be good.All the randomised controlled trials, except one,51met the criteriafor random sequence generation and about half specificallyreported adequate allocation concealment.46 48 50 54 55 57 58 61 Onlytwo randomised controlled trials56 59 were considered to be athigh risk of performance bias. Adequate blinding of outcomeassessment45-48 50 52-59 61 and full description of studywithdrawals44-55 57 58 60 61 were reported in 78% and 89% ofrandomised controlled trials, respectively. The highest risk ofbias was found for potential reporting bias because only tworandomised controlled trials presented results for pneumoniaas a prespecified outcome.49 59 Supplementary figures 1 and 2show the results of the quality appraisal of the randomisedcontrolled trials.All observational studies were considered to have adequateinclusion and exclusion criteria and provided justification forthe cohort. Five studies (26%)62-64 66 69 did not clearly stated howthe drug use was assessed, and four studies (21%)63 64 66 73 didnot provide details about outcome assessment. Eleven studies(58%)21 22 68 70-72 74 75 77 79 provided results after adjustment for atleast one potential variable confounder. In one study76 it wasunclear for which variables the results were adjusted. Fewstudies (26%) reported results adjusted for multiple confounders,and in seven studies (37%) no type of adjustment wasmentioned. Supplementary figures 3 and 4 show the results forthe quality of the observational studies.

Primary outcome: incidence of pneumoniaPrimary outcome data were available from 19 studies comparingACE inhibitors with controls (five randomised controlled trials,eight cohort or nested case-control studies, and six case-controlstudies), 11 studies comparing ARBs with controls (ninerandomised controlled trials and two cohort or nestedcase-control studies), and two studies comparing ACE inhibitorswith ARBs (one randomised controlled trial and one cohortstudy).Use of ACE inhibitors was associated with a significant 34%reduction in risk of pneumonia compared with controls (oddsratio 0.66, 95% confidence interval 0.55 to 0.80; I2=79%). TheNNT for 2.0 years was 65 (48 to 112). The magnitude of therisk reduction was similar across all study designs (P=0.78 for

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subgroup differences). The odds ratios for randomised controlledtrials, cohort or nested case-control studies, and case-controlstudies were 0.69 (0.56 to 0.85; I2=0%), 0.58 (0.38 to 0.88;I2=79%), and 0.67 (0.49 to 0.93; I2=73%), respectively (fig 2⇓).The risk of pneumonia was not, however, different betweenpatients who did or did not use ARBs (0.95, 0.87 to 1.04;I2=14%). Odds ratio estimates for randomised controlled trials(0.90, 0.79 to 1.01; I2=7%) and cohort or nested case-controlstudies (1.01, 0.94 to 1.09; I2=0%) did not differ significantly(P=0.10; fig 3⇓).Pooled results from the two head to head studies showed anon-significant 37% reduction in risk of pneumonia associatedwith use of ACE inhibitors (0.63, 0.28 to 1.44; I2=78%). In thiscase, estimates from the randomised controlled trial and cohortstudy differed significantly (P=0.03) (see supplementary figure5).Indirect comparison of ACE inhibitors with ARBs showed asignificant 30% reduction in risk of pneumonia associated withuse of ACE inhibitors (0.70, 0.56 to 0.86). Similar results wereobtained from pooled direct and indirect estimates (0.69, 0.56to 0.85) without discrepancy (P=0.82) or heterogeneity (I2=0%)between both estimates (fig 4⇓). The NNT for 2.2 years basedon this estimate was 72 (51 to 147).

Subgroup analyses for primary outcomePatients with previous strokeIn patients with previous stroke, use of ACE inhibitors wasassociated with a 54% reduction in risk of pneumonia comparedwith controls (0.46, 0.34 to 0.62, I2=0%; seven studies pooled)(see supplementary figure 6). In the same population, however,use of ARBs was not associated with a significant reduction inrisk (0.86, 0.67 to 1.09; I2=0%; two studies pooled) (seesupplementary 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 asignificant 58% reduction in risk of pneumonia (0.42, 0.22 to0.80; fig 4), without discrepancy (P=0.44) or heterogeneity(I2=0%) between indirect and direct estimates.

Patients with heart failureIn patients with heart failure, two studies evaluated the risk ofpneumonia in those treated with ACE inhibitors44 45 and twoother studies reported data for those treated with ARBs.51 52ACEinhibitors were associated with a significant 37% reduction inrisk of pneumonia (0.63, 0.47 to 0.84; I2=0%), whereas ARBsshowed no significant effect (0.85, 0.49 to 1.47; I2=15%) (seesupplementary figure 8).

Patients with chronic kidney diseaseIn patients with chronic kidney disease, the results from onerandomised controlled trial of ACE inhibitors46 (odds ratio 0.15,95% confidence interval 0.00 to 7.70) and two randomisedcontrolled trials of ARBs52 53 (1.21, 0.32 to 4.52; I2=77%) didnot differ significantly when compared with controls (seesupplementary figure 9).

Asian and non-Asian patientsEleven studies were carried out in Asian countries and 11 weredone outside of Asia. The PROGRESS20 study was the onlymulticentre study carried out worldwide that supplied separatedata for Asian and non-Asian patients. To lower analysis bias,

the other studies carried out worldwide that did not provideseparate data for both groups were excluded.The reduction in risk of pneumonia associated with ACEinhibitors was significantly higher among Asian patients (0.43,0.34 to 0.54; I2=0%) compared with non-Asian patients (0.82,0.67 to 1.00, I2=80%, P<0.001 for subgroup differences) (seesupplementary figure 10). ARBs, however, were not associatedwith a reduction in risk of pneumonia in Asian patients (1.04,0.59 to 1.84; one randomised controlled trial HIJ-CREATE59)or non-Asian patients (0.97, 0.84 to 1.12; I2=27%; five studiespooled; fig 4 and supplementary figure 11).

Secondary outcome: pneumonia relatedmortalityData for secondary outcomes were extracted from seven studiescomparing ACE inhibitors with controls (three randomisedcontrolled trials and four cohort studies),20 49 50 68 70-72 onerandomised controlled trial comparing ARBs with control,55 andone head to head randomised controlled trial.60 Five studiescomparing ACE inhibitors with controls were carried out on anenriched population—that is, enrolled patients withpneumonia.49 68 70-72

Treatment with ACE inhibitors was associated with a significant27% reduction in risk of pneumonia related mortality comparedwith controls (0.73, 0.58 to 0.92; I2=51%), without significantdifferences between estimates from randomised controlled trialsand observational studies (P=0.76). The pooled result fromrandomised controlled trials, however, failed to reach statisticalsignificance (0.61, 0.20 to 1.90; I2=61%) (fig 5⇓).Only one randomised controlled trial55 reported the effect oftreatment with ARBs on pneumonia related mortality (oddsratio 0.63, 95% confidence interval 0.40 to 1.00) (fig 5).The risk of pneumonia related mortality in indirect (1.16, 0.69to 1.94), direct (HEAVEN randomised controlled trial60 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 (fig 4). Therewas no discrepancy (P=0.36) or heterogeneity (I2=0%) betweenindirect and direct estimates.

Publication biasVisual inspection of funnel plots did not reveal any obviousasymmetrical tail (see supplementary figure 12). Publicationbias was not suggested by sensitivity analysis taking into accountpublished and unpublished trials (see supplementary figure 13).

