Persistent C. pneumoniae infection in atherosclerotic lesions: rethinking the clinical trials

The hypothesis that infectious agents are a risk factor for atherosclerosis has implicated multiple viral and bacterial pathogens in contributing either directly or indirectly to disease progression (Rosenfeld and Campbell, 2011). One of the most vigorously studied organisms has been Chlamydia pneumoniae, which has been associated with cardiovascular disease by seroepidemiological studies, detection of the organism by multiple methods in atherosclerotic tissue, and experimental studies demonstrating biological plausibility. Significantly, C. pneumoniae accelerates lesion progression in mouse and rabbit models of atherosclerosis (Muhlestein et al., 1998; Hu et al., 1999; Moazed et al., 1999; Fong, 2000; Blessing et al., 2001). Early small clinical trials determined whether treatment with macrolides (Azithromycin, Roxithromycin, and Clarithromycin) would be efficacious in secondary prevention of coronary heart disease. These studies yielded mixed results and had several limitations including the small numbers of patients and short duration of treatment and follow-up period (Grayston, 2003). However, half of them demonstrated some beneficial effects, which provided enthusiasm for the potential of antibiotic intervention in coronary artery disease. There have since been four large clinical trials collectively enrolling over 20,000 patients with stable coronary artery disease (WIZARD, ACES, and CLARICOR) or acute coronary syndrome (PROVE-IT–TIMI) (O'Connor et al., 2003; Cannon et al., 2005; Grayston et al., 2005; Jespersen et al., 2006). As there were short term beneficial effects in the WIZARD trial following a 3 month course of Azithromycin, two subsequent studies addressed whether longer term treatment would be efficacious in reducing coronary events. In the ACES study, patients were treated with Azithromycin for 1 year and followed for 46.8 months (Grayston et al., 2005). The PROVE IT-TIMI trial treated with gatifloxacin for a mean duration of 2 years (Cannon et al., 2005). Overall, none of these well-designed trials demonstrated any long term benefit of antibiotic treatment. Furthermore, two large scale trials subsequently found that treatment with either roxithromycin or rifalizil (PROVIDENCE-1) had no beneficial effects in patients with peripheral artery disease (Joensen et al., 2008; Jaff et al., 2009). Cumulatively, these trials clearly demonstrated that anti-chlamydial antibiotics should not be recommended for treatment of patients with coronary heart disease or peripheral artery disease. Prior to the completion of the PROVE-IT and ACES trials, Grayston commented that if the trials demonstrated a beneficial effect of antibiotics, this would provide additional evidence for a role of C. pneumoniae in pathogenesis, but would not prove causality (Grayston, 2003). Alternatively, he predicted that negative results would mostly likely dampen interest in the association of C. pneumoniae and atherosclerosis, but noted that failure of the clinical trials would not rule out a pathogenic role (Grayston, 2003). Indeed, the negative outcome led some to conclude that this proved that C. pneumoniae did not play a role in the pathogenesis of atherosclerosis (Danesh, 2005) and diminished interest in infectious agents as contributing factors for cardiovascular disease (Epstein et al., 2009).