Cochrane Clinical Trials Database Research Articles

How is recovery from low back pain measured? A systematic review of the literature

Recovery is commonly used as an outcome measure in low back pain (LBP) research. There is, however, no accepted definition of what recovery involves or guidance as to how it should be measured. The objective of the study was designed to appraise the LBP literature from the last 10 years to review the methods used to measure recovery. The research design includes electronic searches of Medline, EMBASE, CINAHL, Cochrane database of clinical trials and PEDro from the beginning of 1999 to December 2008. All prospective studies of subjects with non-specific LBP that measured recovery as an outcome were included. The way in which recovery was measured was extracted and categorised according to the domain used to assess recovery. Eighty-two included studies used 66 different measures of recovery. Fifty-nine of the measures did not appear in more than one study. Seventeen measures used pain as a proxy for recovery, seven used disability or function and seventeen were based on a combination of two or more constructs. There were nine single-item recovery rating scales. Eleven studies used a global change scale that included an anchor of 'completely recovered'. Three measures used return to work as the recovery criterion, two used time to insurance claim closure and six used physical performance. In conclusion, almost every study that measured recovery from LBP in the last 10 years did so differently. This lack of consistency makes interpretation and comparison of the LBP literature problematic. It is likely that the failure to use a standardised measure of recovery is due to the absence of an established definition, and highlights the need for such a definition in back pain research.

Effectiveness, tolerability and safety of azithromycin 1% in DuraSite for acute bacterial conjunctivitis.

Bacterial eye infections are commonly treated with topical antibiotics, despite limited evidence of effectiveness. Azithromycin 1% in DuraSite((R)) is a new formulation of azithromycin in a gel polymer designed for use in acute bacterial conjunctivitis. We conducted systematic searches of the Cochrane Database of Clinical Trials, PubMed and Google Scholar to find randomized controlled trials of "azithromycin DuraSite((R))". These searches of published literature were supplemented with searches for unpublished trials and trials in progress. We found six reports of randomized controlled trials investigating the role of azithromycin 1% in DuraSite((R)) for the management of acute bacterial conjunctivitis. The quality of these trials was judged to be moderate to high. These trials assessed effectiveness, tolerability and safety outcomes, but we found no trials looking at cost-effectiveness. DuraSite((R)) is a relatively stable formulation and so azithromycin 1% in DuraSite((R)) has a simpler dosing schedule than other available topical antibiotics. It appears to be similar to other topical antibiotics in its effectiveness, but minor side effects are quite common. Acute bacterial conjunctivitis is a relatively mild, typically self-limiting, infection. Antibiotics should seldom be required. If, however, a decision to prescribe antibiotics is made, azithromycin 1% in DuraSite((R)) is likely to be broadly comparable in its effectiveness to most other antibiotics used to treat acute bacterial conjunctivitis. Further research is needed to determine its cost-effectiveness.

Effect of Statins in Preventing Postoperative Atrial Fibrillation Following Cardiac Surgery.

Background: Postoperative occurrence of AF has been associated with less favorable outcomes in patients undergoing cardiac surgery and may result in increased postoperative morbidity and mortality. Objectives: A focused clinical question was designed and a Meta-analysis of published studies was performed to identify the effect of preoperative use of statins on the occurrence of AF after cardiac surgery. Methods: Using the Medline database, the Cochrane clinical trials database and online clinical trial databases, we reviewed all RCTs and observational studies examining the effect of statins on AF occurrence following cardiac surgery. We searched for literature published before April 2009 and earlier. Results: This analysis identified 6 studies (observational studies) which examined the effect of preoperative use of statins on AF occurrence following cardiac surgery, involving 10165 patients. Contradictory to most of previous studies, the overall outcomes suggested that the statins group did not have a significant decrease in AF occurrence following cardiac surgery comparing to control group (P = 0.19). Conclusions: The preoperative medication of statins showed no significant decrease in AF occurrence following cardiac surgery in this Meta-analysis result. More prospective studies and researches are needed to explore and demonstrate the accurate mechanism and effect of statins on postoperative AF.

