(Circulation. 2000;102:1742.)
© 2000 American Heart Association, Inc.
Editorial |
Secondary Prevention Antibiotic Treatment Trials for Coronary Artery Disease
From the Department of Epidemiology, School of Public Health and Community Medicine, University of Washington, Seattle.
Correspondence to Dr J. Thomas Grayston, Department of Epidemiology, School of Public Health and Community Medicine, University of Washington, Box 357236, Seattle, WA 98195.
Key Words: Editorials • coronary disease • antibiotics • Chlamydia pneumonia
Considerable interest was generated in the possible causative role of Chlamydia pneumoniae in coronary artery disease (CAD) by the publication of a small pilot study in London of antibiotic treatment of CAD that reduced coronary events.1 Persons familiar with antibiotic treatment of chlamydia were skeptical that the brief treatment schedule in the London trial (azithromycin either one or two courses once daily for 3 days) could have a significant effect on chlamydia.2 Because of the great importance of CAD and a possible new treatment, further human experimentation was justified. Anderson and coworkers3 and Muhlestein and colleagues4 at the LDS hospital and the University of Utah made a useful contribution by quickly undertaking a pilot study, Azithromycin in Coronary Artery Disease: Elimination of Myocardial Infection With Chlamydia (ACADEMIC), to see if the surprising findings of the English study could be repeated. It was important to perform this study because some cardiologists had begun inappropriate antibiotic treatment of patients after publication of the English study.
In the article by Muhlestein et al4 in this issue, we learn that no miraculous reduction in cardiovascular events was seen in 2 years after a more reasonable 3 months of antibiotic treatment. Whether the modest decrease (statistically not significant) in events in the treated group during the second year of observation indicates a treatment effect can be determined only in a larger study. It is important to emphasize, as did Muhlestein et al, that the ACADEMIC study was not adequately powered (not enough subjects) to prove that antibiotic treatment of CAD does not reduce events. There were 300 subjects in the Utah study, whereas 3500 to 4000 are needed to show whether a reduction in events of a clinically significant 20% to 25% follows antibiotic treatment.
In a preliminary publication of the ACADEMIC study results at 6 months, Anderson et al3 showed that the antibiotic treatment group had some lower values for inflammation markers than did the subjects given placebo. They also found that their more prolonged treatment did not reduce C pneumoniae antibody titers as had been reported by the London group. If these serum markers were also studied after 2 years, the results would be of interest.
There are now at least two adequately powered CAD treatment trials under way (3500 to 4000 subjects) that should give a definitive answer to whether antibiotic treatment can reduce cardiac events. One, the Weekly Intervention With Zithromax for Atherosclerosis and Related Disorders (WIZARD) study that is sponsored by the Pfizer Co, has a 3-month treatment schedule similar to the ACADEMIC trial.5 The other, the Azithromycin Coronary Events Study (ACES), is sponsored primarily by the NHLBI.6 Treatment in this trial is for 1 year with a 4-year observation period. Results are not expected until late 2003.
All of the above trials used azithromycin as the antibiotic for treatment because of its proven effectiveness against chlamydia and its excellent intracellular penetration (The only place chlamydiae are susceptible to antibiotics is inside the infected cell). The long intracellular half-life of this antibiotic allows once-per-week dosing. Other treatment trials of CAD with other antibiotics are being planned or initiated.
The subjects in the ACADEMIC trial and the other trials mentioned above had stable CAD. One other small pilot trial began treatment with roxithromycin when the subjects were hospitalized with a coronary episode.7 Again, this trial was too small (200 subjects) to give a definitive answer, but there was evidence of protection early in the observation period. It is conceivable that antibiotic therapy could have a favorable effect in persons with unstable disease.
What will be the significance of the results of the treatment trials, and how will the results contribute to understanding the role of C pneumoniae infection in the pathogenesis of atherosclerosis and the diseases caused by atherosclerosis?
That there might be an association of C pneumoniae with atherosclerosis was first suggested by seroepidemiological findings that persons with CAD more frequently had antibody against C pneumoniae.8 That an association does exist was proved by finding the organism in atherosclerotic tissue.9 There are now 50 studies of atherosclerosis tissue for the presence of C pneumoniae.10 The organism was found in all but 4 of the studies. The organism was demonstrated by 4 different methods: immunocytochemistry with C pneumoniae–specific monoclonal antibody (the most sensitive), polymerase chain reaction, electron microscopy (original method), and isolation. In studies from laboratories using immunocytochemistry with or without polymerase chain reaction, the organism was found in 40% to 100% of the atherosclerotic lesions examined. Although the finding of a pathogenic organism in the diseased tissue (and not in normal tissue) is suggestive, it does not prove a causal association.
