zithromax and Myocardial-Infarction

The novel coronavirus disease 2019, otherwise known as COVID-19, is a global pandemic with primary respiratory manifestations in those who are symptomatic. It has spread to >187 countries with a rapidly growing number of affected patients. Underlying cardiovascular disease is associated with more severe manifestations of COVID-19 and higher rates of mortality. COVID-19 can have both primary (arrhythmias, myocardial infarction, and myocarditis) and secondary (myocardial injury/biomarker elevation and heart failure) cardiac involvement. In severe cases, profound circulatory failure can result. This review discusses the presentation and management of patients with severe cardiac complications of COVID-19 disease, with an emphasis on a Heart-Lung team approach in patient management. Furthermore, it focuses on the use of and indications for acute mechanical circulatory support in cardiogenic and/or mixed shock.

Topics: Acute Coronary Syndrome; Anti-Bacterial Agents; Antiviral Agents; Arrhythmias, Cardiac; Azithromycin; Betacoronavirus; Cardiotonic Agents; Chronic Disease; Coronavirus Infections; COVID-19; Cytokine Release Syndrome; Enzyme Inhibitors; Extracorporeal Membrane Oxygenation; Heart Failure; Heart-Assist Devices; Humans; Hydroxychloroquine; Intra-Aortic Balloon Pumping; Myocardial Infarction; Myocarditis; Pandemics; Percutaneous Coronary Intervention; Pneumonia, Viral; SARS-CoV-2; Shock, Cardiogenic; Thromboembolism

Topics: Azithromycin; Betacoronavirus; Biomarkers; Coronavirus Infections; COVID-19; Cytokine Release Syndrome; Diagnosis, Differential; Drug Therapy, Combination; Humans; Hydroxychloroquine; Hypoxia; Long QT Syndrome; Myocardial Infarction; Myocarditis; Pandemics; Pericarditis; Pneumonia, Viral; SARS-CoV-2; Systemic Inflammatory Response Syndrome; Tachycardia, Ventricular; Thrombophilia; Ventricular Dysfunction, Left; Ventricular Fibrillation

A meta-analysis of randomized, controlled trials that evaluated the effect of the macrolide antibiotic, azithromycin, on clinical outcomes in patients with coronary artery disease (CAD) was conducted.. A systematic literature search of MEDLINE, EMBASE, Web of Science, and the Cochrane Database of Systematic Reviews was conducted using specific search terms. Randomized, controlled trials comparing azithromycin or placebo in secondary CAD patients with adequately reported data on mortality and clinical cardiac endpoints were included. A random-effects model was used.. Six studies (n=13,778) met the inclusion criteria. The trials varied in their design. On meta-analysis, azithromycin resulted in a nonsignificant reduction in mortality versus placebo (odds ratio [OR], 0.91; 95% confidence interval [CI], 0.77-1.09; p=0.31). Four trials reported the rate of nonfatal myocardial infarction (MI). Azithromycin did not have an effect on the rate of nonfatal MI versus placebo (OR, 0.95; 95% CI, 0.80-1.13; p=0.57). Five trials reported rates of hospitalization in which no significant difference was seen with azithromycin versus placebo (OR, 0.97; 95% CI, 0.80-1.17; p=0.76). Six trials were used to evaluate the composite cardiovascular endpoint. Again, no significant benefit was seen with azithromycin versus placebo (OR, 0.93; 95% CI, 0.84-1.03; p=0.218).. Meta-analysis showed that azithromycin does not appear to reduce the frequency of recurrent cardiac events in patients with CAD. Results from ongoing trials may clarify the role of azithromycin in the secondary prevention of coronary events.

Topics: Anti-Bacterial Agents; Azithromycin; Chlamydophila Infections; Chlamydophila pneumoniae; Coronary Artery Disease; Hospitalization; Humans; Models, Statistical; Myocardial Infarction; Randomized Controlled Trials as Topic

Topics: Anti-Bacterial Agents; Azithromycin; Chlamydophila pneumoniae; Humans; Metronidazole; Myocardial Infarction; Pneumonia, Bacterial; Recurrence; Treatment Failure

