Comparison of rivaroxaban and low molecular weight heparin in the treatment of cancer-associated venous thromboembolism: a Swedish national population-based register study.

BACKGROUND: Treating cancer-associated venous thromboembolism (CAT) with anticoagulation prevents recurrent venous thromboembolism (rVTE), but increases bleeding risk. OBJECTIVES: To compare incidence of rVTE, major bleeding, and all-cause mortality for rivaroxaban versus low molecular weight heparin (LMWH) in patients with CAT. METHODS: We developed a cohort study using Swedish national registers 2013-2019. Patients with CAT (venous thromboembolism within 6 months of cancer diagnosis) were included. Those with other indications or with high bleeding risk cancers were excluded (according to guidelines). Follow-up was from index-CAT until outcome, death, emigration, or end of study. Incidence rates (IR) per 1000 person-years with 95% confidence interval (CI) and propensity score overlap-weighted hazard ratios (HRs) for rivaroxaban versus LMWH were estimated. RESULTS: We included 283 patients on rivaroxaban and 5181 on LMWH. The IR for rVTE was 68.7 (95% CI 40.0-109.9) for rivaroxaban, compared with 91.6 (95% CI 81.9-102.0) for LMWH, with adjusted HR 0.77 (95% CI 0.43-1.35). The IR for major bleeding was 23.5 (95% CI 8.6-51.1) for rivaroxaban versus 49.2 (95% CI 42.3-56.9) for LMWH, with adjusted HR 0.62 (95% CI 0.26-1.49). The IR for all-cause mortality was 146.8 (95% CI 103.9-201.5) for rivaroxaban and 565.6 (95% CI 541.8-590.2) for LMWH with adjusted HR 0.48 (95% CI 0.34-0.67). CONCLUSIONS: Rivaroxaban performed similarly to LMWH for patients with CAT for rVTE and major bleeding. An all-cause mortality benefit was observed for rivaroxaban which potentially may be attributed to residual confounding. TRIAL REGISTRATION NUMBER: NCT05150938 (Registered 9 December 2021).

Andexanet alfa versus four-factor prothrombin complex concentrate for the reversal of apixaban- or rivaroxaban-associated intracranial hemorrhage: a propensity score-overlap weighted analysis.

BACKGROUND: Andexanet alfa is approved (FDA "accelerated approval"; EMA "conditional approval") as the first specific reversal agent for factor Xa (FXa) inhibitor-associated uncontrolled or life-threatening bleeding. Four-factor prothrombin complex concentrates (4F-PCC) are commonly used as an off-label, non-specific, factor replacement approach to manage FXa inhibitor-associated life-threatening bleeding. We evaluated the effectiveness and safety of andexanet alfa versus 4F-PCC for management of apixaban- or rivaroxaban-associated intracranial hemorrhage (ICH). METHODS: This two-cohort comparison study included andexanet alfa patients enrolled at US hospitals from 4/2015 to 3/2020 in the prospective, single-arm ANNEXA-4 study and a synthetic control arm of 4F-PCC patients admitted within a US healthcare system from 12/2016 to 8/2020. Adults with radiographically confirmed ICH who took their last dose of apixaban or rivaroxaban < 24 h prior to the bleed were included. Patients with a Glasgow Coma Scale (GCS) score < 7, hematoma volume > 60 mL, or planned surgery within 12 h were excluded. Outcomes were hemostatic effectiveness from index to repeat scan, mortality within 30 days, and thrombotic events within five days. Odds ratios (ORs) with 95% confidence intervals (CI) were calculated using propensity score-overlap weighted logistic regression. RESULTS: The study included 107 andexanet alfa (96.6% low dose) and 95 4F-PCC patients (79.3% receiving a 25 unit/kg dose). After propensity score-overlap weighting, mean age was 79 years, GCS was 14, time from initial scan to reversal initiation was 2.3 h, and time from reversal to repeat scan was 12.2 h in both arms. Atrial fibrillation was present in 86% of patients. Most ICHs were single compartment (78%), trauma-related (61%), and involved the intracerebral and/or intraventricular space(s) (53%). ICH size was ≥ 10 mL in volume (intracerebral and/or ventricular) or ≥ 10 mm in thickness (subdural or subarachnoid) in 22% of patients and infratentorial in 15%. Andexanet alfa was associated with greater odds of achieving hemostatic effectiveness (85.8% vs. 68.1%; OR 2.73; 95% CI 1.16-6.42) and decreased odds of mortality (7.9% vs. 19.6%; OR 0.36; 95% CI 0.13-0.98) versus 4F-PCC. Two thrombotic events occurred with andexanet alfa and none with 4F-PCC. CONCLUSIONS: In this indirect comparison of patients with an apixaban- or rivaroxaban-associated ICH, andexanet alfa was associated with better hemostatic effectiveness and improved survival compared to 4F-PCC. Trial registration NCT02329327; registration date: December 31, 2014.

