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Effects of Antibiotic Therapy on Outcomes of Patients With Coronary Artery Disease:  A Meta-analysis of Randomized Controlled Trials FREE

Richard Andraws, MD; Jeffrey S. Berger, MD; David L. Brown, MD
[+] Author Affiliations

Author Affiliations: Cardiovascular Medicine, Department of Medicine, Beth Israel Medical Center, New York, NY (Drs Andraws and Berger) and Division of Cardiovascular Medicine, State University of New York-Stony Brook School of Medicine, Stony Brook (Dr Brown).

More Author Information
JAMA. 2005;293(21):2641-2647. doi:10.1001/jama.293.21.2641.
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Published online

Context Although Chlamydia pneumoniae infection has been associated with the initiation and progression of atherosclerosis, results of clinical trials investigating antichlamydial antibiotics as adjuncts to standard therapy in patients with coronary artery disease (CAD) have been inconsistent.

Objective To conduct a meta-analysis of clinical trials of antichlamydial antibiotic therapy in patients with CAD.

Data Sources The MEDLINE and Cochrane Central Register of Controlled Trials databases were searched from 1966 to April 2005 for English-language trials of antibiotic therapy in patients with CAD. Bibliographies of retrieved articles were searched for further studies. Presentations at major scientific meetings (2003-2004) were also reviewed. Search terms included antibacterial agents, myocardial infarction, unstable angina, and coronary arteriosclerosis.

Study Selection Eligible studies were prospective, randomized, placebo-controlled trials of antichlamydial antibiotic therapy in patients with CAD that reported all-cause mortality, myocardial infarction, or unstable angina. Of the 110 potentially relevant articles identified, 11 reports enrolling 19 217 patients were included.

Data Extraction Included studies were reviewed to determine the number of patients randomized, mean duration of follow-up, and end points. End points of interest included all-cause mortality, myocardial infarction (MI), and a combined end point of MI and unstable angina.

Data Synthesis Event rates were combined using a random-effects model. Antibiotic therapy had no impact on all-cause mortality among treated vs untreated patients (4.7% vs 4.6%; odds ratio [OR], 1.02; 95% confidence interval [CI], 0.89-1.16; P = .83), on the rates of MI (5.0% vs 5.4%; OR, 0.92; 95% CI, 0.81-1.04; P = .19), or on the combined end point of MI and unstable angina (9.2% vs 9.6%; OR, 0.91; 95% CI, 0.76-1.07; P = .25).

Conclusion Evidence available to date does not demonstrate an overall benefit of antibiotic therapy in reducing mortality or cardiovascular events in patients with CAD.

Figures in this Article

Infection with Chlamydia pneumoniae has been serologically, pathologically, and clinically associated with the initiation and progression of atherosclerosis as well as the development of coronary heart disease.118 Given the prevalence of C pneumoniae infection19 and the considerable global burden of coronary artery disease (CAD), a causal link between the 2 may have important public health implications. Specifically, the use of antibiotics effective against this pathogen could become an important treatment option.2023

Numerous clinical trials have examined whether treatment of C pneumoniae is beneficial in the secondary prevention of events in patients with stable and unstable CAD, but results have been inconsistent. We therefore conducted a systematic review and meta-analysis of all published randomized clinical trials that evaluated the effect of antichlamydial antibiotic treatment on outcomes of patients with CAD.

Search Strategy

Comprehensive searches of the MEDLINE and Cochrane Central Register of Controlled Trials databases were performed using Web-based search engines (OVID, PubMed) for human studies published in English between 1966 and April 2005. Search terms included antibacterial agents, myocardial infarction, angina, unstable, and coronary arteriosclerosis, as well as combinations. Bibliographies of retrieved articles were searched for other relevant studies. We monitored major scientific meetings for the results of trials presented before publication.