Epidemiologic, laboratory, animal, and clinical studies suggest that there is an association between Chlamydia pneumoniae infection and atherogenesis. We evaluated the efficacy of one year of azithromycin treatment for the secondary prevention of coronary events.. In this randomized, prospective trial, we assigned 4012 patients with documented stable coronary artery disease to receive either 600 mg of azithromycin or placebo weekly for one year. The participants were followed for a mean of 3.9 years at 28 clinical centers throughout the United States.. The primary end point, a composite of death due to coronary heart disease, nonfatal myocardial infarction, coronary revascularization, or hospitalization for unstable angina, occurred in 446 of the participants who had been randomly assigned to receive azithromycin and 449 of those who had been randomly assigned to receive placebo. There was no significant risk reduction in the azithromycin group as compared with the placebo group with regard to the primary end point (risk reduction, 1 percent [95 percent confidence interval, -13 to 13 percent]). There were also no significant risk reductions with regard to any of the components of the primary end point, death from any cause, or stroke. The results did not differ when the participants were stratified according to sex, age, smoking status, presence or absence of diabetes mellitus, or C. pneumoniae serologic status at baseline.. A one-year course of weekly azithromycin did not alter the risk of cardiac events among patients with stable coronary artery disease.

Topics: Aged; Anti-Bacterial Agents; Azithromycin; Chlamydophila Infections; Chlamydophila pneumoniae; Coronary Disease; Double-Blind Method; Female; Hearing Loss; Humans; Male; Middle Aged; Myocardial Infarction; Myocardial Revascularization; Prospective Studies

The anti-chlamydial antibiotic, azithromycin, may improve outcome in patients who survive an acute coronary syndrome. The mechanisms are, however, poorly understood. The aims of this study were to define any relationship between Chlamydia pneumoniae seropositivity and levels of specific markers of endothelial activation (soluble cell adhesion molecules) and more general markers of inflammation (C-reactive protein [CRP] and interleukin-6 [IL-6]) and to assess whether azithromycin had any effect on such markers.. Patients who survived an acute coronary syndrome were randomized to receive treatment with azithromycin (n = 72) or placebo (n = 69) for 5 days. Before therapy, C pneumoniae IgA and IgG titers were checked, with serum levels of soluble intercellular adhesion molecule-1 (sICAM-1), soluble vascular cell adhesion molecule-1, soluble E-selectin (sE-selectin), soluble P-selectin, high-sensitivity CRP, and IL-6. They were rechecked 3 months later.. There were no significant correlations between C pneumoniae titers and levels of CRP, IL-6, or soluble cell adhesion molecules. However, azithromycin treatment significantly reduced mean sICAM-1 levels (P =.006). This effect was more marked in patients with elevated titers of C pneumoniae IgA and IgG. Soluble E-selectin levels were also reduced in patients who were seropositive, but no effects were seen on other endothelial or inflammatory markers.. After an acute coronary syndrome, a 5-day course of azithromycin reduces levels of sICAM-1, a marker of endothelial cell activation. Although these data suggest a potentially beneficial role for azithromycin, they should be interpreted with caution.

Topics: Aged; Anti-Bacterial Agents; Antibodies, Bacterial; Azithromycin; Biomarkers; C-Reactive Protein; Cell Adhesion Molecules; Chlamydophila Infections; Chlamydophila pneumoniae; Double-Blind Method; Female; Humans; Inflammation Mediators; Intercellular Adhesion Molecule-1; Interleukin-6; Male; Middle Aged; Myocardial Infarction

Topics: Anti-Bacterial Agents; Azithromycin; Chlamydophila pneumoniae; Humans; Metronidazole; Myocardial Infarction; Pneumonia, Bacterial; Recurrence; Treatment Failure

