Antibiotic Trials for Coronary Heart Disease - Lab Report Example

Literature critique Literature Critique Antibiotic Trials for Coronary Heart disease Background Information and Problem statement Atherosclerosis is an inflammatory disease and it was believed that high plasma concentrations of cholesterol particularly that of low-density lipoprotein cholesterol was the principal risk factor for atherosclerosis (Rusell, 1999). The possibility that various microbial agents may trigger a cascade of reactions leading to inflammation, atherogenesis, and thrombotic events in vascular system by chronic infection with various agents like Chlamydia pneumoniae, Helicobacter pylori etc. have been implicated in the pathogenesis of coronary artery disease (CAD) (Vijayvergiya, 2007). This interest has been stimulated by the frequent finding of bacterial antigen and occasionally recoverable organism within human atherosclerotic plaque and by seroepidemiologic studies. (Anderson & Muhlestein, 2004) Article Purpose Discussion Atherosclerosis is a disease of epidemic proportions in the western world. Hence a lot of studies have been directed towards this disease till date. Small pilot studies conducted showed a strong association of C. pneuminiae IgG antibody with clinical atherosclerosis. Morever, animal studies have demonstrated the ability of active infection with C. pneumoniae to stimulate or accelerate, and antibiotics to prevent, atherosclerosis ( Anderson & Muhlestein, 2004). This directed the need to study pathogenesis of this disease. This article reviews the various trials conducted and critique the methodologies used and recommends areas of future research. Hypothesis statement C. pneumoniae plays a causative role in artherosclerosis and that antibiotic treatment directed against C. pneumoniae will decrease complications of atherosclerosis. Research design and Method discussion.( Anderson & Muhlestein, 2004) In an initial pilot level study, 60 patients with acute MI and elevated C.pneumoniae antibody titer (>/=1:64) were randomly separated into two groups, one received a placebo and other a three day course of azithromycin (500mg/day), or 2 courses 3 months apart.A relatively small study called ACADEMIC (Azithromycin in Coronary Artery Disease:Elimination of Myocardial Infection with Chlamydia) trial performed on 302 patients with ACS and seropositive for C. pneumoniae was conducted in USA. The patients were randomized to placebo or azithromycin 500 mg/ day for three days followed by 500mg/ week for three months. On the basis of the results of ACADEMIC trial in USA, Gupta etal designed a study with 60 patients in UK. These patients were survivors of Acute Myocardial Infarction (MI) and elevated antibody titers against Chlamydia. Another trial called STAMINA (The South Thames trial of Antibiotics in Myocardial Infarction and unstable angina) (n=325) addressed both C.pneumoniae and H.pylori . Multiple drug therapy using amoxicillin (500mg/day) for H.pylori and azithromycin(500mg/day) for C.pneumoniae . both combined with metronidazole (400 mg twice a day )and omeperazole( 20mg twice a day )was administered to the patients. Follow up of this trial extended for one year. There were two more large and intermediate size trials made with randomized patient groups of ACS viz. AZACS and CLARIFY. AZACS (Azithromycin in acute coronary syndrome) This trial involved 1450 patients in Los Angeles and this trial recruited patients regardless of their serostatus for Chlamydia infection. treatment with azithromycin.was given for 5- days and duration of follow up was 6-months. Another trial CLARIFY (Clarithromycin in Acute Coronary syndrome patients in Finland) also studied the effect of antibiotic therapy on the secondary prevention of ACS on 148 patients. The patient selection criteria was subjects with acute non-Q-wave MI or unstable angina . These patients were randomized to blinded therapy with either clarithromycin or placebo for three months. The primary endpoint was composite of death, MI, or unstable angina during treatment; and the secondary endpoints was occurrence of any cardiovascular events during the entire follow- up period (average,555 days; range,138-924 days). Two Large trials ACES (Azithromycin and Coronary event study) and PROVE-IT (Pravastatin or Atorvastatin Evaluation and Infection therapy) were carried out on Coronary Heart Disease (CHD) patients. ACES (Azithromycin and coronary event study) trial does not require seropositivity to C.pneumoniae,although serological results were assessed. Participants are randomized to azithromycin 600 mg orally once a week for 1 year or placebo. Follow up of cases was carried out for four years. The primary end point was characterized by CHD death, non fatal MI, hospitalization for coronary revascularization . Secondary objective of the study was to evaluate relationships among antibody titres, inflammatory markers, treatment status and outcomes. A