Cardiovascular Disease

Research Studies

Effect of Treatment for Chlamydia pneumoniae and Helicobacter pylori on Markers of Inflammation and Cardiac Events in Patients With Acute Coronary Syndromes South Thames Trial of Antibiotics in Myocardial Infarction and Unstable Angina (STAMINA)
Prospective, randomized, placebo-controlled trial, n= 325, Circulation 2002.
Methods – Acute myocardial infarction or unstable angina (acute coronary syndromes) were randomized to receive a 1-week course of 1 of 3 treatment regimens: (1) placebo; (2) amoxicillin (500 mg twice daily), metronidazole (400 mg twice daily), and omeprazole (20 mg twice daily); or (3) azithromycin (500 mg once daily), metronidazole (400 mg twice daily), and omeprazole (20 mg twice daily).
Result At 12 weeks, there was a 36% reduction in all end points in patients receiving antibiotics compared with placebo (P=0.02). This reduction persisted during the 1-year follow-up.
Conclusion – Antibiotic treatment significantly reduced adverse cardiac events in patients with acute coronary syndromes, but the effect was independent of H pylori or C pneumoniae seropositivity.

 

Antibiotic Treatment of Chlamydia pneumoniae after Acute Coronary Syndrome
Prospective, randomized, placebo-controlled trial, n=4,162, NEJM 2005.
400mg gatifloxacin QD for 2 weeks, then 10 days of treatment per month for (18-32 months, mean 2 years).
Primary efficacy outcome – death from all causes, myocardial infarction, documented unstable angina that required rehospitalization, revascularization with either percutaneous coronary intervention or coronary-artery bypass surgery (if these procedures were performed at least 30 days after randomization), or stroke.
Result – no statistically significant difference between placebo and gatifloxacin groups.
Limitationsduration of antimicrobial therapy (10 day “pulses” versus continuous treatment) and the use of one antimicrobial versus combination therapy to address the various stages in the CpN life cycle and persistence of the organism.

 

 

Azithromycin for the Secondary Prevention of Coronary Events (ACES)

Randomized, double-blind, placebo-controlled trial, n=4012, NEJM 2005.
Methods- Men and women 18 years of age or older who had documented, stable coronary heart disease.  Participants were randomly assigned to receive either a 600-mg azithromycin tablet or a matching placebo tablet once weekly for one year.
Result- This trial found that one year of weekly azithromycin therapy was not associated with any clinically significant benefit in the secondary prevention of coronary events.
Conclusion-  this study suggests that neither C. pneumoniae nor another organism susceptible to azithromycin plays an important role in events associated with late-stage coronary heart disease.
Limitations- “Our study has several limitations, including the advanced stage of disease (described above), the possibility that the antibiotic does not reach the microorganism in the chronic lesions of atherosclerosis, the possibility that the treatment was not continued long enough or that the dose of antibiotic given was too small, and the possibility that the antibiotic was not sufficiently effective against C. pneumoniae. These limitations do not, for practical purposes, weaken the basic conclusion of this study that antibiotic treatment cannot be recommended for the treatment of chronic coronary heart disease.”

Prospective, randomized, placebo-controlled trialn=302, Circulation 1999.
Methods- CAD patients that had a seropositive reaction to C pneumoniae (IgG titers ≥1:16) randomized to receive placebo or azithromycin, 500 mg/d for 3 days, then 500 mg/wk for 3 months.
Result- Azithromycin reduced a global rank sum score of the 4 inflammatory markers at 6 (but not 3) months (P=0.011) as well as the mean global rank sum change score: 531 (SD=201) for active drug and 587 (SD=190) for placebo (P=0.027). Specifically, change-score ranks were significantly lower for CRP (P=0.011) and IL-6 (P=0.043). Antibody titers were unchanged, and number of clinical cardiovascular events at 6 months did not differ by therapy (9 for active drug, 7 for placebo). Azithromycin decreased infections requiring antibiotics (1 versus 12 at 3 months, P=0.002) but caused more mild, primarily gastrointestinal, adverse effects (36 versus 17, P=0.003).
Conclusions- In CAD patients positive for C pneumoniae antibodies, global tests of 4 markers of inflammation improved at 6 months with azithromycin. However, unlike another smaller study, no differences in antibody titers and clinical events were observed. Longer-term and larger studies of antichlamydial therapy are indicated.

