I'm posting this article and editorial for a few reasons.

1) It has been suggested that C.  pneumoniae causes a lot of things,
specifically coronary artery disease (CAD), and that for nefarious reasons
the whole thing is being ignored or suppressed. This is just not so (the
second part, anyway).

2) The story of CAD and infections is highly analogous to that of asthma.
May of the lessons are the same

3) The article is the lead in for the editorial. The editorialists make some
points that I have been trying to get across and I am hoping that their
words and examples will be more persuasive than mine have been.
Specifically, they comment on the relationship of early work to premises
that later turn out to be true. They uses the example of thrombolytics (clot
busters). Early on we knew that MI's were from clots and that we had drugs
that could dissolve them. It seemed to be a "no brianer" to use them but
early studies were disappointing. I think we all know that in the end the
clot busters became standard practice but it took a lot of tinkering to
determine who should be treated and how.

I would add to the list of examples one that was adopted too quickly and as
a result great harm has been done - fetal monitoring in pregnancy. There was
good theory their use and it seemed like a "no brianer" to get a distressed
baby out of the mother before there was permanent damage. Well, the
overwhelming body of work that followed the quick adoption of this new
technology has shown that the only effect is to increase c-section rates.
Yet, it is still the standard practice.

One more comment: Reproducing portions of a journal (even whole articles)
for non-commercial educational purposes is considered fair use of a
subscription and not a copyright violation by most major publishing
associations. Please don't bother posting objections here.

The research article is available in full for free at  (but I don't know for
how long):

http://jama.ama-assn.org/cgi/content/full/290/11/1459

--
CBI, MD

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Azithromycin for the Secondary Prevention of Coronary Heart Disease Events
The WIZARD Study: A Randomized Controlled Trial

Christopher M. O'Connor, MD; Michael W. Dunne, MD; Marc A. Pfeffer, MD, PhD;
Joseph B. Muhlestein, MD; Louis Yao, MD; Sandeep Gupta, MD; Rebecca J.
Benner, PhD; Marian R. Fisher, PhD; Thomas D. Cook, PhD; for the
Investigators in the WIZARD Study

JAMA. 2003;290:1459-1466.

ABSTRACT

Context  Several lines of evidence have implied an association between
Chlamydia pneumoniae infection and atherogenesis.

Objective  To determine the effect of 12 weeks of antibiotic therapy on
coronary heart disease events in patients with stable coronary artery
disease and known C pneumoniae exposure.

Design, Setting, and Participants  Randomized, placebo-controlled trial of
7747 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. Patients were recruited from 271 clinical practices in North America,
Europe, Argentina, and India, from October 10, 1997, to July 22, 2001.

Intervention  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).

Main Outcome Measures  The primary 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.

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). 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 hospitalizations for angina (-1%).
Adverse events related to study drug were reported by 13.2% of those
randomized to receive azithromycin, predominantly a result of diarrhea,
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.

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.

----------------------------------------

Vol. 290 No. 11, September 17, 2003

Antibiotic Therapy for Coronary Artery Disease
Can a WIZARD Change It All?

Sorin V. Pislaru, MD, PhD; Frans Van de Werf, MD, PhD

JAMA. 2003;290:1515-1516.

The possible association between Chlamydia pneumoniae and atherosclerosis
was first reported in 1988 by Saikku et al1 who noted that antichlamydial
antibodies were present more often among patients with acute myocardial
infarction (MI) than among matched controls. Since then, several other
serological studies have yielded conflicting results about this association,
possibly due to lack of uniformity in methods used (ie, different classes of
antibodies tested, different methods, different cutoff points) and by the
high prevalence of C pneumoniae exposure in the population. On the other
hand, data from basic laboratory studies have strongly suggested a possible
role of C pneumoniae in the etiology of atherosclerosis. Cells involved in
atherogenesis (vascular endothelial cells, smooth muscle cells, macrophages,
and platelets) have been found to be infected by C pneumoniae.2 In mouse and
rabbit models, C pneumoniae has been detected in the vasculature after nasal
inoculation and has been associated with various degrees of atherogenesis
and progression.2 Chlamydia pneumoniae also has been documented in
atherosclerotic lesions from patients.2

