A Risk-Benefit Assessment of Dementia Medications: Systematic Review of the Evidence.

BACKGROUND: There is no cure for dementia, and no treatments exist to halt or reverse the course of the disease. Treatments are aimed at improving cognitive and functional outcomes. OBJECTIVE: Our objective was to review the basis of pharmacological treatments for dementia and to summarize the benefits and risks of dementia treatments. METHODS: We performed a systematic literature search of MEDLINE through November 2014, for English-language trials and observational studies on treatment of dementia and mild cognitive impairment. Additional references were identified by searching bibliographies of relevant publications. Whenever possible, pooled data from meta-analyses or systematic reviews were obtained. Studies were included for review if they were randomized trials or observational studies on dementia or mild cognitive impairment that evaluated efficacy outcomes or adverse outcomes associated with treatment. Studies were excluded if they evaluated non-FDA approved treatments, or if they evaluated treatment in disorders other than dementia and mild cognitive impairment. RESULTS: The literature search found 540 potentially relevant studies, of which 257 were included in the systematic review. In pooled trial data, cholinesterase inhibitors (ChEIs) produce small improvements in cognitive, functional, and global benefits in patients with mild to moderate Alzheimer's and Lewy body dementia, but the clinical significance of these effects are unclear. There is no significant benefit seen for vascular dementia. The efficacy of ChEI treatment appears to wane over time, with minimal benefit seen after 1 year. There is no evidence for benefit for those with advanced disease or those aged over 85 years. Adverse effects are significantly increased with ChEIs, in a dose-dependent manner. A two- to fivefold increased risk for gastrointestinal, neurological, and cardiovascular side effects is related to cholinergic stimulation, the most serious being weight loss, debility, and syncope. Those aged over 85 years have double the risk of adverse events compared with younger patients. Memantine monotherapy may provide some cognitive benefit for patients with moderate to severe Alzheimer's and vascular dementia, but the benefit is small and may wane over the course of several months. Memantine exhibits no significant benefit in mild dementia or Lewy body dementia or as an add-on treatment with ChEIs. Memantine has a relatively favorable side-effect profile, at least under controlled trial conditions. CONCLUSIONS: ChEIs produce small, short-lived improvements in cognitive function in mild to moderate dementia, which may not translate into clinically meaningful effects. Marginal benefits are seen with severe disease, long-term treatment, and advanced age. Cholinergic side effects, including weight loss, debility, and syncope, are clinically significant and could be especially detrimental in the frail elderly population, in which the risks of treatment outweigh the benefits. Memantine monotherapy may have minimal benefits in moderate to severe dementia, balanced by minimal adverse effects.

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.

Impact of more restrictive blood transfusion strategies on clinical outcomes: a meta-analysis and systematic review.

BACKGROUND: There is accumulating evidence that restricting blood transfusions improves outcomes, with newer trials showing greater benefit from more restrictive strategies. We systematically evaluated the impact of various transfusion triggers on clinical outcomes. METHODS: The MEDLINE database was searched from 1966 to April 2013 to find randomized trials evaluating a restrictive hemoglobin transfusion trigger of <7 g/dL, compared with a more liberal trigger. Two investigators independently extracted data from the trials. Outcomes evaluated included mortality, acute coronary syndrome, pulmonary edema, infections, rebleeding, number of patients transfused, and units of blood transfused per patient. Extracted data also included information on study setting, design, participant characteristics, and risk for bias of the included trials. A secondary analysis evaluated trials using less restrictive transfusion triggers, and a systematic review of observational studies evaluated more restrictive triggers. RESULTS: In the primary analysis, pooled results from 3 trials with 2364 participants showed that a restrictive hemoglobin transfusion trigger of <7 g/dL resulted in reduced in-hospital mortality (risk ratio [RR], 0.74; confidence interval [CI], 0.60-0.92), total mortality (RR, 0.80; CI, 0.65-0.98), rebleeding (RR, 0.64; CI, 0.45-0.90), acute coronary syndrome (RR, 0.44; CI, 0.22-0.89), pulmonary edema (RR, 0.48; CI, 0.33-0.72), and bacterial infections (RR, 0.86; CI, 0.73-1.00), compared with a more liberal strategy. The number needed to treat with a restrictive strategy to prevent 1 death was 33. Pooled data from randomized trials with less restrictive transfusion strategies showed no significant effect on outcomes. CONCLUSIONS: In patients with critical illness or bleed, restricting blood transfusions by using a hemoglobin trigger of <7 g/dL significantly reduces cardiac events, rebleeding, bacterial infections, and total mortality. A less restrictive transfusion strategy was not effective.

