Thromboembolic and hemorrhagic complications in patients with prosthetic heart valves cared for in a tertiary care center. What have we learned?

BACKGROUND: Heart valve replacement surgery with mechanical or biological prostheses entails a risk of thromboembolism and bleeding complications. OBJECTIVE: To determine the complications related to complementary anticoagulation therapy and the probability of risk. METHODS: One-hundred and sixty-three patients who underwent heart valve replacement between 2002 and 2016 with either mechanical or biological prostheses, and who received vitamin K antagonists after hospital discharge, were studied. Anticoagulation therapy was categorized into optimal and non-optimal according to INR values prior to the development of complications. Patients with comorbidities and other risk factors for thrombosis and/or bleeding were excluded. RESULTS: In total, 68.7 % of patients received mechanical prostheses, and 31.3 %, biological prostheses (p ≤ 0.001); 25.2 % experienced the complications that motivated the study (p ≤ 0.001), which were hemorrhagic in 48.8 %, thromboembolic in 26.8 %, and of both types in 24.4 % (relative risk = 4.229). Among the patients with complications, 95.1 % received mechanical prostheses, and 4.9 %, biological (p = 0.005); non-optimal INR was identified in 49.7 % (p ≤ 0.001). CONCLUSIONS: Given the high risk of thromboembolic and hemorrhagic complications, valve prostheses must be carefully chosen, and care priorities should include prevention and follow-up, especially in those patients who require anticoagulation therapy.

ANTECEDENTES: El reemplazo valvular por prótesis mecánicas o biológicas implica riesgo de tromboembolismo y complicaciones hemorrágicas. OBJETIVO: Determinar las complicaciones relacionadas con la terapia de anticoagulación complementaria y la probabilidad de riesgo en pacientes portadores de prótesis valvulares del corazón. MÉTODOS: Se estudiaron 163 pacientes entre 2002 y 2016, portadores de prótesis mecánicas y biológicas, quienes recibieron antagonistas de la vitamina K posterior al egreso hospitalario. La terapia de anticoagulación se categorizó en óptima y no óptima conforme a los valores de INR previos a las complicaciones. Fueron excluidos los pacientes con comorbilidades y otros factores de riesgo de trombosis y/o sangrado. RESULTADOS: a 68.7 % de los pacientes se les colocó prótesis mecánica y a 31.3 %, biológica (p ≤ 0.001); 25.2 % presentó las complicaciones motivo de estudio (p ≤ 0.001), hemorrágicas en 48.8 %, tromboembólicas en 26.8 % y de ambos tipos en 24.4 % (riesgo relativo = 4.229); a 95.1 % de los pacientes con complicaciones se les colocó prótesis mecánica y a 4.9 %, biológica (p = 0.005); 49.7 % presentó INR no óptimo (p ≤ 0.001). CONCLUSIONES: Ante riesgo alto de complicaciones tromboembólicas y hemorrágicas, la elección de las prótesis valvulares, la prevención y el seguimiento son prioridades, principalmente en quienes requieren terapia de anticoagulación.

Impact of ABC (Atrial Fibrillation Better Care) pathway adherence in high-risk subgroups with atrial fibrillation: A report from the ESC-EHRA EORP-AF long-term general registry.

BACKGROUND: Effects of Atrial Fibrillation Better Care (ABC) adherence among high-risk atrial fibrillation (AF) subgroups remains unknown. We aimed to evaluate the impact of ABC adherence on clinical outcomes in these high-risk patients. METHODS: EORP-AF General Long-Term Registry is a prospective, observational registry from 250 centres across 27 European countries. High-risk patients were defined as those with either CKD (eGFR <60 mL/min/1.73m2), elderly patients (≥75 years) or prior thromboembolism. Primary outcome was a composite event of all-cause death, thromboembolism and acute coronary syndrome. RESULTS: 6646 patients with AF were screened (median age was 70 [IQR 61 - 77] years; 40.2% females). There were 3304 (54.2%) patients with either CKD (n = 1750), older age (n = 2236) or prior thromboembolism (n = 728). Among these, 924 (28.0%) were managed as adherent to ABC. At 2-year follow-up, 966 (14.5%) patients reported the primary outcome. The incidence of the primary outcome was significantly lower in high-risk patients managed as adherent to ABC pathway (IRR 0.53 [95%CI, 0.43 - 0.64]). Consistent results were obtained in the individual subgroups. Using multivariable Cox proportional hazards analysis, ABC adherence in the high-risk cohort was independently associated with a lower risk of the primary outcome (aHR 0.64 [95%CI, 0.51 - 0.80]), as well as in the CKD (aHR 0.51 [95%CI, 0.37 - 0.70]) and elderly subgroups (aHR 0.69 [95%CI, 0.53 - 0.90]). Overall, there was greater reduction in the risk of primary outcome as more ABC criteria were fulfilled, both in the overall high-risk patients (aHR 0.39 [95%CI, 0.25 - 0.61]), as well as in the individual subgroups. CONCLUSION: In a large, contemporary cohort of patients with AF, we demonstrate that adherence to the ABC pathway was associated with a significant benefit among high-risk patients with either CKD, advanced age (≥75 years old) or prior thromboembolism.

