Comparative risk of major bleeding with rivaroxaban and warfarin: Population-based cohort study of unprovoked venous thromboembolism.

OBJECTIVES: To assess the association between rivaroxaban and warfarin and major bleeding risk in unprovoked venous thromboembolism (VTE) patients. METHODS: Using US MarketScan claims from 1/2012-12/2016, we identified patients who had ≥1 primary hospitalization/emergency department visit diagnosis code for an unprovoked VTE, newly initiated on rivaroxaban or warfarin within 30 days after the VTE and ≥12 months of insurance coverage prior to the VTE. Differences in baseline covariates were adjusted using inverse-probability-of-treatment weights based on propensity scores (residual absolute standardized differences <0.1 achieved for all covariates). Endpoints included any major, gastrointestinal, genitourinary, intracranial, and other bleeds. Patients were followed for up to 12 months or until endpoint occurrence, index oral anticoagulant discontinuation/switch, insurance disenrollment or end of follow-up. RESULTS: We identified 10 489 rivaroxaban and 26 364 warfarin patients with an unprovoked VTE. Upon Cox regression, rivaroxaban reduced patients' hazard of major bleeding by 27% (95% confidence interval [CI] = 8%-42%), gastrointestinal bleeding by 38% (95% CI = 14%-55%), and intracranial hemorrhage by 81% (95% CI = 41%-99%) vs warfarin. No subtype of major bleeding occurred statistically more often in rivaroxaban vs warfarin-treated patients. CONCLUSIONS: Rivaroxaban was associated with a reduced risk of overall, gastrointestinal, and intracranial major bleeding vs warfarin in unprovoked VTE. No bleeding subtype was significantly more frequent in rivaroxaban patients.

External validation of three risk stratification rules in patients presenting with pulmonary embolism and cancer.

Numerous risk stratification rules exist to predict post-pulmonary embolism (PE) mortality; however, few were designed for use in cancer patients. In the EPIPHANY registry, adapted versions of common rules (the Hestia criteria, Pulmonary Embolism Severity Index [PESI], and simplified PESI [sPESI]) displayed high sensitivity for prognosticating mortality in PE patients with cancer. These adapted rules have yet to be externally validated. Therefore, we sought to evaluate the performance of an adapted Hestia criteria, PESI, and sPESI for predicting 30-day post-PE mortality in patients with cancer. We identified consecutive, adults presenting with objectively confirmed PE and cancer to our institution (November 2010 to January 2014). The proportion of patients categorized as low or high risk by these three risk stratification rules was calculated, and each rule's accuracy for predicting 30-day all-cause mortality was determined. Of the 124 patients with PE and active cancer identified, 25 (20%) experienced mortality at 30 days. The adapted Hestia criteria categorized 23 (19%) patients as low risk, while exhibiting a sensitivity of 88% (95% confidence interval [CI] = 68-97%), a negative predictive value NPV of 87% (95% CI = 65-97%), and a specificity of 20% (95% CI = 13-30%). A total of 38 (31%) and 30 (24%) patients were low risk by the adapted PESI and sPESI, with both displaying sensitivities of 92% and NPVs > 93%. Specificities were 36% (95% CI = 27-47%) and 28% (95% CI = 20-38%) for PESI and sPESI. In our external validation, the adapted Hestia, PESI, and sPESI demonstrated high sensitivity but low specificity for 30-day PE mortality in patients with cancer. Larger, prospective trials are needed to optimize strategies for risk stratification in this population.

Effectiveness and Safety of Rivaroxaban in Patients With Cancer-Associated Venous Thrombosis.

