Antibiotic Treatment of Chlamydia pneumoniae after Acute Coronary Syndrome
Christopher P. Cannon, M.D., Eugene Braunwald, M.D., Carolyn H. McCabe, B.S., J. Thomas Grayston, M.D., Brent Muhlestein, M.D., Robert P. Giugliano, M.D., Richard Cairns, M.Sc., Allan M. Skene, Ph.D., for the Pravastatin or Atorvastatin Evaluation and Infection Therapy–Thrombolysis in Myocardial Infarction 22 Investigators
BackgroundChlamydia pneumoniae has been found within atheroscleroticplaques, and elevated titers of antibody to this organism havebeen linked to a higher risk of coronary events. Pilot studieshave suggested that antibiotic treatment may reduce the riskof cardiovascular events.
Methods We enrolled 4162 patients who had been hospitalizedfor an acute coronary syndrome within the preceding 10 daysand evaluated the efficacy of long-term treatment with gatifloxacin,a bactericidal antibiotic known to be effective against C. pneumoniae,in a double-blind, randomized, placebo-controlled trial. Subjectsreceived 400 mg of gatifloxacin daily during an initial 2-weekcourse of therapy that began 2 weeks after randomization, followedby a 10-day course every month for the duration of the trial(mean duration, 2 years), or placebo. The primary end pointwas a composite of death from all causes, myocardial infarction,documented unstable angina requiring rehospitalization, revascularization(performed at least 30 days after randomization), and stroke.
Results A Kaplan–Meier analysis revealed that the ratesof primary-end-point events at two years were 23.7 percent inthe gatifloxacin group and 25.1 percent in the placebo group(hazard ratio, 0.95; 95 percent confidence interval, 0.84 to1.08; P=0.41). No benefit was seen in any of the prespecifiedsecondary end points or in any of the prespecified subgroups,including patients with elevated titers to C. pneumoniae orC-reactive protein.
Conclusions Despite long-term treatment with a bactericidalantibiotic effective against C. pneumoniae, no reduction inthe rate of cardiovascular events was observed.
Although epidemiologic studies have identified numerous riskfactors for atherosclerosis, many patients do not exhibit suchrisk factors, and this has prompted a search for additionalcontributors to the progression of the disease.1 Infection withvarious pathogens has been implicated in the development ofcoronary artery disease. Specifically, Chlamydia pneumoniaehas been associated with a doubling of the risk of atherosclerosisor myocardial infarction.2,3,4,5,6,7 The organism has been detectedin human atheroma,5,6 and animal models have shown that newinfection with C. pneumoniae results in more extensive atherosclerosis.7,8,9,10Although not all studies show a significant relationship betweenIgG titers to C. pneumoniae and coronary events, a meta-analysisof more than 20 studies suggests that such a relationship doesexist.11
Given the potential etiologic relationship between C. pneumoniaeand cardiac events, there has been great interest in the treatmentof patients who have coronary artery disease with antibioticsthat are effective against chlamydia. The results of some initialpilot trials were promising,12,13 but more recent, larger studieshave shown mixed results.14,15,16,17 In the largest study, patientswere treated with azithromycin, a bacteriostatic antibiotic,for three months. Although no benefit was seen after a meanduration of 2.5 years of follow-up, a reduction in the rateof death or myocardial infarction was seen at 6 months,15 suggestingthat long-term treatment with antibiotics might be effectivein the prevention of cardiovascular events. In addition, becauseC. pneumoniae has a unique life cycle that includes a long,dormant intracellular phase, long-term treatment would allowbetter potential eradication of this organism from the vasculature.
Accordingly, the Pravastatin or Atorvastatin Evaluation andInfection Therapy–Thrombolysis in Myocardial Infarction(PROVE IT–TIMI) 22 trial was set up as a two-by-two factorialdesign to compare long-term treatment with gatifloxacin withthat of placebo for the prevention of death or major cardiovascularevents in patients who had recently had an acute coronary syndrome.The study also compared standard and intensive statin therapyfor the reduction of low-density lipoprotein cholesterol; theresults of that comparison have been previously reported.18Gatifloxacin is a quinolone antibiotic with bactericidal activityagainst C. pneumoniae and has been shown to prevent atherosclerosisin an animal model.19
Methods
Patients
As previously described, between November 15, 2000, and December22, 2001, 4162 patients underwent randomization at 349 sitesin eight countries.18 Men and women who were at least 18 yearsof age were eligible for inclusion if they had been hospitalizedfor an acute coronary syndrome — either acute myocardialinfarction (with or without electrocardiographic evidence ofST-segment elevation) or high-risk unstable angina — withinthe preceding 10 days. Patients had to be in stable conditionand were to be enrolled after a percutaneous revascularizationprocedure if one had been planned. Exclusion criteria were aspreviously reported.18 The protocol was approved by the relevantinstitutional review boards, and written informed consent wasobtained from all patients.