Implantable cardioverter defibrillator therapy in chronic kidney disease: a meta-analysis

Recent observational studies have shown that implantable cardioverter defibrillator (ICD) patients with chronic kidney disease (CKD) have increased mortality and therefore the value of device therapy in this group has been questioned. The purpose of this meta-analysis was to systematically analyse the effect of renal dysfunction on mortality of ICD patients. Pubmed, Cochrane clinical trials database, and EMBASE were searched until December 2008. In addition, a manual search was performed using review articles, reference lists of papers, and abstracts from conference reports. Of the 90 initially identified studies, 11 observational studies with 3010 patients were analysed. The meta-analysis of these studies showed that CKD was associated with higher mortality risk (HR = 3.44, 95% CI 2.82-4.21, Z = 12.09, P < 0.001) while there were no significant differences between individual trials (P = 0.09, I(2) = 37.8%). A subgroup analysis which included the four studies that used estimated glomerular filtration rate (GFR) <60 mL/min/1.73 m(2) to define CKD showed a higher mortality in the CKD group as well (HR = 3.06, 95% CI 2.31-4.04, Z = 7.84, P < 0.001) without significant heterogeneity (P = 0.38, I(2) = 5.2%). Our meta-analysis suggests that CKD is associated with increased mortality in patients who receive ICD therapy. Undoubtedly, prospective studies are needed in order to elucidate the impact of different stages of CKD in this setting. Given that the CKD prevalence is rapidly increasing, there is an imperative need for better risk stratification of ICD therapy candidates.

Gastric Banding or Bypass? A Systematic Review Comparing the Two Most Popular Bariatric Procedures

Objective Bariatric surgical procedures have increased exponentially in the United States. Laparoscopic adjustable gastric banding is now promoted as a safer, potentially reversible and effective alternative to Roux-en-Y gastric bypass, the current standard of care. This study evaluated the balance of patient-oriented clinical outcomes for laparoscopic adjustable gastric banding and Roux-en-Y gastric bypass. Methods The MEDLINE database (1966 to January 2007), Cochrane clinical trials database, Cochrane reviews database, and Database of Abstracts of Reviews of Effects were searched using the key terms gastroplasty, gastric bypass, laparoscopy, Swedish band, and gastric banding. Studies with at least 1 year of follow-up that directly compared laparoscopic adjustable gastric banding with Roux-en-Y gastric bypass were included. Resolution of obesity-related comorbidities, percentage of excess body weight loss, quality of life, perioperative complications, and long-term adverse events were the abstracted outcomes. Results The search identified 14 comparative studies (1 randomized trial). Few studies reported outcomes beyond 1 year. Excess body weight loss at 1 year was consistently greater for Roux-en-Y gastric bypass than laparoscopic adjustable gastric banding (median difference, 26%; range, 19%-34%; P < .001). Resolution of comorbidities was greater after Roux-en-Y gastric bypass. In the highest-quality study, excess body weight loss was 76% with Roux-en-Y gastric bypass versus 48% with laparoscopic adjustable gastric banding, and diabetes resolved in 78% versus 50% of cases, respectively. Both operating room time and length of hospitalization were shorter for those undergoing laparoscopic adjustable gastric banding. Adverse events were inconsistently reported. Operative mortality was less than 0.5% for both procedures. Perioperative complications were more common with Roux-en-Y gastric bypass (9% vs 5%), whereas long-term reoperation rates were lower after Roux-en-Y gastric bypass (16% vs 24%). Patient satisfaction favored Roux-en-Y gastric bypass ( P = .006). Conclusion Weight loss outcomes strongly favored Roux-en-Y gastric bypass over laparoscopic adjustable gastric banding. Patients treated with laparoscopic adjustable gastric banding had lower short-term morbidity than those treated with Roux-en-Y gastric bypass, but reoperation rates were higher among patients who received laparoscopic adjustable gastric banding. Gastric bypass should remain the primary bariatric procedure used to treat obesity in the United States.

