The use of very-low-dose methadone and haloperidol for pain control in the hospital setting: a preliminary report.

OBJECTIVE: Our aim was to evaluate the use of very-low-dose methadone with haloperidol in the acute-care setting. METHODS: We reviewed the records of 735 hospitalized patients receiving a palliative care consultation between 2011 and 2014. All patients with pain on opiates were offered conversion to methadone, 2.5 mg/day to 15 mg/day, in conjunction with scheduled haloperidol. Additional doses of haloperidol or short-acting opiates were given as needed for pain. Patients receiving an opiate at a morphine-equivalent daily dose (MEDD) of ≥40 mg had pain scores assessed daily, before and after conversion. Descriptive statistics were used to summarize the results. RESULTS: Forty-three patients underwent conversion from another opiate (median MEDD, 78.5 mg) to methadone (median daily dose, 5 mg) and haloperidol (median daily dose, 1.5 mg). The median pain score was 5 in the week prior to conversion, 1 in week 1 after conversion (p<0.001 for difference), and zero in week 2. Similar results were seen for patients with cancer and noncancer diagnoses and for those with the highest and lowest initial opiate doses. CONCLUSION: The use of very-low-dose methadone in conjunction with haloperidol in the acute-care setting resulted in improved pain control after conversion from typical opiates.

Effect of KRAS mutational status in advanced colorectal cancer on the outcomes of anti-epidermal growth factor receptor monoclonal antibody therapy: a systematic review and meta-analysis.

BACKGROUND: Emerging data suggest that somatic KRAS mutation in advanced colorectal cancer is a strong predictor of non-response to anti-epidermal growth factor receptor antibody (anti-EGFR) therapy. PATIENTS AND METHODS: A comprehensive search through March 2010 identified randomized controlled trials in metastatic colorectal cancer that evaluated chemotherapy regimens or best supportive care, with and without anti-EGFR therapy. Outcomes included progression-free survival (PFS), median overall survival (OS), and predictive test performance. RESULTS: In pooled data from 8 trials with 5325 patients, the addition of anti-EGFR to standard chemotherapy resulted in improved PFS (HR 0.66 [95% CI, 0.53-0.82]) in patients with wild-type KRAS in the tumor tissue, but not in patients with KRAS mutation (HR 1.07 [95% CI, 0.91-1.27]). Anti-EGFR treatment in the wild-type group did not significantly improve median OS. As a predictive biomarker, KRAS mutation had a positive likelihood ratio of 2.0 (95% CI, 1.45-2.76) in predicting nonresponse to anti-EGFR treatment. CONCLUSION: In patients with advanced colorectal cancer, the addition of anti-EGFR treatment to standard chemotherapy improves PFS for those with wild-type, but not mutant KRAS status. KRAS gene mutation testing provides a fair biomarker in predicting non-response to anti-EGFR treatment.

Long-acting beta-agonists with and without inhaled corticosteroids and catastrophic asthma events.

BACKGROUND: It is unclear whether long-acting beta-agonists with concomitant inhaled corticosteroids increase asthma-related intubations and deaths. We pooled data on long-acting beta-agonists with variable and concomitant inhaled corticosteroids to evaluate the risk for catastrophic asthma events. METHODS: We conducted searches of electronic databases, the US Food and Drug Administration website, clinical-trials registries, and selected references through December 2008. We analyzed randomized controlled trials in patients with asthma, which lasted at least 3 months, evaluated long-acting beta-agonists compared with placebo or long-acting beta-agonists with inhaled corticosteroids compared with corticosteroids alone, and included at least 1 catastrophic event, defined as asthma-related intubation or death. RESULTS: In pooled trial data that included 36,588 participants, long-acting beta-agonists increased catastrophic events 2-fold (Peto odds ratio [OR] 2.10; 95% confidence interval [CI], 1.37-3.22). Statistically significant increases were seen for long-acting beta-agonists with variable corticosteroids compared with placebo (OR 1.83; 95% CI, 1.14-2.95) and for concomitant treatment with corticosteroids compared with corticosteroids alone (OR 3.65; 95% CI, 1.39-9.55). Similar increases in risk were seen for variable and concomitant corticosteroid use, salmeterol and formoterol, and children and adults. When the analysis was restricted to trials with controlled corticosteroid use, given as part of the study intervention, concomitant treatment still increased catastrophic events compared with corticosteroids alone (OR 8.19; 95% CI, 1.10-61.18). CONCLUSION: Long-acting beta-agonists increase the risk for asthma-related intubations and deaths, even when used in a controlled fashion with concomitant inhaled corticosteroids.