Background: Although not designated as guideline-recommended first-line anticoagulation therapy, patients are receiving rivaroxaban for the treatment and secondary prevention of cancer-associated venous thrombosis (CAT). We sought to estimate the cumulative incidence of recurrent venous thromboembolism (VTE), major bleeding, and mortality/hospice care in patients with CAT treated with outpatient rivaroxaban in routine practice. Methods: Using US MarketScan claims data from January 2012 through June 2015, we identified adults with active cancer (using SEER program coding) who had ≥1 primary hospitalization or emergency department discharge diagnosis code for VTE (index event) and received rivaroxaban as their first outpatient anticoagulant within 30 days of the index VTE. Patients were required to have ≥180 days of continuous medical/prescription benefits prior to the index VTE. Patients with a previous claim for VTE, atrial fibrillation, or valvular disease or receiving anticoagulation during the baseline period were excluded. We estimated the cumulative incidence with 95% CIs of recurrent VTE, major bleeding, and mortality or need for hospice care at 180 days, assuming competing risks. Results: A total of 949 patients with active cancer were initiated on rivaroxaban following their index VTE. Time from active cancer diagnosis to index CAT was ≤90 days for 27% of patients, 91 to 180 days for 19%, and >180 days for 54%. The mean [SD] age of patients was 62.5 [12.8] years, 43.6% had pulmonary embolism, and metastatic disease was present in 42.6%. During follow-up, there were 37 cases of recurrent VTE, 22 cases of major bleeding (17 gastrointestinal, 3 intracranial, 1 genitourinary, and 1 other bleed), and 105 deaths/hospice claims. The cumulative incidence estimate was 4.0% (95% CI, 2.8%-5.4%) for recurrent VTE, 2.7% (95% CI, 1.7%-4.0%) for major bleeding, and 11.3% (95% CI, 9.2%-13.6%) for mortality/hospice care. Conclusions: Event rates observed in this rivaroxaban-treated cohort were overall consistent with previous studies of patients with rivaroxaban- and warfarin-managed CAT.

External Validation of Generic and Cancer-Specific Risk Stratification Tools in Patients With Pulmonary Embolism and Active Cancer.

Background: Numerous risk stratification tools exist to predict early post-pulmonary embolism (PE) mortality; however, few were specifically designed for use in patients with cancer. This study sought to evaluate the performance of 3 cancer-specific (RIETE, POMPE-C, and Font criteria) and 3 generic (Hestia, Pulmonary Embolism Severity Index [PESI], and Geneva prognostic score [GPS]) risk stratification tools for predicting 30-day post-PE mortality in patients with active cancer. Methods: We identified consecutive, adult, objectively confirmed patients with PE and active cancer presenting to our institution from November 2010 to January 2014. We calculated the proportion of patients categorized as low or high risk by each of the 6 risk stratification tools and determined each tools' accuracy for predicting 30-day all-cause mortality. Results: A total of 124 patients with PE and active cancer were included (mean age, 66.2 years; 46.0% with concurrent deep vein thrombosis; 49.2% with metastatic disease; and 46.8%, 16.9%, and 11.3% receiving chemotherapy, radiation, or both, respectively). Mortality at 30 days occurred in 25 patients (20.2%). The cancer-specific tools (POMPE-C, RIETE, and Font criteria) categorized between 32% and 43% of patients as low risk and displayed sensitivities and specificities of 88.0% to 96.0% and 38.4% to 52.5%, respectively. The generic PESI and Hestia tools had sensitivities >96.0%, but classified <19% of patients as low risk; specificity of these tools were low (PESI, 6.1%; Hestia, 23.2%). Although the final noncancer tool, GPS, classified 43.5% of patients as low risk, it did so with a sensitivity of 52.0% and specificity of 42.4%. Conclusions: When risk-stratifying PE in patients with active cancer, cancer-specific tools appeared to exhibit better prognostic accuracy than their generic counterparts. POMPE-C, RIETE, and the Font criteria identified a substantially greater proportion of patients with PE likely to survive to 30 days with comparable sensitivity to the generic tools.

Cost-effectiveness analysis of 1st through 3rd line sequential targeted therapy in HER2-positive metastatic breast cancer in the United States.

