Coronary artery disease & C. pneumoniae

Antibiotic trials in humans

Myocardial infarction and angina

If Chlamydophila pneumoniae or other infection is a significant cause of atherosclerosis and coronary artery disease, it would be expected that antibiotic therapy should have a beneficial effect. Clearly heart disease is common, serious, and expensive to treat. Thus, even a small effect of antibiotics would have major public health benefits.

The initial antibiotic trials generated much enthusiasm and media attention. In the first, 213 male patients from London were recruited after being admitted with myocardial infarction [Gupta et al., 1997]. The risk of subsequent cardiac events was associated with raised IgG antibody levels against C. pneumoniae [a marker of past or present infection]. Importantly, this excess risk could be abolished by a three or six day course of 500mg per day [Main.ArchiveDocsrestrictedlabtestsTreatMacrolides][macrolides]], an anti chlamydial antibiotic. The cardiac event rate in untreated subjects with IgG titres │ 64 was 28% compared with only 8% in similar subjects given antibiotics [P= .03]. Gurfinkel et al., 1997, in Argentina, randomised 202 patients presenting with angina or with non-Q-wave myocardial infarction to placebo or to treatment with macrolides. A statistically significant reduction in recurring angina, myocardial infarction or mortality was observed at one month (2% versus 9%, P=.03) which was not seen at 6 months (8.7% versus 14.6%; P=.26) [Gurfinkel et al., 1997; Gurfinkel et al., 1999].

Another London-based study, the STAMINA [South Thames Trial of Antibiotics in Myocardial Infarction and Unstable Angina; wonderful how people invent these acronyms 4- Good] study, reported that treatment of 325 patients directed against C. pneumoniae and Helicobacter pylori significantly reduced the incidence of coronary events by 40% at 12 months, although the effect was independent of the presence of antibody to C. pneumoniae or to H. pylori[Stone et al., 2001; 2002].

In the United States, the ACADEMIC trial [Azithromycin in Coronary Artery Disease: Elimination of Myocardial Infarction with Chlamydia study; even more ingenious 5 - V.Good], randomised 302 patients with coronary artery disease into 3 months of azithromycin [test] versus placebo [control] groups. There was a trend towards benefit after 12 to 18 months follow up in the treated group, but the difference between treatment and control groups was not statistically significant [Muhlestein et al., 2000]. Azithromycin therapy did, however, lead to a significant reduction in the inflammatory disease markers IL-6 and C-reactive protein [Anderson et al., 1999].

In Germany, a study by Neumann et al., 2001 assessed the effect of macrolides therapy on 1010 patients who had undergone coronary stent procedure in order to remove a blockage in the coronary artery. The clinical outcome studied was whether the antibiotic reduced the recurrence of new blockage (restenosis). The results of this study should not be generalised because the mechanism of restenosis, although incompletely understood, is distinct from the progression of atherosclerosis or plaque rupture [Gershlick, 2001]. In fact, contributory factors to restenosis, such as elastic recoil, are very unlikely to be related to infection. The study found no effect on the restenosis rate after a 28 day course of roxithromycin. However, subjects with higher C. pneumoniae antibody levels [IgG titres ≥ 512] were found to be more likely to benefit from antibiotic therapy. It is difficult to explain these results as antibody levels do not correlate well with chronic infection [see: CAD: Serological evidence].

Another study in Germany of 872 patients with acute myocardial infarction also found that treatment with 300 mg roxithromycin daily for six weeks had no beneficial effect on cardiac event rates over a 12 month follow up period [Zahn et al., 2003].

The problem with all these studies is that they are relatively small, lacking the statistical power to demonstrate a moderate treatment effect comparable to that of other common treatments used in the secondary prevention of cardiovascular disease.

Larger antibiotic treatment trials with greater statistical power and using more prolonged therapy have been designed to overcome the above problems.

Herings et al., 2001 in the Netherlands studying 628 patients and 1615 age-matched control subjects found a protective effect of the use of high-dosage fluoroquinolones (OR 0.34, 95% CI 0.12-0.93) on the incidence of a first time myocardial infarction over a follow-up period of 4.5 years. However this study was restricted to subjects without cardiovascular risk factors.