Study Protocol
The protocol specified that patients receive standard medicaland interventional treatment, including aspirin at a dose of75 to 325 mg daily, with or without clopidogrel or warfarin,for acute coronary syndromes. Eligible patients underwent randomizationin a 1:1 ratio to receive 400 mg of gatifloxacin daily or placebo,to be administered in a double-blind fashion. Subjects in thegatifloxacin group received an initial 2-week course of therapybeginning at the visit on day 15, followed by a 10-day courseevery month for the duration of the trial. The duration of follow-upranged from 18 to 32 months, with a mean duration of 2 years.In addition, in a two-by-two factorial design, as previouslyreported,18 patients also underwent randomization to receive40 mg of pravastatin or 80 mg of atorvastatin daily.
Patients were seen for follow-up visits at 30 days, 4 months,and every 4 months thereafter until a final visit in Augustor September of 2003. Patients who discontinued treatment withthe study drug during the trial were followed by telephone contact.Blood samples for the measurement of antibodies to C. pneumoniaewere obtained at baseline, at 4 months, and at the final visitand underwent assay at a central core laboratory; samples forthe assay (by Denka Seiken) for high-sensitivity C-reactiveprotein were obtained at these times and also at 30 days. Ina substudy at selected centers, blood samples were obtainedat baseline and at four months for assessment by polymerasechain reaction for the presence of DNA of C. pneumoniae.
The dosage of the study drug could be reduced to a five-daycourse per month if patients had symptoms of drug intolerance,including diarrhea or nausea. The trial continued until reportsof 925 events had been received at the coordinating center,after which all patients were asked to return for a final visit.Eight patients (0.2 percent) were lost to follow-up (Figure 1).20
Figure 1. Numbers of Patients Who Were Randomly Assigned to a Treatment Group, Who Started the Assigned Treatment, and Who Discontinued Treatment or Were Lost to Follow-up.
Treatment was discontinued in 699 patients in the gatifloxacin group and 622 in the placebo group for the following reasons: withdrawal of consent to treatment, 178 in the gatifloxacin group and 169 in the placebo group; withdrawal of consent to follow-up, 26 and 27, respectively (data on these patients were censored at the time they withdrew consent); discovery of a violation in protocol, 14 and 6; abnormality on electrocardiogram, 5 and 3; creatinine clearance of less than 40 milliliters per minute, 0 and 3; need for contraindicated medication, 17 and 20; drug-related side effects, 159 and 106; lack of compliance with protocol requirements, 56 and 58; other adverse events, 158 and 139; and other reasons, 86 and 91.
End Points
The measure of the primary efficacy outcome was the time fromrandomization until the first occurrence of a component of theprimary end point — death from all causes, myocardialinfarction, documented unstable angina that required rehospitalization,revascularization with either percutaneous coronary interventionor coronary-artery bypass surgery (if these procedures wereperformed at least 30 days after randomization), or stroke;the definitions of these events have been previously reported.18Secondary end points were the risk of death from coronary heartdisease, nonfatal myocardial infarction, or revascularization(if performed at least 30 days after randomization) and therisk of death from coronary heart disease or of nonfatal myocardialinfarction, as well as the individual components of the primaryend point. Prespecified subgroup analyses were performed amongpatients with elevated C. pneumoniae antibody titers and accordingto quintiles of C-reactive protein levels at baseline as wellas sex, smoking status, and the presence or absence of diabetesmellitus.
Statistical Analysis
We compared the results of treatment with gatifloxacin withthose of placebo using Kaplan–Meier analyses of eventrates as well as Cox proportional-hazards ratios over the durationof follow-up. On the assumption that there would be a two-yearevent rate of 24 percent in the placebo group during an averageof two years of follow-up, a total of 2000 patients per groupwas considered necessary to yield 925 primary end points andgive the study 94 percent power to detect a 19 percent reductionin the primary end point. This was based on a hypothesis thattreatment with antibiotics would lead to a 20 percent reductionin events; however, because we were starting treatment withthe drug on day 15, and no benefit could be derived before this,a 19 percent overall reduction of risk would be expected. Allocationof treatment was based on a central randomization system inwhich treatment was assigned according to the method of randomizedpermuted blocks of patients, stratified according to center.Two interim assessments of efficacy and safety were carriedout by an independent data and safety monitoring board. Rulesfor early cessation due to the superiority of either treatmentwere not prespecified.
All efficacy analyses were based on the intention-to-treat principle.Estimates of hazard ratios and associated 95 percent confidenceintervals for the comparison of gatifloxacin with placebo wereobtained with the Cox proportional-hazards model, with randomizedtreatment as the covariate and stratification according to statingroup. With the two-by-two factorial design, a test for interactionwith statins was carried out, and no interaction was found withthe groups receiving treatment with statins. The investigatorsdesigned the trial and had free and complete access to the data.The study was designed by the TIMI Study Group. Data coordinationwas performed by the Nottingham Clinical Research Group.18 Investigatorsfrom TIMI, the sponsor, and Nottingham performed data analysisjointly, and all groups vouch for the data.