yet another large trial called PROVE-IT ( Pravastatin or Atorvastatin Evaluation and Infection therapy) enrolled over 3000 patients who presented with ACS. Randomization followed a 2x2 factorial design. Treatment included one of the two statin regimen pravastatin or atorvastatin and intermittent courses of gatifloxacin or placebo. The primary end-points is a composite of major cardiovascular clinical effects after at least 18 months of follow up. WIZARD (Weekly Intervention of Zithromax for Atherosclerosis and its related Disorders) trial enrolled over 7724 stable patients with a history of MI and seropositivity to C.pneumoniae and randomized them to recive either placebo or 3 months of treatment with azithromycin (600mg/week).The primary endpoint was a composite of death, MI, hospitalization for unstable angina or need for repeat revascularization at 3 years. ANTIBIO (Antibiotic therapy after Acute Myocardial Infarction) trials examined treatment with roxithromycin (a macrolide antibiotic) versus placebo for 6 weeks in 872 patients with acute MI. In this case the study end point was death. The ISAR-3 (Intracoronary Stenting and Antibiotic Regimen 3) study investigated roxithromycin, an effective anti-chlamydia macrolide for the prevention of restonosis after coronary stent deployment. A total of 1010 patients who had undergone successful coronary stenting were randomized to receive roxithromycin 300 mg daily for 4 weeks or placebo. The primary endpoint was the frequency of restenosis (>50%) at 6-month follow-up angiography. A secondary end-point was target vessel revascularization during the year after stenting. In all the above trails the study design can be affected by confounding variables like previous use of antibiotics. Hence the researchers have carried out randomization of the control and test group on sufficiently large number of subject so that all confounding variables will be equally distributed across all study groups. There can be other potential sources leading to performance bias like negative out comes can be explained not only by incorrect hypothesis that is infection does not cause CHD but also by inadequate study size or design or by ineffective antibiotic regimen to the target organism. Negative results can also be an outcome of reactivation of C. pneumoniae from a persistent state, stimulation of pro-inflammatory mediator production or promotion of atherosclerosis can occur despite an effective course of antibiotics as a result of targeting the wrong stages of disease (late versus early, acute versus chronic). Wrong population tested better markers needed to predict active or latent atherogenic infection amenable to therapy. One of the major flaw in the sample characteristic is that all the above mentioned trials have recruited patients with C.pneumoniae antibody titre. But about 80%-90% of people with CAD have C.pneumoniae antibody. Thus few patients would be excluded from the subject pool by antibody test. Also several investigations have shown that some persons without antibody have C.pneumoniae in their arthematous lesions. However this flaw has been masked in most of the trials by using high titre antibody as a marker. Use of correct antibiotic is crucial to design the study. Chlamydia pneumoniae are sensitive to macrolides, tetracyclines and fluoroquinolines and hence these antibiotics are directed against C. pneumoniae which is considerd as a causal factor for coronary and extra coronary atherosclerosis. Animal models have shown that azithromycin is readily taken into atherosclerotic plaque. Also it is a broad spectrum antibiotic and a single dose of azithromycin takes 10 days for elimination, it is well tolerated during prophylaxis treatment hence Azithromycin is widely used in most of the trials. It is important to correctly define the length of treatment, short periods of trial are inadequate for lasting benefits. Chlamydia is infectious non-replicating form and is not susceptible to action of antibiotics the elementary body of the organism may exist in body for weeks or longer and cause new cellular infection although short term treatment might kill replicating organisms in atheroma and temporarily reduce inflammation it would be unlikely to eliminate the organism from the system. While determining the length of the treatment safety of the subject has to be considered. Length of treatment should be adequate to determine if a favorable outcome of experiment is found. Analysis and Interpretation of Data discussion. In some pilot studies it was found that at the end of three months the antibody titre of patients receiving antibiotic decreased as compared to the placebo treated group and also showed apparent reduction in cardiac problems. This encouraged further trials in this direction. ACADEMIC trial examined 302 seropositive individuals treated to azithromycin or placebo for three months. It showed about 20% to 30% reduction in CHD (Coronary