Although Muhlestein et al3 were the first to demonstrate a protective effect
of antibiotic therapy against accelerated atherosclerosis in a rabbit model,
the "infection hypothesis" of atherosclerosis only gained momentum after
Gurfinkel et al4 reported a 7% absolute reduction in the combined end point
of cardiac ischemic death, MI, and severe recurrent angina after 30 days of
treatment with roxithromycin (in the Randomised Trial of Roxithromycin in
Non-Q-Wave Coronary Syndromes [ROXIS] trial). Since then, the number of
published reports investigating the role of C pneumoniae in atherogenesis
has more than tripled in the last 5 years compared with the preceding
decade.

Yet after this positive initial result, data from laboratory studies and
clinical trials seem to diverge. More evidence in favor of a role of C
pneumoniae emerged from basic laboratory studies, whereas clinical trials of
patients with stable and unstable coronary heart disease failed to
demonstrate a significant benefit of antibiotic therapy.5

In addition to the ROXIS trial, only 3 other trials have suggested a benefit
of antibiotic therapy. In the Clarithromycin in Acute Coronary Syndrome
Patients in Finland (CLARIFY) trial,6 148 patients with unstable angina or
non-Q-wave MI were randomly assigned to receive 3 months of clarithromycin
therapy or placebo. There was no significant effect of antibiotic therapy
noted in the primary end point (death, MI, or unstable angina within the
3-month treatment period). There was an absolute risk reduction of 14.9% in
the secondary end point (combination of death, MI, unstable angina, ischemic
stroke, and critical limb ischemia); this was evident after 3 months of
therapy and persisted throughout the median 555 days of follow-up. However,
in the St George's Hospital trial,7 of 220 consecutive men who survived MI,
60 patients with persistently elevated antibody titers against C pneumoniae
were randomly assigned to receive placebo or a single or double 3-day course
of azithromycin. There was a significantly higher incidence of death, MI, or
unstable angina during the 18-month follow-up among those receiving placebo
than those with negative chlamydial serology (odds ratio [OR], 4.2; P =
.03). On the other hand, patients receiving azithromycin had a similar
outcome as those with negative serology (OR, 0.9; 95% CI, 0.2-4.6). In the
South Thames Trial of Antibiotics in Myocardial Infarction and Unstable
Angina (STAMINA),8 325 patients admitted with acute MI or unstable angina
were randomly assigned to receive placebo or triple therapy (azithromycin or
amoxicillin plus metronidazole plus omeprazole). Patients receiving
antibiotic therapy had a 36% reduction in the incidence of cardiac death,
unstable angina, or MI noted at 12 weeks, and the reduction persisted
throughout the 1-year follow-up.

In this issue of THE JOURNAL, O'Connor and colleagues9 report the results of
the WIZARD (Weekly Intervention with Zithromax for Atherosclerosis and Its
Related Disorders) study. This is by far the largest trial of antibiotic
therapy for coronary artery disease, with 7747 patients enrolled at 271
centers in 9 countries. All patients had documented previous MI in a stable
phase (ie, the MI had occurred >6 weeks before screening) and serological
evidence of exposure to C pneumoniae. Patients were randomly assigned to
receive azithromycin (600 mg/d for 3 days then weekly for the next 11 weeks)
or placebo. After 14 months of follow-up, patients in the antibiotic group
had a nonsignificant 7% reduction in the risk of the primary end point
(death, MI, coronary revascularization, or hospitalization for angina).