Results
The two groups of enrolled patients were similar (Table 1).Their average age was 58 years, and 22 percent were women. Beforetheir index event, 38 percent of patients had evidence of previouscardiovascular disease, and 18 percent had diabetes mellitus.As their index event, approximately one third had high-riskunstable angina, one third had myocardial infarction associatedwith electrocardiographic ST-segment elevation, and one thirdhad myocardial infarction without such elevation. Sixty-ninepercent of patients had undergone percutaneous coronary interventionfor treatment of their index acute coronary syndrome beforerandomization. Concomitant medications were administered topatients during the treatment period as follows: aspirin, 93percent; warfarin, 8 percent; clopidogrel or ticlodipine, 72percent initially and 20 percent at one year; beta-blockers,85 percent; angiotensin-converting–enzyme (ACE) inhibitors,69 percent; and angiotensin-receptor blockers, 14 percent. Thestudy drug was administered for an average of 1.6 years in thegatifloxacin group and 1.7 years in the placebo group. By oneyear, 74.4 percent of patients in the gatifloxacin group and80.0 percent of those in the placebo group were taking the studydrug. There were 3025 and 3272 patient-years of exposure togatifloxacin and placebo, respectively.
Table 1. Baseline Characteristics of the Patients.
For all randomized patients, Kaplan–Meier estimates ofthe event rates for the primary end point at two years were23.7 percent in the gatifloxacin group and 25.1 percent in theplacebo group (Figure 2), representing a hazard ratio of 0.95(95 percent confidence interval, 0.84 to 1.08; P=0.41). Therisk associated with the secondary end point of death due tocoronary heart disease, myocardial infarction, or revascularizationalso was not significantly reduced among patients receivinggatifloxacin, with a rate of 20.4 percent as compared with 21.6percent among those receiving placebo (hazard ratio, 0.95; 95percent confidence interval, 0.84 to 1.09; P=0.48). The riskof death due to coronary heart disease or myocardial infarctionwas also not significantly reduced in the gatifloxacin group,at 7.6 percent as compared with 8.0 percent in the placebo group(hazard ratio, 0.97; P=0.78). There was no reduction in theindividual components of the primary end point among patientstreated with gatifloxacin (Figure 3).
Figure 3. Risk Reduction for Death or a Major Cardiovascular Event and Event Rates at Two Years.
Squares denote hazard ratios, and horizontal lines 95 percent confidence intervals. The primary end point was defined as a composite of death from all causes, myocardial infarction, documented unstable angina requiring rehospitalization, revascularization (performed at least 30 days after randomization), and stroke. Percent change in risk was calculated from hazard ratios.
No benefit from gatifloxacin was observed among prespecifiedclinical subgroups in terms of either the primary end point(Figure 4) or the secondary end point of death from coronaryheart disease or myocardial infarction (data not shown). Testingof baseline IgG antibody titers to C. pneumoniae did not identifya subgroup of patients who benefited from antibiotic treatment(Figure 4), including the 5 percent of patients who had thehighest baseline titers (greater than 1:512) (data not shown).There was no effect of gatifloxacin on antibody titers overthe trial period. In the placebo group, there was a decreasein antibody titers over time, with the percentage of patientsin whom titers were elevated falling from 64.6 percent at baselineto 52.4 percent at the final visit (P<0.001). An identicalpattern was seen in the gatifloxacin group, with a fall from64.0 percent at baseline to 53.5 percent at the final visit(P<0.001). The P value for interaction was not significant,and thus treatment with gatifloxacin did not influence antibodytiters to C. pneumoniae. In the substudy that assessed the presenceof DNA for C. pneumoniae in peripheral mononuclear blood cells,only 6 of 171 patients in the placebo group (3.5 percent) and6 of 172 in the gatifloxacin group (3.5 percent) were positiveat baseline. At four months, among 80 patients who receivedgatifloxacin and 89 who received placebo with follow-up bloodsamples, 3 (3.8 percent) and 4 (4.5 percent), respectively,were positive (P not significant).
Figure 4. Hazard Ratios for Death or a Major Cardiovascular Event, with Two-Year Event Rates, According to Baseline Characteristics.
Squares denote hazard ratios, and horizontal lines 95 percent confidence intervals. None of the tests for interaction were significant. The median C-reactive protein level was 12.1 mg per liter.
Use of levels of C-reactive protein at baseline to define subgroupsaccording to either the median level of 12.1 mg per liter (Figure 4)or according to quintile did not identify any subgroups thathad a benefit from gatifloxacin. Over the duration of the trial,there were no differences in achieved C-reactive protein levelsbetween patients receiving gatifloxacin and those receivingplacebo; in each group, the level was 1.7 mg per liter at fourmonths and 1.8 mg per liter at the final visit (P not significantfor either time).