DiscussionIn this systematic review we found that treatment withangiotensin converting enzyme (ACE) inhibitors was associatedwith a significant reduction in risk of pneumonia compared withcontrol treatment and angiotensin receptor blockers (ARBs);the magnitude of this reduction (about one third) was similaracross studies with different designs (randomised controlledtrials, cohort, and case-control studies). The risk of pneumoniawas also reduced in patients treated with ACE inhibitors whowere at higher risk of pneumonia, in particular those with strokeand heart failure. Most of the potential protective benefit fromACE inhibitors seemed to be in Asian patients; it is unclearwhether the methodology of the studies or the clinical andgenetic characteristics of the patients were responsible for thisfinding. Use of ACE inhibitors was also associated with areduction in pneumonia related mortality, although the resultswere less robust than for overall risk of pneumonia; it is

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uncertain if differences exist between ACE inhibitors and ARBsfor this outcome.The present review was designed to determine the effect oftreatment with ACE inhibitors and ARBs on risk of pneumonia.We combined data from both experimental and observationalstudies to obtain more robust results, mainly because norandomised controlled trial was primarily designed with thisobjective. Pneumonia is not a rare outcome (particularly inpopulations treated with ACE inhibitors or ARBs) or an outcomethat only occurs months to years after use of ACE inhibitors orARBs. Therefore randomised controlled trials would have beenan appropriate study design to deal with this problem.We foundsignificant statistical heterogeneity for ACE inhibitors but notfor ARB results. This was due to the results of observationalstudies (no heterogeneity was found among randomisedcontrolled trials). Nevertheless, the observed statisticalheterogeneity was more quantitative than qualitative becauseall estimates for study designs share the same direction. Thisconsistency, as well as the robustness of reduction in the riskof pneumonia across all study designs, suggests that use of ACEinhibitors deserves attention. Furthermore, that ACE inhibitorsreduced the risk of pneumonia compared not only with thecontrol group but also with ARB treatment, is reassuring becausepatients’ characteristics and risk factors, as well as otherpotential clinical andmethodological confounders are probablysimilar between studies on ARBs and those on ACE inhibitors.We were also conservative in our analysis because we did notconsider undefined data or data on upper respiratory tractinfections, and when studies presented different estimatesaccording to the severity of pneumonia we extracted thosereporting only the most severe cases and the most precise oradjusted measure.Our findings have potential clinical implications. ACE inhibitorsare widely prescribed and prescriptions may be influenced byconcerns about potential adverse effects, in particular cough,which may be protective. The incidence of ACE inhibitorinduced cough has been reported to be in the range of 5% to35%.80 Our results suggest that patients taking ACE inhibitorswho develop cough should, providing that cough is tolerable,persist with treatment. Compliance and persistence withtreatment is important. Furthermore, from an evidence basedperspective, there is little to choose between ACE inhibitorsand the more expensive ARBs. However, in the case of aparticular patient, in whom ACE inhibitors and ARBs arepresumed to have similar clinical benefit, our results may alsoinfluence the choice of prescription in those at high risk ofpneumonia. Therefore patients with risk factors for pneumoniaandmorbidities that require treatment with ACE inhibitors mayhave an additional reason to continue treatment.A further important aspect of our results was the reduction inrisk of pneumonia across high risk patients, which providedconsistency to the overall results. Patients with previous strokehave increased susceptibility to pneumonia owing to risk ofaspiration associated with decreased protective reflexes of therespiratory system mediated by substance P and post-strokedysphagia.14 81 About 20% of these patients will developpneumonia,82which is a predictor of poor functional outcome83 84and a relevant cause of death.84 85 The putative protective effectof ACE inhibitors in this population was predictable given theimportance of dysphagia and substance P in these patients.According to one study, ARBs do not increase the levels ofsubstance P or improve asymptomatic dysphagia.86 Thishighlights the importance of using ACE inhibitors in patientswith previous stroke who have comorbidities for which ACEinhibitors are recommended.

Only a few studies evaluated other populations with increasedrisk, such as patients with heart failure or chronic kidney disease.For patients with heart failure, the decreased risk of pneumoniawas also found in patients treated with ACE inhibitors. Thesuggested effect was significant but this evaluation lacked robustdata. ARBs did not show any protective effect.The putative preventive effect of ACE inhibitors on pneumoniain Asian patients has been suggested.37 We explored thissubgroup and compared the effect with non-Asian patients.Furthermore, we obtained a considerable weight of evidencefrom studies that evaluated Asian patients. ACE inhibitorssignificantly reduced the risk of pneumonia in both Asian andnon-Asian patients, although the odds reduction wassignificantly higher in Asian patients (57% v 12%; P<0.001).ARBs did not reduce the risk of pneumonia in either population.Genetic differences in ACE polymorphisms between Asian andnon-Asian patients have been suggested to explain the differencein protective effects. Polymorphisms I/I and I/D, which are moreprevalent in Asian population, showed a protective trend in thepost-hoc analysis in PROGRESS, whereas the D/Dpolymorphismwas less protective.20 77 87 This last polymorphismis associated with acute respiratory distress syndrome,particularly in white populations.88 This potential loss ofprotective effect may be explained by increased levels of serumACE inhibitors and catabolism of kinins in patients with theD/D polymorphism.89 However, genetic evidence is equivocal.One study did not find an association between any specificgenotype and pneumonia.90Other factors should be explored toexplain these differences in ethnic groups or by geographicallocation to better define those who can benefit more.Our conclusions are weaker for pneumonia related mortalitybecause fewer studies provided data for this outcome andsignificant heterogeneity existed for the results of ACEinhibitors. This uncertainty was reflected by the widerconfidence intervals. Treatment with ACE inhibitors (threerandomised controlled trials and four cohort studies) and ARBs(one randomised controlled trial) were both associated with adecreased risk of pneumonia related mortality. Explanations forsuch findings may rely on modulation of cardiovascular risk byACE inhibitors and ARBs because deaths due to cardiovasculardisease are not uncommon among patients with pneumonia.27 91

Decreased mortality may also be explained by the role of ACEinhibitors in pulmonary injury and production of cytokines,which may be related to severity of pneumonia.92-94 ACEinhibitors may influence the pattern for release of cytokinesexerting anti-inflammatory effects that could reduce the severityof and mortality from pneumonia.95

The influence of ACE inhibitors on survival in these patientsshould be interpreted carefully because observational studieswith enriched populations accounted for most of the weight ofthe pooled analysis, whereas meta-analysis of three randomisedcontrolled trials (one with an enriched population) did not showdifferences between ACE inhibitors and controls. However,there was no significant difference in effects between overallrandomised controlled trials and observational studies. Althoughthe data were not robust, they did suggest that the effects oftreatment with ACE inhibitors on mortality were mostlynoticeable in patients with pneumonia.

