(Circulation. 1999;99:1540-1547.)
© 1999 American Heart Association, Inc.
Clinical Investigation and Reports |
Randomized Secondary Prevention Trial of Azithromycin in Patients With Coronary Artery Disease and Serological Evidence for Chlamydia pneumoniae Infection
The Azithromycin in Coronary Artery Disease: Elimination of Myocardial Infection with Chlamydia (ACADEMIC) Study
From the Department of Medicine, Division of Cardiology, University of Utah, LDS Hospital, Salt Lake City, Utah.
Correspondence to J. Brent Muhlestein, MD, or Jeffrey L. Anderson, MD, Coprincipal Investigators, Division of Cardiology, LDS Hospital, 8th Ave & C St, Salt Lake City, UT 84143.
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Abstract |
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Background—Chlamydia pneumoniae commonly causes respiratory infection, is vasotropic, causes atherosclerosis in animal models, and has been found in human atheromas. Whether it plays a causal role in clinical coronary artery disease (CAD) and is amenable to antibiotic therapy is uncertain.
Methods and Results—CAD patients (n=302) who had a seropositive
reaction to C pneumoniae (IgG titers 
1:16) were
randomized to receive placebo or azithromycin, 500 mg/d for 3 days,
then 500 mg/wk for 3 months. Circulating markers of inflammation
(C-reactive protein [CRP], interleukin [IL]-1, IL-6, and tumor
necrosis factor [TNF]-
), C pneumoniae antibody
titers, and cardiovascular events were assessed at 3
and 6 months. Treatment groups were balanced, with age averaging 64
(SD=10) years; 89% of the patients were male. 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.
Key Words: Chlamydia pneumoniae • antibiotics • coronary disease
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Introduction |
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Atherosclerosis, including coronary heart disease, is highly prevalent in Western society and is the single greatest cause of mortality (
33% of annual deaths in the United
States).1 Although many risk factors for
atherosclerosis are known (eg,
hyperlipidemia, hypertension, smoking, and diabetes),
much of attributable risk remains unexplained.2 Pathologically, atherosclerosis involves injury, inflammation, infiltration, degeneration, and thrombosis.3 4 5 6 A role for both the local inflammatory response in plaque (especially macrophages and T lymphocytes) and systemic inflammation in patients at increased risk for coronary events has been increasingly recognized and documented.3 4 5 6 7 The stimulus for this inflammatory response is unknown. The possibility that infectious agents may directly or indirectly trigger the cascade of biological and biochemical reactions leading to inflammation, atherosclerosis, and vascular thrombotic events has been raised recently.8 With regard to coronary artery disease (CAD), cytomegalovirus and Chlamydia pneumoniae have received increasing attention. Whether these or other infectious agents are a cause, a cofactor, or an innocent commensal relative to atherosclerosis is uncertain.8 However, the possibility that chronic inflammatory/degenerative diseases previously thought to be noninfectious may indeed be infectious and treatable with antibiotics is dramatically exemplified by the response of peptic ulcer disease to antibiotic therapy directed at Helicobacter pylori, now known to play a key etiologic role.9
C pneumoniae is a recently recognized and characterized human pathogen, distinct from other chlamydial species.10 11 12 Epidemiological studies have identified C pneumoniae as the third most common etiologic agent of bronchitis and pneumonia.11 Antibody prevalence studies suggest that >50% of adults have been exposed to it.12 C pneumoniae, an obligate intracellular parasite, is known to readily infect mononuclear phagocytes.8 Macrophages, which derive from monocytes, are characteristically localized within atherosclerotic plaques.8
The link between C pneumoniae and atherosclerosis first came from seroepidemiological studies from Finland13 and subsequently from several additional studies from the same and other groups.14 15 16 17 Although a high prevalence of anti-chlamydial antibodies has consistently been found in CAD patients, its predictive value has varied given the high level of exposure in the general adult population.18 More compelling has been the finding of bacterial antigen, and less commonly other biological evidence for chlamydia, within atherosclerotic tissues.19 20 21 22 23 Stimulated by a small initial autopsy study from South Africa,19 we evaluated plaque from 90 consecutive symptomatic CAD patients undergoing coronary atherectomy; specimens were positive by direct immunofluorescence for chlamydial antigen in 79% compared with only 4% (1) of 24 controls.21 A high prevalence of antigen detection within coronary or carotid plaque has also been noted by others19 20 21 22 23 ; however, detection of chlamydia by electron microscopy or of chlamydial DNA by polymerase chain reaction has been less consistent,23 24 and the organism has been difficult to culture.23 The possibility of a pathogenetic role for chlamydia in CAD has been strengthened by recent animal studies in which intranasal infection of rabbits with C pneumoniae was shown to induce or accelerate atherosclerosis.25 26