 

Azithromycin for the secondary prevention of coronary heart disease events: the WIZARD study: a randomized controlled trial.

Randomized, placebo-controlled trial, n = 7747, JAMA, 2003
Methods- adults with previous myocardial infarction that had occurred at least 6 weeks previously (median, 2.6 years) and a C pneumoniae IgG titer of 1:16 or more.  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).
Results- After a median of 14 months of follow-up, there was no significant risk reduction in the likelihood of a primary event with azithromycin vs placebo (7% [95% confidence interval, -5% to 17%], P =.23).
Conclusion- 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.
Limitations- As in previous studies, the choice of a single antimicrobial (azithromycin) versus combination therapy, and relatively short duration of treatment (3 months) may not address the persistence of the organism, Chlamydia pneumonaie.

 

Clarithromycin for stable coronary heart disease increases all-cause and cardiovascular mortality and cerebrovascular morbidity over 10years in the CLARICOR randomised, blinded clinical trial
Randomized, placebo-controlled trial, n=4373, International Journal of Cardiology, 2015
Methods- patients with stable coronary heart disease were randomized to 2 weeks of clarithromycin 500 mg a day versus placebo. 10 year follow up was performed through Danish public registers and analyzed with Cox regression.

 

Detection of Viable Chlamydia pneumoniae in Abdominal Aortic Aneurysms
Case-control study, n=26 AAA surgical patients compared to 17 autopsy controls, European Journal of Vascular and Endovascular Surgery 2000.

Result – C. pneumoniae was detected in the aortic aneurysms of 20/26 patients by immunohistochemical analysis (IHC).   C. pneumoniae was cultured from 10 of the 20 IHC-positive patients. Only 1/17 controls was positive for C. pneumoniae by IHC (p=0.0001).
Conclusion – C. pneumoniae is often present in AAAs in a viable form and that C. pneumoniae is linked to the pathogenesis of AAA.

 

Roxithromycin Treatment Prevents Progression of Peripheral Arterial Occlusive Disease in Chlamydia pneumoniae Seropositive Men
n= 40, randomized, double-blind, placebo-controlled trial
Methods – roxithromycin 300mg QD for 28 days  versus placebo in C pneumoniae seropositive men with established PAOD.
Results – The effect of macrolide treatment on the number of interventions per patient and on preinterventional walking distance was significant.  Carotid plaque areas monitored over 6 months decreased in the roxithromycin group (mean relative value, 94.4%) but remained constant in the placebo group (100.2%). Regression of carotid plaque size observed in roxithromycin-treated patients was significant for soft plaques.
Conclusion – This study indicates that macrolide treatment for 1 month is effective in preventing C pneumoniae seropositive men from progression of lower limb atherosclerosis for several years.

 

Matrix metalloproteinase-9 expression is associated with the presence of Chlamydia pneumoniae in human coronary atherosclerotic plaques
n=31 coronary atherosclerotic plaque specimens, BMJ Heart 2005.
Methods – immunohistochemistry (IHC), polymerase chain reaction (PCR), and reverse transcription PCR for the presence of C pneumoniae (CpN)  antigen and genomic DNA, and of MMP-9 protein and transcripts.
Results – IHC analysis identified a strong association between the presence of CpN antigen and production of MMP-9 in coronary atherosclerotic plaques (p = 0.001). Analysis of the intralesional amount of CpN and MMP-9 indicated an increased number of cells positive for MMP-9 in arterial sections that had increased CpN positivity (p < 0.05).
Conclusion – This study provides evidence of an association between expression of MMP-9 and the intravascular presence of CpN and may suggest a potential pathological mechanism whereby CpN may contribute to the progression of coronary atherosclerosis.