Thromboembolism, bleeding and vascular death in nonvalvular atrial fibrillation patients with type 2 diabetes receiving rivaroxaban or warfarin.

BACKGROUND: Diabetes increases a patient's risk of developing atrial fibrillation by 49%. Patients with nonvalvular atrial fibrillation are at a fivefold increased risk of stroke and die more frequently from vascular causes. We sought to evaluate the effectiveness and safety of rivaroxaban versus warfarin in nonvalvular atrial fibrillation patients with type 2 diabetes. METHODS: This was an analysis of Optum® De-Identified electronic health record data from 11/2010 to 12/2019. We included adults with nonvalvular atrial fibrillation and type 2 diabetes, newly started on rivaroxaban or warfarin and with ≥ 12-months of prior electronic health record activity. Patients who were pregnant, had alternative indications for oral anticoagulation or valvular heart disease were excluded. We evaluated the incidence rate (%/year) of developing the composite outcome of stroke/systemic embolism or vascular death and major or clinically relevant nonmajor bleeding as well as each endpoint individually. Hazard ratios with 95% confidence intervals were calculated using propensity score-overlap weighted proportional hazards regression. RESULTS: We included 32,078 rivaroxaban (31% initiated on 15 mg dose) and 83,971warfarin users (time-in-therapeutic range = 47 ± 28%). Rivaroxaban was associated with a reduced risk of stroke/systemic embolism or vascular death (3.79 vs. 4.19; hazard ratio = 0.91, 95% confdience interval = 0.88-0.95), driven mostly by reductions in vascular death (2.81 vs 3.18, hazard ratio = 0.90, 95% confidence interval = 0.86-0.95) and systemic embolism (0.13 vs. 0.16; hazard ratio = 0.82, 95% confidence interval = 0.66-1.02). Major/clinically relevant nonmajor bleeding was less frequent with rivaroxaban versus warfarin (2.17 vs. 2.31; hazard ratio = 0.94, 95% confidence interval = 0.89-0.99) due to decreased critical organ bleeding (including intracranial hemorrhage) (0.35 vs. 0.54; hazard ratio = 0.63, 95% confidence interval = 0.55-0.72). CONCLUSIONS: In nonvalvular atrial fibrillation patients with type 2 diabetes, rivaroxaban was associated with an ~ 10% relative reduction in vascular mortality and fewer bleeding-related hospitalizations versus warfarin.

Effectiveness and safety of rivaroxaban versus warfarin in obese patients with acute venous thromboembolism: analysis of electronic health record data.

There is limited data evaluating clinical outcomes of rivaroxaban versus warfarin in obese patients with venous thromboembolism (VTE). Our objective was to evaluate the effectiveness and safety of rivaroxaban versus warfarin in obese VTE patients. We performed a cohort analysis using Optum® De-Identified Electronic Health Record data from 11/1/2012 to 9/30/2018. Patients with a body mass index (BMI) ≥ 30 kg/m2 admitted to the hospital, emergency department or observation unit for VTE, prescribed rivaroxaban or warfarin as their first oral anticoagulant (OAC) within 7-days and had ≥12-months of EHR activity prior were included. We excluded patients with OAC use at baseline or cancer. Patients were 1:1 matched (standard differences<0.10). Primary outcomes were recurrent VTE and major bleeding at 3-, 6- and 12-months using an intent-to-treat approach. Subanalyses of BMI 30.0-34.9, 35.0-39.9 and ≥ 40 kg/m2 were performed. Risk was compared using Cox regression and reported as hazard ratios (HRs) with 95% confidence intervals (CI). We identified 6755 rivaroxaban and 6755 warfarin users with BMI ≥ 30 kg/m2 and incident VTE. At 3-, 6- and 12-months, rivaroxaban was associated with a reduced hazard of recurrent VTE compared to warfarin (HR 0.61, 95%CI 0.51-0.72; HR 0.65, 95%CI 0.55-0.77; HR 0.63, 95%CI 0.54-0.74) with no difference in major bleeding (HR 0.99, 95%CI 0.68-1.44; HR 0.90, 95%CI 0.64-1.26; HR 1.00, 95%CI 0.73-1.36). No statistical difference was found across BMI categories for either recurrent VTE (p-interaction≥0.43) or major bleeding (p-interaction ≥ 0.58) at any time point. In obese VTE patients, prescription of rivaroxaban was associated with a significantly reduced risk of recurrent VTE versus warfarin, without impacting major bleeding. Our findings remained consistent across BMI classes.