Chlamydia, including C pneumoniae, are generally sensitive
to antibiotic therapy with macrolides and tetracyclines. Azithromycin,
a new macrolide antibiotic, is rapidly absorbed and widely distributed
into tissues, where it achieves high and persistent concentrations
(tissue half-life 72 hours). Long-term azithromycin therapy has been
well tolerated except for minor, mostly gastrointestinal side effects
(eg, nausea and diarrhea).27 Azithromycin prevented
the acceleration of atherosclerosis induced by C
pneumoniae in rabbits.26 In a pilot clinical
study, Gupta et al28 29 treated survivors of myocardial
infarction (MI) (n=60) with 1 to 2 brief courses of azithromycin or
placebo; selected markers of inflammation and anti-chlamydial antibody
titers fell over a 3- to 6-month period, and there was an apparent
reduction in clinical events. Stimulated by these initial observations,
we undertook a larger prospective, randomized, secondary prevention
study.
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Methods |
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Study Design and Objectives
The study was designed as a randomized, double-blind, secondary prevention trial of azithromycin (3-month course) versus placebo in patients with documented CAD to test both laboratory and clinical objectives.
The laboratory hypothesis was that azithromycin therapy, compared with
placebo, would reduce a global measure of systemic levels of a cluster
of inflammatory markers (C-reactive protein [CRP], interleukin
[IL]-1, IL-6, and tumor necrosis factor [TNF]-) at 3 months (end
of therapy) and 6 months. The secondary laboratory hypothesis was that
antibiotic therapy would reduce anti-chlamydial IgG and IgA antibody
levels at 6 months.
The clinical hypothesis was that at 6 months (secondary end point, this article) and 2 years (primary end point), cardiovascular events would be reduced in the azithromycin group compared with the placebo group. End-point events were defined as cardiovascular death, resuscitated cardiac arrest, nonfatal MI or stroke, unstable angina requiring hospitalization, and unplanned coronary interventions (catheter based or surgical).
Other clinical objectives included comparison, by treatment group, of all deaths, other cardiovascular hospitalizations or procedures, adverse experiences and drug discontinuations, and clinical infections. Other laboratory comparisons of interest included total leukocyte count and blood pressure and heart rate measurements by group (at 3 and 6 months).
Patient Qualification, Enrollment, and Randomization
Patients qualified for the study if they had CAD (documented by
a previous MI, bypass surgery, or >50% angiographic stenosis
of 1 major coronary artery), were >18 years old, had a life
expectancy of >2 years, and gave written informed consent. Exclusion
criteria included the following: female capable of child bearing
without adequate birth control; New York Heart Association functional
class III or IV or left ventricular ejection fraction
<25%; MI within 5 days, bypass surgery within 4 weeks, or
coronary intervention (any technique) within 3 months; planned
CABG or coronary intervention; significant comorbid illnesses,
including active malignancy, ongoing drug or alcohol abuse, renal
failure requiring dialysis, and liver failure, with a projected
life expectancy of <2 years; known intolerance to azithromycin; and
chronic macrolide (eg, erythromycin) or tetracycline use.
Patients who met all study criteria and gave informed consent were
screened for C pneumoniae serum antibody titers to provide
300 patients for enrollment with anti-chlamydial IgG titers of
1:16 by microimmunofluorescence (MIF). Enrolled
patients were randomized 1:1 to the 2 treatment groups (azithromycin or
placebo) by an unblinded, independent party (pharmacist) who was
uninvolved in clinical management except for provision of blinded drug
supplies; the pharmacist opened an envelope containing the drug
assignment. The order of randomization followed a permuted block design
(alternating blocks of 4 and 6).