Limitations of the reviewThe results and conclusion of this review are weakened bylimitations inherent to meta-analysis and individual studies. Theoverall quality of included studies was good. However, reportingquality for a few studies, particularly observational ones, was

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low as some of these were abstracted from character limitedsections such as letters or comments.The higher risk of bias was found for potential selectivereporting in randomised controlled trials and presentation ofunadjusted risk estimates in observational studies. Both limitthe strength of our conclusions. A key limitation is that not onerandomised controlled trial was primarily designed to assessthe effects of ACE inhibitors or ARBs on pneumonia. Althoughwe searched a large number of studies, only a few reported thisoutcome. Among these, only two randomised controlled trials(<25%) had pneumonia or pneumonia related mortality as apredefined outcome.49 59 As a consequence we were able toextract data only from studies where authors consideredpneumonia to be an important outcome, because of eitherscientific interest or statistical significance.Observational studies had an important weight in the results forthe primary outcome and this should be taken into account wheninterpreting the clinical implications of our findings. Use ofcardiovascular drugs in observational studies could bias results,because patients using drugs could be more concerned for theirhealth and more willing to followmedical advice than controls,the so-called healthy user effect bias.96 However, patients withpneumonia are likely to have a higher risk of cardiovasculardisease91 97 and are more likely to be treated with ACE inhibitors,counterbalancing the bias from a healthy user effect.Additionally, the magnitude of the odds risk reduction wassimilar for randomised controlled trials, cohort studies, andcase-control studies.Pooling data from studies with different designs (confoundingbias in observational studies) that evaluated patients in differentsettings (community based and hospital based studies; referralbias), as well as with different baseline morbidities andheterogeneous risk (membership bias) for pneumonia, shouldalso be taken into account as limitations to our conclusions. Thedegree of statistical heterogeneity was in fact high in somecomparisons. Nevertheless, the pooled estimates fromexperimental and observational studies were similar. In thiscase, pooling experimental and observational data increased thepower and external validity of the findings.Included studies compared different ACE inhibitors and ARBswith different controls, such as placebo, calcium channelblockers, and β blockers. In the present analysis we did not carryout serial subgroup analysis to explore if the effect was differentfor a particular drug because of the scarcity of the data and therisk of obtaining a result by chance.Finally, we used adjusted indirect comparisons to estimate theeffect of ACE inhibitors compared with ARBs. Althoughcombined indirect and direct evidence showed no discrepanciesor heterogeneity, the results should not be thought as definitiveconclusions because of the possibility of imbalanced data fromstudies with different designs, baseline risk of patients, andlength of follow-up.

ConclusionsOur results suggest an important role of ACE inhibitors, but notARBs, in reducing the risk of pneumonia. These data maydiscourage the withdrawal of ACE inhibitors in some patientswith tolerable adverse events (namely, cough) who are atparticularly high risk of pneumonia. Specific designedrandomised controlled trials are required to establish definiteconclusions and to estimate better the true magnitude of thisputative protective effect. Patients with previous stroke andAsian patients are patient populations that could benefit morefrom treatment with ACE inhibitors. ACE inhibitors also

lowered the risk of pneumonia related mortality, mainly inpatients with established disease, but the robustness of theevidence was weaker.

We thank the Cochrane Coordinating Centre in Portugal.Contributors: DC and JA contributed to the concept and design, dataacquisition, data analysis, and interpretation of the data; wrote the firstdraft of the manuscript; critically revised the manuscript; and gave finalapproval of the submitted manuscript. AVC contributed to theinterpretation of data, critically revised the manuscript, and gave finalapproval of the submitted manuscript. JC contributed to the conceptand design, data analysis, and interpretation of the data; wrote the firstdraft of the manuscript; critically revised the manuscript; and gave finalapproval of the submitted manuscript. JC is the guarantor.Funding: This was an academic project not funded by government ornon-government grants.Competing interests: All authors have completed the ICMJE uniformdisclosure form at www.icmje.org/coi_disclosure.pdf (available onrequest from the corresponding author) and declare: no support fromany organisation for the submitted work; no financial relationships withany organisations that might have an interest in the submitted work inthe previous three years; and no other relationships or activities thatcould appear to have influenced the submitted work.Ethical approval: Not required.Data sharing: No additional data available.

1 File TM. Community-acquired pneumonia. Lancet 2003;362:1991-2001.2 LimWS, Baudouin SV, George RC, Hill AT, Jamieson C, Le Jeune I, et al. BTS guidelines

for the management of community acquired pneumonia in adults: update 2009. Thorax2009;64(suppl 3):iii,1-55.

3 Samokhvalov AV, Irving HM, Rehm J. Alcohol consumption as a risk factor for pneumonia:a systematic review and meta-analysis. Epidemiol Infect 2010;138:1789-95.

4 Almirall J, Bolíbar I, Balanzó X, González CA. Risk factors for community-acquiredpneumonia in adults: a population-based case-control study. Eur Respir J 1999;13:349-55.

5 Vinogradova Y, Hippisley-Cox J, Coupland C. Identification of new risk factors forpneumonia: population-based case-control study. Br J Gen Pract 2009;59:e329-38.

6 Fung HB, Monteagudo-Chu MO. Community-acquired pneumonia in the elderly. Am JGeriatr Pharmacother 2010;8:47-62.

7 Lee HC, Chang KC, Lan CF, Hong CT, Huang YC, Chang ML. Factors associated withprolonged hospital stay for acute stroke in Taiwan. Acta Neurol Taiwan 2008;17:17-25.

8 Metersky ML, Tate JP, Fine MJ, Petrillo MK, Meehan TP. Temporal trends in outcomesof older patients with pneumonia. Arch Intern Med 2000;160:3385-91.

9 Eom CS, Jeon CY, Lim JW, Cho EG, Park SM, Lee KS. Use of acid-suppressive drugsand risk of pneumonia: a systematic review and meta-analysis. CMAJ 2011;183:310-9.

10 Tleyjeh IM, Kashour T, Hakim FA, Zimmerman VA, Erwin PJ, Sutton AJ, et al. Statins forthe prevention and treatment of infections: a systematic review and meta-analysis. ArchIntern Med 2009;169:1658-67.

11 Morice AH, Lowry R, Brown MJ, Higenbottam T. Angiotensin-converting enzyme and thecough reflex. Lancet 198;2:1116-8.

12 Fox AJ, Lalloo UG, Belvisi MG, Bernareggi M, Chung KF, Barnes PJ. Bradykinin-evokedsensitization of airway sensory nerves: a mechanism for ACE-inhibitor cough. Nat Med1996;2:814-7.

13 Tomaki M, IchinoseM, Miura M, Hirayama Y, Kageyama N, Yamauchi H, et al. Angiotensinconverting enzyme (ACE) inhibitor-induced cough and substance P. Thorax1996;51:199-201.

14 Sekizawa K, Ujiie Y, Itabashi S, Sasaki H, Takishima T. Lack of cough reflex in aspirationpneumonia. Lancet 1990;335:1228-9.

15 Pontoppidan H, Beecher HK. Progressive loss of protective reflexes in the airway withthe advance of age. JAMA 1960;174:2209-13.

16 Nakayama K, Sekizawa K, Sasaki H. ACE inhibitor and swallowing reflex. Chest1998;113:1425.

17 El Solh AA, Saliba R. Pharmacologic prevention of aspiration pneumonia: a systematicreview. Am J Geriatr Pharmacother 2007;5:352-62.

18 Rafailidis PI, Matthaiou DK, Varbobitis I, Falagas ME. Use of ACE inhibitors and risk ofcommunity-acquired pneumonia: a review. Eur J Clin Pharmacol 2008;64:565-73.

19 Siempos II, Vardakas KZ, Kopterides P, Falagas ME. Adjunctive therapies forcommunity-acquired pneumonia: a systematic review. J Antimicrob Chemother2008;62:661-8.