Study Selection

For inclusion, studies had to be prospective, randomized, placebo-controlled trials of antichlamydial antibiotic treatment as an adjunct to standard medical therapy in patients with established CAD. We assessed quality using criteria that have been previously published including adequate blinding of randomization, blinding of treatment assignment, completeness of follow-up, and objectivity of the outcome assessment.24,25 We identified 110 studies. We excluded 90 articles because they were not randomized clinical trials (reviews, editorials, letters to the editor, case reports, case-control studies, and meta-analyses). Of the randomized trials, 9 clinical trials that did not report clinical end points, used antibiotics as an adjunct to revascularization, were not placebo controlled, or were pilot studies were excluded (Figure 1).

Figure 1. Flow Diagram of the Trial Selection Process
Graphic Jump Location

ROXIS indicates the Roxithromycin in Patients with Acute Non–Q-Wave Coronary Syndromes trial.

End Points and Definitions

End point definitions were those used in the individual trials. All-cause mortality was death from any cause (cardiac or noncardiac). Myocardial infarction (MI) was defined as elevation of serum markers of myocardial injury along with electrocardiographic changes. Unstable angina (UA) was defined as a change in typical anginal pattern including increases in anginal frequency, intensity, or duration, with or without electrocardiographic changes, requiring hospitalization. These 3 end points were extracted from each trial. The composite rate of MI and UA was also analyzed to investigate the possible impact of treatment on the subsequent development of acute coronary syndromes (ACS). Event rates at the end of the follow-up period for each study were used for the analysis.

Statistical Analysis

Because patient-level data from each trial were not available, meta-analyses of summary statistics from individual trials were performed using Comprehensive Meta Analysis software (Biostat, Englewood, NJ). Data were analyzed according to the intention-to-treat principle. Methods based on odds ratios (ORs) (Mantel-Haenszel and Peto methods) were used. The Q statistic failed to indicate statistical heterogeneity. However, because the lack of heterogeneity does not necessarily imply homogeneity, a summary OR was calculated using a random-effects model from the ORs and 95% confidence intervals (CIs) for each end point in each study. Sensitivity analyses were performed for each outcome to assess the contribution of each study to the pooled estimate by excluding individual trials 1 at a time and recalculating the combined OR for the remaining studies. To assess publication bias, we generated a funnel plot of the logarithm of effect size vs the standard error for each trial.

Search Results

Our search identified a total of 11 randomized controlled trials for inclusion in the meta-analysis.2636 These trials randomized a total of 19 217 patients (9613 treated, 9604 placebo). Four studies2628,35 randomized patients with stable CAD whereas 7 trials2934,36 randomized patients presenting with ACS.

Qualitative Findings

Trial details are summarized in Table 1. Baseline characteristics of the patients are presented in Table 2. Patients were predominately men with mean ages between 60 and 66 years. The study by Gupta et al,26 the Randomized Secondary Prevention Trial of Azithromycin in Patients with Coronary Artery Disease (ACADEMIC),27 and the Weekly Intervention with Zithromax for Atherosclerosis and its Related Disorders (WIZARD) trial28 only randomized patients with positive titers to C pneumoniae. Follow-up ranged from 3 months to 4 years.

Table Graphic Jump LocationTable 1. Antibiotic Trials in Patients With Coronary Artery Disease
Treatment

Treatment was most commonly with a single macrolide antibiotic using (1) roxithromycin in the Treatment with the Antibiotic Roxithromycin in Patients with Acute Non-Q-Wave Coronary Syndromes (ROXIS) trial,29 the trial by Leowattana et al,31 and the Antibiotic Therapy after Acute Myocardial Infarction (ANTIBIO) trial33; (2) azithromycin in WIZARD, ACADEMIC, the Effect of Short-Term Treatment with Azithromycin on Recurrent Ischaemic Events in Patients with Acute Coronary Syndromes (AZACS) trial,34 the trial by Gupta et al, and the Azithromycin and Coronary Events Study (ACES)35; and (3) clarithromycin in the Clarithromycin in Acute Coronary Syndrome Patients in Finland (CLARIFY) trial.30 In the South Thames Trial of Antibiotics in Myocardial Infarction and Unstable Angina (STAMINA),32 a regimen that included metronidazole and a proton pump inhibitor (omeprazole) along with azithromycin was used. In addition, there was a third study group designed to evaluate the potential benefit of Helicobacter pylori eradication in which patients were treated with amoxicillin, metronidazole, and omeprazole. We included only the macrolide treatment group of STAMINA in this analysis. The antibiotic group of the Pravastatin or Atorvastatin Evaluation and Infection Therapy (PROVE-IT-TIMI 22) trial36 assessed gatifloxacin. Courses of treatment ranged from 5 days to 2 years. Seven studies2830,3336 reported the pharmacologic regimen the patients were receiving in addition to treatment or placebo. In these trials, rates of use of β-blockers, antiplatelet agents, and statins exceeded 50%.