Supplies and Dosing of Drug and Placebo
Azithromycin, as 250-mg red capsules (Pfizer
Laboratories), was purchased from LDS Hospital Pharmacy.
Matching placebo capsules were purchased from Jolley's Corner Pharmacy
in Salt Lake City, Utah. Enrolled patients were to initiate therapy
with 2 capsules (500 mg/d for 3 days) then maintain therapy with 2
capsules (500 mg/wk, taken on Mondays) for 3 months, to be taken 1
hour before or 2 hours after food.
Study Flow
Eligibility was determined during a screening visit. Venous
blood was drawn from eligible, consenting patients and was tested by
MIF for C pneumoniae antibodies. Patients with titers 1:16
were seen 1 week later for randomization; baseline history and
physical examination were completed, blood was drawn, a 12-lead ECG was
obtained, and study drug was dispensed. At 3 and 6 months, patients
returned to review clinical status and drug compliance; blood was
sampled and an ECG obtained. One- and 2-year clinical follow-up was
scheduled.
Laboratory Testing
Screening for anti-C pneumoniae antibody (IgG) used a
standard MIF test (MRL Diagnostics) on 1:16 diluted serum.
Quantitative IgG and IgA measurements used a sensitive, specific ELISA
(Savyon Diagnostics Ltd). Tests for CRP (Johnson & Johnson
Clinical Diagnostics, Inc), IL-1, IL-6, and TNF-
(Quantikine HS, R&D Systems) were also performed by commercially
available methods. Leukocyte counts were determined by the hospital
laboratory by standard methods. Tests were run in batches that included
sets of baseline and follow-up samples for each patient.
Statistical Considerations
The study was planned to have 90% power to detect differences
in the primary laboratory end points at 3 to 6 months between treatment
groups of 0.385 SD for the markers of inflammation, based on estimates
from literature studies (eg, References 28 and
29 ) and assuming a 5% dropout rate. This was satisfied
with 300 patients (150 in each treatment group).
Clinical event rate estimates were based on the pilot study of Gupta et
al,28 29 who reported a reduction in events from 28% to
8% by 6 to 18 months in treated patients who had falling antibody
titers versus controls (ie, patients taking placebo or untreated
patients with persistently elevated titers). Assuming a placebo event
rate of 28%, 150 patients per group provide 90% power to detect a
study drug–induced reduction in event rate to 14.5% at 6 months
(secondary clinical end point) and at 2 years (primary clinical end
point).
The primary (null) laboratory hypothesis was that there would be no
difference between the azithromycin and placebo groups in global change
scores from baseline in markers of inflammation measured at 3 and 6
months; the alternate hypothesis was that changes would favor
antibiotic therapy. Differences between baseline and 3 and 6 months for
individual markers were checked for normality by the Kolmogorov-Smirnov
test. Given the expectation of improvement in most or all inflammatory
markers and nonnormal distribution of data, the O'Brien
nonparametric rank sum test was chosen as the global test
of the multiple end points (changes in the 4 inflammatory markers for
our primary laboratory analysis).30 31 A global
comparison between the 2 treatment groups was also performed on actual
marker values at 3 and 6 months with the O'Brien test used for a
secondary analysis. Between–treatment-group comparisons were
then made for each marker separately (Mann-Whitney test) to assess
which markers contributed to the global result. Otherwise, categorical
variables in the 2 groups were compared by
2 testing, and continuous variables were
compared by Student's t test or Mann-Whitney testing, as
appropriate. Assessment of clinical events used the intention-to-treat
approach. Laboratory marker analyses excluded only patients
without a blood test result.
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Results |
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Baseline Patient Characteristics
A total of 430 patients were screened; 333 (77%) had positive C pneumoniae serology, and 302 patients consented and were enrolled in the study, with 150 randomly assigned to receive azithromycin and 152 to receive placebo. Overall, patients were 64±10 years of age (mean±SD; range, 30 to 88 years); 89% were male; 60% had suffered a previous MI; 46% had undergone bypass surgery; and 46% had undergone percutaneous coronary interventions. Patient characteristics on admission were well balanced in the randomly assigned treatment groups (Table 1
).