The use of very-low-dose methadone for palliative pain control and the prevention of opioid hyperalgesia.

BACKGROUND: Opioid dose escalation may cause hyperalgesia, mediated by the N-methyl-D-aspartate (NMDA) pathway. Methadone is an atypical opioid that inhibits hyperalgesia through NMDA-blockade, especially at low doses. OBJECTIVE: To evaluate the efficacy of using very-low-dose methadone as the sole long-acting opioid agent in a hospice practice. DESIGN: A retrospective, observational study of the use of methadone, ≤15 mg daily, with as-needed short-acting opiates. Adjuvant nonopioid medications included haloperidol, which may have NMDA-blocking effects. SETTING/SUBJECTS: We reviewed the records of 240 patients admitted to a community-based hospice from July 1, 2011 to April 1, 2012, with data collected until hospice discharge or until April 30, 2012. MEASUREMENTS: Descriptive statistics were used to summarize patient demographics, medication regimens, and reported pain scores measured on a numeric rating scale from 0 to 10. RESULTS: All patients received short-acting opiates, in a morphine-equivalent dose of 5 mg every 4 hours as needed, while 40% also received methadone at a median daily dose of 5 mg. Of those on methadone, almost half received scheduled haloperidol. The population had a median reported pain score of 0 and a peak score of 3, with similar results seen for cancer and noncancer groups. Two-thirds of patients never reported a pain score greater than 3. CONCLUSION: The use of very-low-dose methadone in conjunction with adjuvant haloperidol resulted in excellent pain control without dose escalation or opioid-induced hyperalgesia, for both cancer and noncancer diseases. We conclude that low-dose methadone should be part of first-line treatment in palliative pain management.

Systematic review of noncancer presentations with a median survival of 6 months or less.

PURPOSE: We report on clinical indicators of 6-month mortality in advanced noncancer illnesses and the effect of treatment on survival. METHODS: The MEDLINE database was searched comprehensively to find studies evaluating survival for common advanced noncancer illnesses. We retrieved and evaluated studies that reported a median survival of ≤1 year and evaluated prognostic factors or effect of treatment on survival. We extracted data on presentations with median survivals of ≤6 months for heart failure, chronic obstructive pulmonary disease, dementia, geriatric failure to thrive, cirrhosis, and end-stage renal failure. Independent risk factors for survival were combined and included if their combination was associated with a 6-month mortality of ≥50%. RESULTS: The search identified 1000 potentially relevant studies, of which 475 were retrieved and evaluated, and 74 were included. We report the common clinical presentations that are consistently associated with a 6-month median survival. Even though advanced noncancer syndromes differ clinically, a universal set of prognostic factors signals progression to terminal disease, including poor performance status, advanced age, malnutrition, comorbid illness, organ dysfunction, and hospitalization for acute decompensation. Generally, a 6-month median survival is associated with the presence of 2-4 of these factors. With few exceptions, these terminal presentations are quite refractory to treatment. CONCLUSION: This systematic review summarizes prognostic factors common to advanced noncancer illness. There is little evidence at present that treatment prolongs survival at these terminal stages.

Systematic review of cancer presentations with a median survival of six months or less.