There is serological and epidemiological evidence of an association between Chlamydia pneumoniae infection and coronary artery disease. Results of previous smaller studies have indicated a reduction of recurrent ischaemic events in patients with acute coronary syndrome when given macrolide antibiotics. We aimed to assess whether short-term treatment with the macrolide antibiotic azithromycin reduces recurrent ischaemic events in patients admitted for unstable angina or myocardial infarction.. We assessed the effect of azithromycin in a multicentre, double-blind randomised trial in 1439 patients with unstable angina or acute myocardial infarction. Patients were randomly allocated to receive 500 mg azithromycin on the first day after randomisation, followed by 250 mg daily for 4 days or placebo. Patients were followed up for 6 months. The primary endpoints were death, recurrent myocardial infarction, or recurrent ischaemia necessitating revascularisation. Analysis was done by intention to treat.. Treatment with azithromycin did not result in reduction of either individual endpoints or any of the primary endpoints. Of the 716 patients in the azithromycin group, 23 (3%) died, 17 (2%) developed myocardial infarction, 65 (9%) had recurrent ischaemia needing revascularisation, and 100 (14%) had one or more of these endpoints. In the placebo group (n=723) the corresponding numbers of patients were 24 (4%), 22 (3%), 59 (8%), and 106 (15%), respectively (p=0.664, 95% CI 0.72-1.24). 62 (9%) of patients in the azithromycin group and 59 (8%) in the placebo group reached the secondary endpoint of ischaemia or congestive heart failure necessitating admission (difference 0.5%, 95% CI 0.75-1.53; p=0.707). We recorded few side-effects.. Short-term treatment with azithromycin does not reduce development of recurrent events in patients with acute coronary syndrome.

Topics: Aged; Angina, Unstable; Anti-Bacterial Agents; Azithromycin; Chlamydophila pneumoniae; Double-Blind Method; Endpoint Determination; Female; Humans; Male; Middle Aged; Myocardial Infarction; Secondary Prevention

Several lines of evidence have implied an association between Chlamydia pneumoniae infection and atherogenesis.. To determine the effect of 12 weeks of antibiotic therapy on coronary heart disease events in patients with stable coronary artery disease and known C pneumoniae exposure.. Randomized, placebo-controlled trial of 7747 adults with previous myocardial infarction that had occurred at least 6 weeks previously (median, 2.6 years) and a C pneumoniae IgG titer of 1:16 or more. Patients were recruited from 271 clinical practices in North America, Europe, Argentina, and India, from October 10, 1997, to July 22, 2001.. The patients received either azithromycin (600 mg/d for 3 days during week 1, then 600 mg/wk during weeks 2-12; n = 3879) or placebo (n = 3868).. The primary event was the first occurrence of death from any cause, nonfatal reinfarction, coronary revascularization, or hospitalization for angina. Patients were followed up until 1038 events accrued.. After a median of 14 months of follow-up, there was no significant risk reduction in the likelihood of a primary event with azithromycin vs placebo (7% [95% confidence interval, -5% to 17%], P =.23). Analysis of hazard ratios suggested early benefits of azithromycin on the primary event and on death or reinfarction, but these decreased over time. There were no significant risk reductions for any of the components of the primary end point including death (8%), recurrent myocardial infarction (7%), revascularization procedures (5%), or hospitalizations for angina (-1%). Adverse events related to study drug were reported by 13.2% of those randomized to receive azithromycin, predominantly a result of diarrhea, compared with 4.6% randomized to receive placebo, and resulted in discontinuation of drug in 1.6% of those taking azithromycin and 0.4% taking placebo.. Among stable patients with previous myocardial infarction and with evidence of C pneumoniae exposure, a 3-month course of azithromycin did not significantly reduce the clinical sequelae of coronary heart disease.

Topics: Anti-Bacterial Agents; Antibodies, Bacterial; Azithromycin; Chlamydophila Infections; Chlamydophila pneumoniae; Coronary Disease; Female; Humans; Male; Middle Aged; Myocardial Infarction; Proportional Hazards Models

Infection with Helicobacter pylori and Chlamydia pneumoniae is associated with coronary heart disease. We conducted an intervention study using antibiotics against these bacteria in patients with acute coronary syndromes to determine whether antibiotics reduce inflammatory markers and adverse cardiac events.. Patients (n=325) admitted with acute myocardial infarction or unstable angina (acute coronary syndromes) were randomized to receive a 1-week course of 1 of 3 treatment regimens: (1) placebo; (2) amoxicillin (500 mg twice daily), metronidazole (400 mg twice daily), and omeprazole (20 mg twice daily); or (3) azithromycin (500 mg once daily), metronidazole (400 mg twice daily), and omeprazole (20 mg twice daily). Serum fibrinogen, white cell count, and high-sensitivity C-reactive protein were measured at study entry and at 1, 3, and 12 months during follow-up. Cardiac death and readmission with acute coronary syndrome were considered clinical end points. Patients were followed for 1 year. C-reactive protein levels were reduced (P=0.03) in unstable angina patients receiving amoxicillin, and fibrinogen was reduced in both patient groups receiving antibiotics (P=0.06). There were 17 cardiac deaths and 71 readmissions with acute coronary syndrome. No difference in frequency or timing of end points was observed between the 2 antibiotic groups. At 12 weeks, there was a 36% reduction in all end points in patients receiving antibiotics compared with placebo (P=0.02). This reduction persisted during the 1-year follow-up. Neither C pneumoniae nor H pylori antibody status was significantly related to response to treatment.. Antibiotic treatment significantly reduced adverse cardiac events in patients with acute coronary syndromes, but the effect was independent of H pylori or C pneumoniae seropositivity.

