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Antibiotics for the secondary prevention of ischemic heart disease: a meta-analysis of randomized controlled trials.

BACKGROUND: Infections have been suspected in the pathogenesis of ischemic heart disease (IHD) for more than 100 years. Chlamydia pneumoniae has been identified in atherosclerotic specimens, and in some studies antibody titers to C pneumoniae have been related to the risk of myocardial infarction. The numerous clinical trials that have studied the use of antibiotics in the secondary prevention of IHD have had conflicting results. METHODS: This study is a meta-analysis of the published randomized controlled trials on the secondary prevention of IHD with antibiotics. Studies included in the analysis were limited to those studies that used antibiotics effective against C pneumoniae, enrolled patients with known IHD, and examined clinical outcomes related to IHD. Inclusion in the analysis was limited to well-designed randomized controlled trials that met inclusion criteria established by an expert panel. RESULTS: Nine published studies, with a total of 11 015 participants, were identified that met the criteria for this meta-analysis. Four of the studies reported a benefit from antibiotics, whereas 5 found no effect. A funnel plot of the published studies did not suggest the existence of other unpublished data. The combined effect found no benefit from antibiotics in the prevention of cardiovascular events in subjects with known IHD (relative risk, 0.94 [95% confidence interval, 0.86-1.03]) or mortality (relative risk, 0.94 [95% confidence interval, 0.79-1.12]). CONCLUSION: In patients with known IHD, macrolide antibiotics for C pneumoniae did not result in a statistically significant reduction in recurrent cardiac events or mortality over 3 months to 3 years.

Anti-Bacterial Agents↗

Data monitoring in randomized controlled trials: surveys of recent practice and policies.

BACKGROUND: Data Monitoring Committees (DMCs) are increasingly involved in the conduct of randomized controlled trials, but there is little documented evidence of what they do. Three interlinked surveys were carried out as part of the DAMOCLES project to explore recent and current DMC practice and policy. METHODS: 1) A questionnaire about DMC practice was sent to sample of 45 authors of trials published in selected journals in 2000. The sample was stratified by centre (single/multiple), disease area, and presence of DMC. 2) A sample of investigators in trials ongoing in the United Kingdom in 2001-02 was also sent a questionnaire about DMC practice. The sample was drawn from trials funded by the Medical Research Council, the United Kingdom Department of Health's Health Technology Assessment Programme, and a local and a multicentre research ethics committee. The sample was additionally stratified by funder (public/industry), centre (single/ multiple), and disease area. 3) A sample of major organisations involved in randomised controlled trials was sent a questionnaire about DMC policies. RESULTS: Information about DMC practice from the first survey was obtained from 31 trials (69%), of which four had a DMC. Information about DMC practice from the second survey was obtained about 36 trials (90%), of which 20 had a DMC. Information about DMC policy from the third survey was obtained from 25 out of 25 organisations. There was general agreement about the sorts of trials particularly needing independent DMCs, but there were few uniform approaches to their modes of functioning, and few of the organisations surveyed had developed formal policies. CONCLUSIONS: The roles of existing DMCs and policies governing DMC functioning vary widely across trials and organisations that sponsor or oversee trials, both within the UK and internationally. These findings reinforce previous calls for development of such policies across a wider range of organisations, better means to monitor their implementation within trials, and wider use of structured "charters", which set out DMC modus operandi in advance. Clinical Trials 2005; 2: 22-33. www.SCTjournal.com

Clinical Trials Data Monitoring Committees↗

A randomized controlled trial on the treatment for acute partial ischemic stroke with acupuncture.

The effectiveness of acupuncture in acute stroke remains largely untested and unproved. A randomized, controlled trial was carried out to study the feasibility of acupuncture in combination with conventional supportive treatment for acute stroke patients. A total of 30 patients, aged 46-74, with the onset of symptoms within 36 h were enrolled into the study after appropriate screening. All patients gave informed consent. Basing on the same supportive treatment, patients were randomly assigned to a treatment with or without acupuncture. The procedure and acupoint selection were discussed and decided through several meetings of a group of senior acupuncture doctors in Taiwan. Acupuncture was applied 3 times/week for 4 weeks. During the study period, there were no problems in conducting this trial in terms of patient availability and acceptance, and physician cooperation. A significantly better neurologic outcome was observed in the acupuncture group on day 28 and day 90. The improvement in neurologic status was greatest in patients with a poor neurologic score at baseline. There were no important side effects except for one episode of dizziness related to acupuncture treatment. The data and results of this study will be used as a guideline for planning a full-scale clinical trial, e.g. sample size calculation, method of randomization with stratification of prognostic factors, choosing acupuncture points and technique of acupuncture.