Botanicals used in complementary and alternative medicine treatment of cancer: clinical science and future perspectives

Background: Botanicals and herbal combinations are among the most common complementary and alternative medicine (CAM) approaches used by cancer patients both for cancer treatment and management of cancer symptoms. Despite their widespread use, however, the safety and efficacy of many botanicals has not been established in controlled clinical trials. Objectives: This article reviews the published evidence for the safety and clinical benefit of botanicals used in the treatment of cancer and cancer symptom management and describes the continuing clinical trials of botanicals with applications in oncology. Methods: Literature searches were conducted in PubMed, EMBASE, Cochrane Clinical Trials databases, Pharmaprojects and CRISP (Computer Retrieval of Information on Scientific Projects) clinical trials databases. Conclusion: A number of botanicals have shown promise for cancer symptom management but need further study. A limited number of multi-agent nutritional supplement approaches are being explored in clinical trials. Botanical immunomodulators and botanical products shown to affect pathways of angiogenesis, apoptosis and cell signaling in vitro have stimulated research interest and may broaden the range of available cancer treatments.

Weight loss and asthma: a systematic review

Epidemiological studies first demonstrated the association between obesity and asthma and they have begun to provide additional evidence to support causality: a dose–effect relationship, consistency across studies (especially among women)...

Treatment of elderly hypertensive patients with epithelial sodium channel inhibitors combined with a thiazide diuretic reduces coronary mortality and sudden cardiac death

No reduction in either coronary mortality or sudden cardiac death (SCD) has been demonstrated in overviews of randomized trials of treatment of hypertension with diuretics. An overview was conducted of coronary mortality and SCD in randomized controlled antihypertensive trials in which an epithelial sodium channel (ENaC) inhibitor/hydrochlorothiazide (HCTZ) combination was used. Secondarily, an analogous overview in which thiazide diuretic was used alone was performed. Randomized trials that used an ENaC inhibitor/HCTZ combination (or, alternatively, thiazide diuretic alone) were identified from previous meta-analyses, searches of PubMed, search of the Cochrane Clinical Trials database, and review of publications that addressed the consequences of treating hypertension. Trials in which participants were randomized to either an ENaC inhibitor combined with a thiazide diuretic (or to a thiazide diuretic alone) or to control treatment for at least 1 year and in which coronary mortality was reported were included. Numbers of events in individual trials were abstracted independently by two authors. Significant reductions in both coronary mortality and SCD were observed in the overview of trials in which elderly patients received an ENaC inhibitor/HCTZ combination. The odds ratio (OR) for coronary mortality was 0.59 (95% confidence interval [CI], 0.44 to 0.78) and for SCD was 0.60 (95% CI, 0.38 to 0.94). In contrast, an overview of the trials using thiazide diuretics alone showed no significant reductions of either coronary mortality (OR, 0.94; 95% CI, 0.81 to 1.09) or SCD (OR, 1.27; 95% CI, 0.93 to 1.75). Use of an ENaC inhibitor combined with HCTZ for treatment of hypertension in the elderly results in favorable effects on coronary mortality and SCD.

Association Between C-Reactive Protein and Recurrence of Atrial Fibrillation After Successful Electrical Cardioversion: A Meta-Analysis

We conducted a systematic review and meta-analysis of observational studies to examine the association between baseline C-reactive protein (CRP) levels and the recurrence of atrial fibrillation (AF) after successful electrical cardioversion (EC). Current evidence links AF to the inflammatory state. Inflammatory indexes such as CRP have been related to the development and persistence of AF. However, inconsistent results have been published with regard to the role of CRP in predicting sinus rhythm maintenance after successful EC. Using PubMed, the Cochrane clinical trials database, and EMBASE, we searched for literature published June 2006 or earlier. In addition, a manual search was performed using all review articles on this topic, reference lists of papers, and abstracts from conference reports. Of the 225 initially identified studies, 7 prospective observational studies with 420 patients (229 with and 191 without AF relapse) were finally analyzed. Overall, baseline CRP levels were greater in patients with AF recurrence. The standardized mean difference in the CRP levels between the patients with, and those without AF was 0.35 units (95% confidence interval 0.01 to 0.69); test for overall effect z-score = 2.00 (p = 0.05). The heterogeneity test showed that there were significant differences between individual studies (p = 0.02; I(2) = 60.2%). Further analysis revealed that differences between the CRP assays possibly account for this heterogeneity. Our meta-analysis suggests that increased CRP levels are associated with greater risk of AF recurrence, although there was significant heterogeneity across the studies. The use of CRP levels in predicting sinus rhythm maintenance appears promising but requires further study.