Association of COVID-19 vs Influenza With Risk of Arterial and Venous Thrombotic Events Among Hospitalized Patients.

Importance: The incidence of arterial thromboembolism and venous thromboembolism in persons with COVID-19 remains unclear. Objective: To measure the 90-day risk of arterial thromboembolism and venous thromboembolism in patients hospitalized with COVID-19 before or during COVID-19 vaccine availability vs patients hospitalized with influenza. Design, Setting, and Participants: Retrospective cohort study of 41 443 patients hospitalized with COVID-19 before vaccine availability (April-November 2020), 44 194 patients hospitalized with COVID-19 during vaccine availability (December 2020-May 2021), and 8269 patients hospitalized with influenza (October 2018-April 2019) in the US Food and Drug Administration Sentinel System (data from 2 national health insurers and 4 regional integrated health systems). Exposures: COVID-19 or influenza (identified by hospital diagnosis or nucleic acid test). Main Outcomes and Measures: Hospital diagnosis of arterial thromboembolism (acute myocardial infarction or ischemic stroke) and venous thromboembolism (deep vein thrombosis or pulmonary embolism) within 90 days. Outcomes were ascertained through July 2019 for patients with influenza and through August 2021 for patients with COVID-19. Propensity scores with fine stratification were developed to account for differences between the influenza and COVID-19 cohorts. Weighted Cox regression was used to estimate the adjusted hazard ratios (HRs) for outcomes during each COVID-19 vaccine availability period vs the influenza period. Results: A total of 85 637 patients with COVID-19 (mean age, 72 [SD, 13.0] years; 50.5% were male) and 8269 with influenza (mean age, 72 [SD, 13.3] years; 45.0% were male) were included. The 90-day absolute risk of arterial thromboembolism was 14.4% (95% CI, 13.6%-15.2%) in patients with influenza vs 15.8% (95% CI, 15.5%-16.2%) in patients with COVID-19 before vaccine availability (risk difference, 1.4% [95% CI, 1.0%-2.3%]) and 16.3% (95% CI, 16.0%-16.6%) in patients with COVID-19 during vaccine availability (risk difference, 1.9% [95% CI, 1.1%-2.7%]). Compared with patients with influenza, the risk of arterial thromboembolism was not significantly higher among patients with COVID-19 before vaccine availability (adjusted HR, 1.04 [95% CI, 0.97-1.11]) or during vaccine availability (adjusted HR, 1.07 [95% CI, 1.00-1.14]). The 90-day absolute risk of venous thromboembolism was 5.3% (95% CI, 4.9%-5.8%) in patients with influenza vs 9.5% (95% CI, 9.2%-9.7%) in patients with COVID-19 before vaccine availability (risk difference, 4.1% [95% CI, 3.6%-4.7%]) and 10.9% (95% CI, 10.6%-11.1%) in patients with COVID-19 during vaccine availability (risk difference, 5.5% [95% CI, 5.0%-6.1%]). Compared with patients with influenza, the risk of venous thromboembolism was significantly higher among patients with COVID-19 before vaccine availability (adjusted HR, 1.60 [95% CI, 1.43-1.79]) and during vaccine availability (adjusted HR, 1.89 [95% CI, 1.68-2.12]). Conclusions and Relevance: Based on data from a US public health surveillance system, hospitalization with COVID-19 before and during vaccine availability, vs hospitalization with influenza in 2018-2019, was significantly associated with a higher risk of venous thromboembolism within 90 days, but there was no significant difference in the risk of arterial thromboembolism within 90 days.

Effectiveness and Safety of Dabigatran in Atrial Fibrillation Patients with Severe Obesity: a Real-World Retrospective Cohort Study.