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Baseline levels of inflammatory markers and antibody titers are shown
in Table 2. Individual markers showed
substantial interpatient variability, but no significant differences
were observed between the 2 treatment groups.
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Effect of Therapy on Global Inflammatory Score
Overall, measured values of the 4 inflammatory markers were
similar at 3 months but were reduced at 6 months in the azithromycin
compared with the placebo group: average rank sum scores were 583
(SD=182) versus 593 (SD=168) (P=0.64) at 3 months and 532
(SD=203) versus 598 (SD=205) (P=0.011) at 6 months in the
active and placebo groups, respectively (Figure 1).
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Similarly, for the primary study variable of global change score,
average rank sum score was similar in the 2 treatment groups for the
change in measured values from baseline at 3 months (mean rank sum
score, 584 [SD=198] versus 586 [SD=189]; P=0.92), but it
was reduced compared with baseline at 6 months (mean rank sum score,
531 [SD=201] versus 587 [SD=190]; P=0.027) in the
active-drug and placebo groups, respectively (Figure 2).
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Response of Individual Markers of Inflammation
Over the entire study population, IL-1, IL-6, and TNF fell from
baseline at 3 months (all P<0.01, Wilcoxon rank sum
test), then recovered to less than (IL-6), similar to (TNF), or greater
than baseline (IL-1) at 6 months. The effect of treatment on individual
inflammatory markers is shown in Tables 3 and 4 and Figure 3; all markers tended to show lower
values (ranks) at 6 months with azithromycin, although the magnitude
and significance of the responses varied.
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C-Reactive Protein
CRP measurements were variable in the study population, with
most falling in the normal range. However, a significant difference by
treatment group in the change score was noted at 6 months but not 3
months (Table 4
; Figure 3), with a mean rank of 
CRP
values of 128 in azithromycin versus 150 in placebo patients
(P=0.017).
Interleukin-1
Therapy affected IL-1 measurements at 6 but not 3 months,
preventing the rebound to above-baseline values seen in placebo
patients (Table 3). Median IL-1 at 6 months was 1.45 pg/mL in
patients taking active drug versus 2.20 pg/mL in patients taking
placebo (P=0.027). Change scores did not achieve
significance, however (Table 4).
Interleukin-6
IL-6 levels fell in both treatment groups at 3 months (Table 3) compared with baseline (Table 2), but only active
therapy prevented a subsequent increase back to baseline values (Tables 3 and 4; Figure 3). At 6 months, mean rank for
IL-6 was 118 in active-therapy versus 139 in placebo-treated
patients (P=0.023).
Tumor Necrosis Factor
TNF levels tended to decrease similarly in both groups at 3 months
and return only partially toward baseline by 6 months. The slight trend
to lower TNF values at 6 months with active therapy did not approach
significance (P=0.25; Table 3).
Effect of Therapy on Anti-Chlamydial Antibody Titers
Table 4 shows quantitative measures of anti-C
pneumoniae IgG and IgA titers at baseline and 3 and 6 months in
the 2 treatment groups. Titers were stable or tended to increase
slightly over time. No differences in changes in titers of either
immunoglobulin by treatment group were observed at either 3 or 6
months.
Effect of Therapy on Early (<6 Months) Clinical Events
Table 6 shows the composite
of clinical cardiovascular events that occurred within
6 months in the 2 treatment groups (our secondary time point; primary
end point at 2 years). A total of 9 cardiovascular
events occurred in the azithromycin group, and similarly, 7 events
occurred in the placebo group. The distribution of events was also
generally similar in the 2 groups.
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Effect of Therapy on Total Leukocyte Count and Vital Signs
Leukocyte counts did not change significantly over time in either
group. Vital signs were unchanged over 6 months, with no significant
differences emerging between groups in heart rate or systolic
or diastolic blood pressure.
