Christine G. Kohn

Quality of vitamin K antagonist control and outcomes in atrial fibrillation patients: a meta-analysis and meta-regression

BackgroundAtrial fibrillation (AF) patients frequently require anticoagulation with vitamin K antagonists (VKAs) to prevent thromboembolic events, but their use increases the risk of hemorrhage. We evaluated time spent in therapeutic range (TTR), proportion of international normalized ratio (INR) measurements in range (PINRR), adverse events in relation to INR, and predictors of INR control in AF patients using VKAs.MethodsWe searched MEDLINE, CENTRAL and EMBASE (1990-June 2013) for studies of AF patients receiving adjusted-dose VKAs that reported INR control measures (TTR and PINRR) and/or reported an INR measurement coinciding with thromboembolic or hemorrhagic events. Random-effects meta-analyses and meta-regression were performed.ResultsNinety-five articles were included. Sixty-eight VKA-treated study groups reported measures of INR control, while 43 studies reported an INR around the time of the adverse event. Patients spent 61% (95% CI, 59–62%), 25% (95% CI, 23–27%) and 14% (95% CI, 13-15%) of their time within, below or above the therapeutic range. PINRR assessments were within, below, and above range 56% (95% CI, 53–59%), 26% (95% CI, 23–29%) and 13% (95% CI, 11-17%) of the time. Patients receiving VKA management in the community spent less TTR than those managed by anticoagulation clinics or in randomized trials. Patients newly receiving VKAs spent less TTR than those with prior VKA use. Patients in Europe/United Kingdom spent more TTR than patients in North America. Fifty-seven percent (95% CI, 50-64%) of thromboembolic events and 42% (95% CI, 35 – 51%) of hemorrhagic events occurred at an INR <2.0 and >3.0, respectively; while 56% (95% CI, 48-64%) of ischemic strokes and 45% of intracranial hemorrhages (95% CI, 29-63%) occurred at INRs <2.0 and >3.0, respectively.ConclusionsPatients on VKAs for AF frequently have INRs outside the therapeutic range. While, thromboembolic and hemorrhagic events do occur patients with a therapeutic INR; patients with an INR <2.0 make up many of the cases of thromboembolism, while those >3.0 make up many of the cases of hemorrhage. Managing anticoagulation outside of a clinical trial or anticoagulation clinic is associated with poorer INR control, as is, the initiation of therapy in the VKA-naïve. Patients in Europe/UK have better INR control than those in North America.

Comparative Efficacy and Safety of Antidiabetic Drug Regimens Added to Metformin Monotherapy in Patients with Type 2 Diabetes: A Network Meta-Analysis

Introduction When first line therapy with metformin is insufficient for patients with type 2 diabetes (T2D), the optimal adjunctive therapy is unclear. We assessed the efficacy and safety of adjunctive antidiabetic agents in patients with inadequately controlled T2D on metformin alone. Materials and Methods A search of MEDLINE and CENTRAL, clinicaltrials.gov, regulatory websites was performed. We included randomized controlled trials of 3–12 months duration, evaluating Food and Drug Administration or European Union approved agents (noninsulin and long acting, once daily basal insulins) in patients experiencing inadequate glycemic control with metformin monotherapy (≥1500 mg daily or maximally tolerated dose for ≥4 weeks). Random-effects network meta-analyses were used to compare the weighted mean difference for changes from baseline in HbA1c, body weight (BW) and systolic blood pressure (SBP), and the risk of developing hypoglycemia, urinary (UTI) and genital tract infection (GTI). Results Sixty-two trials evaluating 25 agents were included. All agents significantly reduced HbA1c vs. placebo; albeit not to the same extent (range, 0.43% for miglitol to 1.29% for glibenclamide). Glargine, sulfonylureas (SUs) and nateglinide were associated with increased hypoglycemia risk vs. placebo (range, 4.00–11.67). Sodium glucose cotransporter-2 (SGLT2) inhibitors, glucagon-like peptide-1 analogs, miglitol and empagliflozin/linagliptin significantly reduced BW (range, 1.15–2.26kg) whereas SUs, thiazolindinediones, glargine and alogliptin/pioglitazone caused weight gain (range, 1.19–2.44kg). SGLT2 inhibitors, empagliflozin/linagliptin, liraglutide and sitagliptin decreased SBP (range, 1.88–5.43mmHg). No therapy increased UTI risk vs. placebo; however, SGLT2 inhibitors were associated with an increased risk of GTI (range, 2.16–8.03). Conclusions Adding different AHAs to metformin was associated with varying effects on HbA1c, BW, SBP, hypoglycemia, UTI and GTI which should impact clinician choice when selecting adjunctive therapy.