BACKGROUND: Direct oral anticoagulants such as dabigatran are the preferred anticoagulant in treating atrial fibrillation (AF) patients due to their effectiveness and safety. Whether this applies to severely obese patients needs to be determined. OBJECTIVE: To compare the effectiveness and safety of dabigatran with warfarin among AF patients with severe obesity. DESIGN: Retrospective cohort study. PARTICIPANTS: AF patients with a BMI >40kg/m2 or a weight >120kg receiving dabigatran or warfarin between 10/01/2010 and 12/31/2019 in a large integrated health system and followed through 08/01/2020. INTERVENTIONS: Not applicable. MAIN MEASURES: Primary effectiveness outcome was composite thromboembolism including transient ischemic attack, ischemic stroke, or systemic embolism. Primary safety outcome was composite bleeding including gastrointestinal bleeding, intracranial bleeding, or other bleeding. Secondary outcomes included the individual outcomes and all-cause mortality. Propensity score matching (PSM) was performed to create a 1:1 matched cohort and Cox proportional hazards model was used to estimate the hazard ratio (HR) of each outcome for dabigatran users compared to warfarin users. KEY RESULTS: A total of 6848 patients receiving either dabigatran or warfarin were identified. In a 1:1 matched cohort, dabigatran users had a HR of 0.71 (95% confidence interval (CI): 0.56-0.91) for composite thromboembolism, a HR of 1.24 (95%CI: 1.07-1.42) for composite bleeding, and a HR of 0.57 (95% CI: 0.45-0.71) for all-cause mortality when compared to warfarin users. CONCLUSIONS: Among AF patients with a BMI >40kg/m2 or a weight >120kg in a real-world clinical setting, dabigatran was effective in reducing the risk of thromboembolism and mortality but was associated with an increased risk of bleeding when compared to warfarin. Dabigatran may be a reasonable option for AF patients with severe obesity.

Long-Term Medication Adherence Trajectories to Direct Oral Anticoagulants and Clinical Outcomes in Patients With Atrial Fibrillation.

Background Direct oral anticoagulants (DOACs) are widely used in patients with nonvalvular atrial fibrillation for stroke prevention. However, long-term adherence to DOACs and clinical outcomes in real-world clinical practice is not well understood. This study evaluated long-term medication adherence patterns to DOAC therapy and clinical outcomes in a large US integrated health care system. Methods and Results We included adult patients with nonvalvular atrial fibrillation who newly initiated DOACs between 2012 and 2018 in Kaiser Permanente Southern California. Long-term (3.5 years) adherence trajectories to DOAC were investigated using monthly proportion of days covered and group-based trajectory models. Factors associated with long-term adherence trajectories were investigated. Multivariable Poisson regression analyses were used to investigate thromboembolism and major bleeding events associated with long-term adherence trajectories. Of 18 920 patients newly initiating DOACs, we identified 3 DOAC adherence trajectories: consistently adherent (85.2%), early discontinuation within 6 months (10.6%), and gradually declining adherence (4.2%). Predictors such as lower CHA2DS2-VASc (0-1 versus ≥5) and previous injurious falls were associated with both early discontinuation and gradually declining adherence trajectories. Early discontinuation of DOAC therapy was associated with a higher risk of thromboembolism (rate ratio, 1.40; 95% CI, 1.05-1.86) especially after 12 months from DOAC initiation but a lower risk of major bleed compared with consistent adherence (rate ratio, 0.48; 95% CI, 0.30-0.75), specifically during the first 12 months following DOAC initiation. A gradual decline in adherence to DOACs was not statistically significantly associated with thromboembolism outcomes compared with consistent adherence. Conclusions Although a large proportion of patients with nonvalvular atrial fibrillation were adherent to DOAC therapy over 3.5 years, early discontinuation of DOAC was associated a higher risk of thromboembolic events. Future tailored interventions for early discontinuers may improve clinical outcomes.

Relation of outcomes to ABC (Atrial Fibrillation Better Care) pathway adherent care in European patients with atrial fibrillation: an analysis from the ESC-EHRA EORP Atrial Fibrillation General Long-Term (AFGen LT) Registry.

AIMS: There has been an increasing focus on integrated, multidisciplinary, and holistic care in the treatment of atrial fibrillation (AF). The 'Atrial Fibrillation Better Care' (ABC) pathway has been proposed to streamline integrated care in AF. We evaluated the impact on outcomes of an ABC adherent management in a contemporary real-life European-wide AF cohort. METHODS AND RESULTS: Patients enrolled in the ESC-EHRA EURObservational Research Programme in AF General Long-Term Registry with baseline data to evaluate ABC criteria and available follow-up data were considered for this analysis. Among the original 11 096 AF patients enrolled, 6646 (59.9%) were included in this analysis, of which 1996 (30.0%) managed as ABC adherent. Patients adherent to ABC care had lower CHA2DS2-VASc and HAS-BLED scores (mean ± SD, 2.68 ± 1.57 vs. 3.07 ± 1.90 and 1.26 ± 0.93 vs. 1.58 ± 1.12, respectively; P < 0.001). At 1-year follow-up, patients managed adherent to ABC pathway compared to non-adherent ones had a lower rate of any thromboembolic event (TE)/acute coronary syndrome (ACS)/cardiovascular (CV) death (3.8% vs. 7.6%), CV death (1.9% vs. 4.8%), and all-cause death (3.0% vs. 6.4%) (all P < 0.0001). On Cox multivariable regression analysis, ABC adherent care showed an association with a lower risk of any TE/ACS/CV death [hazard ratio (HR): 0.59, 95% confidence interval (CI): 0.44-0.79], CV death (HR: 0.52, 95% CI: 0.35-0.78), and all-cause death (HR: 0.57, 95% CI: 0.43-0.78). CONCLUSION: In a large contemporary cohort of European AF patients, a clinical management adherent to ABC pathway for integrated care is associated with a significant lower risk for cardiovascular events, CV death, and all-cause death.