Effect of Therapy on Rates of Infection
Azithromycin reduced the number of clinical infections over the
3-month treatment period (12 versus 27; P=0.011), including
those that required antibiotics (1 versus 12; P=0.002). Two
patients in the active-therapy group developed a secondary yeast
(candidal) infection.
Drug Tolerance and Compliance
Compliance was good to excellent; 89% of active-therapy and 85%
of placebo-treated patients followed the treatment plan without
deviation. Only 2 active-therapy and 3 placebo-treated patients
permanently discontinued therapy >2 weeks early. Overall, 36 (24%) of
patients treated with azithromycin and 17 (11%) of patients taking
placebo experienced some adverse effect during the 3-month treatment
period (P=0.003). Adverse effects were believed to be
possibly or probably drug related in 25 of active and 11
placebo-treated patients (P=0.011). They were usually mild,
occasionally moderate, and most frequently gastrointestinal (31 of the
active-therapy patients, 12 of the placebo-treated patients;
P=0.002), including nausea, diarrhea, or flatulence. A yeast
infection was observed in 2 patients taking active therapy; 1 case of
esophageal candidiasis was moderately severe, requiring drug
discontinuation and specific therapy.
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Discussion |
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Summary of Study Results
This double-blind, randomized, moderately large, secondary prevention study in CAD patients with serological evidence of prior C pneumoniae exposure showed no difference in global inflammatory marker scores at the end of the 3-month treatment period, but at 6 months, the global difference score was lower in the active-therapy group, both for change scores (P=0.03) and actual value scores (P=0.01). All measures trended in a favorable direction, with significance reached for CRP, IL-1, and IL-6 on one or the other test. Unlike in a previous report,28 antibody titers were unaffected by therapy. Also in contrast to 2 smaller studies,28 29 32 no difference emerged by 6 months in clinical events. The results of these earlier, smaller studies thus appear overly enthusiastic; however, we believe our results should encourage rather than discourage additional clinical and laboratory studies based on more realistic expectations. Testing of similar and additional inflammatory markers should be undertaken, including others that assess monocyte/macrophage activation (eg, tissue factor and CD11b) and endothelial activation (eg, soluble intercellular adhesion molecule and soluble vascular cell adhesion molecule). Larger and longer studies of clinical outcomes should also proceed.
The utility of our randomized control design is emphasized by the fall in levels of 3 inflammatory markers at 3 months, even in the placebo group; the cause of this unexpected placebo effect is uncertain but might involve, among other things, increased patient compliance with aspirin on study entry or a seasonal effect on inflammation.
Pathophysiological Considerations
How could infectious agents promote atherogenesis? Libby et
al8 suggest that both direct and indirect effects on
vascular wall cells may be involved: infection may cause lethal lytic
damage, or infected cells may survive but show altered function.
Endothelial dysfunction may include increased
procoagulant activity, reduced intrinsic fibrinolysis,
increased leukocyte adhesion, and increased cytokine
production. Smooth muscle cell dysfunction may be associated
with increased proliferation, reduced apoptosis, increased
cholesterol esterification, and increased cytokine
production. Recruitment and activation of leukocytes also
result. Indirect effects on vascular cells may accompany infection or
activation of vessel-associated leukocytes; mononuclear phagocytes may
show increased procoagulant and reduced fibrinolytic behavior, altered
lipid metabolism, increased cytokine
production, and release of toxic oxygen species. T cells may
show increased proliferation, cytokine production, and
lytic activity for vascular wall cells.
With respect to C pneumoniae, little is currently known regarding the biology of vascular wall infection.8 33 C pneumoniae commonly infects mononuclear phagocytes, and chlamydial species can infect epithelial cells persistently under certain conditions. It is known that the chlamydial life cycle involves the elementary body (extracellular, infectious form) and the reticulate body (intracellular, replicative form); under conditions of stress, a metabolically inactive but viable form, the persistent body, has also been described.34 Thus, chlamydia are good candidates to cause chronic, persistent, nonlytic cellular infection.