Postinfectious Irritable Bowel Syndrome-A Meta-Analysis

Irritable bowel syndrome (IBS) is a heterogeneous disorder affecting 12% of the population worldwide. Several studies identify IBS as a sequela of infectious gastroenteritis (IGE) with reported prevalence ranging from 4% to 31% and relative risk from 2.5 to 11.9. This meta-analysis was conducted to explore the differences between reported rates and provide a pooled estimate of risk for postinfectious irritable bowel syndrome (PI-IBS). Electronic databases (MEDLINE, OLDMEDLINE, EMBASE, Cochrane database of clinical trials) and pertinent reference lists (including other review articles). Data were abstracted from included studies by two independent investigators; study quality, heterogeneity, and publication bias were assessed; sensitivity analysis was performed; and a summative effect estimate was calculated for risk of PI-IBS. Eight studies were included for analysis and all reported elevated risk of IBS following IGE. Median prevalence of IBS in the IGE groups was 9.8% (IQR 4.0-13.3) and 1.2% in control groups (IQR 0.4-1.8) (sign-rank test, p= 0.01). The pooled odds ratio was 7.3 (95% CI, 4.7-11.1) without significant heterogeneity (chi2 heterogeneity statistic, p= 0.41). Subgroup analysis revealed an association between PI-IBS risk and IGE definition used. This study provides supporting evidence for PI-IBS as a sequela of IGE and a pooled risk estimate revealing a sevenfold increase in the odds of developing IBS following IGE. The results suggest that the long-term benefit of reduced PI-IBS may be gained from primary prevention of IGE.

Sedative hypnotics in older people with insomnia: meta-analysis of risks and benefits

Objectives To quantify and compare potential benefits (subjective reports of sleep variables) and risks (adverse events and morning-after psychomotor impairment) of short term treatment with sedative hypnotics in older people...

Meta-Analysis: High-Dosage Vitamin E Supplementation May Increase All-Cause Mortality

Background: Experimental models and observational studies suggest that vitamin E supplementation may prevent cardiovascular disease and cancer. However, several trials of high-dosage vitamin E supplementation showed non–statistically significant increases in total mortality. Purpose: To perform a meta-analysis of the dose–response relationship between vitamin E supplementation and total mortality by using data from randomized, controlled trials. Patients: 135 967 participants in 19 clinical trials. Of these trials, 9 tested vitamin E alone and 10 tested vitamin E combined with other vitamins or minerals. The dosages of vitamin E ranged from 16.5 to 2000 IU/d (median, 400 IU/d). Data Sources: PubMed search from 1966 through August 2004, complemented by a search of the Cochrane Clinical Trials Database and review of citations of published reviews and metaanalyses. No language restrictions were applied. Data Extraction: 3 investigators independently abstracted study reports. The investigators of the original publications were contacted if required information was not available. Data Synthesis: 9 of 11 trials testing high-dosage vitamin E (>400 IU/d) showed increased risk (risk difference > 0) for allcause mortality in comparisons of vitamin E versus control. The pooled all-cause mortality risk difference in high-dosage vitamin E trials was 39 per 10 000 persons (95% CI, 3 to 74 per 10 000 persons; P 0.035). For low-dosage vitamin E trials, the risk difference was 16 per 10 000 persons (CI, 41 to 10 per 10 000 persons; P > 0.2). A dose–response analysis showed a statistically significant relationship between vitamin E dosage and all-cause mortality, with increased risk of dosages greater than 150 IU/d. Limitations: High-dosage (>400 IU/d) trials were often small and were performed in patients with chronic diseases. The generalizability of the findings to healthy adults is uncertain. Precise estimation of the threshold at which risk increases is difficult. Conclusion: High-dosage (>400 IU/d) vitamin E supplements may increase all-cause mortality and should be avoided.