PURPOSE: Based on available phase III trial data, we performed a cost-effectiveness analysis of different treatment strategies that can be used in patients with newly diagnosed HER2-positive metastatic breast cancer (mBC). PATIENTS AND METHODS: We constructed a Markov model to assess the cost-effectiveness of four different HER2 targeted treatment sequences in patients with HER2-positive mBC treated in the U.S. The model followed patients weekly over their remaining life expectancies. Health states considered were progression-free survival (PFS) 1st to 3rd lines, and death. Transitional probabilities were based on published phase III trials. Cost data (2015 US dollars) were captured from the U.S. Centers for Medicare and Medicaid Services (CMS) drug payment table and physician fee schedule. Health utility data were extracted from published studies. The outcomes considered were PFS, OS, costs, QALYs, the incremental cost per QALY gained ratio, and the net monetary benefit. Deterministic and probabilistic sensitivity analyses assessed the uncertainty around key model parameters and their joint impact on the base-case results. RESULTS: The combination of trastuzumab, pertuzumab, and docetaxel (THP) as first-line therapy, trastuzumab emtansine (T-DM1) as second-line therapy, and lapatinib/capecitabine third-line resulted in 1.81 QALYs, at a cost of $335,231.35. The combination of trastuzumab/docetaxel as first line without subsequent T-DM1 or pertuzumab yielded 1.41 QALYs, at a cost of $175,240.69. The least clinically effective sequence (1.27 QALYs), but most cost-effective at a total cost of $149,250.19, was trastuzumab/docetaxel as first-line therapy, T-DM1 as second-line therapy, and trastuzumab/lapatinib as third-line therapy. CONCLUSION: Our results suggest that THP as first-line therapy, followed by T-DM1 as second-line therapy, would require at least a 50 % reduction in the total drug acquisition cost for it to be considered a cost-effective strategy.

External validation of prognostic rules for early post-pulmonary embolism mortality: assessment of a claims-based and three clinical-based approaches.

BACKGROUND: Studies show the In-hospital Mortality for Pulmonary embolism using Claims daTa (IMPACT) rule can accurately identify pulmonary embolism (PE) patients at low-risk of early mortality in a retrospective setting using only claims for the index admission. We sought to externally validate IMPACT, Pulmonary Embolism Severity Index (PESI), simplified PESI (sPESI) and Hestia for predicting early mortality. METHODS: We identified consecutive adults admitted for objectively-confirmed PE between 10/21/2010 and 5/12/2015. Patients undergoing thrombolysis/embolectomy within 48 h were excluded. All-cause in-hospital and 30 day mortality (using available Social Security Death Index data through January 2014) were assessed and prognostic accuracies of IMPACT, PESI, sPESI and Hestia were determined. RESULTS: Twenty-one (2.6 %) of the 807 PE patients died before discharge. All rules classified 26.1-38.3 % of patients as low-risk for early mortality. Fatality among low-risk patients was 0 % (sPESI and Hestia), 0.4 % (IMPACT) and 0.6 % (PESI). IMPACT's sensitivity was 95.2 % (95 % confidence interval [CI] = 74.1-99.8 %), and the sensitivities of clinical rules ranged from 91 (PESI)-100 % (sPESI and Hestia). Specificities of all rules ranged between 26.8 and 39.1 %. Of 573 consecutive patients in the 30 day mortality analysis, 33 (5.8 %) died. All rules classified 27.9-38.0 % of patients as low-risk, and fatality occurred in 0 (Hestia)-1.4 % (PESI) of low-risk patients. IMPACT's sensitivity was 97.0 % (95%CI = 82.5-99.8 %), while sensitivities for clinical rules ranged from 91 (PESI)-100 % (Hestia). Specificities of rules ranged between 29.6 and 39.8 %. CONCLUSION: In this analysis, IMPACT identified low-risk PE patients with similar accuracy as clinical rules. While not intended for prospective clinical decision-making, IMPACT appears useful for identification of low-risk PE patient in retrospective claims-based studies.

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

BACKGROUND: Atrial 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. METHODS: We 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. RESULTS: Ninety-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. CONCLUSIONS: Patients 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.

Impact of angina frequency on health utility values of patients with chronic stable angina.

