Robin J. Larson

Risk of Lymphoma Associated With Combination Anti-Tumor Necrosis Factor and Immunomodulator Therapy for the Treatment of Crohn's Disease: A Meta-Analysis

BACKGROUND & AIMS Although anti-tumor necrosis factor (TNF) therapy can effectively treat Crohns disease (CD), there is concern that it might increase the risk of non-Hodgkins lymphoma (NHL). A meta-analysis was performed to determine the rate of NHL in adult CD patients who have received anti-TNF therapy and to compare this rate with that of a population-based registry and a population of CD patients treated with immunomodulators. METHODS MEDLINE, EMBASE, Cochrane Collaboration, and Web of Science were searched. Inclusion criteria included randomized controlled trials, cohort studies, or case series reporting on anti-TNF therapy in adult CD patients. Standardized incidence ratios (SIR) were calculated by comparing the pooled rate of NHL with the expected rate of NHL derived from the Surveillance Epidemiology & End Results (SEER) database and a meta-analysis of CD patients treated with immunomodulators. RESULTS Twenty-six studies involving 8905 patients and 21,178 patient-years of follow-up were included. Among anti-TNF treated subjects, 13 cases of NHL were reported (6.1 per 10,000 patient-years). The majority of these patients had previous immunomodulator exposure. Compared with the expected rate of NHL in the SEER database (1.9 per 10,000 patient-years), anti-TNF treated subjects had a significantly elevated risk (SIR, 3.23; 95% confidence interval, 1.5-6.9). When compared with the NHL rate in CD patients treated with immunomodulators alone (4 per 10,000 patient-years), the SIR was 1.7 (95% confidence interval, 0.5-7.1). CONCLUSIONS The use of anti-TNF agents with immunomodulators is associated with an increased risk of NHL in adult CD patients, but the absolute rate of these events remains low and should be weighed against the substantial benefits associated with treatment.

Initiation of Allopurinol at First Medical Contact for Acute Attacks of Gout: A Randomized Clinical Trial

OBJECTIVE Streamlining the initiation of allopurinol could result in a cost benefit for a common medical problem and obviate the perception that no treatment is required once acute attacks have resolved. Our objective was to test the hypothesis that there is no difference in patient daily pain or subsequent attacks with early versus delayed initiation of allopurinol for an acute gout attack. METHODS A total of 57 men with crystal-proven gout were randomized to allopurinol 300 mg daily or matching placebo for 10 days. All subjects received indomethacin 50 mg 3 times per day for 10 days, a prophylactic dose of colchicine 0.6 mg 2 times per day for 90 days, and open-label allopurinol starting at day 11. Primary outcome measures were pain on visual analogue scale (VAS) for the primary joint on days 1 to 10 and self-reported flares in any joint through day 30. RESULTS On the basis of 51 evaluable subjects (allopurinol in 26, placebo in 25), mean daily VAS pain scores did not differ significantly between study groups at any point between days 1 and 10. Initial VAS pain scores for allopurinol and placebo arms were 6.72 versus 6.28 (P=.37), declining to 0.18 versus 0.27 (P=.54) at day 10, with neither group consistently having more daily pain. Subsequent flares occurred in 2 subjects taking allopurinol and 3 subjects taking placebo (P=.60). Although urate levels decreased rapidly in the allopurinol group (from 7.8 mg/dL at baseline to 5.9 mg/dL at day 3), sedimentation rates and C-reactive protein levels did not differ between groups at any point. CONCLUSIONS Allopurinol initiation during an acute gout attack caused no significant difference in daily pain, recurrent flares, or inflammatory markers.

The efficacy and safety of insulin-sensitizing drugs in HIV-associated lipodystrophy syndrome: a meta-analysis of randomized trials.