OBJECTIVE: To report cancer presentations with a median survival of 6 months or less and the effect of treatment on survival. METHODS: We searched the MEDLINE database to find studies on solid and hematologic cancers that reported presentations consistently shown to have a median survival of 6 months or less. Independent prognostic factors were combined if their combination resulted in greater than 50% 6-month-mortality. For each terminal presentation, we evaluated whether treatment improved survival. RESULTS: The search identified 1500 potentially relevant articles, of which 650 were evaluated and 383 were included. Despite different cancer characteristics, a fairly universal picture of terminal disease included decreasing performance status, advancing age, weight loss, metastatic disease, disease recurrence, and laboratory abnormalities indicating extensive disease. Most of the prognostic indicators found were continuous, independent risk factors for mortality. We found little evidence that treatment improved survival at these terminal stages, with increased risk for toxicity. CONCLUSION: This systematic review summarizes prognostic factors in advanced cancer that are consistently associated with a median survival of 6 months or less. There is little evidence that treatment prolongs survival at this stage.

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.

Risk of fatal and nonfatal lactic acidosis with metformin use in type 2 diabetes mellitus.

BACKGROUND: Metformin is an oral anti-hyperglycemic agent that has been shown to reduce total mortality compared to other anti-hyperglycemic agents, in the treatment of type 2 diabetes mellitus. Metformin, however, is thought to increase the risk of lactic acidosis, and has been considered to be contraindicated in many chronic hypoxemic conditions that may be associated with lactic acidosis, such as cardiovascular, renal, hepatic and pulmonary disease, and advancing age. OBJECTIVES: To assess the incidence of fatal and nonfatal lactic acidosis, and to evaluate blood lactate levels, for those on metformin treatment compared to placebo or non-metformin therapies. SEARCH STRATEGY: A comprehensive search was performed of electronic databases to identify studies of metformin treatment. The search was augmented by scanning references of identified articles, and by contacting principal investigators. SELECTION CRITERIA: Prospective trials and observational cohort studies in patients with type 2 diabetes of least one month duration were included if they evaluated metformin, alone or in combination with other treatments, compared to placebo or any other glucose-lowering therapy. DATA COLLECTION AND ANALYSIS: The incidence of fatal and nonfatal lactic acidosis was recorded as cases per patient-years, for metformin treatment and for non-metformin treatments. The upper limit for the true incidence of cases was calculated using Poisson statistics. In a second analysis lactate levels were measured as a net change from baseline or as mean treatment values (basal and stimulated by food or exercise) for treatment and comparison groups. The pooled results were recorded as a weighted mean difference (WMD) in mmol/L, using the fixed-effect model for continuous data. MAIN RESULTS: Pooled data from 347 comparative trials and cohort studies revealed no cases of fatal or nonfatal lactic acidosis in 70,490 patient-years of metformin use or in 55,451 patients-years in the non-metformin group. Using Poisson statistics the upper limit for the true incidence of lactic acidosis per 100,000 patient-years was 4.3 cases in the metformin group and 5.4 cases in the non-metformin group. There was no difference in lactate levels, either as mean treatment levels or as a net change from baseline, for metformin compared to non-metformin therapies. AUTHORS' CONCLUSIONS: There is no evidence from prospective comparative trials or from observational cohort studies that metformin is associated with an increased risk of lactic acidosis, or with increased levels of lactate, compared to other anti-hyperglycemic treatments.

An update on the safety of long-acting beta-agonists in asthma patients using inhaled corticosteroids.

IMPORTANCE OF THE FIELD: Pooled trial data have shown that long-acting beta-agonists increase the risk for asthma hospitalizations and deaths by two to fourfold compared with placebo. Until recently, it was unclear whether concomitant inhaled corticosteroids (ICSs) could eliminate this risk. AREAS COVERED IN THIS REVIEW: This review summarizes the available data on the safety of long-acting beta-agonist use in asthma, with and without concomitant ICSs. The results from an updated meta-analysis are presented, with data through December 2008. WHAT THE READER WILL GAIN: In pooled trial data, catastrophic asthma events (defined as asthma-related intubation or death) were increased fourfold for concomitant treatment with long-acting beta-agonists and ICSs compared with corticosteroids alone (odds ratio 3.7; 95% CI 1.4 - 9.6). It is estimated that the addition of long-acting beta-agonists to ICS therapy is associated with an absolute increase of one catastrophic event per 1500 patient-years. TAKE HOME MESSAGE: When the available trial data are pooled together, it is clear that long-acting beta-agonists significantly increase the risk for asthma-related intubations and deaths, even when used in a controlled fashion with concomitant ICSs. Clinical guidelines should readdress the role long-acting beta-agonists have in the management of asthma.