Rivaroxaban versus apixaban in non-valvular atrial fibrillation patients with end-stage renal disease or receiving dialysis.

OBJECTIVES: We sought to evaluate the effectiveness and safety of rivaroxaban vs apixaban in non-valvular atrial fibrillation (NVAF) patients with end-stage renal disease (ESRD) and/or receiving dialysis in routine practice. METHODS: Using US MarketScan claims data from January 1, 2014, to December 31, 2017, we identified new-users of rivaroxaban or apixaban during 2015 with at least 12 months of insurance coverage prior to oral anticoagulant (OAC) initiation. Differences in baseline covariates between cohorts were adjusted using inverse probability-of-treatment weighting based on propensity scores. Patients were followed for stroke or systemic embolism (SSE) or major bleeding hospitalizations. Cox proportion hazards regression was used to compare rivaroxaban and apixaban. Analyses stratified by age, sex, CHA2DS2-VASc score, prior stroke, prior bleed, diabetes, and reduced OAC dose were performed. RESULTS: We identified 787 rivaroxaban and 1836 apixaban users. Median (25, 75% range) age = 70 (61, 79), CHA2DS2-VASc score = 3 (2, 4), and follow-up = 0.87 (0.38, 1.56) years. No differences in the risks of SSE (HR = 1.18, 95% CI = 0.53-2.63), ischemic stroke (HR = 1.12, 95%CI = 0.45-2.76), or major bleeding (HR = 1.00, 95% CI = 0.63-1.58) were observed. No significant interactions were observed upon subgroup analysis. CONCLUSION: In NVAF patients with ESRD and/or receiving dialysis, rivaroxaban and apixaban were associated with similar risks of SSE and major bleeding.

Rivaroxaban versus warfarin for treatment and prevention of recurrence of venous thromboembolism in African American patients: a retrospective cohort analysis.

BACKGROUND: African Americans are under-represented in trials evaluating oral anticoagulants for the treatment of acute venous thromboembolism (VTE). The aim of this study was to evaluate the effectiveness and safety of rivaroxaban versus warfarin for the treatment of VTE in African Americans. METHODS: We utilized Optum® De-Identified Electronic Health Record data from 11/1/2012-9/30/2018. We included African Americans experiencing an acute VTE during a hospital or emergency department visit, who received rivaroxaban or warfarin as their first oral anticoagulant within 7-days of the acute VTE event and had ≥1 provider visit in the prior 12-months. Differences in baseline characteristics between cohorts were adjusted using inverse probability-of-treatment weighting based on propensity scores (standard differences < 0.10 were achieved for all covariates). Our primary endpoint was the composite of recurrent VTE or major bleeding at 6-months. Three- and 12-month timepoints were also assessed. Secondary endpoints included recurrent VTE and major bleeding as individual endpoints. Cohort risk was compared using Cox regression and reported as hazard ratios (HRs) with 95% confidence intervals (CIs). RESULTS: We identified 2097 rivaroxaban and 2842 warfarin users with incident VTE. At 6-months, no significant differences in the composite endpoint (HR = 0.96, 95%CI = 0.75-1.24), recurrent VTE (HR = 1.02, 95%CI = 0.76-1.36) or major bleeding alone (HR = 0.93, 95%CI = 0.59-1.47) were observed between cohorts. Analysis at 3- and 12-months provided consistent findings for these endpoints. CONCLUSIONS: In African Americans experiencing an acute VTE, no significant difference in the incidence of recurrent VTE or major bleeding was observed between patients receiving rivaroxaban or warfarin.

Comparative Effectiveness of Analgesics to Reduce Acute Pain in the Prehospital Setting.