Pharmacologic prophylaxis for postoperative atrial tachyarrhythmia in general thoracic surgery: Evidence from randomized clinical trials

Atrial tachyarrhythmia is the most common complication after general thoracic surgery and is associated with significant morbidity, longer hospital stay, and higher costs. We sought to determine whether the use of antiarrhythmic medications is associated with a reduced rate of postoperative atrial tachyarrhythmia. MEDLINE, EMBASE, Cochrane Database of clinical trials (1980-2003), and reference lists of relevant articles were searched for randomized controlled trials with placebo control, general thoracic patients, and noncombined and prophylactic use of the medications. Search, data abstraction, and analyses were performed and confirmed by at least 2 authors. A fixed-effects model was used to perform meta-analyses. There were 11 unique trials (total n = 1294) that met the inclusion criteria. Calcium-channel blockers and beta-blockers reduced the risk of atrial tachyarrhythmia in 4 and 2 trials, respectively (relative risk of 0.50 and 95% confidence interval of 0.34-0.73; relative risk of 0.40 and 95% confidence interval of 0.17-0.95, respectively). However, beta-blockers tended to increase the risk of pulmonary edema (relative risk, 2.15; 95% confidence interval, 0.74-6.23). Magnesium tested in one unblinded trial also reduced the risk of atrial tachyarrhythmia (relative risk, 0.4; 95% confidence interval, 0.21-0.78). On the other hand, digitalis preparations were found to be harmful because they increased the risk of atrial tachyarrhythmia in 3 trials (relative risk, 1.51; 95% confidence interval, 1.00-2.28). Finally, 2 other medications, flecainide and amiodarone, were each tested in a single small trial, and their effects were associated with great uncertainty. Calcium-channel blockers and beta-blockers are effective in reducing postoperative atrial tachyarrhythmia. The use of these medications should be individualized, and possible adverse events of beta-blockers should be taken into account. Randomized clinical trials do not support the use of digitalis in general thoracic surgery. The value of magnesium as a supplement to a main prophylactic regimen should be explored.

Meta-Analysis: High-Dosage Vitamin E Supplementation May Increase All-Cause Mortality

Experimental models and observational studies suggest that vitamin E supplementation may prevent cardiovascular disease and cancer. However, several trials of high-dosage vitamin E supplementation showed non-statistically significant increases in total mortality. To perform a meta-analysis of the dose-response relationship between vitamin E supplementation and total mortality by using data from randomized, controlled trials. 135,967 participants in 19 clinical trials. Of these trials, 9 tested vitamin E alone and 10 tested vitamin E combined with other vitamins or minerals. The dosages of vitamin E ranged from 16.5 to 2000 IU/d (median, 400 IU/d). PubMed search from 1966 through August 2004, complemented by a search of the Cochrane Clinical Trials Database and review of citations of published reviews and meta-analyses. No language restrictions were applied. 3 investigators independently abstracted study reports. The investigators of the original publications were contacted if required information was not available. 9 of 11 trials testing high-dosage vitamin E (> or =400 IU/d) showed increased risk (risk difference > 0) for all-cause mortality in comparisons of vitamin E versus control. The pooled all-cause mortality risk difference in high-dosage vitamin E trials was 39 per 10,000 persons (95% CI, 3 to 74 per 10,000 persons; P = 0.035). For low-dosage vitamin E trials, the risk difference was -16 per 10,000 persons (CI, -41 to 10 per 10,000 persons; P > 0.2). A dose-response analysis showed a statistically significant relationship between vitamin E dosage and all-cause mortality, with increased risk of dosages greater than 150 IU/d. High-dosage (> or =400 IU/d) trials were often small and were performed in patients with chronic diseases. The generalizability of the findings to healthy adults is uncertain. Precise estimation of the threshold at which risk increases is difficult. High-dosage (> or =400 IU/d) vitamin E supplements may increase all-cause mortality and should be avoided.