20 Ohkubo T, Chapman N, Neal B, Woodward M, Omae T, Chalmers J, et al. Effects of anangiotensin-converting enzyme inhibitor-based regimen on pneumonia risk. Am J RespirCrit Care Med 2004;169:1041-5.

21 Etminan M, Zhang B, Fitzgerald M, Brophy JM. Do angiotensin-converting enzymeinhibitors or angiotensin II receptor blockers decrease the risk of hospitalization secondaryto community-acquired pneumonia? A nested case-control study. Pharmacotherapy2006;26:479-82.

22 Van de Garde EM, Souverein PC, van den Bosch JM, Deneer V H, Leufkens HG.Angiotensin-converting enzyme inhibitor use and pneumonia risk in a general population.Eur Respir J 2006;27:1217-22.

23 Dickstein K, Kjekshus J; OPTIMAAL Steering Committee of the OPTIMAAL Study Group.Effects of losartan and captopril on mortality and morbidity in high-risk patients after acutemyocardial infarction: the OPTIMAAL randomised trial. Optimal Trial in Myocardial Infarctionwith Angiotensin II Antagonist Losartan. Lancet 2002;360:752-60.

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BMJ 2012;345:e4260 doi: 10.1136/bmj.e4260 (Published 11 July 2012) Page 6 of 20

RESEARCH

What is already known on this topic

Angiotensin converting enzyme (ACE) inhibitors reduce morbidity and mortality in patients with cardiovascular diseaseThese drugs also have secondary effects on the respiratory system, suggested to protect against pneumoniaMost of the data on this issue are provided by heterogeneous observational studies with inconclusive results

What this study adds

In pooled results from both interventional and observational studies, ACE inhibitors, but not angiotensin receptor blockers (ARBs),showed a statistical and putative clinically significant protective role against pneumoniaThis result may discourage the withdrawal of ACE inhibitors in patients with tolerable adverse events—namely, coughThis protective effect was higher among Asian patients and in those with previous stroke; patient populations that may benefit mostfrom ACE inhibitors

24 Pfeffer MA, McMurray JJ, Velazquez EJ, Rouleau JL, Køber L, Maggioni AP, et al.Valsartan, captopril, or both in myocardial infarction complicated by heart failure, leftventricular dysfunction, or both. N Engl J Med 2003;349:1893-906.

25 Stroup DF, Berlin JA, Morton SC, Olkin I, Williamson GD, Rennie D, et al. Meta-analysisof observational studies in epidemiology: a proposal for reporting. Meta-analysis OfObservational Studies in Epidemiology (MOOSE) group. JAMA 2000;283:2008-12.

26 Liberati A, Altman DG, Tetzlaff J, Mulrow C, Gøtzsche PC, Ioannidis JP, et al. The PRISMAstatement for reporting systematic reviews and meta-analyses of studies that evaluatehealthcare interventions: explanation and elaboration. BMJ 2009;339:b2700.

27 Mortensen EM, Coley CM, Singer DE, Marrie TJ, Obrosky DS, Kapoor WN, et al. Causesof death for patients with community-acquired pneumonia: results from the PneumoniaPatient Outcomes Research Team cohort study. Arch Intern Med 2002;162:1059-64.

28 WongWC, Cheung CS, Hart GJ. Development of a quality assessment tool for systematicreviews of observational studies (QATSO) of HIV prevalence in men having sex with menand associated risk behaviours. Emerg Themes Epidemiol 2008;5:23.

29 Von Elm E, Altman DG, Egger M, Pocock SJ, Gøtzsche PC, Vandenbroucke JP, et al.The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE)statement: guidelines for reporting observational studies. Epidemiology 2007;18:800-4.

30 Carter P, Gray LJ, Troughton J, Khunti K, Davies MJ. Fruit and vegetable intake andincidence of type 2 diabetes mellitus: systematic review and meta-analysis. BMJ2010;341:c4229.

31 Buitrago-Lopez A, Sanderson J, Johnson L, Warnakula S, Wood A, Di Angelantonio E,et al. Chocolate consumption and cardiometabolic disorders: systematic review andmeta-analysis. BMJ 2011;343:d4488.

32 Higgins JPT, Altman DG, Sterne JAC. Assessing risk of bias in included studies. In:Higgins JPT, Green S, eds. Cochrane handbook for systematic reviews of interventionsversion 5.1.0 . Cochrane Collaboration, 2011.

33 Deeks JJ, Altman DG, Bradburn MJ. Statistical methods for examining heterogeneity andcombining results from several studies in metaanalysis. In Egger M, Davey Smith G,Altman DG, eds. Systematic reviews in health care: meta-analysis in context . 2nd ed.BMJ Publishing Group, 2001:313-35.

34 Deeks JJ. Issues in the selection of a summary statistic for meta-analysis of clinical trialswith binary outcomes. Stat Med 2002;21:1575-600.

35 Nakagawa T, Sekizawa K, Arai H, Kikuchi R, Manabe K, Sasaki H. High incidence ofpneumonia in elderly patients with basal ganglia infarction. Arch Intern Med1997;157:321-4.

36 Nakagawa T, Sekizawa K, Nakajoh K, Tanji H, Arai H, Sasaki H. Silent cerebral infarction:a potential risk for pneumonia in the elderly. J Intern Med 2000;247:255-9.

37 Teramoto S, Yamamoto H, Yamaguchi Y, Hanaoka Y, Ishii M, Hibi S, et al. ACE inhibitorsprevent aspiration pneumonia in Asian, but not Caucasian, elderly patients with stroke.Eur Respir J 2007;29:218-9

38 Bucher HC, Guyatt GH, Griffith LE, Walter SD. The results of direct and indirect treatmentcomparisons in meta-analysis of randomized controlled trials. J Clin Epidemiol1997;50:683-91.

39 Song F, Altman DG, Glenny AM, Deeks JJ. Validity of indirect comparison for estimatingefficacy of competing interventions: empirical evidence from published meta-analyses.BMJ 2003;326:472.

40 DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials 1986;7:177-88.41 Glenny AM, Altman DG, Song F, Sakarovitch C, Deeks JJ, D’Amico R, et al. Indirect

comparisons of competing interventions. Health Technol Assess 2005;9:1-134,iii-iv.42 Song F, Harvey I, Lilford R. Adjusted indirect comparison may be less biased than direct

comparison for evaluating new pharmaceutical interventions. J Clin Epidemiol2008;61:455-63.

43 Smeeth L, Haines A, Ebrahim S. Numbers needed to treat derived frommeta-analyses—sometimes informative, usually misleading. BMJ 1999;318:1548-51.

44 Widimský J, Kremer HJ, Jerie P, Uhlír O. Czech and Slovak spirapril intervention study(CASSIS). A randomized, placebo and active-controlled, double-blind multicentre trial inpatients with congestive heart failure. Eur J Clin Pharmacol 1995;49:95-102.

45 Køber L, Torp-Pedersen C, Carlsen JE, Bagger H, Eliasen P, Lyngborg K, et al. A clinicaltrial of the angiotensin-converting-enzyme inhibitor trandolapril in patients with leftventricular dysfunction after myocardial infarction. Trandolapril Cardiac Evaluation (TRACE)Study Group. N Engl J Med 1995;333:1670-6.