All trials were randomized, double-blinded, and placebo-controlled and were of comparable quality. Randomization protocols were available for 10 of the 11 studies. One study26 did not provide details of the randomization scheme. Nine trials reported the use of a blinded end points committee for the adjudication of outcome events. This information was unavailable from 2 studies.26,36 All analyses were conducted by intention-to-treat. Follow-up was 100% in 6 studies26,27,29,31,35,36 and greater than 98% in the remaining 5 studies.28,30,3234 Full or partial funding was provided by the company whose drug was used for the study in 7 of 11 trials.

Quantitative Findings

Mortality. Mortality outcomes were presented in 11 trials that enrolled 19 217 patients. A nonsignificant reduction in mortality was observed in 6 trials. Figure 2 presents the mortality rates for each of the 11 studies as well as for the pooled data. The combined mortality rate was 4.7% among 9613 treated patients vs 4.6% of 9604 participants in the placebo group (OR, 1.02; 95% CI, 0.89-1.16; P = .83). There was minimal quantitative heterogeneity of results (P = .75). However, we performed a sensitivity analysis to assess the potential impact of qualitative differences in study design and patient selection. Exclusion of any single trial from the analysis did not alter the overall finding of this analysis. Furthermore, inclusion of only those studies that enrolled patients with positive serology (n = 4524) revealed a nonsignificant trend toward increased mortality with antibiotic treatment (OR, 1.27; 95% CI; 0.89-1.82; P = .19).

Figure 2. Effect of Antibiotic Treatment on Total Mortality
Graphic Jump Location

Data are based on event rates at the end of follow-up for each study. For fully expanded study names see the footnote in Table 1. CI indicates confidence interval; OR, odds ratio. The sizes of the data markers are proportional to the square root of the numbers of patients in the study.

Myocardial Infarction. Nine trials,2731,3336 randomizing a total of 18 939 patients, reported rates of MI. A nonsignificant reduction in MI was demonstrated in 7 trials and a significant reduction in MI was observed in 1 study. The combined MI rate was 5.0% among 9462 patients treated with antibiotics vs 5.4% in 9477 placebo-treated patients (OR, 0.92; 95% CI, 0.81-1.04; P = .19; Figure 3). There was minimal heterogeneity of results with this analysis (P = .54). A sensitivity analysis revealed that exclusion of any single trial from the analysis did not alter the overall finding.

Figure 3. Effect of Antibiotic Treatment on Myocardial Infarction
Graphic Jump Location

Data are based on event rates at the end of follow-up for each study. For fully expanded study names see the footnote in Table 1. CI indicates confidence interval; OR, odds ratio. The sizes of the data markers are proportional to the square root of the number of patients in the study.

Acute Coronary Syndromes. Of the 10 trials reporting data on ACS (n = 17 778)2633,35,36 eight studies reported nonsignificant reductions in ACS event rates. The pooled event rate was 9.2% among 8897 participants in the antibiotic-treated group vs 9.6% in 8881 placebo-treated subjects (OR, 0.91; 95% CI, 0.76-1.07; P = .25; Figure 4). There was a trend toward heterogeneity in this analysis (P = .09). However, exclusion of any single trial from the analysis did not alterthe overall finding. Analysis of the 3 trials that enrolled only patients with positive antichlamydial titers (n = 4548) found no impact of antibiotic treatment on the development of ACS (OR, 0.92; 95% CI, 0.77-1.11; P = .40).