Safety concerns regarding ephedrine-type alkaloid-containing dietary supplements.

The U.S. Air Force has adopted a policy "strongly discourag(ing) the use of ... ephedra." However, the literature regarding this topic is limited and widely opinioned. In light of growing public and medical debate over the safety and efficacy of ephedrine-type alkaloid-containing dietary supplements, a review of the literature and assessment of the data were accomplished. Studies regarding Ma Huang, ephedra, ephedrine-type alkaloids, ephedrine, and dietary supplements were reviewed (from databases Medline, HealthSTAR, CINAHL, Cochrane Clinical Trials Database). Food and Drug Administration and Government Accounting Office documents (including reports and interagency communications) were reviewed. Significant manufacturing quality control issues exist. Few studies support their efficacy or safety. Weight loss and athletic performance appear to be only modestly improved, for short durations, in the setting of large numbers of (some serious) adverse event reports. Studies examining over-the-counter use are minimal. The current U.S. Air Force policy strongly discouraging the use of ephedrine-type alkaloid-containing dietary supplements appears to be supported.

Cluster headaches—evidence-based guidance

Data sources Medline, Cochrane Database of Clinical Trials and bibliographies of identified articles.Study selection Only English-language papers that clearly stated the defined diagnostic criteria were included. For the management section, controlled trials were used if available.Data abstraction and synthesis A qualitative synthesis of included studies was carried out.Findings Cluster headache is rare (lifetime prevalence of 0.07%). Smoking appears to increase the risk but there is conflicting evidence about the role of coffee and alcohol. Diagnosis is entirely based on clinical features. No laboratory or radiological investigations with sufficient sensitivity and specificity have been identified. The pain is described as very severe and can last for up to 3 h. There is often parasympathetic overactivity such as lacrimation and rhinorrhea. In some patients there is facial flushing or pallor, dysaesthesia of scalp hairs, tenderness of the carotid artery on that side and bradycardia. Sympathetic activity can result in miosis or ptosis on that side of the face. The main differential diagnosis is migraine.Attacks are typically at night (when sleep apnoea can occur) and can be caused by alcohol, notroglycerine and histamine, leading to the hypothesis that oxygen desaturation triggers an attack. Standard treatment of acute attacks is oxygen delivered by facemask but this has only been evaluated in one small double-blind randomised controlled trial (RCT). A review of sumatriptan has shown it to be effective without serous adverse effects or cardiovascular changes. Dihydroergotamine (DHE) and ergotamine have both been reported to be useful but only the nasal for of DHE has been evaluated. Intranasal capsaicin was used successfully in two RCT. There have been few RCT that considered prophylaxis, and surgical-management studies did not include controls and were of varying quality. A case-series of 66 patients did find blockade of the sphenopalatine ganglion and radiofrequency thermocoagulation of the Gasserian ganglion was produced good results in a case series of 27 patients.Conclusions An overview of this condition is presented based on a thorough review of the area with treatment guidelines suggested based on findings.

A systematic review of nonpharmacological and nonsurgical therapies for gastroesophageal reflux in infants.

Nonpharmacological and nonsurgical measures are often recommended for gastroesophageal reflux disease (GERD) in infants, despite ambiguous supporting evidence. To conduct a systematic review of rigorously evaluated nonpharmacological and nonsurgical therapies for GERD in infants. We searched online bibliographic databases, including MEDLINE, EMBASE, the Cochrane Collaboration and Clinical Trials Database, and alternative medicine databases for the terms gastroesophageal reflux and infants. We selected randomized controlled trials of nonpharmacological and nonsurgical GERD therapies in otherwise healthy infants. Data were extracted from the selected articles regarding reflux, emetic episodes and intraesophageal pH. We identified 43 relevant studies, of which 10 met the selection criteria. These studies examined positioning, pacifier use, and feeding changes. Positioning at a 60 degree elevation in an infant seat was found to increase reflux compared with the prone position. No significant difference was shown between the flat and head-elevated prone positions. The impact of pacifier use on reflux frequency was equivocal and dependent on infant position. The protein content of formula was not found to affect reflux. Although no study demonstrated a significant reflux-reducing benefit of thickened infant foods compared with placebo, 1 study detected a significant benefit of formula thickened with carob bean gum compared with rice flour (pH<4 for 5% vs 8% of time). Another study showed that if supplementing with dextrose 5% water or dextrose 10% water, the lower-osmolality fluid was associated with less reflux. Many conservative measures commonly used to treat GERD in infants have no proven efficacy. Although thickened formulas do not appear to reduce measurable reflux, they may reduce vomiting. Further studies with clinical outcomes are needed to answer questions about efficacy definitively.