Objectives: The objectives of this study were to assess comparative effectiveness and harms of opioid and nonopioid analgesics for the treatment of moderate to severe acute pain in the prehospital setting. Methods: We searched MEDLINE®, Embase®, and Cochrane Central from the earliest date through May 9, 2019. Two investigators screened abstracts, reviewed full-text files, abstracted data, and assessed study level risk of bias. We performed meta-analyses when appropriate. Conclusions were made with consideration of established clinically important differences and we graded each conclusion's strength of evidence (SOE). Results: We included 52 randomized controlled trials and 13 observational studies. Due to the absence or insufficiency of prehospital evidence we based conclusions for initial analgesia on indirect evidence from the emergency department setting. As initial analgesics, there is no evidence of a clinically important difference in the change of pain scores with opioids vs. ketamine administered primarily intravenously (IV) (low SOE), IV acetaminophen (APAP) (low SOE), or nonsteroidal anti-inflammatory drugs (NSAIDs) administered primarily IV (moderate SOE). The combined use of an opioid and ketamine, administered primarily IV, may reduce pain more than an opioid alone at 15 and 30 minutes (low SOE). Opioids may cause fewer adverse events than ketamine (low SOE) when primarily administered intranasally. Opioids cause less dizziness than ketamine (low SOE) but may increase the risk of respiratory depression compared with ketamine (low SOE), primarily administered IV. Opioids cause more dizziness (moderate SOE) and may cause more adverse events than APAP (low SOE), both administered IV, but there is no evidence of a clinically important difference in hypotension (low SOE). Opioids may cause more adverse events and more drowsiness than NSAIDs (low SOE), both administered primarily IV. Conclusions: As initial analgesia, opioids are no different than ketamine, APAP, and NSAIDs in reducing acute pain in the prehospital setting. Opioids may cause fewer total side effects than ketamine, but more than APAP or NSAIDs. Combining an opioid and ketamine may reduce acute pain more than an opioid alone but comparative harms are uncertain. When initial morphine is inadequate, giving ketamine may provide greater and quicker acute pain relief than giving additional morphine, although comparative harms are uncertain. Due to indirectness, strength of evidence is generally low, and future research in the prehospital setting is needed.

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.

Effectiveness and safety of rivaroxaban and warfarin for prevention of major adverse cardiovascular or limb events in patients with non-valvular atrial fibrillation and type 2 diabetes.

AIMS: To assess the effectiveness and safety of rivaroxaban versus warfarin for the prevention of major adverse cardiovascular events (MACE) and major adverse limb events (MALE) in patients with type 2 diabetes (T2D) and non-valvular atrial fibrillation (NVAF). MATERIALS AND METHODS: Using MarketScan data from January 2012 to December 2017, we identified oral anticoagulant-naïve patients with NVAF and comorbid T2D and ≥12 months of insurance coverage prior to rivaroxaban or warfarin initiation. Differences in baseline covariates between cohorts were adjusted for using inverse probability of treatment weights based on propensity scores (absolute standardized differences <0.1 achieved for all covariates after adjustment). Patients were followed until a MACE, MALE or major bleeding event, oral anticoagulant discontinuation/switch, insurance disenrolment or end of data availability. Hazard ratios (HRs) and 95% confidence intervals (CIs) comparing the cohorts were calculated using Cox regression. RESULTS: We identified 10 700 rivaroxaban users (24.1% received a reduced dose) and 13 946 warfarin users. The median (25%, 75% range) age was 70 (62, 79) years, CHA2DS2-VASc score was 4 (3, 5) and duration of available follow-up was 1.4 (0.6, 2.7) years. Eleven percent of patients had peripheral artery disease, 5.1% had coronary artery disease, and 5.1% had a prior MALE, at baseline. Rivaroxaban was associated with a 25% (95% CI 4-41) reduced risk of MACE and a 63% (95% CI 35-79) reduced risk of MALE compared to warfarin. Major bleeding risk did not significantly differ between cohorts (HR 0.95). CONCLUSIONS: Among patients with NVAF and T2D treated in routine practice, rivaroxaban was associated with lower risks of both MACE and MALE versus warfarin, with no significant difference in major bleeding.

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.

Safety and effectiveness of oral factor Xa inhibitors versus warfarin in nonvalvular atrial fibrillation patients at high-risk for falls.