Topics: Acute Disease; Adolescent; Adult; Aged; Amoxicillin; Angina, Unstable; Anti-Bacterial Agents; Antibodies, Bacterial; Azithromycin; Biomarkers; Chlamydophila Infections; Chlamydophila pneumoniae; Disease-Free Survival; Double-Blind Method; Female; Helicobacter Infections; Helicobacter pylori; Humans; Inflammation; Male; Middle Aged; Myocardial Infarction; Syndrome

Mounting evidence supports the contention that atherosclerosis is an inflammatory disease. Recently a possible role for infectious microorganisms has gathered attention. Chlamydia pneumoniae is one possible pathogen. If C. pneumoniae is a target organism, antibiotics with antichlamydial activity may be able to ameliorate plaque instability. The WIZARD trial is a secondary prevention study that is assessing the impact of a 3-month course of azithromycin compared with placebo on the progression of clinical coronary heart disease. The study will enroll 3300 patients who have had a prior myocardial infarction and who have a C. pneumoniae IgG titer of >/=1:16. The primary end point is a composite of time to either recurrent myocardial infarction, death, a revascularization procedure, or hospitalization for angina. This study is the first of a series of adequately powered clinical trials that will attempt to bridge insights from preclinical investigations to interventions applicable to patient care.

Topics: Anti-Bacterial Agents; Azithromycin; Chlamydia Infections; Chlamydophila pneumoniae; Coronary Artery Disease; Coronary Disease; Humans; Myocardial Infarction; Randomized Controlled Trials as Topic; Research Design; Treatment Outcome

The clinical significance of the association between elevated anti-Chlamydia pneumoniae (Cp) antibody titres and coronary heart disease (CHD) is unclear. We explored the relationship between antibodies against Cp and future cardiovascular events in male survivors of myocardial infarction (MI). The effect of azithromycin antibiotic therapy was assessed in a subgroup of post-MI patients.. We screened 220 consecutive male survivors of MI for anti-Cp antibodies. Of these, 213 patients were stratified into three groups: group Cp-ve (n=59), no detectable Cp antibodies; group Cp-I (n=74), intermediate titres of 1/8 to 1/32 dilution; and group Cp+ve (n=80), seropositive at > or = 1/64 dilution. Patients with persisting seropositivity of > or = 1/64 were randomized to either oral azithromycin (Cp+ve-A, 500 mg/d for 3 days [n=28] or 500 mg/d for 6 days [n=12]) or placebo (Cp+ve-P, n=20). Cp+ve-NR (n=20) represented patients not recruited into the antibiotic trial. The incidence of adverse cardiovascular events (over a mean follow-up period of 18+/-4 months) was recorded and shown to increase with increasing anti-Cp titre: Cp-ve, n=4 (7%); Cp-I, n=11 (15%); Cp+ve-NR, n=6 (30%); and Cp+ve-P, n=5 (25%). Cp+ve-NR and Cp+ve-P groups had a fourfold-increased risk for adverse cardiovascular events compared with the Cp-ve group (odds ratio [OR], 4.2; 95% confidence interval [CI], 1.2 to 15.5; P=.03). In contrast, the OR for cardiovascular events in patients receiving azithromycin (Cp+ve-A, single or double course) was the same as in the Cp-ve group (OR, 0.9; 95% CI, 0.2 to 4.6, P=NS). Patients receiving azithromycin were more likely to experience a decrease in IgG anti-Cp titres than were those in the placebo group (P=.02).. An increased anti-Cp antibody titre may be a predictor for further adverse cardiovascular events in post-MI patients. Taking a short course of azithromycin may lower this risk, possibly by acting against Cp.