Tolerability and Safety
As expected, the side effects of diarrhea and nausea or vomitingassociated with antibiotic treatment were significantly morecommon among patients receiving gatifloxacin (8.1 percent haddiarrhea, and 7.3 percent nausea or vomiting; P=0.01) than amongthose receiving placebo (6.1 percent and 5.5 percent, respectively;P=0.02). Slight changes in blood glucose levels were noted inthe gatifloxacin group, as previously reported with this agent.21Among patients who did not have diabetes mellitus at baseline,new-onset diabetes (defined as the presence of one or more nonfastingserum glucose values of 200 mg per deciliter, two or more nonfastingserum glucose values of 140 mg per deciliter, or two or morefasting serum glucose values of 126 mg per deciliter) tendedto develop more frequently in patients treated with gatifloxacinthan in those given placebo (4.6 percent vs. 3.4 percent, P=0.08).Among patients with diabetes, there were trends toward morepatients who were treated with gatifloxacin having episodesof hyperglycemia than patients who were treated with placebo(30.7 percent vs. 25.4 percent, P=0.11) and toward more patientswho were treated with gatifloxacin having episodes of hypoglycemia(2.6 percent vs. 1.5 percent, P=0.32). Conversely, fewer upperrespiratory tract infections developed in patients receivingthe monthly courses of gatifloxacin than in patients receivingplacebo (10.9 percent vs. 14.8 percent, P<0.001), and fewersinus infections developed in patients in the gatifloxacin groupthan in those in the placebo group (4.6 percent vs. 6.5 percent,P=0.01).
Discussion
Although there is evidence to suggest that C. pneumoniae hasa role in the development of atherosclerosis, we were not ableto detect a benefit from long-term antibiotic therapy in patientswho had recently been hospitalized for an acute coronary syndrome.These results are in agreement with those of Grayston et al.,reported elsewhere in this issue of the Journal.22 There wasno reduction in the primary end point, the secondary end points,or any of the individual components of the primary end pointas a result of antibiotic treatment. None of the prespecifiedsubgroups, distinguished by high-risk clinical characteristics,C-reactive protein levels, antibody titers to C. pneumoniae,or the presence of C. pneumoniae within peripheral mononuclearblood cells, showed any benefit from the antibiotic treatment.Thus, our findings suggest that for patients who have had arecent acute coronary syndrome and who have established cardiovasculardisease, antibiotic therapy is not effective in reducing therisk of recurrent cardiovascular events. When these findingsare juxtaposed with the significant benefit of intensive statintherapy as compared with standard statin therapy that was observedin the same trial,18 the results reinforce the importance ofusing proven therapies for secondary prevention in this population.
Our trial differed from prior studies of antibiotics12,13,14,15,16,17in that it involved a large number of high-risk patients withacute coronary syndromes, among whom more than 1000 primaryend points were observed; the trial thus had a more than 97percent power to detect (or rule out) a benefit from antibiotictreatment of 19 percent and an 85 percent power to detect (orrule out) a benefit of 17 percent. In addition, we continuedantibiotic treatment longer than any of the prior trials, usingmonthly courses of therapy throughout the two-year durationof the trial. We studied patients with acute coronary disease,the severity of which, it had been thought, would allow C. pneumoniaeto be potentially active within coronary lesions. Finally, full-dosegatifloxacin, a bactericidal quinolone antibiotic known to bedestructive to C. pneumoniae, was used, in contrast to the bacteriostaticmacrolide antibiotics that were used in prior studies. Despitethe long-term, full-dose antibiotic treatment, no reductionin cardiac events was observed with antibiotic treatment inpatients who had recently been hospitalized for an acute coronarysyndrome.
In determining the potential reasons why antibiotic treatmentwas not effective, we assessed disease activity in several ways.The substudies point to an absence of active infection in themiddle-aged patients with established coronary disease who wereenrolled. With the use of serial antibodies to C. pneumoniae,no increase in titers was observed, as would be expected ifpatients had active infection with the organism. These findingswere supported by the substudy that found that only 4 percentof patients had evidence of C. pneumoniae in their mononuclearblood cells (a marker that has been shown in other studies tobe well correlated with the presence of C. pneumoniae in arterialplaque).2,23 Finally, there was no effect of antibiotic treatmenton levels of C-reactive protein, a marker of inflammation, whichmight have been elevated by C. pneumoniae. Thus, the overallclinical results and the results of the three substudies withinthe trial suggest that patients were not actively infected withC. pneumoniae and that, accordingly, antibiotic therapy hadno detectable effect.
Because the serologic and pathological evidence supports thelikelihood of prior infection and the presence of C. pneumoniaewithin arterial plaque, it is possible that infection with C.pneumoniae is part of the initiation of atherosclerosis in theearly decades of life but not an active part of the progressionof disease later, when patients have established coronary arterydisease. Indeed, the animal model that has shown a benefit ofantibiotic therapy with either azithromycin or gatifloxacinis that of cholesterol-fed rabbits, in which antibiotic treatmentat the time of initial infection can reduce the developmentof atherosclerosis.7,19 No model of established vascular diseasehas been used to show that the use of antibiotics reverses orslows the progression of the disease. The situation may be similarto that of other infections such as those involving the Epstein–Barrvirus, which is a well-established cause of Burkitt's lymphoma.However, among patients in whom the lymphoma develops, treatmentis not with antiviral agents but, rather, with chemotherapeuticagents. Thus, it is possible that C. pneumoniae is a cause ofearly atherosclerosis but that once the process is established,with the appearance of cholesterol-laden plaque and inflammation,therapy with antichlamydial antibiotics is not effective.