Safety Outcomes in Meta-analyses of Phase 2 vs Phase 3 Randomized Trials

Recent studies have reported disagreement between meta-analysis of small trials and subsequent large trials addressing the same question. However, disagreement for uncommon but serious adverse safety outcomes has not been examined. To explore disagreement for serious adverse safety (intracranial hemorrhage [ICH]) and efficacy outcomes between meta-analysis of phase 2 (small) vs meta-analysis of phase 3 (large) randomized controlled trials comparing the efficacy of bolus thrombolytic therapy with infusion for acute myocardial infarction (AMI). Electronic databases (MEDLINE, Cochrane Database of Clinical Trials) between January 1980 and December 1999 using the search terms thrombolysis, thrombolytic therapy, and myocardial infarction; conference proceedings; and reference lists. Fifteen randomized trials comparing thrombolytic agents administered by bolus injection with standard infusion therapy in patients with AMI. Data on ICH, other causes of stroke, total mortality, and reinfarction were independently extracted from each study by 2 observers. Meta-analysis of 9 phase 2 trials (n = 3956) revealed a lower risk of ICH with bolus thrombolytic therapy (odds ratio [OR], 0.53; 95% confidence interval [CI], 0.27-1.01), which was not statistically significant. Meta-analysis of 6 phase 3 trials (n = 62 673) indicated a significant increase in risk of ICH (OR, 1.25; 95% CI, 1.06-1.49). These results were significantly different (P =.01). There was no disagreement for efficacy outcomes. Phase 2 trials included younger and heavier patients with lower baseline blood pressures, and were more often open-label. Subgroup analyses suggested that each of these factors was associated with a lower estimate of risk of ICH with bolus agents. Our results suggest that when therapeutic interventions are associated with a potential for uncommon but serious adverse safety outcomes, there may be differences between small phase 2 and large phase 3 trials that result in their disagreement for safety but not necessarily efficacy outcomes. Further investigation of the frequency and causes of disagreement between small and large trials for safety outcomes is warranted.

A systematic review of treatments for the painful heel.

To establish the efficacy for treatments of pain on the plantar aspect of the heel. Systematic review of the published and unpublished literature. Electronic search of Medline, BIDS and the Cochrane database of clinical trials. An assessment of the quality of the reporting was made of studies included in the review. patients' pain scores. randomized controlled trials, published or unpublished, that evaluated treatments used for plantar heel pain. Foreign language papers were excluded. Eleven randomized controlled trials were included in the review. These evaluated some of the most frequently described treatments (steroid injections and orthoses) and some experimental therapies (extracorporeal shock wave therapy and directed electrons). The methodological assessment scores of the published trials were low; small sample sizes and failure to conceal the treatment allocation from study participants prevents more definitive statements about the efficacy of treatments. In 10 of the included trials, patients in both the intervention and control arms reported improved pain scores at the final outcome measure. Although much has been written about the treatment of plantar heel pain, the few randomized controlled trials involve small populations of patients and do not provide robust scientific evidence of treatment efficacy.

Should we pay the patient? Review of financial incentives to enhance patient compliance

Objective: To determine whether financial incentives increase patients' compliance with healthcare treatments.Data sources: Systematic literature review of computer databases—Medline, Embase, PsychLit, EconLit, and the Cochrane Database of Clinical Trials. In...