46 Randomised placebo-controlled trial of effect of ramipril on decline in glomerular filtrationrate and risk of terminal renal failure in proteinuric, non-diabetic nephropathy. The GISENGroup (Gruppo Italiano di Studi Epidemiologici in Nefrologia). Lancet 1997;349:1857-63.

47 Yusuf S, Sleight P, Pogue J, Bosch J, Davies R, Dagenais G. Effects of anangiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-riskpatients. The Heart Outcomes Prevention Evaluation Study Investigators. N Engl J Med2000;342:145-53.

48 PROGRESS Collaborative Group. Randomised trial of a perindopril-basedblood-pressure-lowering regimen among 6,105 individuals with previous stroke or transientischaemic attack. Lancet 2001;358:1033-41.

49 Kanda A, Ebihara S, Yasuda H, Takashi O, Sasaki T, Sasaki H. A combinatorial therapyfor pneumonia in elderly people. J Am Geriatr Soc 2004;52:846-7.

50 Hou FF, Zhang X, Zhang GH, Xie D, Chen PY, Zhang WR, et al. Efficacy and safety ofbenazepril for advanced chronic renal insufficiency. N Engl J Med 2006;354:131-40.

51 Weber M. Clinical safety and tolerability of losartan. Clin Ther 1997;19:604-16.52 Lewis EJ, Hunsicker LG, Clarke WR, Berl T, Pohl MA, Lewis JB, et al. Renoprotective

effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy dueto type 2 diabetes. N Engl J Med 2001;345:851-60.

53 Parving HH, Lehnert H, Bröchner-Mortensen J, Gomis R, Andersen S, Arner P, et al. Theeffect of irbesartan on the development of diabetic nephropathy in patients with type 2diabetes. N Engl J Med 2001;345:870-8.

54 Dahlöf B, Devereux RB, Kjeldsen SE, Julius S, Beevers G, de Faire U, et al. Cardiovascularmorbidity and mortality in the Losartan Intervention For Endpoint reduction in hypertensionstudy (LIFE): a randomised trial against atenolol. Lancet 2002;359:995-1003.

55 Pfeffer MA, Swedberg K, Granger CB, Held P, McMurray JJ, Michelson EL, et al. Effectsof candesartan on mortality and morbidity in patients with chronic heart failure: theCHARM-Overall programme. Lancet 2003;362:759-66.

56 Schrader J, Lüders S, Kulschewski A, Hammersen F, Plate K, Berger J, et al. Morbidityandmortality after stroke, eprosartan compared with nitrendipine for secondary prevention:principal results of a prospective randomized controlled study (MOSES). Stroke2005;36:1218-26.

57 Telmisartan Randomised AssessmeNt Study in ACE iNtolerant subjects with cardiovascularDisease (TRANSCEND) Investigators: Yusuf S, Teo K, Anderson C, Pogue J, Dyal L,Copland I, et al. Effects of the angiotensin-receptor blocker telmisartan on cardiovascularevents in high-risk patients intolerant to angiotensin-converting enzyme inhibitors: arandomised controlled trial. Lancet 2008;372:1174-83.

58 Yusuf S, Diener HC, Sacco RL, Cotton D, Ounpuu S, Lawton WA, et al. Telmisartan toprevent recurrent stroke and cardiovascular events. N Engl J Med 2008;359:1225-37.

59 Kasanuki H, Hagiwara N, Hosoda S, Sumiyoshi T, Honda T, Haze K, et al. AngiotensinII receptor blocker-based vs non-angiotensin II receptor blocker-based therapy in patientswith angiographically documented coronary artery disease and hypertension: the HeartInstitute of Japan Candesartan Randomized Trial for Evaluation in Coronary Artery Disease(HIJ-CREATE). Eur Heart J 2009;30:1203-12.

60 Willenheimer R, Helmers C, Pantev E, Rydberg E, Löfdahl P, Gordon A, et al. Safety andefficacy of valsartan versus enalapril in heart failure patients. Int J Cardiol 2002;85:261-70.

61 ONTARGET Investigators: Yusuf S, Teo KK, Pogue J, Dyal L, Copland I, SchumacherH, et al. Telmisartan, ramipril, or both in patients at high risk for vascular events. N EnglJ Med 2008;358:1547-59.

62 Sekizawa K, Matsui T, Nakagawa T, Nakayama K, Sasaki H. ACE inhibitors andpneumonia. Lancet 1998;352:1069.

63 Teramoto S, Ouchi Y. ACE inhibitors and prevention of aspiration pneumonia in elderlyhypertensives. Lancet 1999;353:843.

64 Arai T, Yasuda Y, Takaya T, Toshima S, Kashiki Y, Yoshimi N, et al. ACE inhibitors andreduction of the risk of pneumonia in elderly people. Am J Hypertens 2000;13:1050-1.

65 Arai T, Yasuda Y, Toshima S, Yoshimi N, Kashiki Y. ACE inhibitors and pneumonia inelderly people. Lancet 1998;352:1937-8.

66 Arai T, Yasuda Y, Takaya T, Toshima S, Kashiki Y, Shibayama M, et al.Angiotensin-converting enzyme inhibitors, angiotensin-II receptor antagonists, andpneumonia in elderly hypertensive patients with stroke. Chest 2001;119:660-1.

67 Arai T, Sekizawa K, Ohrui T, Fujiwara H, Yoshimi N, Matsuoka H, et al. ACE inhibitorsand protection against pneumonia in elderly patients with stroke.Neurology 2005;64:573-4.

68 Mortensen EM, Restrepo MI, Anzueto A, Pugh J. The impact of prior outpatient ACEinhibitor use on 30-day mortality for patients hospitalized with community-acquiredpneumonia. BMC Pulm Med 2005;5:12.

69 Harada J, Sekizawa K. Angiotensin-converting enzyme inhibitors and pneumonia in elderlypatients with intracerebral hemorrhage. J Am Geriatr Soc 2006;54:175-6.

70 Mortensen EM, PughMJ, Copeland LA, Restrepo MI, Cornell JE, Anzueto A, et al. Impactof statins and angiotensin-converting enzyme inhibitors onmortality of subjects hospitalisedwith pneumonia. Eur Respir J 2008;31:611-7.

71 Chalmers JD, Singanayagam A, Murray MP, Hill AT. Prior statin use is associated withimproved outcomes in community-acquired pneumonia. Am J Med 2008;121:1002-7.

72 Myles PR, Hubbard RB, Gibson JE, Pogson Z, Smith CJ, McKeever TM. The impact ofstatins, ACE inhibitors and gastric acid suppressants on pneumonia mortality in a UKgeneral practice population cohort. Pharmacoepidemiol Drug Saf 2009;18:697-703.

73 Poster presentations from the World Congress of Cardiology Scientific Sessions 2010.Circulation 2010;xx:e348.

74 Mukamal KJ, Ghimire S, Pandey R, O’Meara ES, Gautam S. Antihypertensive medicationsand risk of community-acquired pneumonia. J Hypertens 2010;28:401-5.

75 Okaishi K, Morimoto S, Fukuo K, Niinobu T, Hata S, Onishi T, et al. Reduction of risk ofpneumonia associated with use of angiotensin I converting enzyme inhibitors in elderlyinpatients. Am J Hypertens 1999;12:778-83.

76 El Solh AA, Brewer T, Okada M, Bashir O, Gough M. Indicators of recurrent hospitalizationfor pneumonia in the elderly. J Am Geriatr Soc 2004;52:2010-5.