The much larger WIZARD trial [acronym for Weekly Intervention with Zithromax for Atherosclerosis and its Related Disorders] determined the effect of 12 weeks of antibiotic therapy on coronary heart disease events in patients with stable coronary artery disease and, importantly, known C. pneumoniae exposure. The patients received either azithromycin (600 mg/d for 3 days during week 1, then 600 mg/wk during weeks 2-12; n = 3879) or placebo (n = 3868). The primary outcome event was the first occurrence of death from any cause, nonfatal reinfarction, coronary revascularization, or hospitalization for angina. Patients were followed up until 1038 events accrued. The main finding was that after a median of 14 months of follow-up, there was no significant risk reduction in the likelihood of a primary outcome event with azithromycin vs placebo (7% [95% confidence interval, -5% to 17%], P =.23). Analysis of hazard ratios suggested early benefits of azithromycin on the primary event and on death or reinfarction, but these decreased over time. There were no significant risk reductions for any of the components of the primary end point including death (8%), recurrent myocardial infarction (7%), revascularization procedures (5%), or hospitalisations for angina (-1%). Adverse events related to the study drug were reported by 13.2% of those randomized to receive azithromycin, mainly a result of diarrhoea, compared with 4.6% randomized to receive placebo, and resulted in discontinuation of drug in 1.6% of those taking azithromycin and 0.4% taking placebo. Thus, among stable patients with previous myocardial infarction and with evidence of C. pneumoniae exposure, a 3-month course of azithromycin did not significantly reduce the clinical sequelae of coronary heart disease [O'Connor et al., 2003].

Another large study is the AZithromycin in Acute Coronary Syndrome, or AZACS study. Cercek et al., 2003 assessed the effect of azithromycin in a multicentre, double-blind randomised trial based on 1439 patients with unstable angina or acute myocardial infarction. The patients were randomly allocated to receive 500 mg azithromycin on the first day after randomisation, followed by 250 mg daily for 4 days or placebo. They were followed up for 6 months using as the primary endpoints death, recurrent myocardial infarction, or recurrent ischaemia necessitating revascularisation. It was found that treatment with azithromycin did not result in reduction of either individual endpoints or any of the primary endpoints. Of the 716 patients in the azithromycin group, 23 (3%) died, 17 (2%) developed myocardial infarction, 65 (9%) had recurrent ischaemia needing revascularisation, and 100 (14%) had one or more of these endpoints. In the placebo group (n=723) the corresponding numbers of patients were 24 (4%), 22 (3%), 59 (8%), and 106 (15%), respectively (p=0.664, 95% CI 0.72-1.24). 62 (9%) of patients in the azithromycin group and 59 (8%) in the placebo group reached the secondary endpoint of ischaemia or congestive heart failure necessitating admission (difference 0.5%, 95% CI 0.75-1.53; p=0.707). Few side-effects were recorded. The authors concluded that short-term treatment with azithromycin does not reduce the development of recurrent events in patients with acute coronary syndrome.

The Azithromycin and Coronary Events Study (ACES) sponsored by the National Institutes of Health in the US involves 4,012 patients with angiographically defined stable coronary artery disease who received either a single 600mg of azithromycin or placebo every week for 1 year [Jackson, 2000; Knirsch 2002]. The participants were followed for a mean of 3.9 years at 28 clinical centers throughout the United States. The primary end point, a composite of death due to coronary heart disease, nonfatal myocardial infarction, coronary revascularization, or hospitalization for unstable angina, occurred in 446 of the participants who had been randomly assigned to receive azithromycin and 449 of those who had been randomly assigned to receive placebo. There was no significant risk reduction in the azithromycin group as compared with the placebo group with regard to the primary end point (risk reduction, 1 percent [95 percent confidence interval, -13 to 13 percent). There were also no significant risk reductions with regard to any of the components of the primary end point, death from any cause, or stroke. The results did not differ when the participants were stratified according to sex, age, smoking status, presence or absence of diabetes mellitus, or C. pneumoniae serologic status at baseline. It was concluded that a one-year course of weekly azithromycin did not alter the risk of cardiac events among patients with stable coronary artery disease [Grayston et al., 2005].

The discriminatory power of large, suitable studies can be enhanced by effectively combining the participants and reanalysing, a process termed meta-analysis. Several meta-analyses have been performed of the effects of azithromycin treatment on cardiovascular events in patients with acute coronary syndromes. They present a depressingly consistent picture of no significant beneficial effect [see: conclusion]. As an example of this approach, Baker & Couch (2007) conducted a systematic literature search of MEDLINE, EMBASE, Web of Science, and the Cochrane Database of Systematic Reviews for randomised controlled trials of the effect of azithromycin on clinical outcomes in patients with secondary coronary artery disease. Six studies with a total of 13,778 participants met the inclusion criteria. On meta-analysis, azithromycin resulted in a non significant reduction in mortality versus placebo (odds ratio [OR], 0.91; 95% confidence interval [CI], 0.77-1.09; p=0.31). Four trials reported the rate of nonfatal myocardial infarction (MI). Azithromycin did not have an effect on the rate of nonfatal MI versus placebo (OR, 0.95; 95% CI, 0.80-1.13; p=0.57). Five trials reported rates of hospitalization in which no significant difference was seen with azithromycin versus placebo (OR, 0.97; 95% CI, 0.80-1.17; p=0.76). Six trials were used to evaluate the composite cardiovascular endpoint. Again, no significant benefit was seen with azithromycin versus placebo (OR, 0.93; 95% CI, 0.84-1.03; p=0.218). It was therefore concluded that azithromycin does not reduce the frequency of recurrent cardiac events in patients with coronary artery disease.