It is known that infection increases the level of
production of the inflammatory cytokines IL-1ß, IL-6,
and TNF-; TNF and IL-1 upregulate IL-8.35
Hepatocytes respond to IL-1 and IL-6 by producing
CRP,36 and CRP can induce expression of monocyte tissue
factor.37 Thus, these interrelated inflammatory mediators,
all resulting from and/or enhancing macrophage/monocyte
activation, were used together in the present study to define a
global marker of inflammation/macrophage activation. The use of
these multiple, interdependent markers was more attractive than 1
arbitrarily selected variable. Indeed, the findings of our study
suggest an overall beneficial action of antibiotic therapy on serum
markers of inflammation, although the effect was somewhat delayed (to 6
months) and modest in extent.
Comparisons With Previous Antibiotic Trials
Our performance of a secondary prevention antibiotic study
was stimulated by the finding of a surprisingly high prevalence of
chlamydial antigen in coronary atheroma extracted
by us at atherectomy, together with promising results from antibiotic
therapy in our animal model and in a pilot clinical study from the
United Kingdom.26 28 29 In one approach to examining the
question of whether chlamydia play a pathogenetic or commensal role, we
repeatedly infected 30 rabbits intranasally with C
pneumoniae or saline, then randomly assigned them to 2 months of
azithromycin or no therapy and assessed aortic maximal intimal
thickness (MIT) and plaque area index (PAI) at 3
months.26 MIT and PAI were increased 3-fold in
infected, untreated animals compared with uninfected controls; in
contrast, infected animals treated with antibiotics showed MITs and
PAIs similar to uninfected animals. These results suggested that
C pneumoniae infection may accelerate atherogenesis and
antichlamydial therapy may prevent it, at least in some models.
Gupta et al28 29 stimulated interest in antibiotic trials
in humans with a recent pilot study in the United Kingdom: 60 survivors
of acute MI with persistently elevated anti-chlamydial antibody titers
(1:64) were randomized to receive placebo, a single 3-day course of
azithromycin (500 mg/d), or 2 courses 3 months apart. At 6 months,
anti-chlamydial antibody titers fell to <1:16 in 43% of patients in
the azithromycin group versus 10% of subjects in the placebo group
(P=0.02). Reductions in some of several measured markers of
inflammation were also observed, specifically,
monocyte/macrophage tissue factor and the surface adhesion
molecule CD11b.28 In addition, compared with patients
in the placebo group plus a nonrandomized group with high antibody
titers, azithromycin-treated patients showed an apparent reduction in
cardiovascular events within 6 to 18 months (from 28%
to 8%; P=0.03).
Subsequent to the initiation of our study, Gurfinkel et al37 reported on a pilot antibiotic trial from Argentina: 202 patients presenting with unstable angina or non–Q-wave MI were randomized on hospital admission to roxithromycin, 150 mg twice daily, or placebo for 30 days. Rates of recurrent angina (2 versus 5), acute MI (0 versus 2), death (0 versus 2), or any event (2 versus 9) tended to be reduced at 1 month (adjusted P=0.064). The study suffers from the small number of events, poor characterization of patients, and short follow-up but raises the question of the role of inflammation in unstable coronary syndromes and the possibility that antibiotic therapy might provide benefit in the acute or subacute setting.
Our study results contrast with these earlier results in several ways. We randomized a much larger sample than Gupta (300 versus 60 patients) and gave more intensive antibiotic therapy (7.5 versus 1.5 to 3.0 g of azithromycin over 3 months) but did not confirm C pneumoniae antibody titer responsiveness. Furthermore, we did not confirm a dramatic early reduction in clinical events, although a comparison at 6 months cannot be strictly made between studies because the time distribution of observed events was not reported in their published report.29 The study of Gurfinkel et al32 was of intermediate size (202 patients); their report of a strong trend in reduction in number of adverse events (2 versus 9) at 1 month also stands in contrast to our study of a much larger patient follow-up (1800 versus 202 patient-months). Because Gurfinkel et al32 studied acute coronary syndrome patients, differences in outcome based on differences in the patient population, although unlikely, cannot be entirely excluded. In keeping with our study, they found no reduction in anti-chlamydial antibody titers in response to therapy, at least at 1 month.