Prescribers' concern regarding falls resulting in intracranial hemorrhage is often cited as a justification for under-utilization of oral anticoagulation. We evaluated the safety and effectiveness of oral factor Xa inhibitors versus warfarin in nonvalvular atrial fibrillation patients at high-risk for falls. Using MarketScan claims from 11/2012-3/2017, we identified adult, oral anticoagulation-naïve, new-initiators of oral factor Xa inhibitors or warfarin with nonvalvular atrial fibrillation, ≥ 12 months of insurance coverage prior to starting oral anticoagulation and a predicted 2-year risk of falls ≥ 15%. Differences in baseline covariates between cohorts were balanced using inverse probability-of-treatment weights based on propensity scores. Hazard ratios (HRs) and 95% confidence intervals (CIs) for intracranial hemorrhage and stroke or systemic embolism were estimated. Among 25,144 nonvalvular atrial fibrillation patients at high-risk for falls (observed fall rate = 11.8%/person-year), oral factor Xa inhibitor use was associated with a 43% (95% CI = 5-65%) reduced hazard of intracranial hemorrhage compared to warfarin. Oral factor Xa inhibitors did not significantly reduce the hazard of stroke or systemic embolism versus warfarin (HR = 0.86, 95% CI = 0.66-1.11). Findings for the intracranial hemorrhage and stroke or systemic embolism endpoints were similar when apixaban and rivaroxaban were evaluated separately versus warfarin (p-interaction ≥ 0.64 for all). Oral factor Xa inhibitors reduced patients' risk of intracranial hemorrhage and were at least as effective in preventing stroke or systemic embolism as warfarin in nonvalvular atrial fibrillation patients at high-risk for falls.

The value of sPESI for risk stratification in patients with pulmonary embolism.

INTRODUCTION: Various risk stratification methods exist for patients with pulmonary embolism (PE). We used the simplified Pulmonary Embolism Severity Index (sPESI) as a risk-stratification method to understand the Veterans Health Administration (VHA) PE population. MATERIALS AND METHODS: Adult patients with ≥ 1 inpatient PE diagnosis (index date = discharge date) from October 2011-June 2015 as well as continuous enrollment for ≥ 12 months pre- and 3 months post-index date were included. We defined a sPESI score of 0 as low-risk (LRPE) and all others as high-risk (HRPE). Hospital-acquired complications (HACs) during the index hospitalization, 90-day follow-up PE-related outcomes, and health care utilization and costs were compared between HRPE and LRPE patients. RESULTS: Of 6746 PE patients, 95.4% were men, 67.7% were white, and 22.0% were African American; LRPE occurred in 28.4% and HRPE in 71.6%. Relative to HRPE patients, LRPE patients had lower Charlson Comorbidity Index scores (1.0 vs. 3.4, p < 0.0001) and other baseline comorbidities, fewer HACs (11.4% vs. 20.0%, p < 0.0001), less bacterial pneumonia (10.6% vs. 22.3%, p < 0.0001), and shorter average inpatient lengths of stay (8.8 vs. 11.2 days, p < 0.0001) during the index hospitalization. During follow-up, LRPE patients had fewer PE-related outcomes of recurrent venous thromboembolism (4.4% vs. 6.0%, p = 0.0077), major bleeding (1.2% vs. 1.9%, p = 0.0382), and death (3.7% vs. 16.2%, p < 0.0001). LRPE patients had fewer inpatient but higher outpatient visits per patient, and lower total health care costs ($12,021 vs. $16,911, p < 0.0001) than HRPE patients. CONCLUSIONS: Using the sPESI score identifies a PE cohort with a lower clinical and economic burden.

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.

Effectiveness and safety of rivaroxaban versus warfarin in patients with provoked venous thromboembolism.