Although the findings from the WIZARD trial show, once more, that antibiotic
therapy failed to prove useful in the treatment of coronary artery disease,
the question is then whether a true contradiction exists between laboratory
data and clinical trials. The answer is impossible to give at present, but
some points need to be highlighted. Most laboratory data come from in vitro
experiments. Although such studies are unequaled in their power to identify
mechanisms that may link C pneumoniae infection and atherogenesis, their
true validity is difficult to ascertain in vivo. Questions that have been
raised ask whether C pneumoniae detected in atheromatous lesions plays an
active role or simply represents an innocent bystander in the process.2 In
addition, most in vivo experimental data are derived from small-animal
models, which have inherent limitations.10 Data from large-animal models of
chlamydial infection are practically nonexistent.11 Studies on the effects
of antibiotic therapy on atherogenesis in animal models are limited.
Moreover, animal models are just what they are, experimental models. Indeed,
the literature abounds with studies of interventions that are highly
successful in animals but fail to have similar effects in patients. Yet
despite these concerns, the bulk of experimental data favor a role for C
pneumoniae in atherosclerosis. Although this pathogen is unlikely the unique
cause of atherosclerosis, current data strongly suggest that C pneumoniae is
a plausible and potentially modifiable risk factor in cardiovascular
diseases.2

Several factors might help explain the negative results of clinical trials
with antibiotic therapy. Since C pneumoniae is not uniformly present in
atherosclerotic plaques, this organism probably does not play a role in all
patients. The challenging task is to identify individuals who may benefit
most from antibiotics. In the WIZARD trial, post hoc analysis showed trends
toward a favorable effect of antibiotic therapy in men who smoke or who have
diabetes or hypercholesterolemia; a significant 55% reduction in events was
noted in individuals who have diabetes and who smoke. Another approach may
be to select potential candidates for antibiotic therapy based on the
detection of chlamydial DNA in peripheral leukocytes. Alveolar macrophages
may take up C pneumoniae during the course of pulmonary infection and
deliver the organism to the site of vascular inflammation or injury, where
it can induce chronic inflammation, potentially leading to the formation of
atherosclerotic lesions.12 Identification of chlamydial DNA in these cells
may be more revealing than positive serological studies.

In addition, the optimal timing, dose, and duration of antibiotic therapy
needed for an antiatherogenic effect are not known. Some clinical studies
seem to suggest an early benefit that is lost when antibiotic therapy is
discontinued.5 Considering that late antibiotic treatment of C pneumoniae
infection does not seem to prevent atherogenesis in animal models,13 it is
possible that inclusion of stable patients at a median time of 31 months
after the acute event in the WIZARD trial may have reduced the chance of
detecting a beneficial effect of azithromycin.

In the end, the main question is whether antibiotics fail to improve
outcomes in coronary artery diseases because C pneumoniae does not play a
role in atherogenesis or because the proper antibiotic regimen has not been
used in the proper clinical setting. Before completely rejecting the
"infection hypothesis" of atherosclerosis, clinicians should remember
lessons from the past. In the 1950s, streptokinase therapy for MI was
considered only marginally effective.14 It took more than 20 years and
large-scale clinical trials to realize that improper patient selection and
inadequate dosage were responsible for the limited efficacy noted in initial
studies; today thrombolytic therapy is established as one of the most
beneficial interventions for patients with acute MI. Will antibiotic therapy
follow the same pattern? It is hoped that ongoing large clinical trials with
longer-term antibiotic therapy (such as the Azithromycin and Coronary Events
Study [ACES]15 and the Pravastatin or Atorvastatin Evaluation and Infection
Therapy [PROVE IT]16 study-a gatifloxacin trial) will help provide more
answers. Until then, the evidence appears insufficient to support use of
antibiotics for primary or secondary prevention of coronary heart disease.

AUTHOR INFORMATION

Corresponding Author and Reprints: Frans Van de Werf, MD, PhD, Gasthuisberg
University Hospital, Department of Cardiology, Herestraat 49, B-3000,
Leuven, Belgium (e-mail: frans.vandewerf@uz.kuleuven.ac.be).

Editorials represent the opinions of the authors and THE JOURNAL and not
those of the American Medical Association.

Author Affiliations: Department of Cardiology, Mayo Clinic and Foundation,
Rochester, Minn (Dr Pislaru) and Department of Cardiology, Gasthuisberg
University Hospital and University of Leuven, Leuven, Belgium (Dr Van de
Werf).

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