Accordingly, the two components of the PROVE IT–TIMI 22trial highlight the proven benefit of intensive statin therapyafter acute coronary syndromes, as recently advocated in anupdate to the guidelines of the National Cholesterol EducationProgram.24 Efforts toward secondary prevention in patients withthese syndromes should be aimed at proven therapies, includingantiplatelet therapy, treatment with beta-blockers and ACE inhibitors,and intensive lowering of lipid levels with the use of statins.
Supported by Bristol-Myers Squibb and Sankyo.
Dr. Cannon reports having received grant support from AstraZeneca,Bristol-Myers Squibb, Merck, and Sanofi–Aventis and havingserved on paid advisory boards for AstraZeneca, Bristol-MyersSquibb, GlaxoSmithKline, Pfizer, Sanofi–Aventis, and theMerck–Schering-Plough partnership. Dr. Braunwald reportshaving received grant support from Sanofi–Aventis andBristol-Myers Squibb. Ms. McCabe reports having received grantsupport from AstraZeneca, Sanofi–Aventis, and Bristol-MyersSquibb. The Azithromycin and Coronary Events Study, for whichDr. Grayston was the principal investigator, received partialgrant support from Pfizer. Dr. Muhlestein reports having receivedgrant support from and having served on paid advisory boardsfor Bristol-Myers Squibb. Dr. Giugliano reports having receivedlecture fees from Bristol-Myers Squibb.
Source Information
From the Thrombolysis in Myocardial Infarction Study Group, Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston (C.P.C., E.B., C.H.M., R.P.G.); the Department of Epidemiology, University of Washington, Seattle (J.T.G.); LDS Hospital, Salt Lake City (B.M.); and Nottingham Clinical Research Group, Nottingham, United Kingdom (R.C., A.M.S.).
Address reprint requests to Dr. Cannon at the TIMI Study Group, Cardiovascular Division, Brigham and Women's Hospital, 75 Francis St., Boston, MA 02115, or at cpcannon{at}partners.org.
References
Libby P, Ridker PM, Maseri A. Inflammation and atherosclerosis. Circulation 2002;105:1135-1143. [Free Full Text]
Danesh J, Collins R, Peto R. Chronic infection and coronary heart disease: is there a link? Lancet 1997;350:430-436. [CrossRef][Web of Science][Medline]
Libby P, Egan D, Skarlatos S. Roles of infectious agents in atherosclerosis and restenosis: an assessment of the evidence and need for future research. Circulation 1997;96:4095-4103. [Free Full Text]
Kuo CC, Shor A, Campbell LA, Fukushi H, Patton DL, Grayston JT. Demonstration of Chlamydia pneumoniae in atherosclerotic lesions of coronary arteries. J Infect Dis 1993;167:841-849. [Web of Science][Medline]
Muhlestein JB, Hammond EH, Carlquist JF, et al. Increased incidence of Chlamydia species within the coronary arteries of patients with symptomatic atherosclerotic versus other forms of cardiovascular disease. J Am Coll Cardiol 1996;27:1555-1561. [Abstract]
Kuo CC, Grayston JT, Campbell LA, Goo YA, Wissler RW, Benditt EP. Chlamydia pneumoniae (TWAR) in coronary arteries of young adults (15-34 years old). Proc Natl Acad Sci U S A 1995;92:6911-6914. [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. [Free Full Text]
Fong IW, Chiu B, Viira E, Fong MW, Jang D, Mahony J. Rabbit model for Chlamydia pneumoniae infection. J Clin Microbiol 1997;35:48-52. [Free Full Text]
Moazed TC, Campbell LA, Rosenfeld ME, Grayston JT, Kuo CC. Chlamydia pneumoniae infection accelerates the progression of atherosclerosis in apolipoprotein E-deficient mice. J Infect Dis 1999;180:238-241. [CrossRef][Web of Science][Medline]
Danesh J, Whincup P, Walker M, et al. Chlamydia pneumoniae IgG titres and coronary heart disease: prospective study and meta-analysis. BMJ 2000;321:208-213. [Free Full Text]
Danesh J, Whincup P, Walker M, et al. Low grade inflammation and coronary heart disease: prospective study and updated meta-analyses. BMJ 2000;321:199-204. [Free Full Text]
Gupta S, Leathan EW, Carrington D, Mendall MA, Kaski JC, Camm AJ. Elevated Chlamydia pneumoniae antibodies, cardiovascular events, and azithromycin in male survivors of myocardial infarction. Circulation 1997;96:404-407. [Free Full Text]
Gurfinkel E, Bozovich G, Daroca A, Beck E, Mautner B. Randomised trial of roxithromycin in non-Q-wave coronary syndromes: ROXIS Pilot Study. Lancet 1997;350:404-407. [CrossRef][Web of Science][Medline]