Prognostic Accuracy of Clinical Prediction Rules for Early Post-Pulmonary Embolism All-Cause Mortality: A Bivariate Meta-analysis

BACKGROUND Studies suggest outpatient treatment or early discharge of patients with acute pulmonary embolism (aPE) is reasonable for those deemed to be at low risk of early mortality. We sought to determine clinical prediction rule accuracy for identifying patients with aPE at low risk for mortality. METHODS We performed a literature search of Medline and Embase from January 2000 to March 2014, along with a manual search of references. We included studies deriving/validating a clinical prediction rule for early post-aPE all-cause mortality and providing mortality data over at least the index aPE hospitalization but ≤ 90 days. A bivariate model was used to pool sensitivity and specificity estimates using a random-effects approach. Traditional random-effects meta-analysis was performed to estimate the weighted proportion of patients deemed at low risk for early mortality and their ORs for death compared with high-risk patients. RESULTS Forty studies (52 cohort-clinical prediction rule analyses) reporting on 11 clinical prediction rules were included. The highest sensitivities were observed with the Global Registry of Acute Coronary Events (0.99, 95% CI = 0.89-1.00), Aujesky 2006 (0.97, 95% CI = 0.95-0.99), simplified Pulmonary Embolism Severity Index (0.92, 95% CI = 0.89-0.94), Pulmonary Embolism Severity Index (0.89, 95% CI = 0.87-0.90), and European Society of Cardiology (0.88, 95% CI = 0.77-0.94) tools, with remaining clinical prediction rule sensitivities ranging from 0.41 to 0.82. Of these five clinical prediction rules with the highest sensitivities, none had a specificity > 0.48. They suggested anywhere from 22% to 45% of patients with aPE were at low risk and that low-risk patients had a 77% to 97% lower odds of death compared with those at high risk. CONCLUSIONS Numerous clinical prediction rules for prognosticating early mortality in patients with aPE are available, but not all demonstrate the high sensitivity needed to reassure clinicians.

Original Research Pulmonary Vascular DiseasePrognostic Accuracy of Clinical Prediction Rules for Early Post-Pulmonary Embolism All-Cause Mortality: A Bivariate Meta-analysis

BACKGROUND Studies suggest outpatient treatment or early discharge of patients with acute pulmonary embolism (aPE) is reasonable for those deemed to be at low risk of early mortality. We sought to determine clinical prediction rule accuracy for identifying patients with aPE at low risk for mortality. METHODS We performed a literature search of Medline and Embase from January 2000 to March 2014, along with a manual search of references. We included studies deriving/validating a clinical prediction rule for early post-aPE all-cause mortality and providing mortality data over at least the index aPE hospitalization but ≤ 90 days. A bivariate model was used to pool sensitivity and specificity estimates using a random-effects approach. Traditional random-effects meta-analysis was performed to estimate the weighted proportion of patients deemed at low risk for early mortality and their ORs for death compared with high-risk patients. RESULTS Forty studies (52 cohort-clinical prediction rule analyses) reporting on 11 clinical prediction rules were included. The highest sensitivities were observed with the Global Registry of Acute Coronary Events (0.99, 95% CI = 0.89-1.00), Aujesky 2006 (0.97, 95% CI = 0.95-0.99), simplified Pulmonary Embolism Severity Index (0.92, 95% CI = 0.89-0.94), Pulmonary Embolism Severity Index (0.89, 95% CI = 0.87-0.90), and European Society of Cardiology (0.88, 95% CI = 0.77-0.94) tools, with remaining clinical prediction rule sensitivities ranging from 0.41 to 0.82. Of these five clinical prediction rules with the highest sensitivities, none had a specificity > 0.48. They suggested anywhere from 22% to 45% of patients with aPE were at low risk and that low-risk patients had a 77% to 97% lower odds of death compared with those at high risk. CONCLUSIONS Numerous clinical prediction rules for prognosticating early mortality in patients with aPE are available, but not all demonstrate the high sensitivity needed to reassure clinicians.

Impact of mobility impairment on indirect costs and health-related quality of life in multiple sclerosis.