A paucity of real-world data evaluating rivaroxaban in provoked venous thromboembolism (VTE) exists. We assessed the effectiveness and safety of rivaroxaban versus warfarin in provoked VTE patients treated in routine practice. Using MarketScan claims data from 1/2012 to 12/2016, we identified adults who had ≥ 1 primary hospitalization/emergency department discharge diagnosis code for VTE (index event) and a provoking factor, received rivaroxaban or warfarin as their first outpatient oral anticoagulant within 30-days of the index event and had ≥ 12-month of insurance coverage prior the index VTE. Provoking factors included cancer, hospital admission for ≥ 3-consecutive days over the prior 3-months, major surgery, trauma or fracture within 90-days or pregnancy within 42-weeks of the index VTE. Differences in baseline covariates between cohorts were adjusted using inverse probability-of-treatment weights based on propensity-scores (residual standardized differences < 0.1 achieved for all covariates after adjustment). The incidence of the composite endpoint of recurrent VTE or major bleeding at 3- and 6-months was compared using Cox regression and reported as hazard ratios (HRs) and 95% confidence intervals (CIs). We included 4454 rivaroxaban and 13,164 warfarin users with provoked VTE. At 3- and 6-months, rivaroxaban was associated with a reduced hazard of the composite endpoint (HR 0.72, 95% CI 0.61-0.84 and HR 0.69, 95% CI 0.60-0.80) and recurrent VTE (HR 0.70, 95% CI 0.59-0.84 and HR 0.71, 95% CI 0.60-0.84) versus warfarin. Major bleeding was non-significantly reduced at 3-months (HR 0.77, 95% CI 0.57-1.06) and significantly reduced at 6-months (HR 0.68, 95% CI 0.53-0.88) with rivaroxaban. Rivaroxaban reduces recurrent VTE and major bleeding risk versus warfarin in provoked VTE patients treated in routine practice.

Meta-Analysis of Time in Therapeutic Range in Continuous-Flow Left Ventricular Assist Device Patients Receiving Warfarin.

Continuous-flow left ventricular assist devices (CF-LVADs) prolong survival in advanced heart failure patients. Anticoagulation control is critical in CF-LVAD patients due to increased thromboembolic and bleeding risk. We assessed the quality of INR control in CF-LVAD patients measured by time in therapeutic range (TTR). We performed a systematic literature search of MEDLINE and SCOPUS through July 2017 to identify studies evaluating TTR in anticoagulated adult CF-LVAD patients. Data on key characteristics and the TTR end point were then extracted from each study by two investigators using a standardized tool. Using a Hartung-Knapp random effects model, a weighted mean TTR estimate with accompanying 95% confidence interval (CI) was calculated. Statistical heterogeneity was estimated using the I2 statistic. Five published studies were included. All studies were single-center, retrospective investigations that calculated TTR using the Rosendaal method. Sample sizes ranged from 11 to 115 patients (total of 270 patients) with durations of follow-up ranging from 9 to 76 person-years. On meta-analysis, CF-LVAD patients had a weighted mean TTR of 46.6% (95% CI: 36.0-57.3%, I2 = 94%). This suggests that warfarin is difficult to manage in CF-LVAD patients, which may contribute to high rates of bleeding and thromboembolic complications.

Association of Inhaled Corticosteroids and Long-Acting Muscarinic Antagonists With Asthma Control in Patients With Uncontrolled, Persistent Asthma: A Systematic Review and Meta-analysis.

Importance: Long-acting muscarinic antagonists (LAMAs) are a potential adjunct therapy to inhaled corticosteroids in the management of persistent asthma. Objective: To conduct a systematic review and meta-analysis of the effects associated with LAMA vs placebo or vs other controllers as an add-on therapy to inhaled corticosteroids and the use of a LAMA as add-on therapy to inhaled corticosteroids and long-acting ß-agonists (LABAs; hereafter referred to as triple therapy) vs inhaled corticosteroids and LABA in patients with uncontrolled, persistent asthma. Data Sources: MEDLINE, EMBASE, Cochrane databases, and clinical trial registries (earliest date through November 28, 2017). Study Selection: Two reviewers selected randomized clinical trials or observational studies evaluating a LAMA vs placebo or vs another controller as an add-on therapy to inhaled corticosteroids or triple therapy vs inhaled corticosteroids and LABA in patients with uncontrolled, persistent asthma reporting on an outcome of interest. Data Extraction and Synthesis: Meta-analyses using a random-effects model was conducted to calculate risk ratios (RRs), risk differences (RDs), and mean differences (MDs) with corresponding 95% CIs. Citation screening, data abstraction, risk assessment, and strength-of-evidence grading were completed by 2 independent reviewers. Main Outcomes and Measures: Asthma exacerbations. Results: Of 1326 records identified, 15 randomized clinical trials (N = 7122 patients) were included. Most trials assessed adding LAMA vs placebo or LAMA vs LABA to inhaled corticosteroids. Adding LAMA vs placebo to inhaled corticosteroids was associated with a significantly reduced risk of exacerbation requiring systemic corticosteroids (RR, 0.67 [95% CI, 0.48 to 0.92]; RD, -0.02 [95% CI, -0.04 to 0.00]). Compared with adding LABA, adding LAMA to inhaled corticosteroids was not associated with significant improvements in exacerbation risk (RR, 0.87 [95% CI, 0.53 to 1.42]; RD, 0.00 [95% CI, -0.02 to 0.02]), or any other outcomes of interest. Triple therapy was not significantly associated with improved exacerbation risk vs inhaled corticosteroids and LABA (RR, 0.84 [95% CI, 0.57 to 1.22]; RD, -0.01 [95% CI, -0.08 to 0.07]). Conclusions and Relevance: In this systematic review and meta-analysis, the use of LAMA compared with placebo as add-on therapy to inhaled corticosteroids was associated with a lower risk of asthma exacerbations; however, the association of LAMA with benefit may not be greater than that with LABA. Triple therapy was not associated with a lower risk of exacerbations.