Observational studies (seroepidemiology and tissue studies) cannot prove causation. To prove causation, experimental studies are needed. It is not expected that a single innovative study can answer the question of whether C pneumoniae does or does not cause atherosclerosis. Rather, an accumulation of evidence from a variety of different studies will be required. These will include basic mechanisms, animal models, and antibiotic treatment trials.
Studies of basic mechanisms by which C pneumoniae might cause atherosclerosis have shown some possibilities.11 12 Animal model studies in rabbits and mice have clearly shown that when the organism is inoculated into the respiratory tract, it can soon be found in the aorta, presumably transmitted by mononuclear cells.13 Inflammatory lesions, possibly early atherosclerotic lesions, have been demonstrated in animals on normal diets.14 In mice or rabbits that were fed cholesterol or had genetic defects causing hypercholesterolemia, C pneumoniae respiratory infection accelerates development of atherosclerosis.15 16 Early antibiotic treatment of the C pneumoniae infection blocked the accelerating effect of C pneumoniae.
So far, there are no definitive findings from secondary prevention antibiotic treatment trials. Although considerable expectation has been built up about the results of the adequately powered trials now underway, it is important to consider what they can and cannot tell us about an infectious cause of atherosclerosis. The hypothesis on which the trials are being conducted is that C pneumoniae plays a causative role in atherosclerosis and that antibiotic treatment directed against C pneumoniae will decrease complications of atherosclerosis.
C pneumoniae could play a causative role in one or more of the many different stages in the development of atherosclerosis, which is a nearly life-long disease process. It could be in initiation of the disease or in the development or acceleration of the process. The animal model studies most strongly support C pneumoniae involvement, along with lipids, in the development and acceleration of the disease but do not rule out a role in the initiation of the disease. The organism could also play a role in the final stages of the disease when complications of atherosclerosis lead to such events as myocardial infarction. The treatment trials will give information only on this final stage of the process. There are no animal models of these late complications of atherosclerosis, so human trials are justified.
If there is a significant decrease in cardiac events in the treatment arm of the clinical trials, it will provide evidence that C pneumoniae plays a causative role in the pathogenesis of complications of atherosclerosis, in this case CAD. This evidence will be indirect in that there is the unlikely possibility that the antibiotic effect is on an unknown organism rather than C pneumoniae. There is also an unlikely possibility that a positive result could be due to the anti-inflammatory effect of macrolide antibiotics. This effect should not continue after the antibiotic administration has stopped. A decrease in events will not provide any knowledge concerning the role of C pneumoniae in the initiation or development of atherosclerosis.
If there is not a significant decrease in cardiac events in the treatment arm of the clinical trials, it will suggest that antibiotic treatment should not be used in CAD and that C pneumoniae does not play a causative role in complications of atherosclerosis. What it will not do is provide evidence that C pneumoniae does or does not play a role in the initiation or progression of atherosclerosis.
A negative result from the clinical trials will clearly dampen interest in the association of C pneumoniae and atherosclerosis, probably more than it should. The organism will still be present in most atherosclerotic lesions, and the animal studies will be watched for more pro or con data.
A positive result will raise interesting and difficult issues about who should receive antibiotic treatment.
Footnotes
The opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.
References
-
Gupta S, Leatham EW, Carrington D, et
al. Elevated Chlamydia pneumoniae antibodies,
cardiovascular events, and azithromycin in male
survivors of myocardial infarction. Circulation. 1997;96:404–407.
[Abstract/Free Full Text]
-
Grayston JT. Antibiotic treatment of Chlamydia
pneumoniae for secondary prevention of
cardiovascular events. Circulation. 1998;97:1669–1670. Editorial.
[Free Full Text]
-
Anderson JL, Muhlestein JB, Carlquist J, et al.
Randomized secondary prevention trail of azithromycin in patients with
coronary artery disease and serologic evidence for
Chlamydia pneumoniae infection: the Azithromycin in
Coronary Artery Disease: Elimination of Myocardial Infection
With Chlamydia (ACADEMIC) study. Circulation. 1999;100:1540–1547.
[Abstract/Free Full Text]
-
Muhlestein JB, Anderson JL, Carlquist JF, et al.
Randomized secondary prevention trial of azithromycin in patients with
coronary artery disease: primary clinical results of the
ACADEMIC study. Circulation. 2000;12:1755–1760.