This study was conducted to estimate the indirect costs and health-related quality of life (HRQoL) (utilities) of multiple sclerosis (MS) patients in the United States (US), and to determine the impact of worsening mobility on these parameters. In collaboration with the North American Research Committee on Multiple Sclerosis (NARCOMS) registry we conducted a cross-sectional study of participants who completed the biannual update and supplemental spring 2010 survey. Demographic, employment status, income, mobility impairment, and health utility data were collected from a sample of registry participants who met the study criteria and agreed to participate in the supplemental Mobility Study. Mean annual indirect costs per participant in 2011US

Meta-Analysis to Assess the Quality of International Normalized Ratio Control and Associated Outcomes in Venous Thromboembolism Patients

and mean utilities for the population and for cohorts reporting different levels of mobility impairment were estimated. Analyses included 3,484 to 3,611 participants, based on survey completeness. Thirty-seven percent of registrants were not working or attending school and 46.7% of these reported retiring early. Indirect costs per participant per year, not including informal caregiver cost, were estimated at

Cost-Effectiveness of Immune Checkpoint Inhibition in BRAF Wild-Type Advanced Melanoma

30,601±31,184. The largest relative increase in indirect costs occurred at earlier mobility impairment stages, regardless of the measure used. Participants’ mean utility score (0.73±0.18) was lower than that of a similarly aged sample from the general US population (0.87). As with indirect costs, larger decrements in utility were seen at earlier mobility impairment stages. These results suggest that mobility impairment may contribute to increases in indirect costs and declines in HRQoL in MS patients.

Efficacy and safety of antihyperglycaemic drug regimens added to metformin and sulphonylurea therapy in Type 2 diabetes: a network meta-analysis

INTRODUCTION Patients with venous thromboembolism (VTE) frequently require vitamin K antagonists (VKAs) to prevent recurrent events, but their use increases hemorrhage risk. We performed a meta-analysis to assess the quality of international normalized ratio (INR) control, identify study-level predictors of poor control and to examine the relationship between INR control and adverse outcomes in VTE patients. MATERIALS AND METHODS We searched bibliographic databases (1990-June 2013) for studies of VTE patients receiving adjusted-dose VKAs that reported time in range (2.0-3.0) or proportion of INRs in range and/or reported INR measurements coinciding with thromboembolic or hemorrhagic events. Meta-analysis and meta-regression analysis was performed. RESULTS Upon meta-analysis, studies found 59% (95%CI: 54-64%) of INRs measured and 61% (95%CI: 59-63%) of the time patients were treated were spent outside the target range of 2.0-3.0; with a tendency for under- versus over-anticoagulation. Moreover, this poor INR control resulted in a greater chance of recurrent VTE (beta-coefficient=-0.46, p=0.01) and major bleeding (beta-coefficient=-0.30, p=0.02). Patients with an INR<2.0 made up 58% (95%CI: 39-77%) of VTE cases, while those with an INR>3.0 made up 48% (95%CI: 34-61%) of major hemorrhage cases. Upon meta-regression, being VKA-naïve (-14%, p=0.04) and treated in the community (-7%, p<0.001) were associated with less time in range, while being treated in Europe/United Kingdom (compared to North America) was associated with (11%, p=0.003) greater time. CONCLUSIONS Strategies to improve INR control or alternative anticoagulants, including the newer oral agents, should be widely implemented in VTE patients to reduce the rate of recurrent events and bleeding.

Derivation and validation of the In-hospital Mortality for PulmonAry embolism using Claims daTa (IMPACT) prediction rule

Purpose Patients who are diagnosed with stage IV metastatic melanoma have an estimated 5-year relative survival rate of only 17%. Randomized controlled trials of recent US Food and Drug Administration-approved immune checkpoint inhibitors-pembrolizumab (PEM), nivolumab (NIVO), and ipilumumab (IPI)-demonstrate improved patient outcomes, but the optimal treatment sequence in patients with BRAF wild-type metastatic melanoma remains unclear. To inform policy makers about the value of these treatments, we developed a Markov model to compare the cost-effectiveness of different strategies for sequencing novel agents for the treatment of advanced melanoma. Materials and Methods We developed Markov models by using a US-payer perspective and lifetime horizon to estimate costs (2016 US

Cost-Effectiveness of Ranolazine Added to Standard-of-Care Treatment in Patients With Chronic Stable Angina Pectoris

) and quality-adjusted life years (QALYs) for treatment sequences with first-line NIVO, IPI, NIVO + IPI, PEM every 2 weeks, and PEM every 3 weeks. Health states were defined for initial treatment, first and second progression, and death. Rates for drug discontinuation, frequency of adverse events, disease progression, and death obtained from randomized phase III trials were used to determine the likelihood of transition between states. Deterministic and probabilistic sensitivity analyses were conducted to evaluate model uncertainty. Results PEM every 3 weeks followed by second-line IPI was both more effective and less costly than dacarbazine followed by IPI then NIVO, or IPI followed by NIVO. Compared with the first-line dacarbazine treatment strategy, NIVO followed by IPI produced an incremental cost effectiveness ratio of