BACKGROUND: Chronic angina is a profoundly symptomatic disease. We evaluated the relationship between angina frequency and health utility. METHODS: We used data from stable angina patients reporting ≥3 attacks/week enrolled in the Efficacy of Ranolazine in Chronic Angina (ERICA) trial. Angina frequency was classified using the Seattle Angina Questionnaire angina frequency (SAQAF) domain into no (100); monthly (61-99); weekly (31-60); and daily (0-30) angina. EuroQol (EQ)-5D health utility scores were derived from SAQ data using two mapping equations. Median EQ-5D utility scores for each SAQAF classification after the 6-week trial period were calculated (reported as: Equation 1/Equation 2). Changes in EQ-5D utility scores from baseline to end-of-trial for patients achieving and not achieving a ≥20-point improvement in SAQAF score and improving and not improving ≥1 SAQAF classification were compared. RESULTS: Median EQ-5D utility scores (n = 548) were 0.68/0.60. Compared to patients reporting no angina symptoms (n = 28; 0.89/0.87) patients reporting monthly (n = 188; 0.80/0.76), weekly (n = 283; 0.72/0.65) and daily (n = 49; 0.65/0.54) symptoms had poorer health utility (p < 0.001 for both equations). Patients improving ≥1SAQAF classification (n = 254/541, 47%) experienced a median 0.05/0.07 greater improvement in EQ-5D health utility compared to those not improving ≥1 classification (p < 0.001 for both equations). Patients improving ≥20-points on the SAQAF (n = 355/541, 66%) experienced a median 0.06/0.07 greater improvement in health utility compared to those not achieving a ≥20-point improvement (p < 0.001 for both). CONCLUSIONS: Chronic angina patient health utility decreases as angina frequency increases. Patients reporting clinically important improvement in angina frequency experience a tangible improvement in health utility. CLINICAL TRIAL REGISTRATION: NCT00091429.

Estimating a minimal clinically important difference for the EuroQol 5-Dimension health status index in persons with multiple sclerosis.

BACKGROUND: Limited data define what constitutes a minimal clinically important difference (MCID) on the EuroQol 5-Dimension (EQ-5D) health status index in persons with multiple sclerosis (PwMS). We sought to estimate the MCID for the EQ-5D health index in North American PwMS. METHODS: PwMS completing the Patient Determined Disease Steps (PDDS) scale, 12-Item Multiple Sclerosis Walking Scale (MSWS-12) and EQ-5D as part of the North American Research Committee on Multiple Sclerosis (NARCOMS) registry's spring 2011 update and supplemental survey were included in this retrospective, cross-sectional study. Distribution-based (standard error of measurement [SEM], 0.50 standard deviation [SD] and 0.33 SD unit) approaches were used to estimate a range of MCIDs for the EQ-5D based upon disease severity groups determined by the PDDS and MSWS-12 tertiles. RESULTS: A total of 3,044 participants were included. Moderately strong correlations between the EQ-5D and the PDDS and MSWS-12 were observed (Spearman's r = -0.56 and -0.59, respectively, p < 0.0001 for both). MCID estimates based on PDDS score categories ranged from 0.065-0.158 (SEMs), 0.059-0.142 (0.50 SDs) and 0.039-0.095 (0.33 SDs). MCID estimates as measured by MSWS-12 tertile categories ranged from 0.068-0.098 (SEMs), 0.061-0.088 (0.50 SDs), and 0.041-0.059 (0.33 SDs). Across both the PDDS and tertiles of MSWS-12, MCID estimates tended to be larger as disease severity worsened. Mean weighted MCID estimates ranged from 0.05-0.084 for both the PDDS and MSWS-12 tertiles. CONCLUSION: MCID estimates for the EQ-5D in PwMS were within the range of estimates seen for other disease states and appeared to be larger in those reporting more severe disease.

Effectiveness and safety of rivaroxaban compared with low-molecular-weight heparin in cancer-associated thromboembolism.

Guidelines provide differing recommendations regarding direct-acting oral anticoagulants vs low-molecular-weight heparin (LMWH) for treatment of cancer-associated thrombosis (CAT). This study was undertaken to evaluate the effectiveness and safety of rivaroxaban vs LMWH for treatment of CAT. Using US Surveillance, Epidemiology and End Results-Medicare-linked data from 2013 through 2016, we evaluated adults with active breast, lung, ovarian, or pancreatic cancer, who were admitted to the hospital or treated in the emergency department for CAT and were prescribed rivaroxaban or LMWH for outpatient anticoagulation. Patients with luminal gastrointestinal or genitourinary cancers were excluded. Rivaroxaban and LMWH users were 1:1 propensity score matched. Outcomes included the composite of recurrent thrombosis or major bleeding, each outcome separately, and mortality at 6 months, using an intent-to-treat approach. On-treatment analysis after 12 months was also performed. Proportional hazards models for the subdistribution of competing risk were used to estimate hazard ratios (HRs) with 95% confidence intervals (CIs). We included 529 rivaroxaban- and 529 LMWH-treated patients with CAT. Rivaroxaban was not associated with differences in risk of the composite outcome (HR, 0.71; 95% CI, 0.41-1.22), major bleeding (HR, 1.01; 95% CI, 0.50-2.01), or mortality (HR, 0.87; 95% CI, 0.70-1.07) vs LMWH, but it reduced recurrent thrombosis (HR, 0.37; 95% CI, 0.15-0.95). On-treatment analysis at 12 months showed similar results. Rivaroxaban may be a reasonable alternative to LMWH for patients with CAT without gastrointestinal or genitourinary cancer.