Acupuncture Points↗

Effect of pre-treatment with nicotine patch on withdrawal symptoms and abstinence rates in smokers subsequently quitting with the nicotine patch: a randomized controlled trial.

AIMS: To determine whether 2-week pre-treatment with transdermal nicotine influences withdrawal symptoms or success rate of subsequent smoking cessation using nicotine patches. DESIGN: Randomized controlled trial. SETTING: Smoking cessation clinic. PARTICIPANTS: Healthy smokers (n = 200, 45% female) were allocated randomly to either active nicotine-patch (AP, 15 mg daily, n = 100) or placebo-patch (PP, n = 100) pre-treatment. Baseline characteristics were well balanced except for daily cigarette consumption: mean (+/- SD) 23.1 (8) and 26.4 (11) for AP and PP groups, respectively (P = 0.021). INTERVENTION: At the screening visit (-2 weeks) subjects were counselled and started pre-treatment with daily patches (AP or PP). From the quit date (week 0) onwards all subjects received active nicotine patches for 12 weeks (15 mg daily for 8 weeks, 10 and 5 mg daily for 2 weeks each) and counselling. MEASUREMENTS: Follow-up visits included measurement of exhaled carbon monoxide at the quit date, 2, 6, 10 and 26 weeks. Subjects documented daily cigarette consumption and severity of withdrawal symptoms (Wisconsin scale) from -2 weeks to week 2. Outcome measures were withdrawal symptoms composite score and abstinence rates. FINDINGS: There was no significant difference in withdrawal symptoms, but more subjects in the AP group were smoke-free during the 6-month study period. Overall sustained abstinence was documented in 17% of subjects at 6 months; 22% and 12% for AP and PP, respectively (P = 0.03). Retrospective subgroup analysis showed for subjects smoking >16 cigarettes/day sustained cessation rates were 22% and 9% for AP and PP, respectively (P = 0.01). No difference in adverse event rates was observed. CONCLUSIONS: Nicotine patch pre-treatment before cessation did not reduce early withdrawal symptoms but increased sustained abstinence rates at 6 months. The nicotine pre-treatment was equally effective in light and heavy smokers.

Administration, Cutaneous↗

Oxerutins in the prevention of recurrence in chronic venous ulceration: randomized controlled trial.

The value of oxerutins [O-(beta-hydroxyethyl)-rutosides] in the prevention of venous ulcer recurrence was investigated in a double-blind randomized controlled trial of 138 patients with recently healed chronic venous ulcers. Oxerutins in the form of Paroven 500 mg twice daily or identical placebo were given, and all patients were provided with elastic compression stockings. At follow-up 3 months later, patients were assessed for re-ulceration and for tablet and stocking compliance. Oxerutins (n = 69) and placebo (n = 69) groups were well matched for age, sex, duration of previous ulceration and deep vein thrombosis. Cumulative re-ulceration by life-table analysis at 12 and 18 months was 22 and 32 per cent respectively for placebo, and 23 and 34 per cent respectively for oxerutins (P = 0.93). Recurrence was more frequent in patients who complied with both tablets and stockings, suggesting that compliance was influenced by continued symptoms (P = 0.006). This trial failed to demonstrate that oxerutins influenced ulcer recurrence.

Anticoagulants↗

Randomized controlled trial of specific spinal stabilization exercises and conventional physiotherapy for recurrent low back pain.