Of course it might be that macrolides like azithromycin or clarithromycin are just the wrong antibiotics to use, perhaps because they are insufficiently bactericidal for C. pneumoniae. However a large study involving long term treatment (up to two years) with a quinolone, gatifloxacin, which is bactericidal for C. pneumoniae, was also ineffective at preventing cardiovascular events in 4,162 patients hospitalised with acute coronary syndrome [Cannon et al., 2005].

Effect of coincidental antibiotic on heart disease

Another approach is to examine the health records of individuals who have been given antibiotics for other conditions which, coincidentally, have activity against chlamydiae. This provides a much larger set of patients whose records can be analysed prospectively to determine if the antibiotic had any impact on subsequent cardiac or ischaemic events.

Meier et al., 1999 used 3315 cases of acute first-time myocardial infarction and 13,139 control subjects from the UK-based General Practice Research Database. Their study showed a reduced risk of developing an acute first-time myocardial infarction with the exclusive use of tetracyclines or quinolones in the preceding 3 years (OR 0.7, 95% CI 0.55-0.90, and OR 0.45, 95% CI 0.21-0.95, respectively). The findings were consistent across the age strata in patients aged less than 75 years, and no effect was found for previous use of macrolides, sulfonamides, penicillins, or cephalosporins. The study was, however, restricted to younger and previously healthy subjects. It is unclear why, if chlamydiae were the prime infective agent, tetracycline and quinolone had an effect whereas macrolides, also anti chlamydial, did not.

Jackson et al., 2001 in Seattle studying 1796 patients and 4882 control subjects among a group of elderly patients found no association on the occurrence of myocardial infarction with the use of tetracycline, doxycycline, and erythromycin in the previous year or in the past 5 years but did not report on the effect of quinolones.

Herings et al., 2001 in the Netherlands studying 628 patients and 1615 age-matched control subjects found a protective effect of the use of high-dosage fluoroquinolones (OR 0.34, 95% CI 0.12-0.93) on the incidence of a first time myocardial infarction over a follow-up period of 4.5 years. However this study was restricted to subjects without cardiovascular risk factors.

Luchsinger et al., 2002 analysed a health care claims database covering the records for at least two years of 354,258 patients who were treated for a whole range of conditions. The incidental use of antibiotics with activity against chlamydiae was found to have little or no positive impact on the subsequent development of myocardial infarction. A similar study by the same group on 199, 553 subjects in a claims database which assessed the impact of anti chlamydial antibiotics on ischaemic stroke in the elderly and also found little or no positive effect [Luchsinger et al., 2001]. Obviously optimal anti chlamydial therapy was not used since that was not the purpose of treatment. Worryingly, macrolides in the heart disease study and quinolones in the stroke study were associated with slight but significantly increased disease.

Ostegaarde et al., 2001 performed a primary prevention cohort study with community subjects aged 50 to 69 years and examined the time-dependent effect of macrolide therapy on the risk of going to hospital with cardiovascular disease. Patients who took macrolides (anti chlamydial) but not penicillins (less anti chlamydial) had a decreased admission rate for cardiovascular disease (relative risk 0.48, 95% confidence interval 0.27 - 0.88).

Pilote et al., 2002 studied the relationship of antichlamydial and sulfa-derivative antibiotic use in relation to prognosis post myocardial infarction in a group of elderly patients. Antibiotic use was assesssed either three months before or six months after the initial infarction. Among patients treated in the 6-month period before their initial infarction, the adjusted risks of both dying and of having a recurrent MI were similar in the sulfa-derivative antibiotic and non exposed groups compared to the antichlamydial groups Exposure to antibiotics in the three months after myocardial infarction had a small beneficial effect.