Topics: Administration, Oral; Aged; Anti-Bacterial Agents; Antibodies, Bacterial; Azithromycin; Biomarkers; Chlamydia Infections; Chlamydophila pneumoniae; Humans; Male; Middle Aged; Myocardial Infarction

The study focuses on the effects of azithromycin on severity of ischemia/reperfusion myocardial injury during simulated systemic inflammatory response syndrome (SIRS) in primary visceral obesity (PVO). Total ischemia/reperfusion was modeled by Langendorff perfusion of isolated heart with following estimation of the size of myocardial infarction. SIRS was accompanied by an increase in blood levels of proinflammatory cytokines and LPS. Combination of PVO and SIRS produced no significant changes in the infarct size compared to the control. Administration of azithromycin to rats with PVO and SIRS resulted in pronounced alterations of biochemical and immunological parameters, although it did not affect the infarct size. In contrast, the use of tetracycline increased the size of myocardial infarction. This phenomenon should be taken into consideration in antimicrobial therapy.

Topics: Animals; Azithromycin; Cytokines; Lipopolysaccharides; Male; Myocardial Infarction; Myocardial Reperfusion Injury; Obesity; Obesity, Abdominal; Rats; Systemic Inflammatory Response Syndrome

A growing body of evidence shows that altering the inflammatory response by alternative macrophage polarization is protective against complications related to acute myocardial infarction (MI). We have previously shown that oral azithromycin (AZM), initiated prior to MI, reduces inflammation and its negative sequelae on the myocardium. Here, we investigated the immunomodulatory role of a liposomal AZM formulation (L-AZM) in a clinically relevant model to enhance its therapeutic potency and avoid off-target effects. L-AZM (40 or 10 mg/kg, IV) was administered immediately post-MI and compared to free AZM (F-AZM). L-AZM reduced cardiac toxicity and associated mortality by 50% in mice. We observed a significant shift favoring reparatory/anti-inflammatory macrophages with L-AZM formulation. L-AZM use resulted in a remarkable decrease in cardiac inflammatory neutrophils and the infiltration of inflammatory monocytes. Immune cell modulation was associated with the downregulation of pro-inflammatory genes and the upregulation of anti-inflammatory genes. The immunomodulatory effects of L-AZM were associated with a reduction in cardiac cell death and scar size as well as enhanced angiogenesis. Overall, L-AZM use enhanced cardiac recovery and survival after MI. Importantly, L-AZM was protective from F-AZM cardiac off-target effects. We demonstrate that the liposomal formulation of AZM enhances the drug's efficacy and safety in an animal model of acute myocardial injury. This is the first study to establish the immunomodulatory properties of liposomal AZM formulations. Our findings strongly support clinical trials using L-AZM as a novel and clinically relevant therapeutic target to improve cardiac recovery and reduce heart failure post-MI in humans.

Topics: Animals; Azithromycin; Cardiotonic Agents; Disease Models, Animal; Drug Compounding; Drug Delivery Systems; Immunologic Factors; Liposomes; Macrophage Activation; Male; Mice, Inbred C57BL; Myocardial Infarction

Acute myocardial infarction (MI) is a primary cause of worldwide morbidity and mortality. Macrophages are fundamental components of post-MI inflammation. Pro-inflammatory macrophages can lead to adverse cardiac remodeling and heart failure while anti-inflammatory/reparative macrophages enhance tissue healing. Shifting the balance between pro-inflammatory and reparative macrophages post-MI is a novel therapeutic strategy. Azithromycin (AZM), a commonly used macrolide antibiotic, polarizes macrophages towards the anti-inflammatory phenotype, as shown in animal and human studies. We hypothesized that AZM modulates post-MI inflammation and improves cardiac recovery.. Male WT mice (C57BL/6, 6-8 weeks old) were treated with either oral AZM (160 mg/kg/day) or vehicle (control) starting 3 days prior to MI and continued to day 7 post-MI. We observed a significant reduction in mortality with AZM therapy. AZM-treated mice showed a significant decrease in pro-inflammatory (CD45+/Ly6G-/F4-80+/CD86+) and increase in anti-inflammatory (CD45+/Ly6G-/F4-80+/CD206+) macrophages, decreasing the pro-inflammatory/anti-inflammatory macrophage ratio in the heart and peripheral blood as assessed by flow cytometry and immunohistochemistry. Macrophage changes were associated with a significant decline in pro- and increase in anti-inflammatory cytokines. Mechanistic studies confirmed the ability of AZM to shift macrophage response towards an anti-inflammatory state under hypoxia/reperfusion stress. Additionally, AZM treatment was associated with a distinct decrease in neutrophil count due to apoptosis, a known signal for shifting macrophages towards the anti-inflammatory phenotype. Finally, AZM treatment improved cardiac recovery, scar size, and angiogenesis.. Azithromycin plays a cardioprotective role in the early phase post-MI through attenuating inflammation and enhancing cardiac recovery. Post-MI treatment and human translational studies are warranted to examine the therapeutic applications of AZM.