Neumann F, Kastrati A, Miethke T, et al. Treatment of Chlamydia pneumoniae infection with roxithromycin and effect on neointima proliferation after coronary stent placement (ISAR-3): a randomised, double-blind, placebo-controlled trial. Lancet 2001;357:2085-2089. [CrossRef][Web of Science][Medline]
O'Connor CM, Dunne MW, Pfeffer MA, et al. Azithromycin for the secondary prevention of coronary heart disease events: the WIZARD study: a randomized controlled trial. JAMA 2003;290:1459-1466. [Free Full Text]
Cercek B, Shah PK, Noc M, et al. Effect of short-term treatment with azithromycin on recurrent ischaemic events in patients with acute coronary syndrome in the Azithromycin in Acute Coronary Syndrome (AZACS) trial: a randomised controlled trial. Lancet 2003;361:809-813. [CrossRef][Web of Science][Medline]
Zahn R, Schneider S, Frilling B, et al. Antibiotic therapy after acute myocardial infarction: a prospective randomized study. Circulation 2003;107:1253-1259. [Free Full Text]
Cannon CP, Braunwald E, McCabe CH, et al. Intensive versus moderate lipid lowering with statins after acute coronary syndromes. N Engl J Med 2004;350:1495-1504. [Free Full Text]
Jones HU, Muhlestein JB, Lim TH, et al. Short-term therapy with gatifloxacin or azithromycin prevents the acceleration of atherosclerosis after infection with Chlamydia pneumoniae in a rabbit model but does not eradicate the organism from plaque. J Am Coll Cardiol 2003;41:289A-289A. abstract.
Wang SP, Kuo CC, Grayston JT. Formalinized Chlamydia trachomatis organisms as antigen in the micro-immunofluorescence test. J Clin Microbiol 1979;10:259-261. [Free Full Text]
Gajjar DA, LaCreta FP, Kollia GD, et al. Effect of multiple-dose gatifloxacin or ciprofloxacin on glucose homeostasis and insulin production in patients with noninsulin-dependent diabetes mellitus maintained with diet and exercise. Pharmacotherapy 2000;20:76S-86S. [CrossRef][Web of Science][Medline]
Grayston JT, Kronmal RA, Jackson LA, et al. Azithromycin for the secondary prevention of coronary events. N Engl J Med 2005;352:1637-1645. [Free Full Text]
Juvonen J, Juvonen T, Laurila A, et al. Demonstration of Chlamydia pneumoniae in the walls of abdominal aortic aneurysms. J Vasc Surg 1997;25:499-505. [CrossRef][Web of Science][Medline]
Grundy SM, Cleeman JI, Merz CNB, et al. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines. Circulation 2004;110:227-239. [Free Full Text]
Chlamydia pneumoniae and Acute Coronary Syndrome
Wong B. Y.L., Gnarpe J., Mitchell W. M., Stratton C. W., Frothingham R., Paul M., Fraser A., Leibovici L., Grayston J. T., Cannon C. P., the ACES Investigators , the PROVE IT–TIMI 22 Investigators
Extract |
Full Text |
PDF
N Engl J Med 2005;
353:525-528, Aug 4, 2005.
Correspondence
This article has been cited by other articles:
Hogh, A., Vammen, S., Ostergaard, L., Joensen, J. B., Henneberg, E. W., Lindholt, J. S.
(2009). Intermittent Roxithromycin for Preventing Progression of Small Abdominal Aortic Aneurysms: Long-Term Results of a Small Clinical Trial. VASC ENDOVASCULAR SURG
43: 452-456
[Abstract]
Chen, C., Chai, H., Wang, X., Lin, P. H., Yao, Q.
(2009). Chlamydia heat shock protein 60 decreases expression of endothelial nitric oxide synthase in human and porcine coronary artery endothelial cells. Cardiovasc Res
83: 768-777
[Abstract][Full Text]
Nieto, F J.
(2009). Commentary: Understanding the pathophysiology of poverty. Int J Epidemiol
38: 787-790
[Full Text]
Jaff, M. R., Dale, R. A., Creager, M. A., Lipicky, R. J., Constant, J., Campbell, L. A., Hiatt, W. R.
(2009). Anti-Chlamydial Antibiotic Therapy for Symptom Improvement in Peripheral Artery Disease: Prospective Evaluation of Rifalazil Effect on Vascular Symptoms of Intermittent Claudication and Other Endpoints in Chlamydia pneumoniae Seropositive Patients (PROVIDENCE-1). Circulation
119: 452-458
[Abstract][Full Text]
Lamontagne, F. MD MSc, Garant, M.-P. PhD, Carvalho, J.-C. MD, Lanthier, L. MD MSc, Smieja, M. MD PhD, Pilon, D. MD MSc
(2008). Pneumococcal vaccination and risk of myocardial infarction. CMAJ
179: 773-777
[Abstract][Full Text]
Volanen, I., Kallio, K., Saarinen, M., Jarvisalo, M. J., Vainionpaa, R., Ronnemaa, T., Viikari, J., Marniemi, J., Simell, O., Raitakari, O. T.
