Antibiotics in acute and chronic coronary syndromes.

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Tryfon Vainas, MD and Saiqa Sayed, MBChB, MRCS1

Dept of Surgery, Maastricht University Hospital, Maastricht, The Netherlands and 1Department of Vascular Surgery, St George’s Hospital Medical School, London, UK



Background

The first hint that chlamydial infections may be related to arterial disease stems from the observation in the early 1940’s that patients with cardiovascular disease and no history of lymphogranuloma venereum often demonstrated a positive intradermal Frei test, a test used to measure hypersensitivity to all chlamydial species. 1-3 Saikku and colleagues demonstrated in 1988 that Chlamydia pneumoniae serology is associated with stable and acute coronary phenomena.4 Since this time evidence has gathered to suggest that Chlamydia pneumoniae infections play a (modulatory) role in the development of atherosclerosis.5 The interest in the potential role of Chlamydia pneumoniae in cardiovascular disease was intensified by two independent reports which showed that prophylactic antibiotic treatment of patients with coronary artery disease may reduce the incidence of cardiovascular events.6,7 This remarkable finding prompted the initiation and publication of a great number of retrospective and prospective studies that explored the anti-atherogenic properties of antichlamydial antibiotics and that often demonstrated contradictory results. Recently the New England Journal of Medicine published the results of two mega-trials adding solid level 1 evidence to the discussion of whether antibiotics contribute to secondary prevention in cardiovascular disease.8,9


Linking Chlamydia pneumoniae to atherosclerosis

Chlamydia pneumoniae serology has been associated with all manifestations of atherosclerotic disease (i.e., coronary artery disease, cerebrovascular disease, peripheral arterial disease and aneurysm disease), and Chlamydia pneumoniae traces (DNA and/or proteins) have been detected in atherosclerotic plaques throughout the vascular tree.10 It is believed that Chlamydia pneumoniae reaches the vasculature through infected alveolar monocytes/macrophages after a respiratory tract infection.11 The bacterium has shown to infect all cells of the vascular wall, i.e. endothelial cells, monocytes/macrophages and smooth muscle cells,12 inducing pro-atherogenic phenomena such as foam cell formation, 13 lipoprotein oxidation, 14,15 secretion of inflammatory molecules, 16-19 endothelial hypercoagulability,20,21 and smooth muscle cell proliferation.22 In addition, the association between infection and atherosclerosis may be mediated by the systemic effects of (non) vascular Chlamydia pneumoniae infection or by the host response to Chlamydial infection. In this context we have shown Chlamydia pneumoniae serology is associated with hypercoagulability rather than histological atherosclerotic plaque instability.23 This conforms with the finding that in patients with Chlamydia pneumoniae infections, plasma fibrinogen levels are elevated, and that these levels decrease upon anti-microbial treatment. Furthermore, the systemic pro-atherogenic effects of Chlamydia pneumoniae infection may result from induction and/or maintenance of an inflammatory response characterized by chronically elevated pro-inflammatory cytokine levels and increased gelatinolytic activity, or may alternatively result from induction of an autoimmune reaction based on antigenic mimicry between chlamydial and human heat shock protein 60.24,25 Animals studies have shown that Chlamydia pneumoniae induces experimental atherosclerosis that can be prevented by antibiotics.26 Repeated inoculations and a hyperlipidemic background are prerequisites for the demonstration of the atherogenic properties of Chlamydia pneumoniae infection in animal models. In these models, the Chlamydia pneumoniae related atherosclerosis progression can only be prevented by antibiotics when they are administered within 5 days of inoculation of the animals.27

The sero-epidemiological and experimental data showing the possible association between Chamydia pneumoniae infection and atherosclerosis triggered the interest of (cardio)vascular clinicians for the role of anti-chlamydial antibiotics as a new treatment modality for patients with atherosclerotic vascular disease. Indeed, two early small randomised clinical trials suggested that antibiotics may reduce cardiovascular risk in patients with coronary artery disease.6,7


Antibiotics in atherosclerotic disease

Several investigators have tried to evaluate the effect of antibiotics on cardiovascular risk by observational case-control studies. A number of these studies demonstrated a survival benefit from exposure to anti-chlamydial antibiotics,28-31 although others refuted it.32-36 Considering the methodological shortcomings of these studies, randomised clinical trials were needed to determine the effectiveness of antibiotics in atherosclerotic disease prevention. Following the two initial positive pilot studies6,7 a number of antibiotic trials have been designed and carried out worldwide with contradictory results.8,9,37-55 In general, favourable results were shown in studies with small sample size and/or limited follow up,6,7,44,45,56 trials that have included patients with abdominal aortic aneurysms42,43 or studied surrogate endpoints such as carotid intima media thickness,56 basal NO production,37 flow mediated dilatation,47,52 aortic expansion rate42,43 and matrix metalloproteinase metabolism.48 Recent larger studies, involving patients with coronary artery disease8,9,49-51 or peripheral arterial disease55, demonstrated no beneficial effect of antibiotics in the prevention of cardiovascular events or death.