Topics: Administration, Oral; Animals; Antigens, Differentiation; Azithromycin; Cardiotonic Agents; Cytokines; Inflammation; Macrophages; Male; Mice; Myocardial Infarction; Neovascularization, Physiologic

Drug-related adverse events remain an important cause of morbidity and mortality and impose huge burden on healthcare costs. Routinely collected electronic healthcare data give a good snapshot of how drugs are being used in 'real-world' settings.. To describe a strategy that identifies potentially drug-induced acute myocardial infarction (AMI) from a large international healthcare data network.. Post-marketing safety surveillance was conducted in seven population-based healthcare databases in three countries (Denmark, Italy, and the Netherlands) using anonymised demographic, clinical, and prescription/dispensing data representing 21,171,291 individuals with 154,474,063 person-years of follow-up in the period 1996-2010. Primary care physicians' medical records and administrative claims containing reimbursements for filled prescriptions, laboratory tests, and hospitalisations were evaluated using a three-tier triage system of detection, filtering, and substantiation that generated a list of drugs potentially associated with AMI. Outcome of interest was statistically significant increased risk of AMI during drug exposure that has not been previously described in current literature and is biologically plausible.. Overall, 163 drugs were identified to be associated with increased risk of AMI during preliminary screening. Of these, 124 drugs were eliminated after adjustment for possible bias and confounding. With subsequent application of criteria for novelty and biological plausibility, association with AMI remained for nine drugs ('prime suspects'): azithromycin; erythromycin; roxithromycin; metoclopramide; cisapride; domperidone; betamethasone; fluconazole; and megestrol acetate.. Although global health status, co-morbidities, and time-invariant factors were adjusted for, residual confounding cannot be ruled out.. A strategy to identify potentially drug-induced AMI from electronic healthcare data has been proposed that takes into account not only statistical association, but also public health relevance, novelty, and biological plausibility. Although this strategy needs to be further evaluated using other healthcare data sources, the list of 'prime suspects' makes a good starting point for further clinical, laboratory, and epidemiologic investigation.

Topics: Acute Disease; Adverse Drug Reaction Reporting Systems; Azithromycin; Betamethasone; Cisapride; Domperidone; Electronic Health Records; Fluconazole; Humans; Megestrol Acetate; Metoclopramide; Myocardial Infarction

Topics: Angina, Unstable; Anti-Bacterial Agents; Azithromycin; Cardiovascular Diseases; Chlamydophila Infections; Chlamydophila pneumoniae; Coronary Disease; Fluoroquinolones; Gatifloxacin; Humans; Myocardial Infarction; Treatment Failure

Topics: Acute Disease; Angina, Unstable; Azithromycin; Chlamydophila Infections; Humans; Inflammation; Intercellular Adhesion Molecule-1; Myocardial Infarction; Survivors; Syndrome

Topics: Anti-Bacterial Agents; Azithromycin; Chlamydophila Infections; Chlamydophila pneumoniae; Coronary Artery Disease; Fluoroquinolones; Gatifloxacin; Humans; Myocardial Infarction; Treatment Failure

Topics: Anti-Bacterial Agents; Antibodies, Bacterial; Arteriosclerosis; Azithromycin; Chlamydophila Infections; Chlamydophila pneumoniae; Follow-Up Studies; Humans; Morbidity; Myocardial Infarction; Randomized Controlled Trials as Topic; Recurrence; Roxithromycin; Sample Size; Treatment Outcome

Topics: Azithromycin; Chlamydia Infections; Chlamydophila pneumoniae; Double-Blind Method; Humans; Myocardial Infarction; Randomized Controlled Trials as Topic; Recurrence; Treatment Failure