STUDY DESIGN: Pragmatic, multicentered randomized controlled trial, with 12-month follow-up. OBJECTIVE: To evaluate the effect of adding specific spinal stabilization exercises to conventional physiotherapy for patients with recurrent low back pain (LBP) in the United Kingdom. SUMMARY OF BACKGROUND DATA: Spinal stabilization exercises are a popular form of physiotherapy management for LBP, and previous small-scale studies on specific LBP subgroups have identified improvement in outcomes as a result. METHODS: A total of 97 patients (18-60 years old) with recurrent LBP were recruited. Stratified randomization was undertaken into 2 groups: "conventional," physiotherapy consisting of general active exercise and manual therapy; and conventional physiotherapy plus specific spinal stabilization exercises. Stratifying variables used were laterality of symptoms, duration of symptoms, and Roland Morris Disability Questionnaire score at baseline. Both groups received The Back Book, by Roland et al. Back-specific functional disability (Roland Morris Disability Questionnaire) at 12 months was the primary outcome. Pain, quality of life, and psychologic measures were also collected at 6 and 12 months. Analysis was by intention to treat. RESULTS: A total of 68 patients (70%) provided 12-month follow-up data. Both groups showed improved physical functioning, reduced pain intensity, and an improvement in the physical component of quality of life. Mean change in physical functioning, measured by the Roland Morris Disability Questionnaire, was -5.1 (95% confidence interval -6.3 to -3.9) for the specific spinal stabilization exercises group and -5.4 (95% confidence interval -6.5 to -4.2) for the conventional physiotherapy group. No statistically significant differences between the 2 groups were shown for any of the outcomes measured, at any time. CONCLUSIONS: Patients with LBP had improvement with both treatment packages to a similar degree. There was no additional benefit of adding specific spinal stabilization exercises to a conventional physiotherapy package for patients with recurrent LBP.

Adolescent↗

Postoperative sore throat and hoarseness following tracheal intubation using air or saline to inflate the cuff--a randomized controlled trial.

Sore throat and hoarseness following tracheal intubation is common. The aetiology may include high tracheal cuff pressures. We performed a double-blind, randomized controlled trial in 126 intubated patients to compare the incidence and severity of sore throat and hoarseness following inflation of the cuff using air or saline. Intra-cuff pressures were compared to assess any change due to inward diffusion of nitrous oxide. The incidence of significant sore throat and/or hoarseness overall was 15.0%. There was no statistically significant difference between the groups (air 15.9%, saline 14.5%). In the air group mean intra-cuff pressure increased significantly (start 14.0 mmHg, end 40.9 mmHg), while in the saline group there was no significant increase (start 12.7 mmHg, end 14.6 mmHg). The substitution of saline reliably results in sustained low intra-cuff pressures but high tracheal cuff pressure is not an important factor in the development of sore throat or hoarseness postoperatively within the pressure range and duration of operation studied.

Double-Blind Method↗

House dust mite allergen avoidance: a randomized controlled trial of surface chemical treatment and encasement of bedding.

To test the effectiveness of a house dust mite (HDM) allergen avoidance strategy we conducted a randomized controlled trial in 35 atopic subjects with asthma, aged 13 to 60 living in Sydney - a high HDM allergen environment. After a 3 month run-in period, subjects were randomized to active allergen avoidance treatment (n = 17) or placebo (n = 18) groups and followed for 6 months. The active treatment involved placing impermeable covers over the mattress, pillows and duvet and spraying the remaining bedding, as well as the carpets and furniture, with a tannic acid/acaricidal spray. Subjects kept a daily record of symptoms and peak expiratory flow rates and had 3 monthly assessments of lung function and airway hyperresponsiveness (AHR). Dust samples were collected from the bed, the bedroom floor and the living room floor at 3 monthly intervals and 2 weeks after the treatment. Mean HDM allergen levels at baseline at these sites were, in the active group, 15.5, 9.6 and 10.2 micrograms Der p I/g of fine dust, and, in the placebo group 25.7, 11.8 and 6.3 micrograms/g. Two weeks after the allergen avoidance treatment the HDM allergen level in the beds was reduced to 29% of baseline (95% CI 16-50%, P = 0.038 compared with placebo), but was not significantly different at 3 or 6 months. There was also no significant effect of the allergen avoidance treatment on symptom scores, peak flow variability, lung function or AHR P > 0.1).(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗

Outpatient treatment of pyelonephritis in pregnancy: a randomized controlled trial.