The non-medical switching of prescription medications.

Non-medical switching of medication, whereby a patient's treatment regimen is changed for reasons other than efficacy, side effects, or adherence, is often related to drug formulary changes aimed at reducing drug costs. In the era of health care reform, while cost-cutting measures are important, there is considerable evidence that non-medical switching, particularly when applied to medication used to treat chronic conditions such as diabetes, may impact patient outcomes, medication-taking behavior, and use of health care services. Ultimately, overall costs may be increased, as savings by insurers are cancelled out by higher costs to the health care system as a whole, such as extra administration, treatment failure from new medicines, and increased adverse events. The emergence of biosimilar and follow-on biologic treatments raises further questions among patients receiving biologic treatments, with patient advocacy groups calling for clear legislation to ensure that patients with complex or chronic conditions continue to receive effective, evidence-based medications for their disease. This article will discuss non-medical switching in the US, taking into account the different parties involved, such as patients, health care providers, pharmacists, payers, and pharmacy benefit managers, with the aim of providing a detailed overview of this complex and evolving topic.

Cost and inpatient burden of peripheral artery disease: Findings from the National Inpatient Sample.

BACKGROUND AND AIMS: We aimed to examine the prevalence, demographics, clinical outcomes and economic burden of hospitalizations for patients with PAD. METHODS: Using the National Inpatient Sample, we retrospectively evaluated patients hospitalized with PAD in 2014. Hospitalizations in patients with PAD were identified by the presence of an International Classification of Diseases-9th Revision (ICD-9) diagnosis code of 440.20-440.24. We calculated hospitalization rates/100,000 patients, the proportion of hospitalizations with a major adverse limb event (MALE), as well as minor amputation, mortality, median (interquartile range) length-of-stay (LOS) and treatment costs (in 2017 US$). A separate analysis of hospitalizations of patients with clinical limb ischemia defined as Fontaine class III or IV PAD (440.22, resting pain; 440.23-440.24, ulcers or gangrene) was also performed. RESULTS: We identified 286,160 hospitalizations for patients with PAD. The rate of hospitalizations for PAD was 89.5/100,000, with 137,050 (or 45%) of these having Fontaine class III-IV disease. The proportion of hospitalizations resulting in MALE, major or minor lower extremity amputation or in-hospital death was 45.8%, 8.9%, 8.2% and 3.1%, respectively. Median hospital LOS was 5 (3, 9) days and costs were $15,755 ($8972, $27,800), resulting in an annual cost burden for hospitalization of patients with PAD of ∼$6.31 billion. In hospitalizations of Fontaine class III-IV PAD, MALE, major and minor amputation and death occurred in 60.9%, 16.8%, 15.8% and 3.3% of cases, respectively. Median LOS and costs were 7 (4, 11) days and $18,984 ($10,913, $31,816). CONCLUSIONS: Hospitalizations of patients with PAD represent a substantial medical and financial burden for patients and the US healthcare system.

Ranolazine in patients with type 2 diabetes and chronic angina: A cost-effectiveness analysis and assessment of health-related quality-of-life.