Association of Inhaled Corticosteroids and Long-Acting ß-Agonists as Controller and Quick Relief Therapy With Exacerbations and Symptom Control in Persistent Asthma: A Systematic Review and Meta-analysis.

Importance: Combined use of inhaled corticosteroids and long-acting ß-agonists (LABAs) as the controller and the quick relief therapy termed single maintenance and reliever therapy (SMART) is a potential therapeutic regimen for the management of persistent asthma. Objective: To conduct a systematic review and meta-analysis of the effects of SMART in patients with persistent asthma. Data Sources and Study Selection: The databases of MEDLINE via OVID, EMBASE, the Cochrane Central Register of Controlled Trials, and the Cochrane Database of Systematic Reviews were searched from database inception through August 2016 and updated through November 28, 2017. Two reviewers selected randomized clinical trials or observational studies evaluating SMART vs inhaled corticosteroids with or without a LABA used as the controller therapy and short-acting ß-agonists as the relief therapy for patients aged 5 years or older with persistent asthma and reporting on an outcome of interest. Data Extraction and Synthesis: Meta-analyses were conducted using a random-effects model to calculate risk ratios (RRs), risk differences (RDs), and mean differences with corresponding 95% CIs. Citation screening, data abstraction, risk assessment, and strength of evidence grading were completed by 2 independent reviewers. Main Outcomes and Measures: Asthma exacerbations. Results: The analyses included 16 randomized clinical trials (N = 22 748 patients), 15 of which evaluated SMART as a combination therapy with budesonide and formoterol in a dry-powder inhaler. Among patients aged 12 years or older (n = 22 524; mean age, 42 years; 14 634 [65%] were female), SMART was associated with a reduced risk of asthma exacerbations compared with the same dose of inhaled corticosteroids and LABA as the controller therapy (RR, 0.68 [95% CI, 0.58 to 0.80]; RD, -6.4% [95% CI, -10.2% to -2.6%]) and a higher dose of inhaled corticosteroids and LABA as the controller therapy (RR, 0.77 [95% CI, 0.60 to 0.98]; RD, -2.8% [95% CI, -5.2% to -0.3%]). Similar results were seen when SMART was compared with inhaled corticosteroids alone as the controller therapy. Among patients aged 4 to 11 years (n = 341; median age, 8 [range, 4-11] years; 69 [31%] were female), SMART was associated with a reduced risk of asthma exacerbations compared with a higher dose of inhaled corticosteroids as the controller therapy (RR, 0.55 [95% CI, 0.32 to 0.94]; RD, -12.0% [95% CI, -22.5% to -1.5%]) or the same dose of inhaled corticosteroids and LABA as the controller therapy (RR, 0.38 [95% CI, 0.23 to 0.63]; RD, -23.2% [95% CI, -33.6% to -12.1%]). Conclusions and Relevance: In this meta-analysis of patients with persistent asthma, the use of single maintenance and reliever therapy compared with inhaled corticosteroids as the controller therapy (with or without a long-acting ß-agonist) and short-acting ß-agonists as the relief therapy was associated with a lower risk of asthma exacerbations. Evidence for patients aged 4 to 11 years was limited.

Comparative Effectiveness and Safety of Apixaban and Vitamin K Antagonist Therapy in Patients With Nonvalvular Atrial Fibrillation Treated in Routine German Practice.