77 Takahashi T, Morimoto S, Okaishi K, Kanda T, Nakahashi T, Okuro M, et al. Reductionof pneumonia risk by an angiotensin I-converting enzyme inhibitor in elderly Japaneseinpatients according to insertion/deletion polymorphism of the angiotensin I-convertingenzyme gene. Am J Hypertens 2005;18:1353-9.

78 Van de Garde EM, Souverein PC, Hak E, Deneer VH, van den Bosch JM, Leufkens HG.Angiotensin-converting enzyme inhibitor use and protection against pneumonia in patientswith diabetes. J Hypertens 2007;25:235-9.

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RESEARCH

79 Marciniak C, Korutz AW, Lin E, Roth E, Welty L, Lovell L. Examination of selected clinicalfactors and medication use as risk factors for pneumonia during stroke rehabilitation: acase-control study. Am J Phys Med Rehabil 2009;88:30-8.

80 Dicpinigaitis PV. Angiotensin-converting enzyme inhibitor-induced cough: ACCPevidence-based clinical practice guidelines. Chest 2006;129:169-73S.

81 Walter U, Knoblich R, Steinhagen V, Donat M, Benecke R, Kloth A. Predictors ofpneumonia in acute stroke patients admitted to a neurological intensive care unit. J Neurol2007;254:1323-9.

82 Roth EJ, Lovell L, Harvey RL, Heinemann AW, Semik P, Diaz S. Incidence of and riskfactors for medical complications during stroke rehabilitation. Stroke 2001;32:523-9.

83 Vermeij FH, Scholte op Reimer WJ, de Man P, van Oostenbrugge RJ, Franke CL, deJong G, et al. Stroke-associated infection is an independent risk factor for poor outcomeafter acute ischemic stroke: data from the Netherlands Stroke Survey. Cerebrovasc Dis2009;27:465-71.

84 Hilker R, Poetter C, Findeisen N, Sobesky J, Jacobs A, Neveling M, et al. Nosocomialpneumonia after acute stroke: implications for neurological intensive care medicine. Stroke2003;34:975-81.

85 Katzan IL, Cebul RD, Husak SH, Dawson NV, Baker DW. The effect of pneumonia onmortality among patients hospitalized for acute stroke. Neurology 2003;60:620-5.

86 Arai T, Yasuda Y, Takaya T, Toshima S, Kashiki Y, Yoshimii N, et al.Angiotensin-converting enzyme inhibitors, angiotensin II receptor antagonists, andsymptomless dysphagia. Chest 2000;117:1819-20.

87 Sagnella GA, Rothwell MJ, Onipinla AK,Wicks PD, Cook DG, Cappuccio FP. A populationstudy of ethnic variations in the angiotensin-converting enzyme I/D polymorphism:relationships with gender, hypertension and impaired glucose metabolism. J Hypertens1999;17:657-64.

88 Hu Z, Jin X, Kang Y, Liu C, Zhou Y, Wu X, et al. Angiotensin-converting enzymeinsertion/deletion polymorphism associated with acute respiratory distress syndromeamong caucasians. J Int Med Res 2010;38:415-22.

89 Brown NJ, Blais C Jr, Gandhi SK, Adam A. ACE insertion/deletion genotype affectsbradykinin metabolism. J Cardiovasc Pharmacol 1998;32:373-7.

90 Van de Garde EM, Endeman H, Deneer VH, Biesma DH, Sayed-Tabatabaei FA, RuvenHJ, et al. Angiotensin-converting enzyme insertion/deletion polymorphism and risk andoutcome of pneumonia. Chest 2008;133:220-5.

91 Ramirez J, Aliberti S, Mirsaeidi M, Peyrani P, Filardo G, Amir A, et al. Acute myocardialinfarction in hospitalized patients with community-acquired pneumonia. Clin Infect Dis2008;47:182-7.

92 Kranzhöfer R, Schmidt J, Pfeiffer CA, Hagl S, Libby P, Kübler W. Angiotensin inducesinflammatory activation of human vascular smooth muscle cells. Arterioscler Thromb VascBiol 1999;19:1623-9.

93 Wösten-van Asperen RM, Lutter R, Haitsma JJ, Merkus MP, van Woensel JB, van derLoos CM, et al. ACE mediates ventilator-induced lung injury in rats via angiotensin II butnot bradykinin. Eur Respir J 2008;31:363-71.

94 AntunesG, Evans SA, Lordan JL, Frew AJ. Systemic cytokine levels in community-acquiredpneumonia and their association with disease severity. Eur Respir J 2002;20:990-5.

95 Gullestad L, Aukrust P, Ueland T, Espevik T, Yee G, Vagelos R, et al. Effect of high-versus low-dose angiotensin converting enzyme inhibition on cytokine levels in chronicheart failure. J Am Coll Cardiol 1999;34:2061-7.

96 Majumdar SR, McAlister FA, Eurich DT, Padwal RS, Marrie TJ. Statins and outcomes inpatients admitted to hospital with community acquired pneumonia: population basedprospective cohort study. BMJ 2006;333:999.

97 Corrales-Medina VF, Suh KN, Rose G, Chirinos JA, Doucette S, Cameron DW, et al.Cardiac complications in patients with community-acquired pneumonia: a systematicreview and meta-analysis of observational studies. PLoS Med 2011;8:e1001048.

Accepted: 10 May 2012

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RESEARCH

Tables

Table 1| Main characteristics of randomised controlled trials included in review

Data*Outcomesabstracted

Primaryoutcome

Mean(SD)ageNo (total)ComparisonPatients

Meanfollow-up(years)LocationStudy

ACE inhibitorsv control:

PublishedSerious pneumonia†Assessment ofchanges inexercisetolerance

57.5(10)

200 v 48(248)

Spirapril or enalapril v placeboPatients withchronic congestiveheart failure

0.2MulticentreCzechRepublicandSlovakia

CASSIS199544

PublishedPneumonia†Death from anycause

67.5876 v 873(1749)

Trandolapril v placeboPatients with leftventricular ejectionfraction aftermyocardialinfarction

4.0MulticentreDenmark

TRACE 199545

PublishedDrug withdrawal duetobronchopneumonia†

Rate of declinein glomerularfiltration

49.3(13.6)

78 v 88(166)

Ramipril v placeboPatients withchronicnephropathy andpersistentproteinuria

1.3MulticentreItaly

GISEN 199746

UnpublishedSerious pneumonia†Myocardialinfarction,stroke, or deathdue tocardiovasculardisease

66 (7)4645 v 4652(9297)

Ramipril v placeboPatients at highrisk of developinga majorcardiovascularevent

4.0Multicentreworldwide(not Asia)

HOPE 200047

PublishedFatal and non-fatalpneumonia

Fatal ornon-fatal stroke

64(10)

3051 v 3054(6105)

Perindopril v placeboPatients withprevious stroke ortransientischaemic attack

3.9Multicentreworldwide

PROGRESS200420 48

PublishedHospital deathIn-hospitalmortality,duration ofantibiotic use,and infectionwith MRSA

78 (8)33 v 35 (68)Imidapril+amantadine+standardcare v standard care

Patients aged ≥65with history ofstroke andadmitted withcommunityacquiredpneumonia

4.0SinglecentreJapan

Kanda 200449

PublishedPneumonia as causeof mortality

Composite ofdoubling ofserum creatininelevel, end stagerenal disease,and death

44.8(14.6)