BACKGROUND: Type 2 diabetes (T2D) is associated with a high burden of angina. Ranolazine has been shown to reduce angina frequency versus placebo in patients with T2D and stable angina. We sought to estimate the cost-effectiveness of ranolazine when added to standard-of-care (SoC) versus SoC alone in patients with T2D and stable, but symptomatic coronary disease despite treatment with 1-2 antianginals. METHODS: A Markov model was developed and evaluated using cohort simulation. The model utilized a US societal perspective, 1-month cycle length and 1-year time horizon and was developed to estimate the cost-effectiveness of ranolazine versus SoC. Patients entered the model in 1 of 4 angina frequency health states based on baseline Seattle Angina Questionnaire Angina Frequency scores (100 = no; 61-99 = monthly; 31-60 = weekly; 0-30 = daily) and could transition between health states (first cycle only) or to death (any cycle) based on probabilities derived from the Type 2 Diabetes Evaluation of Ranolazine in Subjects with Chronic Stable Angina trial. RESULTS: Our model estimated patients treated with ranolazine lived a mean of 0.728 quality adjusted life years (QALYs) at a cost of $16,654. Those not receiving ranolazine lived a mean of 0.702 QALYs and incurred costs of $15,476. The incremental cost-effectiveness ratio for the addition of ranolazine to SoC was $45,308/QALY. Short Form-36 data suggest improvements in patients' bodily pain drove the gain in QALYs associated with ranolazine (2.73 versus 3.96, p = 0.01). CONCLUSION: Our model suggests the addition of ranolazine to SoC is likely cost-effective from a US societal perspective for the treatment of patients with T2D and stable, symptomatic coronary disease despite treatment with 1-2 antianginals.

Wearable Cardioverter-defibrillators for the Prevention of Sudden Cardiac Death: A Meta-analysis.

Wearable cardioverter-defibrillators (WCDs) protect patients from sudden cardiac death (SCD) by detecting and treating life-threatening ventricular tachycardia/fibrillation (VT/VF). Recently, two large studies evaluating WCDs were published. However, the results of older and newer studies have yet to be systematically summarized. The objective of the current study was to conduct a meta-analysis assessing the use and effectiveness of WCDs. We searched MEDLINE and Scopus (January 1998-July 2017) as well as the gray literature. We included registry/observational studies that (1) evaluated adult patients using WCDs; (2) provided data on one or more outcomes of interest; and (3) were full-text studies published in English. We calculated pooled incidence and/or rate [with 95% confidence intervals (CIs)] estimates from nonoverlapping populations using a random-effects meta-analysis model. Statistical heterogeneity was assessed via the I2 statistic. We identified 11 studies (19,882 patients) with nonoverlapping populations/endpoints; seven of them evaluated WCD use across various indications, while the remaining studies restricted their focus to a single indication. Most of the studies were retrospective (82%) and multicenter (64%) in nature, with 45% using manufacturers' registry data. The median duration of WCD use was three or more months in nine (82%) studies, and daily wear time ranged from a mean/median of 17 hours to 24 hours per day across included studies. Seven (64%) studies reported a mean/median daily wear time of more than 20 hours. This meta-analysis showed that the incidences of all-cause and SCD-related mortality among WCD patients were 1.4% (95% CI: 0.7%-2.4%) and 0.2% (95% CI: 0.1%-0.3%), respectively. VT/VF occurred in 2.6% (95% CI: 1.8%-3.5%) of patients. Across patients, 1.7% (95% CI: 1.4%-2.0%) received appropriate WCD treatment, corresponding to a rate of 9.1 patients/100 person-years (95% CI: 6.2-11.9 patients/100 person-years). Successful VT/VF termination following appropriate treatment occurred in 95.5% of patients (95% CI: 92.0%-98.0%) and the incidence of inappropriate treatment was infrequent (0.9%; 95% CI: 0.5%-1.4%). A moderate-to-high degree of statistical heterogeneity was observed in pooled analyses of mortality, VT/VF occurrence, and appropriate/inappropriate treatment (I2 ≥ 41% for all). In conclusion, WCDs appear to be successful in terms of terminating VT/VF in patients with an elevated risk of SCD and are appropriate for use while long-term risk management strategies are being identified.

Mechanical endovascular therapy for acute ischemic stroke: An indirect treatment comparison between Solitaire and Penumbra thrombectomy devices.