Brassard et al., 2003 in Quebec performed a case-control study on the effect of coincidental antibiotic treatment on heart disease which was nested within a cohort of 29,937 elderly subjects in whom antihypertensive therapy was initiated. 1047 subjects receiving hospital treatment for myocardial infarction were matched on calendar time to 5 randomly selected control subjects. Conditional logistic regression analyses were conducted to adjust for predisposing factors for myocardial infarction. No clear consistent effect of antibiotics use in relation to myocardial infarction was found, though a trend towards a decreased risk of acute myocardial infarction was observed in patients receiving a prescription for antichlamydial antibiotics in the preceding 3 months (odds ratio 0.68, 95% CI 0.46-1.00). Antibiotics without antichlamydial activity showed no benefit. The authors concluded that the beneficial effect of certain antichlamydial antibiotics in reducing the risk of myocardial infarction cannot be excluded on the basis of this study. Howerver larger prospective studies are required to confirm the usefulness of antibiotics in the primary prevention of myocardial infarction [Brassard et al., 2003].

Kardara et al., (2006) in a general practice based study of 129 patients with newly diagnosed coronary artery disease versus 196 controls found that the coincidental administration of doxycycline to treat brucellosis resulted in a significant reduction in the occurence of coronary artery disease (OR 0.37 with 95% confidence intervals of 0.17 - 0.78). This finding should be treated cautiously, because of the small size of the study and the absence of any information about C. pneumoniae infection in the group.

Bjerrum et al., 2006 conducted a population-based case-control study of 4166 patients hospitalised due to MI from 1 January 1994 to 1 September 1999 in
the County of Funen, Denmark. Controls (n=16,664) were a random sample of inhabitants, matched for age and sex. Confounders controlled for in the analysis were gender, age, obstructive pulmonary disease, diabetes, previous MI and known atherosclerotic antecedents. Previous use of antibiotics active against C. pneumoniae (macrolides, tetracyclines, and quinolones) and of antibiotics not active against this organism was analysed among the cases and controls. The risk of myocardial infarction was not associated with the use of macrolides, quinolones or tetracyclines, or combinations thereof.

[Comment: The weakness of this approach, as well discussed by Brassard et al., 2003, is that: antibiotics are only a proxy for infection; general databases often don't include details of relevant confounding factors such as smoking; no laboratory testing of infection is included. Studies were also subject to varying systematic biases]

Antibiotics and endothelial function

Endothelial cells may be infected with C. pneumoniae, leading to endothelial damage, the upregulation of adhesion molecules such as E-selectin and of plasminogen activator inhibitor-1 and tissue factor. C. pneumoniae infection of phagocytes may also lead to free oxygen radical formation and bystander damage to the endothelia. Thus antibiotic active against C. pneumoniae might improve endothelial function.

Parchure et al., 2002 performed a randomized, prospective, double-blind, placebo-controlled trial of azithromycin (500 mg per day for 3 days then maintenance therapy of 500 mg weekly for 4 weeks) in 40 male patients with angiographically documented coronary artery disease and positive IgG antibody titers. Flow-mediated dilation of the brachial artery and E-selectin, von Willebrand factor, and C-reactive protein (CRP) levels were measured at study entry and at the end of the treatment period. Patients who received azithromycin therapy had a significant improvement in flow mediated dilation (mean change, 2.1+/-1.1%; P<0.005) unlike those in the placebo group (mean change, -0.02+/-0.2%, P=0.64). Azithromycin therapy resulted in a significant decrease of E-selectin and von Willebrand factor [markers of endothelial dysfunction] but not of C-reactive protein [inflammatory marker]. The beneficial effects of azithromycin were independent of C. pneumoniae antibody titres. Whether these favourable effects of azithromycin treatment on endothelial function were due to the anti microbial or anti inflammatory action of azithromycin is unclear [Parchure et al., 2002]. Wiesli and Schulthess (2002) working in Zurich also reported a beneficial effect of roxithromycin on flow mediated dilation, but the effect was not sustained. This may have been due to differences in the study population. However a positive finding was that roxithromycin treatment for one month significantly improved the walking distance and reduced the number of revascularization procedures required in C. pneumoniae seropositive men with peripheral arterial occlusive disease followed over 2.7 years [Wiesli et al., 2002]. Macrolides had no effect on serum homocysteine levels in C. pneumoniae positive patients [Schulthess et al., 2002].

In a small study, Kuvin et al., 2003 found that two regimens of azithromycin therapy involving short (14 days) or long (3 months) term treatment had no beneficial effect on brachial artery vasomotor function. However, it is unclear whether any beneficial effects on endothelial function would significantly impact on atherogenesis and coronary disease.

Conclusion

"Empirical treatment of individuals with anti chlamydial antibiotic in the hope of preventing acute cardiac disease is not indicated and might even cause harm."