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.

Risk of fatal and nonfatal lactic acidosis with metformin use in type 2 diabetes mellitus.

BACKGROUND: Metformin is an oral anti-hyperglycemic agent that has been shown to reduce total mortality compared to other anti-hyperglycemic agents, in the treatment of type 2 diabetes mellitus. Metformin, however, is thought to increase the risk of lactic acidosis, and has been considered to be contraindicated in many chronic hypoxemic conditions that may be associated with lactic acidosis, such as cardiovascular, renal, hepatic and pulmonary disease, and advancing age. OBJECTIVES: To assess the incidence of fatal and nonfatal lactic acidosis, and to evaluate blood lactate levels, for those on metformin treatment compared to placebo or non-metformin therapies. SEARCH STRATEGY: A comprehensive search was performed of electronic databases to identify studies of metformin treatment. The search was augmented by scanning references of identified articles, and by contacting principal investigators. SELECTION CRITERIA: Prospective trials and observational cohort studies in patients with type 2 diabetes of least one month duration were included if they evaluated metformin, alone or in combination with other treatments, compared to placebo or any other glucose-lowering therapy. DATA COLLECTION AND ANALYSIS: The incidence of fatal and nonfatal lactic acidosis was recorded as cases per patient-years, for metformin treatment and for non-metformin treatments. The upper limit for the true incidence of cases was calculated using Poisson statistics. In a second analysis lactate levels were measured as a net change from baseline or as mean treatment values (basal and stimulated by food or exercise) for treatment and comparison groups. The pooled results were recorded as a weighted mean difference (WMD) in mmol/L, using the fixed-effect model for continuous data. MAIN RESULTS: Pooled data from 347 comparative trials and cohort studies revealed no cases of fatal or nonfatal lactic acidosis in 70,490 patient-years of metformin use or in 55,451 patients-years in the non-metformin group. Using Poisson statistics the upper limit for the true incidence of lactic acidosis per 100,000 patient-years was 4.3 cases in the metformin group and 5.4 cases in the non-metformin group. There was no difference in lactate levels, either as mean treatment levels or as a net change from baseline, for metformin compared to non-metformin therapies. AUTHORS' CONCLUSIONS: There is no evidence from prospective comparative trials or from observational cohort studies that metformin is associated with an increased risk of lactic acidosis, or with increased levels of lactate, compared to other anti-hyperglycemic treatments.

Do inhaled anticholinergics increase or decrease the risk of major cardiovascular events?: a synthesis of the available evidence.

There has been recent uncertainty about whether the inhaled anticholinergic agents ipratropium bromide and tiotropium bromide increase or decrease cardiovascular risk in the treatment of patients with chronic obstructive pulmonary disease (COPD). This article synthesizes the available data in order to understand the controversy. COPD is a common cause of hospitalizations and is a rapidly increasing cause of mortality worldwide. Despite the heavy burden of COPD-related illness, the leading cause of hospitalization in COPD patients is cardiovascular disease. This link between COPD and cardiovascular disease is in part due to the fact that both diseases share common risk factors, such as tobacco smoking and advanced age. It is also hypothesized that systemic inflammation in COPD increases the risk for cardiac events such as myocardial infarction. Inhaled anticholinergics reduce COPD-related hospitalizations and respiratory deaths compared with placebo, and tiotropium bromide is more effective than ipratropium bromide. In randomized trials, patients receiving tiotropium bromide have lower discontinuation rates than those receiving placebo and, therefore, contribute more person-years to the analyses. In a recent large 4-year tiotropium bromide trial, the proportion of patients who died was similar in the tiotropium bromide and placebo groups, whereas the death rate per person-years was lower with tiotropium bromide, indicating longer overall survival. There has been conflicting evidence concerning cardiovascular risk associated with inhaled anticholinergics. One meta-analysis found that the risk for major cardiovascular events was higher with anticholinergics compared with placebo or active comparator controls, whereas two subsequent meta-analyses that included new trial data found no difference in risk. In a recent pooled safety analysis, when incidence rates of events over time were evaluated, tiotropium bromide was associated with a lower rate of major cardiovascular events and cardiovascular deaths compared with placebo. This risk reduction was mainly because of a reduction in serious cardiac events such as myocardial infarction and congestive heart failure. In conclusion, inhaled anticholinergics, especially tiotropium bromide, reduce COPD-related hospitalizations and deaths, and may improve total survival over time. Many COPD patients have concomitant cardiovascular disease processes. Thus, trials may observe more cardiovascular events associated with anticholinergics than with placebo, but this differential is eliminated when evaluating the rate of events per person-years of exposure. New evidence indicates that tiotropium bromide may actually reduce the incidence of cardiovascular events and deaths over time. It is possible that the reduction in respiratory morbidity could improve functional status and reduce adverse cardiac outcomes over time. Further studies are needed to address this important issue.