216 v112(328)

Benazepril v placeboPatients withnon-diabeticchronic kidneydisease

3.4SinglecentreChina

Hou 200650

ARBs v control:

PublishedPneumonia†Adverse events54125 v 29Losartan v placeboPatients withessentialhypertension andheart failure

0.3WorldwideWeber 199751

UnpublishedPulmonary infection†Time to firstoccurrence ofdoubling ofbaseline serumcreatinine level,end stage renal

58.9(7.8)

579 v 569(placebo)(1148)

Irbesartan v placebo oramlodipine

Patients withhypertension andwith type 2diabetes and overtproteinuria

4.8Multicentreworldwide

IDNT 200152

disease, ordeath

UnpublishedPulmonary infection†Time tooccurrence ofclinical overtalbuminuria

58.0(8.1)

389 v 201(590)

Irbesartan 100 mg v irbesartan300 mg v placebo

Patients withhypertension andwith type 2diabetes,microalbuminuria,and normal renalfunction

2.0MulticentreEurope

IRMA-2 200153

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RESEARCH

Table 1 (continued)

Data*Outcomesabstracted

Primaryoutcome

Mean(SD)ageNo (total)ComparisonPatients

Meanfollow-up(years)LocationStudy

Publishedandunpublished

Pneumonia andserious pneumonia†

Morbidity andmortality due tocardiovasculardisease

66.9(7.0)

4605 v 4588(9193)

Losartan v atenololPatients withessentialhypertension andsigns of left

4.8MulticentreEuropeand USA

LIFE 200254

ventricularhypertrophy onelectrocardiogram

UnpublishedSerious pneumoniaand death due topneumonia†

All causemortality

66.6(10.7)

3803 v 3796(7599)

Candesartan v placeboPatients withsymptomatic heartfailure andreduced orpreserved leftventricular ejectionfraction

3.1Multicentreworldwide

CHARM200355

PublishedPneumonia†Total mortalityand allcardiovascularandcerebrovascularevents

67.9(10)

681 v 671(1352)

Eprosartan v nitrendipineHigh risk patientswith hypertensionand with cerebralevent during past24 months

2.5MulticentreGermanyand Austria

MOSES200556

UnpublishedSerious pneumonia†Compositeendpointconsisting ofdeath due tocardiovasculardisease,

66.9(7.4)

2954 v 2972(5926)

Telmisartan v placeboPatients with highrisk of developinga cardiovascularevent and whowere intolerant toACE inhibitors

4.8Multicentreworldwide

TRANSCEND200857

non-fatalmyocardialinfarction,non-fatal stroke,and admissionto hospital forcongestive heartfailure

UnpublishedSerious pneumonia†Time to firstrecurrent stroke

66.2(8.6)

5589 v 5277(10866)

Telmisartan v placeboPatients withrecent ischaemicstroke withouttreatment withACE inhibitors

2.0Multicentreworldwide

PRoFESS200858

PublishedPneumonia†Time to firstmajor adversecardiovascularevent

65 (9)1024 v 1025(2049)

Candesartan v non-ARBPatients admittedto hospital withcoronary arterydisease andhypertensionbetween 20 and80 years old

4.2MulticentreJapan

HIJ-CREATE200959

ACE inhibitorsv ARBs:

PublishedDeath due topneumonia

Exercisecapacitymeasured asdistance walkedduring sixminute walk test

6871 v 70(141)

Enalapril v valsartanPatients withstable mild ormoderate heartfailure and systolicdysfunction

0.2SwedenHEAVEN200260

UnpublishedSerious pneumonia†Time to firstoccurrence ofeither death duecardiovasculardisease,myocardial

66.48576(ramipril) v

8542(telmisartan)(17118)

Ramipril v telmisartan vtelmisartan+ramipril

Patients at highrisk of developingmajorcardiovascularevent

4.6Multicentreworldwide

ONTARGET200861

infarction,stroke, oradmission tohospital for

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RESEARCH

Table 1 (continued)

Data*Outcomesabstracted

Primaryoutcome

Mean(SD)ageNo (total)ComparisonPatients

Meanfollow-up(years)LocationStudy

congestive heartfailure

ACE=angiotensin converting enzyme; ARB=angiotensin receptor blocker; MRSA=meticillin resistant Staphylococcus aureus.*Data for unpublished articles were obtained from FDA regulatory documents.†Adverse event.

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RESEARCH

Table 2| Main characteristics of cohort studies included in review

Outcomeadjustments

Ascertainment

Outcomemeasures

Mean(SD)age

No(total)ComparisonPatients

Data source;period ofstudy

Studylength(years)

Location,studydesignStudy OutcomesDrug use

forconfounders

NRNRNRPneumonia77 (8)127 v313(440)

Imidapril,enalapril orcaptopril vCCB or βblocker

Patients withstroke treatedwithhypertensivedrugs

March 1996-982.5Japan,prospective(patients inlong termfacilities)

Sekizawa199862

NRNRNRPneumoniaNR234(ACE

inhibitor)v 264(CCB)(498)

ACE inhibitorv CCB v ACEinhibitor+CCB

Outpatientswithhypertension

1995-984.0Japan,retrospective

Teramoto199963

NRNRNRPneumonia75.9466 v413(879)

Imidapril vCCB

Elderly patientswithhypertension

January1995-December1999

4.0Japan,prospective

Arai 200064and Arai199865

NRNRNRPneumoniaNR209 v195(404)

ACE inhibitorv ARB

Elderly patientswithhypertensionand stroke

January1998-May 2002

2.0Japan,prospective

Arai 200166

NRNRNRPneumonia75 (1)430 v409 v351 v160

(1350)

ACE inhibitorv CCB vdiuretics vcontrol

Patients withstroke whowere notbedridden andwere followedfor >6 monthsafter stroke

April 1999-20023.0Japan,prospective

Arai 200567

Pneumoniaseverity andhistory ofhypertensionand diabetesmellitus

ICD-9 codesSelf reportingandelectronicmedicalrecords

30 daymortality

60(16)

194 v593(787)

ACE inhibitorv control

Patients withprimarydischargediagnosis ofpneumonia orsecondary

TexasDepartment ofHealth andDepartment ofVeteran Affairsclinical

4.0USA,retrospective(hospitalbasedcohort)

Mortensen200568

dischargedatabase;diagnosis ofJanuarypneumoniawith1999-December

2002 primarydiagnosis ofrespiratoryfailure or sepsis

NRNRNRPneumonia68 (2)22 v 61(83)

ACE inhibitorv control

Elderly patientsadmitted tohospital withintracerebralhaemorrhage

2 years2.0Japan,prospective

Harada200669

Age, sex,marital status,classes ofdrugs, andCharlsoncompositescore

Pharmacydata fromPharmacyBenefitsManagementgroupdatabases

Assessedfrombeneficiaryidentificationrecordslocatorsubsystem

30 daymortality

75.2(6.1)

2930 v5722(8652)

ACE inhibitorv control

Elderly patientsadmitted tohospital withcommunityacquiredpneumonia

National patientcare databasefrom AustinAutomationCenter; July1999-January2000

1 yearUSA,retrospective

Mortensen200870

and nationalpatient caredatabase

Age,pneumoniaseverity,comorbidity,smokingstatus, and

NRSelf report ofdrugsconfirmedwith generalpractitionerafteradmission

30 daymortality

66136/31 v871

(1038)