-
Dunne M. Wizard and the design of trials for secondary
prevention of atherosclerosis with antibiotics.
Am Heart J. 1999;138:S542–S544.[Medline]
[Order article via Infotrieve]
-
Grayston JT, Jackson LA, Kennedy WJ, et al. Secondary
prevention trials for coronary artery disease with antibiotic
treatment for Chlamydia pneumoniae: design issues. Am
Heart J. 1999;138:S545–S549.[Medline]
[Order article via Infotrieve]
-
Gurfinkel E, Bozovich G, Beck E, et al. Treatment with
the antibiotic roxithromycin patients with acute non-Q-wave
coronary syndromes. Eur Heart J. 1999;20:121–127.
[Abstract/Free Full Text]
-
Saikku P, Mattila K, Nieminen MS, et al. Serological
evidence of an association of a novel Chlamydia, TWAR, with
chronic coronary heart disease and acute myocardial infarction.
Lancet. 1988;2:983–986.[Medline]
[Order article via Infotrieve]
-
Kuo C-C, Shor A, Campbell LA, et al. Demonstration of
Chlamydia pneumoniae in atherosclerotic lesions of
coronary arteries. J Infect Dis. 1993;167:841–849.[Medline]
[Order article via Infotrieve]
-
Grayston, JT. Does Chlamydia pneumoniae
cause atherosclerosis? Arch Surg. 1999;134:930–934.
[Free Full Text]
-
Kol A, Sukhova GK, Lichtman AH, et al. Chlamydia heat
shock protein 60 localizes in human atheroma and regulates
macrophage tumor necrosis factor-
and matrix
metalloproteinase expression. Circulation. 1998;98:300–307.[Abstract/Free Full Text]
-
Kalayoglu MV, Byrne GI. Induction of macrophage
foam cell formation by Chlamydia pneumoniae. J
Infect Dis. 1998;177:725–729.[Medline]
[Order article via Infotrieve]
-
Moazed TC, Kuo C-C, Grayston JT, et al. Evidence of
systemic dissemination of Chlamydia pneumoniae via
macrophages in the mouse. J Infect Dis. 1998;177:1322–1325.[Medline]
[Order article via Infotrieve]
-
Fong IW, Chiu B, Viira E, et al. De novo induction of
atherosclerosis by Chlamydia pneumoniae in a
rabbit model. Infect Immun. 1999;67:6048–6055.
[Abstract/Free Full Text]
-
Muhlestein JB, Anderson JL, Hammond EH, et al.
Infection with Chlamydia pneumoniae accelerates the
development of atherosclerosis and treatment with
azithromycin prevents it in a rabbit model. Circulation. 1998;97:633–636.
[Abstract/Free Full Text]
-
Moazed TC, Campbell LA, Rosenfeld ME, et al.
Chlamydia pneumoniae infection accelerates the progression
of atherosclerosis in apolipoprotein (Apo E)-deficient
mice. J Infect Dis. 199;180:238–241.
This article has been cited by other articles:
 |
|
 |
|
  S. A Voils, M. E Evans, M. T Lane, R. H Schosser, and R. P Rapp Use of Macrolides and Tetracyclines for Chronic Inflammatory Diseases Ann. Pharmacother., January 1, 2005; 39(1): 86 - 94. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Madjid, M. Naghavi, S. Litovsky, and S. W. Casscells Influenza and Cardiovascular Disease: A New Opportunity for Prevention and the Need for Further Studies Circulation, December 2, 2003; 108(22): 2730 - 2736. [Full Text] [PDF]
|
|
|
|
 |
|
 P. Lavallee, V. Perchaud, M. Gautier-Bertrand, D. Grabli, and P. Amarenco Association Between Influenza Vaccination and Reduced Risk of Brain Infarction Stroke, February 1, 2002; 33(2): 513 - 518. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. M. Ridker On Evolutionary Biology, Inflammation, Infection, and the Causes of Atherosclerosis Circulation, January 1, 2002; 105(1): 2 - 4. [Full Text] [PDF]
|
|
|
|
 |
|
 K. Aalto-Setala, K. Laitinen, L. Erkkila, M. Leinonen, M. Jauhiainen, C. Ehnholm, M. Tamminen, M. Puolakkainen, I. Penttila, and P. Saikku Chlamydia pneumoniae Does Not Increase Atherosclerosis in the Aortic Root of Apolipoprotein E-Deficient Mice Arterioscler. Thromb. Vasc. Biol., April 1, 2001; 21(4): 578 - 584. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||