Registry of Arterial and Venous Thromboembolic Complications in Patients With COVID-19.

BACKGROUND: Cardiovascular complications, including myocardial infarction, ischemic stroke, and pulmonary embolism, represent an important source of adverse outcomes in coronavirus disease-2019 (COVID-19). OBJECTIVES: To assess the frequency of arterial and venous thromboembolic disease, risk factors, prevention and management patterns, and outcomes in patients with COVID-19, the authors designed a multicenter, observational cohort study. METHODS: We analyzed a retrospective cohort of 1,114 patients with COVID-19 diagnosed through our Mass General Brigham integrated health network. The total cohort was analyzed by site of care: intensive care (n = 170); hospitalized nonintensive care (n = 229); and outpatient (n = 715). The primary study outcome was a composite of adjudicated major arterial or venous thromboembolism. RESULTS: Patients with COVID-19 were 22.3% Hispanic/Latinx and 44.2% non-White. Cardiovascular risk factors of hypertension (35.8%), hyperlipidemia (28.6%), and diabetes (18.0%) were common. Prophylactic anticoagulation was prescribed in 89.4% of patients with COVID-19 in the intensive care cohort and 84.7% of those in the hospitalized nonintensive care setting. Frequencies of major arterial or venous thromboembolism, major cardiovascular adverse events, and symptomatic venous thromboembolism were highest in the intensive care cohort (35.3%, 45.9%, and 27.0 %, respectively) followed by the hospitalized nonintensive care cohort (2.6%, 6.1%, and 2.2%, respectively) and the outpatient cohort (0% for all). CONCLUSIONS: Major arterial or venous thromboembolism, major adverse cardiovascular events, and symptomatic venous thromboembolism occurred with high frequency in patients with COVID-19, especially in the intensive care setting, despite a high utilization rate of thromboprophylaxis.

Emergent reversal of oral factor Xa inhibitors with four-factor prothrombin complex concentrate.

BACKGROUND: Controversy exists regarding first-line use of the recently approved reversal agent andexanet alfa due to limitations of the ANEXXA-4 study, thrombotic risks, and high medication acquisition cost. The purpose of this study was to evaluate the safety and effectiveness of 4F-PCC for the reversal of emergent oral fXa inhibitor-related bleeding. Furthermore, we aimed to evaluate a subgroup using strict ANNEXA-4 patient selection criteria. METHODS: This was a retrospective study conducted utilizing chart review of adult patients that received 4F-PCC for oral fXa inhibitor-related bleeding. The primary endpoint was the rate of clinical success defined as achieving excellent or good hemostatic effectiveness following the administration of 4F-PCC. Secondary endpoints included in-hospital mortality and arterial/venous thromboembolism, and cost compared with andexanet alfa. RESULTS: A total of 119 patients were included, with 83 patients in the ANNEXA-4 criteria subgroup. Eighty-five of the 119 patients (71%) required reversal due to intracranial bleeding. Prior to reversal, 70 patients (59%) were taking apixaban and 49 patients (41%) were taking rivaroxaban. Clinical success was achieved in 106 of 119 patients (89%) and 74 of 83 patients (90%) in the strict criteria subgroup. Three of 119 patients (2.5%) had a thrombotic event during hospital stay and the overall mortality rate was 13%. The average cost increase of andexanet alfa compared to 4F-PCC would have been $29,500 per patient. CONCLUSIONS: Administration of 4F-PCC for the reversal of oral fXa inhibitors was effective with relatively low thrombotic risk. Further direct prospective comparison of 4F-PCC to andexanet alfa is warranted.

Incidence of Thromboembolic Events in Oncology Patients Receiving Intraoperative Tranexamic Acid During Orthopedic Surgery: A Retrospective Review at a Comprehensive Cancer Center.

Despite an abundance of evidence, routine perioperative antifibrinolytics have been avoided in oncology patients due to concern of thrombosis when given to patients with a preexisting hypercoagulable state. We present a retrospective review of 104 patients with an oncologic diagnosis who received intraoperative tranexamic acid during orthopedic surgery. Overall, complication rates were low, including deep vein thrombosis (1.0%), pulmonary embolism (4.8%), stroke (0%), and myocardial infarction (0%). This preliminary evidence shows that antifibrinolytics such as tranexamic acid may be considered perioperatively in oncology patients without increased risk of thromboembolic events; however, further prospective trials are encouraged.

Effectiveness and Safety of Four Direct Oral Anticoagulants in Asian Patients With Nonvalvular Atrial Fibrillation.