BACKGROUND: Randomized controlled trials (RCTs) have compared mechanical endovascular therapy (MET) in addition to intravenous tissue plasminogen activator (IVtPA) to IVtPA alone for the management of acute ischemic stroke (AIS). Direct comparative studies between individual METs are not available. In lieu of head-to-head randomized control trials, we performed an adjusted indirect treatment comparison (ITC) meta-analysis to assess the comparative efficacy and safety of different METs, Solitaire+IVtPA and Penumbra+IVtPA in AIS patients. METHODS AND FINDINGS: We searched MEDLINE, the Cochrane Central Register of Controlled Trials and Embase from January 1, 2005 through April 1, 2017 for RCTs in AIS patients, comparing a single MET+IVtPA to IVtPA alone and reporting shift in ordinal modified Rankin Scale (mRS) score at 90 days. Secondary endpoints included 90 day mortality and symptomatic intracranial hemorrhage (sICH). Endpoints were pooled using traditional random effects meta-analysis methods, producing odds ratios and 95% confidence intervals. Adjusted ITCs using pooled estimates were then performed. Three studies (SWIFT PRIME, EXTEND-IA, THERAPY) were included; two evaluating the Solitaire stent retriever and one the Penumbra system. Traditional meta-analysis demonstrated that each MET+IVtPA resulted in increased odds of improving ordinal mRS score vs. IVtPA alone, but did not alter the odds of death or sICH. Adjusted ITC showed no significant difference between the METs for any outcome. CONCLUSION: No significant difference in efficacy or safety between the Solitaire and Penumbra devices was observed.

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

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$) 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 $90,871/QALY, and first-line NIVO + IPI followed by carboplatin plus paclitaxel chemotherapy produced an incremental cost effectiveness ratio of $198,867/QALY. Conclusion For patients with treatment-naive BRAF wild-type advanced melanoma, first-line PEM every 3 weeks followed by second-line IPI or first-line NIVO followed by second-line IPI are the most cost-effective, immune-based treatment strategies for metastatic melanoma.

Association between rivaroxaban use and length of hospital stay, treatment costs and early outcomes in patients with pulmonary embolism: a systematic review of real-world studies.

BACKGROUND: In the EINSTEIN-Pulmonary Embolism (PE) trial, subjects randomized to rivaroxaban versus enoxaparin bridging to vitamin K antagonist (VKA) therapy experienced a reduced index hospital length of stay (LOS). We sought to conduct a systematic review of real-world studies comparing LOS, costs and early outcomes among patients treated with rivaroxaban or parenterally bridged VKA in routine practice. METHODS: We searched Medline and Scopus from 1 January 2011 to 30 November 2016 to identify observational studies comparing acute PE patients anticoagulated with rivaroxaban or parenterally bridged VKA and reporting data on index hospital LOS, costs and/or early post-PE outcomes. Studies not using appropriate methods for minimizing confounding bias or not published in English were excluded. RESULTS: Five studies met inclusion criteria. Rivaroxaban use was associated with decreased index hospital LOS (range: 1.36-1.70 days) and treatment costs (range: $1818-$2688) during an index stay compared to parenterally bridged warfarin. No differences in early readmission for recurrent thrombosis were noted between anticoagulation strategies. Readmission for major bleeding was rare in both cohorts. Similar reductions in LOS (range: 0.23-4.3 days) and costs (range: $251-$7094) were observed with rivaroxaban in studies restricted to patients deemed low risk for early complications by clinical gestalt or by a clinical- or claims-based risk stratification tool. CONCLUSIONS: Regardless of patient predicted risk of post-PE complications, real-world studies suggest that rivaroxaban is associated with a reduced hospital LOS and costs versus parenterally bridged warfarin, without increasing readmission.

External Validation of the Hestia Criteria for Identifying Acute Pulmonary Embolism Patients at Low Risk of Early Mortality.