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.

Systematic review: the effects of growth hormone on athletic performance.

BACKGROUND: Human growth hormone is reportedly used to enhance athletic performance, although its safety and efficacy for this purpose are poorly understood. PURPOSE: To evaluate evidence about the effects of growth hormone on athletic performance in physically fit, young individuals. DATA SOURCES: MEDLINE, EMBASE, SPORTDiscus, and Cochrane Collaboration databases were searched for English-language studies published between January 1966 and October 2007. STUDY SELECTION: Randomized, controlled trials that compared growth hormone treatment with no growth hormone treatment in community-dwelling healthy participants between 13 and 45 years of age. DATA EXTRACTION: 2 authors independently reviewed articles and abstracted data. DATA SYNTHESIS: 44 articles describing 27 study samples met inclusion criteria; 303 participants received growth hormone, representing 13.3 person-years of treatment. Participants were young (mean age, 27 years [SD, 3]), lean (mean body mass index, 24 kg/m2 [SD, 2]), and physically fit (mean maximum oxygen uptake, 51 mL/kg of body weight per minute [SD, 8]). Growth hormone dosage (mean, 36 microg/kg per day [SD, 21]) and treatment duration (mean, 20 days [SD, 18] for studies giving growth hormone for >1 day) varied. Lean body mass increased in growth hormone recipients compared with participants who did not receive growth hormone (increase, 2.1 kg [95% CI, 1.3 to 2.9 kg]), but strength and exercise capacity did not seem to improve. Lactate levels during exercise were statistically significantly higher in 2 of 3 studies that evaluated this outcome. Growth hormone-treated participants more frequently experienced soft tissue edema and fatigue than did those not treated with growth hormone. LIMITATIONS: Few studies evaluated athletic performance. Growth hormone protocols in the studies may not reflect real-world doses and regimens. CONCLUSION: Claims that growth hormone enhances physical performance are not supported by the scientific literature. Although the limited available evidence suggests that growth hormone increases lean body mass, it may not improve strength; in addition, it may worsen exercise capacity and increase adverse events. More research is needed to conclusively determine the effects of growth hormone on athletic performance.

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.

Bronchodilators in COPD: impact of beta-agonists and anticholinergics on severe exacerbations and mortality.

This review summarizes the long-term clinical outcomes associated with beta-agonist and anticholinergic bronchodilator use in patients with chronic obstructive pulmonary disease (COPD). Pooled data from randomized placebo-controlled trials of at least three months duration were used to evaluate the risk for COPD hospitalizations, respiratory mortality, and total mortality. The results show that anticholinergic use is associated with a 30% reduction in COPD hospitalizations, a 70% reduction in respiratory mortality, and without a significant effect on total mortality. In contrast, beta-agonist use had no effect on COPD hospitalizations and was associated with a two-fold increased risk for respiratory death compared with placebo. When the two bronchodilators were directly compared with each other, beta-agonists were associated with a two-fold increased risk for COPD hospitalization and a five-fold increased risk for total mortality compared with anticholinergics. When beta-agonists were added to either anticholinergic use or inhaled corticosteroid use alone, there was no significant improvement in any long-term clinical outcome. These results indicate that anticholinergics should be the bronchodilator of choice in COPD, while beta-agonists may be associated with poorer disease control.