BACKGROUND: Whether four direct oral anticoagulants (DOACs) are superior to warfarin in Asian patients with nonvalvular atrial fibrillation (NVAF) remains unclear. METHODS: This nationwide retrospective cohort study was based on data from Taiwan's National Health Insurance Research Database from June 1, 2012, to December 31, 2017, covering patients with NVAF taking edoxaban (n = 4,577), apixaban (n = 9,952), rivaroxaban (n = 33,022), dabigatran (n = 22,371), and warfarin (n = 19,761). Propensity score weighting was used to balance covariates across study groups. Patients were followed up until occurrence of study outcomes or end date of study. RESULTS: Edoxaban, apixaban, and rivaroxaban were associated with a lower risk of ischemic stroke/systemic embolism than warfarin. All DOACs had a lower risk of major bleeding than warfarin. Apixaban was associated with a lower risk of major bleeding than rivaroxaban and dabigatran, whereas the risk of major bleeding was comparable between edoxaban and apixaban. The reduced risks of thromboembolism/major bleeding for the four DOACs persisted in high-risk subgroups, including those with chronic kidney disease, elderly patients (age ≥ 75 years), secondary stroke prevention, or CHA2DS2-VASc score (congestive heart failure, hypertension, age ≥ 75 years, diabetes mellitus, previous stroke/transient ischemic attack, vascular disease, age 65-74 years, and female sex) ≥ 4. A total of 2,924 (64%), 6,359 (64%), 31,108 (94%), and 19,821 (89%) patients received low-dose edoxaban (15-30 mg/d), apixaban (2.5 mg bid), rivaroxaban (10-15 mg/d), and dabigatran (110 mg bid), respectively. The effectiveness/safety outcomes with the four low-dose DOACs compared with warfarin were consistent with the main analysis. CONCLUSIONS: In the largest real-world practice study among Asian patients with NVAF, four DOACs were associated with a comparable or lower risk of thromboembolism, and a lower risk of bleeding than warfarin. There was consistency even among high-risk subgroups and whether standard-or low-dose regimens were compared.

Prophylactic anticoagulation in nephrotic syndrome prevents thromboembolic complications.

BACKGROUND: An increased incidence of thromboembolic events (TE) are reported in nephrotic syndrome (NS) leading to recommendations for prophylactic anticoagulation (PAC). However, as no randomized clinical trial has established the efficacy or risks associated with PAC, guidelines are empiric or substantiated only by estimates of risks and benefits. This study evaluates the risk of TE and hemorrhagic complications in patients with NS treated with PAC and compares to patients not receiving PAC. METHODS: We included patients diagnosed with NS from two Danish nephrology departments with different practices for the use of PAC. Patients were included if presenting with NS from September 2006 to January 2012, a P-albumin < 30 g/L, and renal biopsy confirming non-diabetic, glomerular disease. Patients aged < 16 years, on renal replacement therapy, or administered anticoagulants at the onset of NS were excluded. Bleeding episodes and/or TE were identified from patient records. Bleeding episodes were divided into minor and major bleeding. RESULTS: Of the 79 patients included, 44 patients received PAC either as low or high dose low-molecular-weight heparin (LMWH) or as warfarin with or without LMWH as bridging, while 35 did not receive PAC. P-albumin was significant lower in the PAC group compared to those not receiving PAC. Significantly more TEs was observed in the non-PAC group compared to the PAC group (4 versus 0 episodes, P = 0.035). The TEs observed included one patient with pulmonary embolism (PE), one with PE and deep vein thrombosis, one with PE and renal vein thrombosis, and one with a stroke. Five patients with bleeding episodes were identified among those receiving PAC, of which two were major and three were minor, while two patients in the non-PAC group experienced a minor bleeding episode (P = 0.45 between groups). The major bleeding episodes only occurred in patients receiving PAC in combination with low dose aspirin. CONCLUSIONS: In patients with NS the use of PAC was associated with a decreased risk of clinically significant TE, but may also be associated with more bleeding episodes although not statistically significant. Only patients treated with PAC in combination with anti-platelet therapy had major bleeding episodes.

Association of Rivaroxaban With Thromboembolic Events in Patients With Heart Failure, Coronary Disease, and Sinus Rhythm: A Post Hoc Analysis of the COMMANDER HF Trial.