BACKGROUND: Scarce data comparing real-world outcomes between apixaban and vitamin K antagonist (VKA) users with nonvalvular atrial fibrillation (NVAF) are available. We sought to assess the effectiveness and safety of newly-initiated apixaban vs. VKA in German NVAF patients. MATERIALS AND METHODS: We performed a retrospective analysis in German outpatients using IMS Disease Analyzer data. Adults newly-initiated on apixaban or a VKA from January 2013 to March 2015 with a diagnosis of NVAF on the day of the first qualifying oral anticoagulant (OAC) prescription (index date) or any time during 1 year prior, and at least 1 year of follow-up were included. Patients experiencing a prior event in the composite endpoint, receiving an OAC before the index date, >1 OAC on the index date or switched to another OAC during follow-up were excluded. Apixaban and VKA users were 1:1 propensity-score matched. We evaluated the composite of ischaemic stroke, transient ischaemic attack (TIA), myocardial infarction (MI) or intracranial haemorrhage (ICH) in the year after OAC initiation. Cox regression was used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs). RESULTS: In total, 835 apixaban and 835 VKA users were matched. Forty-one composite events were identified. Hazard of the composite endpoint did not differ between apixaban and VKA users (HR=0.87, 95%CI=0.47-1.60). Ischaemic stroke and MI occurred at dissimilar (albeit not statistically significant) rates between apixaban and VKA therapy (HR=1.51, 95%CI=0.54-4.24) and (HR=0.33, 95%CI=0.11-1.03). Only two patients (both in the apixaban cohort) experienced an ICH. CONCLUSIONS: Apixaban and VKA therapy were associated with a similar impact on the composite endpoint in real-world German practice. Additional investigation is needed to evaluate the numeric trends of ischaemic stroke and decreased number of MIs observed with apixaban, as well as the high rate of reduced dose apixaban use found in this analysis.

Effectiveness and Safety of Apixaban, Dabigatran, and Rivaroxaban Versus Warfarin in Patients With Nonvalvular Atrial Fibrillation and Previous Stroke or Transient Ischemic Attack.

BACKGROUND AND PURPOSE: Limited real-world data exist comparing each non-vitamin K antagonist oral anticoagulant (NOAC) to warfarin in patients with nonvalvular atrial fibrillation who have had a previous ischemic stroke or transient ischemic attack. METHODS: Using MarketScan claims from January 2012 to June 2015, we identified adults newly initiated on oral anticoagulation, with ≥2 diagnosis codes for nonvalvular atrial fibrillation, a history of previous ischemic stroke/transient ischemic attack, and ≥180 days of continuous medical and prescription benefits before anticoagulation initiation. Three analyses were performed comparing 1:1 propensity score-matched cohorts of apixaban versus warfarin (n=2514), dabigatran versus warfarin (n=1962), and rivaroxaban versus warfarin (n=5208). Patients were followed until occurrence of a combined end point of ischemic stroke and intracranial hemorrhage (ICH) or major bleed, switch/discontinuation of index oral anticoagulation, insurance disenrollment, or end of follow-up. Mean follow-up was 0.5 to 0.6 years for all matched cohorts. RESULTS: Using Cox regression, neither apixaban nor dabigatran reduced the combined primary end point of ischemic stroke or ICH (hazard ratio [HR], 0.70; 95% confidence interval [CI], 0.33-1.48 and HR, 0.53; 95% CI, 0.26-1.07) and had nonsignificant effect on hazards of major bleeding (HR, 0.79; 95% CI, 0.38-1.64 and HR, 0.58; 95% CI, 0.26-1.27) versus warfarin. Rivaroxaban reduced the combined end point of ischemic stroke or ICH (HR, 0.45; 95% CI, 0.29-0.72) without an effect on major bleeding (HR, 1.07; 95% CI, 0.71-1.61). ICH occurred at rates of 0.16 to 0.61 events per 100 person-years in the 3 NOAC analyses, with no significant difference for any NOAC versus warfarin. CONCLUSIONS: Results from our study of the 3 NOACs versus warfarin in nonvalvular atrial fibrillation patients with a previous history of stroke/transient ischemic attack are relatively consistent with their respective phase III trials and previous stroke/transient ischemic attack subgroup analyses. All NOACs seemed no worse than warfarin in respect to ischemic stroke, ICH, or major bleeding risk.