OBJECTIVE: To compare the safety and efficacy of outpatient and inpatient treatment of pyelonephritis in pregnancy. METHODS: We performed a randomized controlled trial of pregnant women with pyelonephritis before 24 weeks' estimated gestational age, comparing inpatient and outpatient treatment. Sixty inpatients received cefazolin intravenously until afebrile for 48 hours, and 60 outpatients received two injections of ceftriaxone intramuscularly. All patients completed a 10-day course of oral cephalexin. We performed a urine culture 5-14 days after completion of therapy. RESULTS: The two groups were similar with respect to age, parity, temperature, estimated gestational age, initial white blood cell count, and incidence of bacteremia. Escherichia coli was the major uropathogen isolated (86% of cultures, 95 of 111). Twelve percent (13 of 111) of bacteria were resistant to cefazolin. Eleven outpatients and 12 inpatients had positive urine cultures after therapy (relative risk 0.9, 95% confidence interval 0.4-1.9). Three patients in each group had recurrent pyelonephritis. We switched six inpatients to gentamicin because of a worsening clinical picture (two) or a prolonged febrile course (four); no outpatients required a change in antibiotic (Fisher exact test, P = .03). One preterm delivery occurred in an inpatient with recurrent pyelonephritis. CONCLUSION: Outpatient antibiotic therapy is effective and safe in selected pregnant women with pyelonephritis.

Administration, Oral↗

A comparison between intravaginal and oral misoprostol for labor induction: a randomized controlled trial.

AIM: To compare the effectiveness and safety between intravaginal and oral misoprostol for labor induction. METHODS: One hundred and six pregnant women at term with unfavorable cervix (Bishop score < or = 4) and no contraindication to prostaglandin therapy were randomized to receive either intravaginal misoprostol 50 microg every 4 h or oral misoprostol 50 microg every 4 h for prospective randomized controlled trial study. Treatment interval from induction to vaginal delivery, maternal and neonatal complications were the main outcome measures. RESULTS: There were no statistical differences of baseline characteristics and Bishop score prior to intervention between both groups. Time interval from induction to vaginal delivery in the oral group was slightly, but significantly, longer than that of the intravaginal group (886.1 +/- 443.5 min vs 637.0 +/- 373.3 min, respectively.) Additionally, the number of doses required was significantly higher in the oral group. Nonetheless, there was no significant difference between both groups with regard to failure of induction and maternal-neonatal complications. CONCLUSION: The effectiveness in terms of failed induction and safety were comparable between intravaginal and oral misoprostol, but intravaginal route was better with respect to treatment interval and number of required doses. Both routes of administration can alternatively be used for labor induction.

Administration, Intravaginal↗

Long-term treatment of irritable bowel syndrome: results of a randomized controlled trial.

To examine the long-term management of irritable bowel syndrome we conducted a two-part controlled therapeutic trial on 28 patients who had recovered completely after four to six weeks of treatment with ispaghula husk and propantheline. In part I patients were randomly divided into two groups. Group A received a placebo capsule while Group B continued with treatment as before. After six months the response to treatment was assessed according to a scoring system. The overall relapse rate in Group B was 46 per cent compared to 82 per cent in group A. With continued treatment patients in Group B became asymptomatic from the fourth month while patients in Group A continued to deteriorate. In part II, patients who had relapsed whilst on placebo received active treatment. Six of the seven who agreed to continue with the study became asymptomatic within four weeks. However, all the patients who were asymptomatic while on active treatment relapsed on discontinuation and again recovered on reinstitution of active treatment. We conclude that irritable bowel syndrome is a chronic relapsing disorder and that treatment with a combination of ispaghula husk and propantheline is effective, both in relieving symptoms and in the maintenance of remission.

Adult↗

Effects of exercise training on home blood pressure values in older adults: a randomized controlled trial.