Importance: Whether anticoagulation benefits patients with heart failure (HF) in sinus rhythm is uncertain. The COMMANDER HF randomized clinical trial evaluated the effects of adding low-dose rivaroxaban to antiplatelet therapy in patients with recent worsening of chronic HF with reduced ejection fraction, coronary artery disease (CAD), and sinus rhythm. Although the primary end point of all-cause mortality, myocardial infarction, or stroke did not differ between rivaroxaban and placebo, there were numerical advantages favoring rivaroxaban for myocardial infarction and stroke. Objective: To examine whether low-dose rivaroxaban was associated with reduced thromboembolic events in patients enrolled in the COMMANDER HF trial. Design, Setting, and Participants: Post hoc analysis of the COMMANDER HF multicenter, randomized, double-blind, placebo-controlled trial in patients with CAD and worsening HF. The trial randomized 5022 patients postdischarge from a hospital or outpatient clinic after treatment for worsening HF between September 2013 and October 2017. Patients were required to be receiving standard care for HF and CAD and were excluded for a medical condition requiring anticoagulation or a bleeding history. Patients were randomized in a 1:1 ratio. Analysis was conducted from June 2018 and January 2019. Intervention: Patients were randomly assigned to receive 2.5 mg of rivaroxaban given orally twice daily or placebo in addition to their standard therapy. Main Outcomes and Measures: For this post hoc analysis, a thromboembolic composite was defined as either (1) myocardial infarction, ischemic stroke, sudden/unwitnessed death, symptomatic pulmonary embolism, or symptomatic deep venous thrombosis or (2) all of the previous components except sudden/unwitnessed deaths because not all of these are caused by thromboembolic events. Results: Of 5022 patients, 3872 (77.1%) were men, and the overall mean (SD) age was 66.4 (10.2) years. Over a median (interquartile range) follow-up of 19.6 (11.7-30.8) months, fewer patients assigned to rivaroxaban compared with placebo had a thromboembolic event including sudden/unwitnessed deaths: 328 (13.1%) vs 390 (15.5%) (hazard ratio, 0.83; 95% CI, 0.72-0.96; P = .01). When sudden/unwitnessed deaths were excluded, the results analyzing thromboembolic events were similar: 153 (6.1%) vs 190 patients (7.6%) with an event (hazard ratio, 0.80; 95% CI, 0.64-0.98; P = .04). Conclusions and Relevance: In this study, thromboembolic events occurred frequently in patients with HF, CAD, and sinus rhythm. Rivaroxaban may reduce the risk of thromboembolic events in this population, but these events are not the major cause of morbidity and mortality in patients with recent worsening of HF for which rivaroxaban had no effect. While consistent with other studies, these results require confirmation in prospective randomized clinical trials. Trial Registration: ClinicalTrials.gov identifier: NCT01877915.

Comparison of warfarin dosage fluctuation with time in therapeutic range for bleeding or thromboembolism rate in Chinese patients.

BACKGROUND/PURPOSE: Warfarin treatment benefits vary with the clinical skill of warfarin dosage adjustment. However, optimal dosage adjustment in response to the out-of-range international normalized ratio (INR) is not completely understood. METHODS: Data for 2014-2016 from an integrated health care information system of a single hospital were analyzed. Based on their warfarin dosage fluctuation (WDF), defined as the standard deviation of all prescribed warfarin dosages divided by the mean dosage, the patients were classified into Groups 1 (0-0.10), 2 (0.10-0.20), and 3 (>0.20). Target and in-range INRs were 2.0-2.5 and 1.5-3.0, respectively. Based on time in therapeutic range (TTR), patients were also categorized into Groups 1 (<0.6), 2 (0.6-0.9), and 3 (>0.9). The primary outcome was emergency department visits for bleeding or thromboembolism (TE) events. RESULTS: Eighty-three events were retrieved from 17,397 records (1834 patients). Annual incidence rates were 0.9%, 2.5%, and 4.5% for WDF Groups 1, 2, and 3, respectively (p < 0.05), and 2.3%, 1.7%, and 1.7% for TTR Groups 1, 2, and 3, respectively (p = 0.41). Area under the receiver operator characteristic curves for WDF and TTR were 0.686 and 0.519, respectively, indicating that WDF exhibited superior predictive performance than TTR. CONCLUSION: High WDF rather than low TTR was associated with increased bleeding and TE incidence rates.

Complication rate of intraarterial treatment of severe cerebral vasospasm after subarachnoid hemorrhage with nimodipine and percutaneous transluminal balloon angioplasty: Worth the risk?

BACKGROUND AND PURPOSE: Delayed cerebral ischemia (DCI) is a complication of aneurysmal subarachnoid hemorrhage (SAH). Arterial cerebral vasospasm (CVS) is discussed as the main pathomechanism for DCI. Due to positive effects of per os nimodipine, intraarterial nimodipine application is used in patients with DCI. Further, percutaneous transluminal balloon angioplasty (PTA) is applied in focal high-grade spasm of intracranial arteries. However, clinical benefits of those techniques are unconfirmed in randomized trials so far, and complications might occur. We analyzed the occurrence of new infarcts in patients with severe CVS treated intra-arterially to assess benefits and risks of those techniques in a large single-center collective. MATERIALS AND METHODS: All imaging and clinical data of 88 patients with CVS after SAH and 188 procedures of intraarterial nimodipine infusion and additional PTA in selected cases (18 patients, 20 PTA procedures) treated at our institution were reviewed. In the event of new infarcts after endovascular treatment of CVS, infarct patterns were analyzed to determine the most probable etiology. RESULTS: Fifty-three percent of patients developed new cerebral infarction after intraarterial nimodipine and additional PTA in selected cases. Hereunder 47% were caused by persisting CVS. In 6% of patients, 3% of procedures respectively, new infarcts occurred due to complications of the intraarterial treatment including thromboembolism and arterial dissection. Of those, 3% of patients, 2% of procedures respectively, were assigned to thrombembolic complications of digital substraction angiography for intraarterial nimodipine. 17% of all patients treated with PTA (3/18=17%) showed infarction as a complication of PTA (15% of all PTA procedures). In 1% of patients, etiology of new infarction remained unclear. CONCLUSION: Ischemic complications occur in about 6% of patients treated intraarterially for CVS, 3% of procedures respectively. Further, to date a benefit for patients treated with this therapy could not be proven. Therefore, intraarterial treatment of CVS should be performed only in carefully selected cases.