The table lists all the randomised clinical trials carried out to assess the effects of antibiotics on cardiovascular endpoints in patients with atherosclerotic disease of the coronary, cerebral and/or peripheral circulation. Overall these data suggest that antibiotics are not able to reduce cardiovascular risk in atherosclerotic patients. More than 21.000 patients were randomised to an antibiotic or placebo. The studies reporting beneficial effects of antibiotics on cardiovascular risk reduction have included 1583 patients, and 858 of these were randomised to receive the experimental treatment. In contrast 19.693 were included and 9.842 were randomised to receive an antibiotic in the negative trials.

Despite this convincing evidence for a lack of effect of antibiotics on cardiovascular risk, several critical issues should be highlighted. A methodological limitation of all Chlamydia pneumoniae related cardiovascular studies is the inability to select patients with clinically relevant (vascular) Chlamydia pneumoniae infection. In general, Chlamydia pneumoniae IgA or IgG antibody titres are not related to presence of Chlamydia pneumoniae in the vascular tissue, 57-59 whereas high antibody titers are related to the development of cardiovascular events. Despite the numerous sero-epidemiological studies showing a relation between Chlamydia serology and cardiovascular events,60 no consensus has been reached regarding the serological detection of chronic active or persistent Chlamydia pneumoniae infection.61 Antibiotics have shown no effect on Chlamydia pneumoniae titers in cardiovascular patients.42,44,53,62,63 Furthermore, the lack of any effect of antibiotics on cardiovascular risk reduction was observed, both, in studies that included only patients with Chlamydia pneumoniae antibodies39,49 as well as in studies that included patients regardless of their serological status.8,9,50,51,54,55,62

Inadequate study medication may also have influenced the results of the antibiotic intervention trials. Although, all the studied antibiotics (azithromycine, clarithromycin, roxithromycin, and gatifloxacin) have proven antichlamydial properties, it is likely that other microbes such as helicobacter pylori,64 cytomegalovirus65 and herpes simplex virus66 that are not sensitive for the studied drugs may also have pro-atherogenic properties. In fact, it seems that the total pathogen burden more than an individual micro-organism is associated with cardiovascular risk.67,68 Other antibiotic related variables such as dosage and treatment-duration may have also affected the results. Published data suggest that the possible effect of antibiotics on risk reduction may decline with time. A preliminary report of the ROXIS trial showed a significant reduction of the primary endpoint (cardiac ischaemic death, myocardial infarction, and severe recurrent ischaemia) by roxithromycin at 31 days7 whereas this effect had worn off at 6 months.62 Similarly, roxithromycin seemed to reduce intima-media thickness progression in patients with cerebrovascular disease during the first 2 years after treatment, however this effect was lost after 4 years.53 A temporary effect of antibiotic treatment has also been suggested by the data of the WIZARD trial. The results of this trial showed a reduced risk of death or myocardial infarction at 6 months after randomisation but not after a longer follow up.49 Antibiotics may have only a transient effect, as patients may contract recurrent Chlamydia pneumoniae infections or suffer from Chlamydia pneumoniae reactivation, after the microbe has been forced into a latent state instead of being eliminated by the antibiotic treatment. In fact, effective treatment of chronic (vascular) Chlamydia pneumoniae infection may be more troublesome than initially anticipated. Recent in vitro evidence suggests that Chlamydia pneumoniae carried within macrophages is refractory to anti-chlamydial antibiotics69 and that even prolonged antibiotic treatment failed to completely eliminate Chlamydia pneumoniae from infected epithelial cells.70 It may therefore not be surprising that the prolonged treatment strategies, varying from 3 to 24 months, employed in the recently published mega-trials have not resulted in a significant reduction of cardiovascular events.8,9,49 Considering the fact that in animals the Chlamydia pneumoniae related progression of atherosclerosis can only be prevented by antibiotics when they are administered within 5 days of inoculation of the animals, and that in humans the majority of Chlamydia pneumoniae respiratory tract infections remain clinically unnoticed whereas Chlamydia pneumoniae antibody titers rise already during early childhood, it might be concluded that antibiotics may only contribute to cardiovascular risk reduction when administered early in life as part of a primary preventive strategy.

Cardiovascular events are the result of various vascular biological phenomena, such as atherosclerotic plaque growth and rupture, (neo)intimal hyperplasia after bypass grafting or angioplasty, and thrombosis. In contrast to cardiovascular survival, antibiotics may protect against aneurysm expansion rate42,43 and restenosis after coronary stent placement.41 The few trials assessing the effect of antibiotic treatment on these outcome criteria have shown positive results, but have small sample sizes and should therefore be verified by more data before definitive conclusions can be drawn.

To conclude it would appear that antibiotics do not offer any (cardiovascular) survival benefits in patients with atherosclerotic disease. Nevertheless, the limited data available suggest that anti-chlamydial antibiotics may have beneficial effects on two vascular biological processes, i.e. aortic aneurysm expansion rate42,43 and post-stent intimal hyperplasia and restenosis.41 The clinical relevance of aneurysm expansion and restenosis after stenting or bypass grafting warrants further investigations into the role of infections and antibiotics in these phenomena.


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