Figure 4. Effect of Antibiotic Treatment on Acute Coronary Syndromes (Myocardial Infarction and Unstable Angina)
Graphic Jump Location

Data are based on event rates at the end of follow-up for each study. For fully expanded study names see the footnote in Table 1. CI indicates confidence interval; OR, odds ratio. The sizes of the data markers are proportional to the square root of the number of patients in the study.

Publication Bias. To assess publication bias, we generated a funnel plot of the logarithm of effect size vs the standard error for each trial. There was no evidence of significant publication bias.

To date, 11 randomized trials have examined the effects of antichlamydial antibiotic therapy on cardiovascular events in patients with established CAD. This meta-analysis was designed to examine and synthesize the disparate results of these trials to gain a clearer understanding of the role of antimicrobials in this patient population. We examined the pooled effects of antibiotic therapy on total mortality, MI, and ACS and found that, based on available data, there was no significant benefit on any of these end points.

It is well recognized that traditional risk factors do not identify many patients with coronary events.37 Furthermore, measurement of markers of inflammation provides prognostic value beyond traditional risk factors in risk assessment. The recognition that bacteria and other pathogens are avid inducers of inflammation3840 along with the demonstration of a causal relationship between H pylori and peptic ulcer disease provided a theoretical template to consider infectious agents as an etiology of common, important chronic diseases, including CAD.41

C pneumoniae was first associated with CAD and MI in 1988 by Saikku et al.1 In a retrospective study, 68% of patients with acute MI and 50% of patients chronic CAD had positive titers to C pneumoniae, a significantly greater prevalence than among matched controls. Moreover, a significant number of those with acute MI had evidence of acute seroconversion. Since this initial epidemiological observation, C pneumoniae has been shown to infect all of the cells involved in atherosclerosis and to induce inflammation within plaques.1418 In addition, in a recent prospective study, chlamydial antigens were identified by immunofluoresence in 73% of atheromas.42 Furthermore, treatment of chlamydial infection has been shown to improve endothelial function, halt plaque progression, and reduce inflammation.1013 The 60-patient study by Gupta et al26 was the first to examine the effects of antibiotic treatment on clinical end points and showed a 68% reduction in cardiovascular events, including mortality. This initial observation stimulated investigations seeking to extend the findings to different cohorts.

Subsequent trials have been unable to consistently reproduce these findings possibly because of differences in patient populations, trial designs, and antibiotic regimens. For example, only 3 trials (all involving patients with stable CAD) used seropositivity for Chlamydia as an inclusion criterion.2628 Treating both patients with and without evidence of prior Chlamydia infection may reduce the ability to demonstrate a benefit on clinical end points. There is evidence that increasing “pathogen burden,” as defined by serum levels of immunoglobulins to various infectious agents, correlates with an increased risk of adverse outcomes.2,6 Patients with higher pathogen burden may benefit from treatment with antibiotics more robustly than those with lower burdens.10 However, this analysis, as well as a subgroup analysis of the PROVE-IT trial,36 found no improvement in outcomes among patients with positive C pneumoniae titers.

The duration of treatment differs significantly between studies and early trends toward benefit have been lost on longer follow-up. For example, WIZARD demonstrated that patients treated for 3 months had a statistically significant 33% decrease in death and MI at 6 months, which was not apparent at 12 months. ACES and PROVE-IT were designed, in part, to test the hypothesis that longer therapy would improve clinical outcomes. Both enrolled more than 4000 patients but neither trial showed benefits on any clinical end point. Thus, longer treatment duration is unlikely to be beneficial.

Studies performed from 1997-2002 were modestly sized, analyzed composite end points, and were inadequately powered to detect differences in individual end points. STAMINA was actually designed to detect changes in serologic markers as its primary outcome. ANTIBIO, the first of the larger studies, had several post hoc flaws. Although designed adequately, it enrolled only 22% of its intended cohort due to poor accrual. More patients in the roxithromycin group had anterior wall MIs; thus, the treatment group may have been sicker at baseline. Moreover, significantly fewer patients were compliant with antibiotic treatment than were compliant with placebo. Since ANTIBIO, there have been 4 large, well-designed trials with adequate power to investigate the effects of antibiotics on events. None of these demonstrated improvements in clinical outcome nor did the pooled analysis. Thus, it appears unlikely that larger trials will yield different results.