BackgroundHIV-associated lipodystrophy syndrome (HALS) is characterized by insulin resistance, abnormal lipid metabolism and redistribution of body fat. To date, there has been no quantitative summary of the effects of insulin sensitizing-agents for the treatment of this challenging problem.MethodsWe searched MEDLINE, the Cochrane Library, clinical trial registries, conference proceedings and references for randomized trials evaluating rosiglitazone, pioglitazone or metformin in patients with evidence of HALS (last update December 2009). Two reviewers independently abstracted data and assessed quality using a standard form. We contacted authors for missing data and calculated weighted mean differences (WMD) and 95% confidence intervals (CI) for each outcome.ResultsSixteen trials involving 920 patients met inclusion criteria. Rosiglitazone modestly improved fasting insulin (WMD -3.67 mU/L; CI -7.03, -0.31) but worsened triglycerides (WMD 32.5 mg/dL; CI 1.93, 63.1), LDL (WMD 11.33 mg/dL; CI 1.85, 20.82) and HDL (WMD -2.91 mg/dL; CI -4.56, -1.26) when compared to placebo or no treatment in seven trials. Conversely, pioglitazone had no impact on fasting insulin, triglycerides or LDL but improved HDL (WMD 7.60 mg/dL; CI 0.20, 15.0) when compared to placebo in two trials. Neither drug favorably impacted measures of fat redistribution. Based on six trials with placebo or no treatment controls, metformin reduced fasting insulin (WMD -8.94 mU/L; CI -13.0, -4.90), triglycerides (WMD -42.87 mg/dL; CI -73.3, -12.5), body mass index (WMD -0.70 kg/m2; CI -1.09, -0.31) and waist-to-hip ratio (WMD -0.02; CI -0.03, 0.00). Three trials directly compared metformin to rosiglitazone. While effects on insulin were comparable, lipid levels and measures of fat redistribution all favored metformin. Severe adverse events were uncommon in all 16 trials.ConclusionBased on our meta-analysis, rosiglitazone should not be used in HALS. While pioglitazone may be safer, any benefits appear small. Metformin was the only insulin-sensitizer to demonstrate beneficial effects on all three components of HALS.

Should Aspirin be Continued in Patients Started on Warfarin

AbstractBACKGROUND AND OBJECTIVE: Clinicians frequently face the decision of whether to continue aspirin when starting patients on warfarin. We performed a meta-analysis to characterize the tradeoffs involved in this common clinical dilemma. DATA SOURCES: Multiple computerized databases (1966 to 2003), reference lists of relevant articles, conference proceedings, and queries of primary authors. STUDY SELECTION: Randomized trials comparing warfarin plus aspirin versus warfarin alone. Studies with target international normalized ratios (INRs) <2 were excluded. DATA EXTRACTION: Two reviewers independently extracted baseline data and major outcomes: rates of thromboembolism, hemorrhage, and all-cause mortality. DATA SYNTHESIS: Nine studies met the inclusion criteria. Of the five that enrolled patients with mechanical heart valves, four used the same target INR in both groups, while one used a reduced target INR for the warfarin plus aspirin group. Pooling the results of the first four studies demonstrated that combination of warfarin plus aspirin significantly decreased thromboembolic events (relative risk [RR], 0.33; 95% confidence interval [CI], 0.19 to 0.58), increased major bleeding (RR, 1.58; 95% CI, 1.02 to 2.44), and decreased all-cause mortality (RR, 0.43; 95% CI, 0.23 to 0.81) compared to warfarin alone. The one valve trial using a reduced INR in the warfarin plus aspirin group reported no difference in thromboembolic outcomes but found decreased major bleeding and a significant mortality benefit with combination therapy. Of the remaining trials, three evaluated a warfarin indication not routinely used in the United States (post-myocardial infarction), and the only trial that considered atrial fibrillation was terminated early due to inadequate enrollment. CONCLUSIONS: For mechanical heart valve patients, the benefits of continuing aspirin when starting warfarin therapy are clear. For other routine warfarin indications, there are not adequate data to guide this common clinical decision.

Reevaluating the role of antidepressants in cancer-related depression: a systematic review and meta-analysis

OBJECTIVE Prior reviews evaluating the role of antidepressants in cancer-related depression have drawn conflicting conclusions. These reviews have also not explored differences in efficacy and tolerability between antidepressants. We conducted a meta-analysis to address these limitations. METHOD We searched Medline (1948-2013), the Cochrane Library (1800-2013), the Cumulative Index to Nursing and Allied Health Literature (1986-2013), ClinicalTrials.gov (2013) and meeting abstracts. We included randomized trials comparing antidepressants to placebo or no treatment for cancer-related depression. We used random effects to calculate standardized mean differences (SMD). RESULTS Of 5178 potentially eligible citations, 9 trials (1169 subjects) met inclusion criteria. Trials of mianserin found a robust reduction in depression scores at ≥4 weeks of treatment (SMD: 0.60, 95% confidence interval (CI): 0.24-0.95). Similar, but less robust, results were observed with paroxetine (SMD: 0.22, 95% CI: 0.01-0.42) and fluoxetine (SMD 0.34, 95% CI: 0.02-0.66). Conversely, there was no advantage with amitriptyline or desipramine. Compared to placebo, the odds of dropping out due to side effect were higher with fluoxetine and paroxetine and lower with mianserin. Methodological quality was moderate. CONCLUSIONS Paroxetine, fluoxetine and mianserin improve cancer-related depression but may vary in efficacy and tolerability. High-quality, randomized trials of newer antidepressant agents are needed to identify optimal treatments for managing cancer-related depression.