(2008). Arterial Intima-Media Thickness in 13-Year-Old Adolescents and Previous Antichlamydial Antimicrobial Use: A Retrospective Follow-up Study. Pediatrics
122: e675-e681
[Abstract][Full Text]
Alamowitch, S, Labreuche, J, Touboul, P-J, Eb, F, Amarenco, P, for the GENIC Investigators,
(2008). Chlamydia pneumoniae seropositivity in aetiological subtypes of brain infarction and carotid atherosclerosis: a case control study. J. Neurol. Neurosurg. Psychiatry
79: 147-151
[Abstract][Full Text]
Spagnoli, L. G., Pucci, S., Bonanno, E., Cassone, A., Sesti, F., Ciervo, A., Mauriello, A.
(2007). Persistent Chlamydia pneumoniae Infection of Cardiomyocytes Is Correlated with Fatal Myocardial Infarction. Am. J. Pathol.
170: 33-42
[Abstract][Full Text]
Napoli, C., Lerman, L. O., de Nigris, F., Gossl, M., Balestrieri, M. L., Lerman, A.
(2006). Rethinking Primary Prevention of Atherosclerosis-Related Diseases. Circulation
114: 2517-2527
[Full Text]
Ahmed, S., Cannon, C. P., Murphy, S. A., Braunwald, E.
(2006). Acute coronary syndromes and diabetes: is intensive lipid lowering beneficial? Results of the PROVE IT-TIMI 22 trial. Eur Heart J
27: 2323-2329
[Abstract][Full Text]
Burman, W. J., Goldberg, S., Johnson, J. L., Muzanye, G., Engle, M., Mosher, A. W., Choudhri, S., Daley, C. L., Munsiff, S. S., Zhao, Z., Vernon, A., Chaisson, R. E., and the Tuberculosis Trials Consortium,
(2006). Moxifloxacin versus Ethambutol in the First 2 Months of Treatment for Pulmonary Tuberculosis. Am. J. Respir. Crit. Care Med.
174: 331-338
[Abstract][Full Text]
Hankey, G. J.
(2006). Potential New Risk Factors for Ischemic Stroke: What Is Their Potential?. Stroke
37: 2181-2188
[Abstract][Full Text]
Goldstein, L. B., Adams, R., Alberts, M. J., Appel, L. J., Brass, L. M., Bushnell, C. D., Culebras, A., DeGraba, T. J., Gorelick, P. B., Guyton, J. R., Hart, R. G., Howard, G., Kelly-Hayes, M., Nixon, J.V., Sacco, R. L.
(2006). Primary Prevention of Ischemic Stroke: A Guideline From the American Heart Association/American Stroke Association Stroke Council: Cosponsored by the Atherosclerotic Peripheral Vascular Disease Interdisciplinary Working Group; Cardiovascular Nursing Council; Clinical Cardiology Council; Nutrition, Physical Activity, and Metabolism Council; and the Quality of Care and Outcomes Research Interdisciplinary Working Group: The American Academy of Neurology affirms the value of this guideline.. Circulation
113: e873-e923
[Abstract][Full Text]
Goldstein, L. B., Adams, R., Alberts, M. J., Appel, L. J., Brass, L. M., Bushnell, C. D., Culebras, A., DeGraba, T. J., Gorelick, P. B., Guyton, J. R., Hart, R. G., Howard, G., Kelly-Hayes, M., Nixon, J.V., Sacco, R. L.
(2006). Primary Prevention of Ischemic Stroke: A Guideline From the American Heart Association/American Stroke Association Stroke Council: Cosponsored by the Atherosclerotic Peripheral Vascular Disease Interdisciplinary Working Group; Cardiovascular Nursing Council; Clinical Cardiology Council; Nutrition, Physical Activity, and Metabolism Council; and the Quality of Care and Outcomes Research Interdisciplinary Working Group: The American Academy of Neurology affirms the value of this guideline.. Stroke
37: 1583-1633
[Abstract][Full Text]
Roth-Cline, M. D.
(2006). Clinical Trials in the Wake of Vioxx: Requiring Statistically Extreme Evidence of Benefit to Ensure the Safety of New Drugs. Circulation
113: 2253-2259
[Full Text]
Scirica, B. M., Morrow, D. A., Verma, S., Devaraj, S., Jialal, I., Scirica, B. M., Morrow, D. A., Verma, S., Devaraj, S., Jialal, I.
(2006). The Verdict Is Still Out. Circulation
113: 2128-2151
[Full Text]
Tedgui, A., Mallat, Z.
(2006). Cytokines in Atherosclerosis: Pathogenic and Regulatory Pathways. Physiol. Rev.