ACE inhibitoror ARB vcontrol

Patients withcommunityacquiredpneumonia

NHS LothianUniversityHospitalsDivision January2005-November2007

3 yearsUK,prospective(communitybasedcohort)

Chalmers200871

othercardiovasculardrugs

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Table 2 (continued)

Outcomeadjustments

forconfounders

Ascertainment

Outcomemeasures

Mean(SD)age

No(total)ComparisonPatients

Data source;period ofstudy

Studylength(years)

Location,studydesignStudy OutcomesDrug use

Age, sex,Townsend

ICD-9 codesDataextracted

30 daymortality

>40795 v2886(3681)

ACE inhibitorv control

Patients withpneumonia

The HealthImprovementNetwork

2.8UK,retrospective(population

Myles200972

deprivationfrom alldatabase; July2001-July 2005

basedcohort)

score, currentsmoking,

recordedprescriptions

Charlsonwithin 30comorbiditydays fromindex, andpneumonia

index date other use ofdrugs

NRNRNRPneumonia>60147 v342(489)

ACE inhibitorv control

Patients withhypertensionand stroke

NRNRChina,prospective

Cuifang201073

CCB=calcium channel blockers; ACE=angiotensin converting enzyme; ARB=angiotensin receptor blocker; NR=not reported.

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Table 3| Main characteristics of case-control studies included in review

Outcomeadjustments

Ascertainment

Outcome

Mean(SD)age

No withpneumoniav controls(total)

ACEinhibitoror ARBMatchingPatients

Data source;period of study

Datalength(years)

Location,study designStudy OutcomeDrug use

Nestedcase-controlstudies:

Sex, comorbidities,previous heartfailure, number ofphysician visits,and drugs used

ICD-9 codesDatabaserecords

Admitted tohospitalwithpneumonia

71(8.3)

1666 v 33315(47 148)

NRRatio 1:20;time offollow-up,samecalendaryear of

Patients whowent for coronaryrevascularisationprocedure andhad incidentpneumonia after

Databases ofadministrativehealthcareprogrammesoffered toresidents of

5.0Canada,retrospective

Etminan200621

cohorthospitaldischarge

Quebec;1996-2000 entry, and

age

Diabetes,inflammatorydiseases,cardiovasculardiseases, chronickidney disease,

ICD-9 codesRecords offilledpharmacyclaims

Pneumonia58.2(12.7)

7429 v 73571(81 000)

NRRatio 1:10;age, sex,residence,insuranceplan,subscriber

Patients withhypertension andincidentpneumonia

Data on adultswith hypertensioninsured by largecommercial plans;January2000-November2007

7.0USA, PuertoRico, and USVirgin Islands,retrospective

Mukamal201074

organstatus, andtransplantation,and drugs used

date ofenrolment

Case-controlstudies:

Age, sex,dementia,hypoalbuminemia,bedridden state,lung disease, andantacid use

Personalphysicians.Questionableeventsreviewed byphysician

Hospitalcomputerisedpharmacydatabase

Admissionforpneumonia

81.1(7.7)

55 v 220(275)

Temocapril,alacepril,cilazapril,captopril

Ratio 1:4;sex andage

Patients aged≥65 years withfatal or non-fatalpneumonia

Department ofInternal MedicineofHanwa-SenbookuHospital; July1996-June 1997

1.0Japan,prospective18

(hospital-basedstudy)

Okaishi199975

blinded topatients’drugs

Multivariate, notdefined

Databaserecords

Databaserecords

Hospitaladmissionforpneumonia

78.5(8.2)

204 v 204(408)

NRRatio 1:1;age,admissiondate, andresidence

Patients aged>65 yearsreadmitted tohospital withpneumonia over1 year from firstepisode

Electronicdatabase from 3tertiary carehospitals; March1999-August 2003

4.0USA,retrospective

El Solh200476

Age, sex,bedridden state,congestive heartfailure, diabetesmellitus, lungdisease, ACE

Informationcollected byfull timenurses underphysicians’supervision.

Hospitalcomputerisedpharmacydatabase

Pneumonia82.8(8)

105 v 420(525)

TemocaprilRatio 1:4;sex andage

Patients withadmission period>3 months whopresented withfatal or non-fatalpneumonia

April1999-November1999

0.7Japan,retrospective(hospital basedstudy)

Takahashi200577

polymorphism, andQuestionableuse of otherantihypertensives

events werereviewed byphysicianwithoutknowledge ofpatients’drugs

Diabetes,respiratorydiseases, heartfailure, use ofsystemiccorticosteroids,

ICD-9 codesATCclassification

Hospitaladmissionforcommunityacquiredpneumonia

67(0.51)

1108 v 3817(4925)

NRRatio 1:4;age andsex

Patients admittedto hospital withprimary diagnosisof pneumonia

PHARMO recordlinkage systemand PRISMANTrecords; January1995-December2000

6.0Netherlands,retrospective(populationbased study)

Van deGarde 200622

and use of gastricacid suppressants

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Table 3 (continued)

Outcomeadjustments

Ascertainment

Outcome

Mean(SD)age

No withpneumoniav controls(total)

ACEinhibitoror ARBMatchingPatients

Data source;period of study

Datalength(years)

Location,study designStudy OutcomeDrug use

Age, congestiveheart failure,

Codes ofOxford

Receipt ofprescriptions

Pneumonia73(11)

4719 v 15332 (20 041)

Cilazapril,captopril,

Ratio 1:4;age, sex,

Patients withdiabetes who had

UK GeneralPractice Research

14.0UK,retrospective

Van deGarde 200778

history of stroke,Medicalwithin yearenalapril,type offirst diagnosis ofpneumonia

Database; June1987-January2001

evident alcoholmisuse, pulmonary

InformationSystem

before indexdate

fosinopril,lisinopril,

stroke, NIHStroke

diseases, smoking,perindopril,Scalenumber of generalquinapril,score, sidepractitioner visits aramipril,

trandolapriland depthof stroke year, oral

glucocorticoid use,statin use,pneumococcalvaccination, anduse of gastric acidsuppressants

Presence oftracheostomy orfeeding tube

Medicalrecords,chestradiographyconfirmation

Medicalrecords

Pneumonia66.3(12.1)

36 v 36 (72)NRNRPatients admittedfor inpatientrehabilitationwithin 90 daysafter stroke onsetwho developedpneumonia

Strokerehabilitationregistry database,September1999-August 2003

4.0USA,retrospective

Marciniak200979

ACE=angiotensin converting enzyme; ARB=angiotensin receptor blocker; NR=not reported; ATC=anatomical therapeutic chemical system.

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Figures

Fig 1 Flow of studies through review. ACE=angiotensin converting enzyme; ARBs=angiotensin receptor blockers

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Fig 2 Risk of pneumonia with use of angiotensin converting enzyme (ACE) inhibitors compared with control treatment

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Fig 3 Risk of pneumonia with use of angiotensin receptor blockers (ARBs) compared with control treatment

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Fig 4Summary of meta-analysis estimates and subgroup analyses. ACE=angiotensin converting enzyme; ARBs=angiotensinreceptor blockers

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Fig 5 Pneumonia related mortality in studies comparing angiotensin converting enzyme (ACE) inhibitors or angiotensinreceptor blockers (ARBs) with control treatment

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