Heart Disease) and Acute coronary syndromes (ACS). Both the groups exhibited similar cardiovascular events. CI- 0.5-1.6, P=0.7. But a downward trend in cardiovascular events was seen in the second year of the trials with CI=0.23-1.5 P=0.26. WIZARD trial showed only a 7 % non-significant reduction in the incidence of cardiac disease after a 3 month azithromycin treatment but there was a 33% fall in MI at the end of 6 months, P=0.064. STAMINA trial conducted for one year did not show any statistically significant differences in frequency or timing of major adverse cardiac events among the azithromycin, amoxicillin, and placebo groups (P=0.02). The benefit persisted through one year. Seropositivity to C.pneumoniae or H. pylori did not affect treatment outcome. Due to the limited size of the trial, benefits related to the antimicrobial and anti-inflammatory properties of the specific regimens could not be distinguished. Larger clinical trials were recommended. The AZAC trial reliably indicated that there is no important benefit of this treatment regimen of azithromycin at the onset of ACS. The CLARIFY trial conducted to test the secondary prevention of ACS with antibiotic therapy showed fewer patients meeting the end-point in the test group (11 versus 19 patients; relative risk, 0.54;CI, 0.26-0.92;P=0.03) Statistically significant reduction in cardiovascular events were found (R.R, 0.49; CI, 0.26-0.92; P=0.03). ANTBIO trial results showed no reduction in cardiac events (odd ratio,1.1;95% CI,0.6-1.9,P=0.74.) The ACES trial after 4 years showed no difference between the groups with regards to the composite primary outcome (coronary heart disease death, non fatal MI, hospitalization for unstable angina and coronary revascularization) (22.4% of the placebo group versus 22.3% for the azithromycin group) ((RR)=1).There was a trend towards fewer events during the second and third year in the azithromycin group, but this trend was reversed in the fourth year. The largest component primary event in both groups was coronary revascularization (13.2% and 13% in the azithromycin and placebo group, respectively), but there was no difference between the 2 treatment groups with regard to any of the primary event components or with regards to secondary endpoints (Grayston, 2004). PROVE-IT trial also did not reveal any significant difference in outcome from the treatment. The ISAR-3 study did not show any significant results in the first six months. The angiographic restonosis rate (roxithromycin, 31%; placebo, 29%), in target -vessel revascularization (19% vs 17%), or in 1 year rates of death or M I (7% vs 6%) This was the only exceptional study that showed a positive correlation between Chlamydia titre and treatments of restenosis and revascularization. Roxithromycin was found useful for patients with severe infection than for patients with mild infections (adjusted odds ratio 0.44 for titres more than or equal to 1:512). One of the major flaw in the study is the difference between the pathogenesis of coronary events and atherosclerosis. Plaque instability and rupture are thought to play a larger role in coronary events than occlusive diseases .Because of all these differences in pathogenesis it is difficult to hypothesize the effect of C.pneumoniae in atherosclerotic diseases.(Grayston 2003) Also the sample selection criteria should include factors like lifestyle, lDL/HDL ratio, family history etc along with the present points of study. Further trials should consider alternative durations of therapy or analyse different subsets of patient with cardiovascular diseases. Conclusion Results of the clinical trials have not proved the efficacy of antibiotics in primary and secondary prevention of CHD. The smaller studies have shown a short -term benefit of antibiotics. Specifically the WIZARD trial showed a short term benefit of antibiotics. ISAR trial showed benefits to patients with high titre. An early intervention before palque formation may result in a better out come. More long term large scale trials of multiple antimicrobials are needed before they are recommended for the prevention of cardiac events (Tarbutton & Mitra 2007) Other trials underway involving ACS, MI, or planned bypass surgery might give a clearer picture about usefulness of antibiotic treatment for the secondary prevention of CHD. If the trials are positive there will be a new therapy for CHD and an additional type of evidence for a pathogenic assosciation of C. pneumoniae and atherosclerosis. If the trials are negative there will be less interest in the association of C.pneumoniae, but will say little about the possible role of C. Pneumoniae in the initiation and acceleration of atherosclerosis. References Anderson, .L. J & Muhlestein,. J. B. (2004). Antibiotic trials for Coronary Heart Disease. Texas Heart Institute Journal, 31, 33-38. Mitra,.A. K & Tarbutton,.G. L (2007). 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