OBJECTIVE: To determine the effects of exercise training on the blood pressure (BP) values of older adults, using home blood pressure measurement. DESIGN: Randomized controlled trial. PARTICIPANTS: A total of thirty-nine free-living older adults (including 19 men) aged from 60-81 years with home systolic blood pressure > 120 mmHg and without significant cardiopulmonary-musculoskeletal disease, were randomly allocated to either 25 weeks of exercise training (exercise group) or to a control program (control group). MAIN OUTCOME MEASUREMENTS: Change in the 2-week averages of home systolic and diastolic blood pressure values measured with a validated automatic device before, during and after the intervention period. RESULTS: Compared with the control group, the exercise group showed a significant decrease in values for home systolic blood pressure (maximum between-group difference = 7.7 mmHg, P = 0.003) and home diastolic blood pressure (4.2 mmHg, P = 0.001). These changes were observed for both genders. CONCLUSIONS: Exercise training was effective for older adults in lowering home blood pressure values. This is the first trial to demonstrate the usefulness of home blood pressure measurement in examining the effect of exercise training on blood pressure values.

Aged↗

Prophylaxis of anaphylactoid reactions to a polypeptidal plasma substitute by H1- plus H2-receptor antagonists: synopsis of three randomized controlled trials.

To demonstrate the efficacy of a premedication with H1- + H2-receptor antagonists against histamine-release responses in anaesthesia and surgery 3 randomized controlled trials were conducted in patients, volunteers and experimental animals (dogs). Cutaneous anaphylactoid reactions following infusion of polygeline (Haemaccel) in orthopedic patients were successfully abolished by premedication with 0.1 mg/kg dimethpyrindene (Fenistil) and 5 mg/kg cimetidine (Tagamet). Chlorpheniramine (Piriton) was also useful, but dimethpyrindene was more effective in the doses recommended and used. Side-effects of the premedication were not observed when the 2 drugs were slowly administered (2 min each). Systemic anaphylactoid reactions following infusion of polygeline were completely prevented in volunteers by the same premedication (0.1 mg/kg dimethpyrindene and 10 mg/kg cimetidine). Life-threatening reactions could not be tested in human subjects, but were elicited in experimental animals (dogs). In this species which resembles man in its sensitivity against histamine, in plasma histamine levels and in response to polygeline life-threatening reactions were prevented or in especially severe cases diminished to such an extent by the premedication with H1- + H2-blockers that this premedication was finally judged to be very effective against histamine-release responses of any grade of severity. To confirm this clinically very important hypothesis more clinical trials in patients at risk for anaphylactoid reactions to drugs are urgently needed.

Adult↗

Vitamin E for prophylaxis against chemotherapy-induced neuropathy: a randomized controlled trial.

BACKGROUND: The authors conducted a pilot, randomized, open label with blind assessment, controlled trial to determine whether vitamin E supplementation has a neuroprotective effect in chemotherapy-induced peripheral nerve damage. METHODS: Thirty-one patients with cancer treated with six courses of cumulative cisplatin, paclitaxel, or their combination regimens were randomly assigned in two groups and followed by neurologic examination and electrophysiologic study. Patients assigned in Group I (n = 16) received oral vitamin E at a daily dose of 600 mg/day during chemotherapy and 3 months after its cessation were compared to patients of Group II (n = 15), who received no supplementation and served as controls. The severity of neurotoxicity was summarized by means of a modified peripheral neuropathy score. RESULTS: The incidence of neurotoxicity differed between the two groups, occurring in 4/16 (25%) patients assigned in the vitamin E supplementation group and in 11/15 (73.3%) patients assigned in the control group (p = 0.019). Mean peripheral neuropathy scores were 3.4 +/- 6.3 for patients of Group I and 11.5 +/- 10.6 for patients of Group II (p = 0.026). The relative risk (RR) of developing neurotoxicity was significantly higher in case of control patients, RR = 0.34, 95% CI = 0.14 to 0.84. CONCLUSION: Vitamin E supplementation in cancer patients may have an important neuroprotective effect.

Administration, Oral↗

Treatment of histologically mild hepatitis C virus infection with interferon and ribavirin: a multicentre randomized controlled trial.