Pharmacy Technician Management of Stable, In-Range INRs Within a Clinical Pharmacy Anticoagulation Service.

BACKGROUND: There is increasing demand on pharmacist time within clinical pharmacy services, and pharmacy technicians are a crucial resource for expanding pharmacy practice. OBJECTIVE: To assess the safety and effectiveness of pharmacy technician management of stable, in-range international normalized ratio (INR) results compared with usual care. METHODS: This retrospective, longitudinal, noninferiority cohort study was conducted at an integrated health care delivery system with a centralized anticoagulation service. Adult patients receiving chronic warfarin therapy with therapeutic INR results over a 3-month period (i.e., 100% time in therapeutic range [TTR] during the 3 months before the index date) were eligible for referral to technician warfarin management between March 1, 2015, and December 31, 2015. Patients with similar INR control during the same period but not referred to technician management were included as comparators in the usual care group. A one-sided noninferiority margin for the technician management group was set to -2.5% for mean TTR. Propensity scoring was used in regression modeling via inverse probability of treatment weights to compare between-group differences to account for covariates that may have influenced assignment to the technician group. Finally, bleeding, thromboembolic, and mortality outcomes were compared. RESULTS: 1,840 and 1,116 patients were included in the technician and usual care groups, respectively. The mean age of included patients was 73.1 years, and the majority (77.9%) had received warfarin for > 3 years. TTR during follow-up was 83.3% and 77.7% in the technician and usual care groups, respectively (mean difference = 5.7%; 95% CI = 4.1%-7.2%). The risk of thromboembolism was similar between the technician and usual care groups (HR = 0.84; 95% CI = 0.17-4.22; P = 0.832); however, bleeding (HR = 0.60; 95% CI = 0.39-0.94; P = 0.026) and all-cause mortality (HR = 0.44; 95% CI = 0.25-0.77; P = 0.004) were lower in the technician group during follow-up. CONCLUSIONS: Technician management of stable patients receiving chronic warfarin therapy within an integrated health care delivery system's centralized anticoagulation service was associated with noninferior TTR results compared with usual care pharmacist management. DISCLOSURES: This study was internally funded by the Kaiser Permanente Pharmacy Department. The study sponsor had no role in the study design, analysis, or interpretation. The authors have no relevant financial conflicts of interest to disclose.

Effectiveness and Safety of Standard- and Low-Dose Rivaroxaban in Asians With Atrial Fibrillation.

BACKGROUND: Low-dose rivaroxaban (10 mg/day) has been widely used in Asia for patients with atrial fibrillation (AF), although there is a lack of evidence regarding its effectiveness. In Asians, it is unclear whether low-dose rivaroxaban is equally effective as that of the standard dose or is associated with less bleeding risk. OBJECTIVES: The aim of this study was to evaluate the effectiveness and safety of standard-dose (15 or 20 mg/day) and low-dose (10 mg/day) rivaroxaban in Asians with AF. METHODS: Using data files from the National Health Insurance Research Database between May 1, 2014, and September 30, 2015, a retrospective population-based cohort study was conducted in patients diagnosed with AF or atrial flutter and treated with low- or standard-dose rivaroxaban. Patients were followed up until the first occurrence of the study outcome or the end of the observation period (December 31, 2015). RESULTS: Among 6,558 eligible patients, a total of 2,373 and 4,185 patients took low- and standard-dose rivaroxaban, respectively. Compared to standard-dose rivaroxaban, low-dose rivaroxaban was associated with a significantly higher risk of myocardial infarction (subdistribution hazard ratio: 2.26; 95% confidence interval: 1.13 to 4.52), with similar risk of ischemic stroke, systemic embolism, major bleeding, and nonmajor clinically relevant bleeding. CONCLUSIONS: Compared to standard-dose rivaroxaban, low-dose rivaroxaban in Asian patients with AF was associated with similar risks of thromboembolism and bleeding except myocardial infarction.

Rivaroxaban vs warfarin in high-risk patients with antiphospholipid syndrome.