86: 515-581
[Abstract][Full Text]
Park-Wyllie, L. Y., Juurlink, D. N., Kopp, A., Shah, B. R., Stukel, T. A., Stumpo, C., Dresser, L., Low, D. E., Mamdani, M. M.
(2006). Outpatient Gatifloxacin Therapy and Dysglycemia in Older Adults. NEJM
354: 1352-1361
[Abstract][Full Text]
Njamnshi, A. K., Blackett, K. N., Mbuagbaw, J. N., Gumedze, F., Gupta, S., Wiysonge, C. S.
(2006). Chronic Chlamydia pneumoniae Infection and Stroke in Cameroon: A Case-Control Study. Stroke
37: 796-799
[Abstract][Full Text]
Jespersen, C. M, Als-Nielsen, B., Damgaard, M., Hansen, J. F., Hansen, S., Helo, O. H, Hildebrandt, P., Hilden, J., Jensen, G. B, Kastrup, J., Kolmos, H. J., Kjoller, E., Lind, I., Nielsen, H., Petersen, L., Gluud, C., CLARICOR Trial Group,
(2006). Randomised placebo controlled multicentre trial to assess short term clarithromycin for patients with stable coronary heart disease: CLARICOR trial. BMJ
332: 22-27
[Abstract][Full Text]
Johnston, S. C., Zhang, H., Messina, L. M., Lawton, M. T., Dean, D.
(2005). Chlamydia pneumoniae Burden in Carotid Arteries Is Associated With Upregulation of Plaque Interleukin-6 and Elevated C-Reactive Protein in Serum. Arterioscler. Thromb. Vasc. Bio.
25: 2648-2653
[Abstract][Full Text]
Gotto, A. M. Jr
(2005). Evolving Concepts of Dyslipidemia, Atherosclerosis, and Cardiovascular Disease: The Louis F. Bishop Lecture. J Am Coll Cardiol
46: 1219-1224
[Full Text]
Giugliano, R. P., Braunwald, E.
(2005). The Year in Non--ST-Segment Elevation Acute Coronary Syndromes. J Am Coll Cardiol
46: 906-919
[Full Text]
Espinola-Klein, C., Blankenberg, S., Munzel, T.
(2005). Editorial Comment--Is Heme Oxygenase-1 a Causal Player for Plaque Stability?. Stroke
36: 1901-1903
[Full Text]
Taylor-Robinson, D., Boman, J.
(2005). The failure of antibiotics to prevent heart attacks. BMJ
331: 361-362
[Full Text]
Wong, B. Y.L., Gnarpe, J., Mitchell, W. M., Stratton, C. W., Frothingham, R., Paul, M., Fraser, A., Leibovici, L., Grayston, J. T., Cannon, C. P., the ACES Investigators, , the PROVE IT-TIMI 22 Investigators,
(2005). Chlamydia pneumoniae and Acute Coronary Syndrome. NEJM
353: 525-528
[Full Text]
Williams, K. J., Tabas, I.
(2005). Lipoprotein Retention--and Clues for Atheroma Regression. Arterioscler. Thromb. Vasc. Bio.
25: 1536-1540
[Abstract][Full Text]
Malik, I.
(2005). JournalScan. Heart
91: 991-992
[Full Text]
Andraws, R., Berger, J. S., Brown, D. L.
(2005). Effects of Antibiotic Therapy on Outcomes of Patients With Coronary Artery Disease: A Meta-analysis of Randomized Controlled Trials. JAMA
293: 2641-2647
[Abstract][Full Text]
Ajijola, O. A., Goldschmidt-Clermont, P. J., Satterwhite, L. L.
(2005). CD40 Ligand: Not Bad to the Bone (Marrow), After All. Arterioscler. Thromb. Vasc. Bio.
25: 1088-1090
[Full Text]
(2005). No CHD Secondary-Prevention Benefit of Gatifloxacin. Journal Watch Cardiology
2005: 4-4
[Full Text]
(2005). Cardiac Events Unaffected by Antibiotic Treatment for Chlamydia pneumoniae. JWatch Infect. Diseases
2005: 2-2
[Full Text]
(2005). Antibiotic Treatment Fails Again in Coronary Disease. JWatch General
2005: 2-2
[Full Text]
Grayston, J. T., Kronmal, R. A., Jackson, L. A., Parisi, A. F., Muhlestein, J. B., Cohen, J. D., Rogers, W. J., Crouse, J. R., Borrowdale, S. L., Schron, E., Knirsch, C., the ACES Investigators,
(2005). Azithromycin for the Secondary Prevention of Coronary Events. NEJM
352: 1637-1645
[Abstract][Full Text]
Hansson, G. K.
(2005). Inflammation, Atherosclerosis, and Coronary Artery Disease. NEJM
352: 1685-1695
[Full Text]
Anderson, J. L.
(2005). Infection, Antibiotics, and Atherothrombosis -- End of the Road or New Beginnings?. NEJM
352: 1706-1709
[Full Text]
200 mg per deciliter, two or more nonfasting serum glucose values of 
Previous