INTRODUCTION: There are limited studies evaluating the ability of the Hestia criteria to accurately identify patients with acute pulmonary embolism (PE) at low risk of early mortality. We sought to externally validate the Hestia criteria for predicting in-hospital and 30-day post-PE mortality. METHODS: We retrospectively identified consecutive, adult, objectively confirmed PE patients presenting to the emergency department at our institution from November 21, 2010, to January 31, 2014. We ascertained the total number of Hestia criteria met for each patient, calculated the proportion of patients categorized as low risk (ie, no Hestia criteria met), and determined the accuracy of the Hestia criteria for predicting in-hospital and 30-day all-cause mortality. Mortality was determined through Social Security Death Index searches. RESULTS: A total of 577 patients with PE were included, of which 19 (3.3%) and 35 (6.6%) died in hospital or within 30 days of presentation. Both in-hospital and 30-day case fatality rates rose as the number of Hestia criteria increased. One-hundred forty nine (25.8%) patients were classified as low risk for early mortality, and none of these patients died within 30 days (negative predictive values of 100%). The Hestia criteria had excellent sensitivity (100%, 95% confidence interval [CI] = 79.1%-100% and 100%, 95% CI = 87.7%-100%) for predicting in-hospital and 30-day mortality but low specificity (<27.5% for both). The c-statistics for in-hospital and 30-day mortality were 83.5%, 95% CI = 77.1%-89.9% and 78.5%, 95% CI = 71.9%-85.1%. The predictive accuracy of the Hestia criteria remained acceptable in patients >80 years of age, with active cancer or chronic cardiopulmonary disease. CONCLUSION: The Hestia criteria have an acceptable predictive accuracy to identify patients with PE at low risk for in-hospital or 30-day mortality.

External validation of a claims-based and clinical approach for predicting post-pulmonary embolism outcomes among United States veterans.

The In-hospital Mortality for PulmonAry embolism using Claims daTa (IMPACT) rule can accurately identify pulmonary embolism (PE) patients at low risk of early complications using claims data. We sought to externally validate the IMPACT and simplified Pulmonary Embolism Severity Index (sPESI) tools for predicting all-cause mortality and readmission. We used Veteran Health Administration data (10/1/2010-9/30/2015) to identify adults with ≥1 inpatient diagnosis code for acute PE, ≥12 months continuous medical and pharmacy benefits prior to the index PE, ≥90 days of post-event follow-up (unless death occurred) and ≥1 claim for an anticoagulant during the index PE stay. Prognostic accuracies of IMPACT and sPESI for 30- and 90-day all-cause mortality and 90-day readmission were estimated. Of 6,746 PE patients, 7.5 and 12.6% died at 30 and 90 days. Within 90 days, 20.1% were readmitted for any reason. Hospitalization for recurrent VTE and major bleeding occurred in 5.6 and 1.7% of patients. IMPACT classified 15.2% as low risk, while 28.4% were low risk per sPESI. Both tools displayed sensitivity >90% and negative predictive values (NPVs) >97% for 30-day mortality, but low specificity (range 16.2-30.0) and positive predictive values (PPVs) (range 8.7-9.5); with similar results observed for 90-day mortality. IMPACT's sensitivity for all-cause readmission was numerically higher than sPESI (88.2 vs. 79.0%), but both had comparable NPVs (85.1 vs. 84.2%). Similar trends were observed for VTE or major bleeding readmissions. IMPACT classified patients for post-PE outcomes with similar accuracy as sPESI. IMPACT appears useful for identifying PE patients at low risk for early mortality or readmission in claims-based studies.

Economics of ramucirumab for metastatic colorectal cancer.

INTRODUCTION: Despite its FDA approval and incorporation into the National Comprehensive Cancer Network (NCCN) treatment guidelines, ramucirumab (RAM) is associated with a drug acquisition cost that is substantially higher than other approved options. Given its substantial cost, the presence of a viable alternative treatment option, and its minimal survival improvement, the usefulness of RAM in clinical practice has been called into question. Areas covered: In this paper, we outline the cost, benefits, and economic implications of RAM from a US perspective, as it is used in the treatment of mCRC. We also dissect its use in other tumor types and in other healthcare systems around the world, and briefly compare it with similar drugs targeting the vascular endothelial growth factor pathway. We used the search engine PubMed using the following as search terms: cost-effectiveness; ramucirumab; metastatic colon cancer; angiogenesis; and value-based medicine. Expert commentary: The use of ramucirumab in the treatment of mCRC serves as a microcosm of the worsening healthcare crisis within the US and the ongoing controversy regarding oncology drug costs, benefits, and value. Therefore, there must be a joint effort in moving towards value based pricing models.