Study Strengths and Limitations
This study adds substantially to the small amount of previous work
relating C pneumoniae to atherosclerosis in
humans8 and antibiotic therapy directed at chlamydia
in patients with CAD manifestations.29 32 The validity of
the statistical inferences of the study are bolstered by its
prospective, randomized, double-blind design and moderately large size.
The power of the study is excellent for the laboratory end points.
Indeed, overall stabilization of marker levels was observed. For the
clinical end point, it was recognized that event rates at 6 months
might be too low to demonstrate a clear therapeutic benefit, although
previous pilot studies suggested this possibility.29 32
Hence, the primary clinical end point is at 2 years. Given our
event-rate comparison at 6 months, however, we believe that even larger
studies of at least a few thousand patients and at least a few years'
follow-up should be pursued.
The optimal dose and duration of azithromycin therapy are unknown in the setting of chronic CAD. We based our 3-month course on the conjecture that a persistent, low-grade, indolent infection might require a longer duration of therapy than acute infections. Also, therapy in the promising pilot study of Gupta et al extended over 3 months, although our treatment course was much more intense. Safety assessment for the use of chronic azithromycin is not yet available beyond 3 to 6 months. Chlamydia in a persistent, metabolically inactive state might not be immediately susceptible to antibiotic therapy. Longer-term and/or intermittent (eg, monthly) treatment may be required to ensure lasting benefit. Also, reinfection with C pneumoniae is known to be possible, even in adulthood, and appears to occur on the order of 2% to 3% annually.
An additional limitation is the uncertainty that the effects of azithromycin are due to a specific antichlamydial action and not a more general anti-infectious or anti-inflammatory effect. A similar uncertainty arises in attempting to explain the recently demonstrated benefits of tetracycline therapy in rheumatoid arthritis.38 Although additional work will be needed to resolve this concern, a beneficial effect on atherosclerosis by either specific or nonspecific mechanisms is of interest.
We included only seropositive patients in this study; inclusion of seronegative patients in future studies might help to answer the question of specific versus nonspecific antichlamydial effects of azithromycin. However, seropositivity is an imperfect marker of persistent chlamydial arteritis and is associated with uncertain, possibly substantial rates of false positivity and negativity. In a small subgroup of patients with atherectomy samples positive for chlamydial antigen, 8 of 9 also were seropositive (J.B. Muhlestein, MD, et al, unpublished observations, 1997). Chronic vascular infection with chlamydia, not prior systemic exposure (eg, acute respiratory infection), underlies our study hypothesis, but a direct means of detection of chronic vasculitis, short of atherectomy, is not yet available.
Conclusions
We tested the hypothesis that C pneumoniae infection
may be an additional atherosclerotic risk factor in patients with CAD
by performing a prospective, double-blind, randomized, secondary
prevention trial (n=302 patients) with the potent antichlamydial
antibiotic azithromycin. We found that in CAD patients positive for
C pneumoniae antibodies, a global test on a cluster of 4
inflammatory markers showed lower rank scores with active therapy at 6
but not 3 months, both for change scores (P=0.03) and for
actual value scores (P=0.01). However, no differences were
observed in antibody levels or clinical events at 6 months. Although
our results suggest that 2 previous smaller studies were overly
enthusiastic in their conclusions, our findings should stimulate rather
than discourage larger and longer-term clinical trials, as well as
preclinical research, to explore the intriguing but as yet unproved
hypothesis that infectious agents may play a role as causative factors
or cofactors in at least a subgroup of patients with CAD who might be
amenable to antibiotic or other preventive therapies.
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Acknowledgments |
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This study was supported in part by a grant from the Deseret Foundation, LDS Hospital, Salt Lake City, Utah. We thank members of the Data and Safety Monitoring Committee: Sheldon Litwin, MD, Jay Jacobsen, MD, and Al Hallstrom, PhD. We recognize statisticians Steven M. Snapinn, PhD, and Joseph F. Heyse, PhD, Merck Research Laboratories, Blue Bell, Pa, for their assistance with O'Brien test analyses of inflammatory markers. We also thank Alan Scholl, University of Utah, for statistical technical support.
Received August 14, 1998; revision received December 11, 1998; accepted December 18, 1998.
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