Current guidelines advocate no treatment for patients with histologically mild hepatitis C virus (HCV) infection. This was a UK multicentre randomized controlled trial comparing alpha-interferon (3 MU thrice weekly) + ribavirin (1000-1200 mg/day) for 48 weeks with no treatment in treatment naive, adult patients with histologically mild chronic HCV infection. The aim was to compare benefits, safety and efficacy of combination therapy with alpha-interferon 2b and ribavirin for 48 weeks with no treatment (current standard management) in this patient group. In the treatment group 32 of 98 (33%) patients achieved a sustained virological response (SVR). Patients infected with genotype 1 had a lower SVR than those infected with genotype non-1 (18% vs 49% P = 0.02). No patients who failed to achieve a 2-log drop in viral load at 12 weeks achieved SVR. Improvements in quality of life 24 weeks postcessation of therapy compared with baseline using the SF-36 questionnaire measures were observed in the treated group. For patients with mild HCV infection with viral genotype non-1, the results are sufficiently good to suggest that therapeutic decisions should no longer be biopsy-driven. For patients infected with genotype 1, a liver biopsy is still indicated as the low chance of SVR is outweighed by an unacceptable burden of side-effects. Patients who fail to respond by 12 weeks of therapy should have their treatment curtailed early.

Adult↗

Randomized, controlled trial of dexamethasone in neonatal chronic lung disease: 13- to 17-year follow-up study: II. Respiratory status, growth, and blood pressure.

OBJECTIVES: To study the growth, health status, and respiratory outcomes at 13 to 17 years of infants enrolled in a double-blind, randomized, controlled trial of dexamethasone for the treatment of neonatal chronic lung disease. PARTICIPANTS: A total of 287 infants who were chronically dependent on supplementary oxygen between 2 and 12 weeks of age were recruited from 31 centers in 6 countries to a double-blind, randomized, controlled trial of dexamethasone base (0.5 mg/kg per day for 1 week) or placebo, and survivors were evaluated at 3 years. Children from the 25 British and Irish centers were traced for reassessment at 13 to 17 years of age. OUTCOME MEASURES: Respiratory symptoms, lung-function testing, height, weight, head circumference, blood pressure, health resource usage, and school absences. RESULTS: There was no significant difference in respiratory outcomes between the dexamethasone and placebo groups. Lung function was impaired but with no difference between the 2 groups. Growth was also impaired in both groups, with height z score of -0.7, weight z score of -0.4, and head circumference z score of -1.1. Systolic blood pressure was >95th percentile for age and height for 15% of children, but with no difference between the 2 groups. There was no difference in the numbers of hospital admissions for respiratory causes or other causes. CONCLUSIONS: Despite a shorter duration of neonatal assisted ventilation, there is no evidence that dexamethasone use is associated with long-term improvement in lung function. Impaired growth and poor health status are long-term consequences of neonatal chronic lung disease, irrespective of exposure to neonatal dexamethasone.

Adolescent↗

Impact of a computerized clinical decision support system on reducing inappropriate antimicrobial use: a randomized controlled trial.

OBJECTIVE: Many hospitals utilize antimicrobial management teams (AMTs) to improve patient care. However, most function with minimal computer support. We evaluated the effectiveness and cost-effectiveness of a computerized clinical decision support system for the management of antimicrobial utilization. DESIGN: A randomized controlled trial in adult inpatients between May 10 and August 3, 2004. Antimicrobial utilization was managed by an existing AMT using the system in the intervention arm and without the system in the control arm. The system was developed to alert the AMT of potentially inadequate antimicrobial therapy. MEASUREMENTS: Outcomes assessed were hospital antimicrobial expenditures, mortality, length of hospitalization, and time spent managing antimicrobial utilization. RESULTS: The AMT intervened on 359 (16%) of 2,237 patients in the intervention arm and 180 (8%) of 2,270 in the control arm, while spending approximately one hour less each day on the intervention arm. Hospital antimicrobial expenditures were $285,812 in the intervention arm and $370,006 in the control arm, for a savings of $84,194 (23%), or $37.64 per patient. No significant difference was observed in mortality (3.26% vs. 2.95%, p = 0.55) or length of hospitalization (3.84 vs. 3.99 days, p = 0.38). CONCLUSION: Use of the system facilitated the management of antimicrobial utilization by allowing the AMT to intervene on more patients receiving inadequate antimicrobial therapy and to achieve substantial time and cost savings for the hospital. This is the first study that demonstrates in a patient-randomized controlled trial that computerized clinical decision support systems can improve existing antimicrobial management programs.

Adult↗