The failure to improve clinical outcomes by treatment with antichlamydial antibiotics does not exclude C pneumoniae infection as a potential etiology of acute coronary events. Rather the negative results of this analysis may be related to the pathobiology of chlamydial infection. Eradication of C pneumoniae in vivo is extremely difficult, if not impossible, to achieve, even with long courses of antibiotics. Infected monocytes may provide a treatment sanctuary for the organisms. In addition, while under immune stress, chlamydiae enter a persistent phase in their life cycle that renders them resistant to treatment yet capable of inciting inflammation.43 Furthermore, the ability of antimicrobials to effectively penetrate atheromas has also been questioned.23,44 Finally, reinfection with C pneumoniae is common,19 rendering a single course of treatment potentially ineffective over the lifetime of a patient.

Limitations

Our study must be viewed in the context of its potential limitations. First, this meta-analysis only extracted data from randomized clinical trials. Patients enrolled in such trials may not be representative of patients actually seen in clinical practice. Second, only macrolides and a fluoroquinolone were used in these studies, so the effect of treatment of additional pathogens that may be involved in atherosclerosis but are not in the spectrum of activity of these drugs was not evaluated.35 Third, our pooled analysis combines studies performed during a time of rapid improvements in medical therapy for patients with CAD. It is possible that the treatment effect observed with antibiotic therapy in earlier studies was masked in later trials because of a greater impact of the improved medical therapy on enhancing survival and reducing adverse events.

Conclusion

Despite these limitations, this systematic review and meta-analysis demonstrates that, based on evidence available to date, antichlamydial antibiotic therapy does not significantly improve major clinical outcomes in patients with CAD. Management of patients with CAD should focus on optimization of proven lifestyle interventions (exercise, weight loss, smoking cessation) and medical therapies (aspirin, β-blockers, angiotensin-converting enzyme inhibitors, and statins).

Corresponding Author: David L. Brown, MD, Division of Cardiovascular Medicine, State University of New York-Stony Brook School of Medicine, Health Sciences Center T16-080, Stony Brook, NY 11794 (david.brown@stonybrook.edu).

Author Contributions: Dr Brown had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Andraws, Berger, Brown.

Acquisition of data: Andraws, Brown.

Analysis and interpretation of data: Andraws, Berger, Brown.

Drafting of the manuscript: Andraws, Berger, Brown.

Critical revision of the manuscript for important intellectual content: Andraws, Berger, Brown.

Statistical analysis: Andraws, Berger, Brown.

Administrative, technical, or material support: Andraws.

Study supervision: Brown.

Financial Disclosures: None reported.

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Figures

Figure 1. Flow Diagram of the Trial Selection Process
Graphic Jump Location

ROXIS indicates the Roxithromycin in Patients with Acute Non–Q-Wave Coronary Syndromes trial.

Figure 2. Effect of Antibiotic Treatment on Total Mortality
Graphic Jump Location

Data are based on event rates at the end of follow-up for each study. For fully expanded study names see the footnote in Table 1. CI indicates confidence interval; OR, odds ratio. The sizes of the data markers are proportional to the square root of the numbers of patients in the study.

Figure 3. Effect of Antibiotic Treatment on Myocardial Infarction
Graphic Jump Location

Data are based on event rates at the end of follow-up for each study. For fully expanded study names see the footnote in Table 1. CI indicates confidence interval; OR, odds ratio. The sizes of the data markers are proportional to the square root of the number of patients in the study.

Figure 4. Effect of Antibiotic Treatment on Acute Coronary Syndromes (Myocardial Infarction and Unstable Angina)
Graphic Jump Location

Data are based on event rates at the end of follow-up for each study. For fully expanded study names see the footnote in Table 1. CI indicates confidence interval; OR, odds ratio. The sizes of the data markers are proportional to the square root of the number of patients in the study.

Tables

Table Graphic Jump LocationTable 1. Antibiotic Trials in Patients With Coronary Artery Disease

References

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