Surgery Versus Interferon Alpha-2b Treatment Strategies for Ocular Surface Squamous Neoplasia: A Literature-Based Decision Analysis.

Purpose: To compare treatment strategies for ocular surface squamous neoplasia (OSSN), ranging from surgical excision to empiric topical interferon alpha-2b (IFN-&agr;2b). Methods: A decision model was constructed to determine which of 4 treatment strategies minimized expected persistence/recurrence of disease in patients with OSSN: excision followed by repeat excision for positive surgical margins, excision followed by IFN-&agr;2b for positive margins, incisional biopsy followed by IFN-&agr;2b for positive biopsies, and empiric treatment with IFN-&agr;2b. Probabilities were estimated from literature published between 1983 and 2015. Expected values for the probability of recurrence could range from 0 (no persistence/recurrence) to 1 (persistence/recurrence). Sensitivity analyses were performed for each variable. Results: Excision followed by IFN-&agr;2b for positive margins was estimated to minimize persistence/recurrence of OSSN (expected value 0.13 versus 0.17 for empiric IFN-&agr;2b, 0.22 for excision-only, and 0.30 for incisional biopsy-directed IFN-&agr;2b). The optimal strategy was sensitive to 3 variables: efficacy of IFN-&agr;2b, recurrence after negative surgical margins, and accuracy of excisional biopsy. Conclusions: In our decision analysis using studies published between 1983 and 2015, surgical excision followed by IFN-&agr;2b for positive margins is the favored strategy for minimizing persistence/recurrence of OSSN. Future prospective studies would add to the certainty of these conclusions.

Effect of just-in-time simulation training on provider performance and patient outcomes for clinical procedures: a systematic review

Background Providing simulation training directly before an actual clinical procedure—or ‘just-in-time’ (JiT)—is resource intensive, but could improve both provider performance and patient outcomes. Objectives To assess the effects of JiT simulation training versus no JiT training on provider performance and patient complications following clinical procedures on patients. Study selection We searched MEDLINE, Cochrane Library, CINAHL, PsycINFO, ERIC, ClinicalTrials.gov, simulation journals indexes and references of included studies during October 2014 for randomised trials, non-randomised trials and before-after studies comparing JiT simulation training versus no JiT training among providers performing clinical procedures. Findings were synthesised qualitatively. Findings Of 1805 records screened, 8 studies comprising 3540 procedures and 1969 providers were eligible. 5 involved surgical procedures; the other 3 included paediatric endotracheal intubations, central venous catheter dressing changes, or infant lumbar puncture. Methodological quality was high. Of the 8 studies evaluating provider performance, 5 favoured JiT simulation training with 18–48% relative improvement on validated clinical performance scales, 16–20% relative reduction in surgical time and 12% absolute reduction in corrective prompts during central venous catheter dressing changes; 3 studies were equivocal with no improvement in intubation success, lumbar puncture success or urological surgery clinical performance scores. 3 studies evaluated patient complications; 1 favoured JiT simulation training with 45% relative reduction in central line-associated blood stream infections; 2 studies found no differences following intubation or laparoscopic nephrectomy. Conclusions JiT simulation training improves provider performance, but currently available literature does not demonstrate a reduction in patient complications.

Interventions to Improve the Quality of Outpatient Specialty Referral Requests A Systematic Review

Requests for outpatient specialty consultations occur frequently but often are of poor quality because of incompleteness. The authors searched bibliographic databases, trial registries, and references during October 2014 for studies evaluating interventions to improve the quality of outpatient specialty referral requests compared to usual practice. Two reviewers independently extracted data and assessed quality. Findings were qualitatively summarized for completeness of information relayed in a referral request within naturally emerging intervention categories. Of 3495 articles screened, 11 were eligible. All 3 studies evaluating software-based interventions found statistically significant improvements. Among 4 studies evaluating template/pro forma interventions, completeness was uniformly improved but with variable or unreported statistical significance. Of 4 studies evaluating educational interventions, 2 favored the intervention and 2 found no difference. One study evaluating referral management was negative. Current evidence for improving referral request quality is strongest for software-based interventions and templates, although methodological quality varied and findings may be setting specific.