The consistent picture which has now emerged from human trials and their meta-anlyses is that anti chlamydial antibiotic has little or no beneficial effect in reducing subsequent acute cardiac events [Andraws et al., 2005; Baker & Couch., 2007; Bjerrum et al., 2006; Wells et al., 2004]. Indeed, the possibility that antibiotic may have a harmful effect cannot be excluded. Thus in the CLARICOR trial of 13,702 patients in Denmark who had a discharge diagnosis of myocardial infarction or angina pectoris in 1993-9 and who were alive in August 1999, there was evidence that mortality was significantly higher in those who received two weeks treatment with clarithromycin, an anti-chlamydial macrolide antibiotic, (Odds ratio 1.45, 95% confidence intervals 1.09 to 1.92; P = 0.01) [Jespersen et al., 2006]. Worryingly, one meta-analysis of trials of macrolide therapy on cardiac outcome found no difference except in studies with more than two years follow-up, where antimicrobial therapy was associated with a statistically significant increase in mortality [Anon, 2006]. This needs to be further investigated. Overall the data indicate that empirical treatment of individuals with anti chlamydial antibiotic in the hope of preventing acute cardiac disease is not indicated and might even cause harm.

There are several problems. Firstly there are statistical limitations, discussed by Danesh et al., 2000; 2002, which mean that even the largest of the current prospective studies is unlikely to be able to demonstrate small treatment effects. However recent meta-analyses now involve large numbers of participants with substantial statistical power, so it seems unlikely that this is the explanation. Secondly, although C. pneumoniae in vitro has similar antibiotic susceptibility to other chlamydiae, it is not known what is effective antibiotic treatment for chronic / persisting C. pneumoniae infection deep-seated in the vasculature; indeed persistent C. pneumoniae infection in monocytes is reported by Gieffers et al., 2001 to resist standard antichlamydial therapy, presumably because of low chlamydial metabolic turnover. In one small study, patients who had CAD and who were waiting for coronary artery bypass graft surgery were enrolled in a randomized, double-blind, placebo-controlled trial. Patients were treated with the anti-chlamydial macrolide clarithromycin at 500 mg or placebo once daily from the day of inclusion in the study until surgery. Coronary artery tissue was then collected from these patients at surgery. Clarithromycin treatment made no difference to the presence of C. pneumonia antigen in coronary tissue nor to the levels of antibody to C. pneumoniae. This supports the notion that macrolide is ineffective at eradicating C. pneumoniae from coronary tissue. Animal studies suggest that treatment with azithromycin plus a rifamycin such as rifampin or rifalazil is more effective than treatment with azithromycin alone [see: Rifampicins]; this combination has not yet been tried in human trials of antibiotic prophylaxis of coronary artery disease. Thirdly, most of the clinical trials to date have involved patients with established, relatively stable cardiac disease. It is conceivable that prophylactic antibiotic might be of greater benefit in subjects who have not yet developed overt cardiac disease or, alternatively, in subjects with unstable cardiac disease. In other words, the current trials may be directed at the wrong group of people. Fourthly, if infection does play a role, it is illogical, as this author has long argued, to think that only C. pneumoniae is important. It is important to consider the overall burden of infection in relation to cardiovascular disease [Kiechl et al., 2001; Zhu et al., 2001]. Moreover it is conceivable, as Paju et al., 2007 speculate, that periodontal bacteria may play a role. In their pilot study, long term clarithromycin treatment reduced recurrent cardiovascular events in subjects without periodontitis but failed to show any benefit in subjects with periodontitis.

Some of these possibilities may be resolved by animal experiments which, while less immediately relevant, are more easily controlled. In this respect the beneficial effects of azithromycin on experimental C. pneumoniae infection of the aorta in rabbits [Muhlestein et al., 1998] are encouraging. Unfortunately the consistent lack of demonstrated benefit for antibiotic treatment in coronary artery disease means that many investigators since 2005 have turned to other topics.

Original article [YW] Jan 2002;

Updated [MEW] January 2008

NEXT: C. pneumoniae and Cerebrovascular incident / stroke

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Paju S, Sinisalo J, Pussinen PJ, Valtonen V, Nieminen MS (2007). Is periodontal infection behind the failure of antibiotics to prevent coronary events? Atherosclerosis. 2007 Jul;193(1):193-5. Epub 2006 Jul 28. [Interesting pilot study that warrants extension]

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Zhu, J., Nieto, F. J., Horne, B. D., Anderson, J. L., Muhlestein, J. B. & Epstein, S. E. (2001). Prospective study of pathogen burden and risk of myocardial infarction or death. CirculationFull article [Acrobat] 103, 45 - 51.

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Topic revision: r5 - 2011-04-14 - MeWard
 
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