Bayesian meta-analysis of hormone therapy and mortality in younger postmenopausal women.

BACKGROUND: There is uncertainty over the risks and benefits of hormone therapy. We performed a Bayesian meta-analysis to evaluate the effect of hormone therapy on total mortality in younger postmenopausal women. This analysis synthesizes evidence from different sources, taking into account varying views on the issue. METHODS: A comprehensive search from 1966 through January 2008 identified randomized controlled trials of at least 6 month's duration that evaluated hormone therapy in women with mean age <60 years and reported at least one death, and prospective observational cohort studies that evaluated the relative risk of mortality associated with hormone therapy after adjustment for confounding variables. RESULTS: The results were synthesized using a hierarchical random-effects Bayesian meta-analysis. The pooled results from 19 randomized trials, with 16,000 women (mean age 55 years) followed for 83,000 patient-years, showed a mortality relative risk of 0.73 (95% credible interval 0.52-0.96). When data from 8 observational studies were added to the analysis, the resultant relative risk was 0.72 (credible interval 0.62-0.82). The posterior probability that hormone therapy reduces total mortality in younger women is almost 1. CONCLUSIONS: The synthesis of data using Bayesian meta-analysis indicates a reduction in mortality in younger postmenopausal women taking hormone therapy compared with no treatment. This finding should be interpreted taking into account the potential benefits and harms of hormone therapy.

Gene expression profiles as predictors of poor outcomes in stage II colorectal cancer: A systematic review and meta-analysis.

PURPOSE: The use of adjuvant therapy in stage II colorectal cancer (CRC) remains controversial. There is a need to identify more effective predictors than the traditional staging system to aid therapeutic decision-making. We performed a systematic review and meta-analysis of gene expression profiles (GEPs) to assess their utility for risk stratification and prediction of poor outcomes in stage II CRC. PATIENTS AND METHODS: We performed a comprehensive literature search through December 2007. Studies were included if they reported GEP-based assays in patients with stage II CRC, and either subsequent cancer recurrence or death within 3 years. The prognostic likelihood ratio (LR) and odds ratio (OR) were calculated with 95% confidence intervals and pooled using the fixed-effects method. The weighted average sensitivity, specificity, and accuracy were also reported. RESULTS: Eight cohorts involving 271 patients contributed to the analysis. The average accuracy, sensitivity, and specificity were 81.9%, 76.2%, and 84.5%, respectively, with a prognostic LR of 4.7 (95% CI, 3.2-6.8) and a prognostic OR of 15.1 (95% CI, 7.9-28.6). No evidence for significant interstudy heterogeneity was noted in either analysis. Subgroup analysis found no difference in results for the prediction of cancer recurrence or death. CONCLUSION: This analysis demonstrates the promising potential of using GEP assays as predictors of poor outcomes in stage II CRC, such as cancer recurrence or death. To maximize their utility and availability, further studies will be needed to identify and validate specific gene signatures for poor prognosis in stage II CRC.

The cost-effectiveness of hormone therapy in younger and older postmenopausal women.

PURPOSE: To evaluate the health and economic outcomes of hormone therapy in younger and older postmenopausal women. METHODS: We developed a cost-effectiveness model to evaluate outcomes associated with hormone therapy in younger and older postmenopausal women, using data sources from published literature through March 2008. The target population was 50-year-old and 65-year-old women given hormone therapy or no therapy, and then followed over their lifetime. Primary outcomes measured were quality-adjusted life-years (QALYs) and incremental cost per QALY gained. RESULTS: For the base-case analysis, hormone therapy for 15 years in the younger cohort resulted in a gain of 1.49 QALYs with an incremental cost of $2438 per QALY gained, compared with no therapy. The results for younger women were robust to all sensitivity analyses, and treatment remained highly cost-effective (<$10,000 per QALY gained) within the range of individual assumptions used. Treatment durations of 5 years and 30 years also were highly cost-effective. In the older cohort, treatment for 15 years resulted in a net gain of 0.11 QALYs with a cost of $27,953 per QALY gained. However, a loss of QALYs was seen in the first 9 years. The results for older women were sensitive to many of the assumptions used. CONCLUSIONS: Hormone therapy for 5 to 30 years in younger postmenopausal women increases quality-adjusted life-years and is cost-effective. Hormone therapy started in later years results in a loss of quality-adjusted life for several years before a net gain can be realized.