Rivaroxaban is an effective and safe alternative to warfarin in patients with atrial fibrillation and venous thromboembolism. We tested the efficacy and safety of rivaroxaban compared with warfarin in high-risk patients with thrombotic antiphospholipid syndrome. This is a randomized open-label multicenter noninferiority study with blinded end point adjudication. Rivaroxaban, 20 mg once daily (15 mg once daily based on kidney function) was compared with warfarin (international normalized ratio target 2.5) for the prevention of thromboembolic events, major bleeding, and vascular death in patients with antiphospholipid syndrome. Only high-risk patients triple positive for lupus anticoagulant, anti-cardiolipin, and anti-ß2-glycoprotein I antibodies of the same isotype (triple positivity) were included in the study. The trial was terminated prematurely after the enrollment of 120 patients (59 randomized to rivaroxaban and 61 to warfarin) because of an excess of events among patients in the rivaroxaban arm. Mean follow-up was 569 days. There were 11 (19%) events in the rivaroxaban group, and 2 (3%) events in the warfarin group. Thromboembolic events occurred in 7 (12%) patients randomized to rivaroxaban (4 ischemic stroke and 3 myocardial infarction), whereas no event was recorded in those randomized to warfarin. Major bleeding occurred in 6 patients: 4 (7%) in the rivaroxaban group and 2 (3%) in the warfarin group. No death was reported. The use of rivaroxaban in high-risk patients with antiphospholipid syndrome was associated with an increased rate of events compared with warfarin, thus showing no benefit and excess risk. This trial was registered at www.clinicaltrials.gov as #NCT02157272.

Clinical profile, management and outcomes in a cohort of elderly and highly comorbid patients with nonvalvular atrial fibrillation treated with rivaroxaban in routine practice.

AIM: To analyze clinical profile and management of patients with nonvalvular atrial fibrillation treated with rivaroxaban in clinical practice according to age and to ascertain rates of thromboembolic and bleeding events during rivaroxaban therapy. METHODS: Retrospective study of nonvalvular atrial fibrillation patients that started rivaroxaban therapy between May 2013 and February 2017 in the cardiology department of two hospitals from Huesca, Spain. RESULTS: A total of 137 patients (mean age 78.2 ± 8.9 years; CHA2DS2-VASc 3.5 ± 1.3; HAS-BLED 1.6 ± 0.7) were included. Comorbidity was common. After a mean duration of treatment of 30.5 ± 17.2 months, no strokes were reported. Rates of transient ischemic attack, major bleeding and intracranial bleeding were low. CONCLUSION: In this cohort of elderly and highly comorbid patients treated with rivaroxaban, rates of thromboembolic and bleeding events were low.

Effectiveness and safety of rivaroxaban in a cohort of 142 patients with nonvalvular atrial fibrillation treated with rivaroxaban for the prevention of stroke.

AIM: To evaluate the clinical profile and effectiveness/safety of patients taking rivaroxaban in clinical practice. METHODS: Retrospective study that included patients with nonvalvular atrial fibrillation treated with rivaroxaban for the prevention of stroke between January 2012 and December 2016 in a tertiary hospital in Spain. RESULTS: A total of 142 patients (median age 78 years, 40.1% men, 32.4% creatinine clearance <50 ml/min; 96.5% CHA2DS2-VASc ≥2; 44.3% HAS-BLED ≥3) were included. Only two patients had a thromboembolic event (in both cases ischemic stroke) and three patients had major bleeding (rates of 1.3 and 1.9 events/100 patient years, respectively). CONCLUSION: Data regarding effectiveness and safety in our cohort were consistent with previous studies, showing that rivaroxaban can be effective and safely used in our setting.

Clinical profile, adequacy of dosage and thromboembolic and bleeding outcomes in patients with nonvalvular atrial fibrillation treated with rivaroxaban in a regional hospital of Asturias, Spain.

AIM: To analyze the clinical profile and outcomes of patients with nonvalvular atrial fibrillation treated with rivaroxaban in a regional hospital. METHODS: Retrospective study of patients with nonvalvular atrial fibrillation that started treatment with rivaroxaban between July 2013 and May 2017 in a regional hospital. RESULTS: 189 patients (age 76.0 ± 9.4 years; CHA2DS2-VASc 4.1 ± 1.7; HAS-BLED 2.1 ± 0.9) were included. Rivaroxaban 20 mg was taken by 74.1% of patients. Among patients treated with rivaroxaban 20 and 15 mg, only 3.6 and 22.5%, respectively, received an inadequate dose. After 26.6 ± 11.6 months of treatment, annual discontinuation rate was 1%. Rates of stroke, major bleeding and intracranial hemorrhage were 0.45, 0.22 and 0.22 events/100 patient years, respectively. CONCLUSION: In our practice of regional hospital, rates of discontinuation, thromboembolic and bleeding outcomes are low.