Two cardiovascular risk factors in one? Homocysteine and its relation to glomerular filtration rate. A meta-analysis of 41 studies with 27,000 participants.

BACKGROUND: Hyperhomocysteinemia is thought to be an independent risk factor for cardiovascular disease, but the association between renal dysfunction and homocysteine may not have been fully taken into account. We performed a meta-analysis of studies that report correlations between glomerular filtration rate (GFR) and homocysteine plasma levels. METHODS: Using a prespecified research strategy, we identified 41 studies involving 26,617 participants that reported Pearson or Spearman correlation coefficients for the association between 1/GFR and homocysteine. The summary correlation coefficients with 95% CI were obtained by pooling the logarithmic Z values derived from the individual trial correlation coefficients. Subgroup analysis was performed to compare results for measured GFR using clearance methods and various estimates of GFR. RESULTS: The pooled correlation coefficient between homocysteine and 1/GFR was 0.37 (CI 0.32-0.40, p < 0.0001). The correlation coefficient based on various estimates of GFR was 0.33 (CI 0.29-0.38, p < 0.0001), and for measured GFR it was 0.45 (CI 0.39-0.51, p < 0.0001). The correlation coefficient was higher when GFR was measured using clearance methods compared with various estimates GFR (1.36 [CI 1.13-1.65], p = 0.0014). CONCLUSIONS: Homocysteine plasma levels significantly depend on renal function. This correlation is even more robust when GFR is measured using clearance methods. Therefore, in order to assess whether homocysteine is an independent cardiovascular risk factor, accurate adjustments for renal dysfunction are essential.

Meta-analysis: metformin treatment in persons at risk for diabetes mellitus.

PURPOSE: We performed a meta-analysis of randomized controlled trials to assess the effect of metformin on metabolic parameters and the incidence of new-onset diabetes in persons at risk for diabetes. METHODS: We performed comprehensive English- and non-English-language searches of EMBASE, MEDLINE, and CINAHL databases from 1966 to November of 2006 and scanned selected references. We included randomized trials of at least 8 weeks duration that compared metformin with placebo or no treatment in persons without diabetes and evaluated body mass index, fasting glucose, fasting insulin, calculated insulin resistance, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, triglycerides, and the incidence of new-onset diabetes. RESULTS: Pooled results of 31 trials with 4570 participants followed for 8267 patient-years showed that metformin reduced body mass index (-5.3%, 95% confidence interval [CI], -6.7--4.0), fasting glucose (-4.5%, CI, -6.0--3.0), fasting insulin (-14.4%, CI, -19.9--8.9), calculated insulin resistance (-22.6%, CI, -27.3--18.0), triglycerides (-5.3%, CI, -10.5--0.03), and low-density lipoprotein cholesterol (-5.6%, CI, -8.3--3.0%), and increased high-density lipoprotein cholesterol (5.0%, CI, 1.6-8.3) compared with placebo or no treatment. The incidence of new-onset diabetes was reduced by 40% (odds ratio 0.6; CI, 0.5-0.8), with an absolute risk reduction of 6% (CI, 4-8) during a mean trial duration of 1.8 years. CONCLUSION: Metformin treatment in persons at risk for diabetes improves weight, lipid profiles, and insulin resistance, and reduces new-onset diabetes by 40%. The long-term effect on morbidity and mortality should be assessed in future trials.

Systematic review of clinical outcomes in chronic obstructive pulmonary disease: beta-agonist use compared with anticholinergics and inhaled corticosteroids.

Much controversy surrounds the use of beta-agonists in obstructive lung disease. Regular beta2- agonist use in asthma results in tolerance to its effects and an increase in asthma-related deaths. Less is known about clinical outcomes in chronic obstructive pulmonary disease (COPD). This systematic review and meta-analysis evaluates the long-term effect of beta2-agonist use on severe exacerbations requiring hospitalization or trial withdrawal, respiratory deaths, and total mortality in patients with COPD. Results for beta2-agonists are compared with results for anticholinergics and inhaled corticosteroids. Pooled results from randomized controlled trials show that anticholinergics, such as tiotropium and ipratropium, significantly reduce severe exacerbations and respiratory deaths compared with placebo. Conversely, beta2-agonists increase respiratory deaths, probably because of tolerance that develops to their bronchodilator and bronchoprotective effects. Anticholinergics significantly reduce exacerbations and total mortality compared with beta-agonists. The combination of the two bronchodilators is not more effective than anticholinergics alone in improving long-term clinical outcomes. Inhaled corticosteroids significantly reduce severe exacerbations and the decline in lung function over time, without affecting mortality. In conclusion, inhaled anticholinergic bronchodilators and corticosteroids should be used to improve long-term clinical outcomes in patients with COPD. beta-Agonists increase respiratory deaths in COPD, possibly as a result of poorer disease control.

Meta-analysis: anticholinergics, but not beta-agonists, reduce severe exacerbations and respiratory mortality in COPD.

BACKGROUND: Anticholinergics and beta2-agonists have generally been considered equivalent choices for bronchodilation in chronic obstructive pulmonary disease (COPD). OBJECTIVE: To assess the safety and efficacy of anticholinergics and beta2-agonists in COPD. DESIGN: We comprehensively searched electronic databases from 1966 to December 2005, clinical trial websites, and references from selected reviews. We included randomized controlled trials of at least 3 months duration that evaluated anticholinergic or beta2-agonist use compared with placebo or each other in patients with COPD. MEASUREMENTS: We evaluated the relative risk (RR) of exacerbations requiring withdrawal from the trial, severe exacerbations requiring hospitalization, and deaths attributed to a lower respiratory event. RESULTS: Pooled results from 22 trials with 15,276 participants found that anticholinergic use significantly reduced severe exacerbations (RR 0.67, confidence interval [CI] 0.53 to 0.86) and respiratory deaths (RR 0.27, CI 0.09 to 0.81) compared with placebo. Beta2-agonist use did not affect severe exacerbations (RR 1.08, CI 0.61 to 1.95) but resulted in a significantly increased rate of respiratory deaths (RR 2.47, CI 1.12 to 5.45) compared with placebo. There was a 2-fold increased risk for severe exacerbations associated with beta2-agonists compared with anticholinergics (RR 1.95, CI 1.39 to 2.93). The addition of beta2-agonist to anticholinergic use did not improve any clinical outcomes. CONCLUSION: Inhaled anticholinergics significantly reduced severe exacerbations and respiratory deaths in patients with COPD, while beta2-agonists were associated with an increased risk for respiratory deaths. This suggests that anticholinergics should be the bronchodilator of choice in patients with COPD, and beta2-agonists may be associated with worsening of disease control.

Meta-analysis: effect of long-acting beta-agonists on severe asthma exacerbations and asthma-related deaths.

BACKGROUND: Long-acting beta-agonists may increase the risk for fatal and nonfatal asthma exacerbations. PURPOSE: To assess the risk for severe, life-threatening, or fatal asthma exacerbations associated with long-acting beta-agonists. DATA SOURCES: English- and non-English-language searches of MEDLINE, EMBASE, and Cochrane databases; the U.S. Food and Drug Administration Web site; and references of selected reviews through December 2005. STUDY SELECTION: Randomized, placebo-controlled trials that lasted at least 3 months and evaluated long-acting beta-agonist use in patients with asthma. All trials allowed the use of as-needed short-acting beta-agonists. DATA EXTRACTION: Outcomes measured were Peto odds ratio (OR) and risk difference of severe exacerbations requiring hospitalization, life-threatening exacerbations requiring intubation and ventilation, and asthma-related deaths. The OR for asthma-related deaths was obtained from the Salmeterol Multi-center Asthma Research Trial (SMART). DATA SYNTHESIS: Pooled results from 19 trials with 33 826 participants found that long-acting beta-agonists increased exacerbations requiring hospitalization (OR, 2.6 [95% CI, 1.6 to 4.3]) and life-threatening exacerbations (OR, 1.8 [CI, 1.1 to 2.9]) compared with placebo. Hospitalizations were statistically significantly increased with salmeterol (OR, 1.7 [CI, 1.1 to 2.7]) and formoterol (OR, 3.2 [CI, 1.7 to 6.0]) and in children (OR, 3.9 [CI, 1.7 to 8.8]) and adults (OR, 2.0 [CI, 1.1 to 3.9]). The absolute increase in hospitalization was 0.7% (CI, 0.1% to 1.3%) over 6 months. The risk for asthma-related deaths was increased (OR, 3.5 [CI, 1.3 to 9.3]), with a pooled risk difference of 0.07% (CI, 0.01% to 0.1%). LIMITATIONS: The small number of deaths limited the reliability in assessing this risk, and 28 studies did not report information on the outcomes of interest. CONCLUSIONS: Long-acting beta-agonists have been shown to increase severe and life-threatening asthma exacerbations, as well as asthma-related deaths.