Association of Direct Oral Anticoagulation Management Strategies With Clinical Outcomes for Adults With Atrial Fibrillation.

Importance: Anticoagulation management services (AMSs; ie, warfarin clinics) have evolved to include patients treated with direct oral anticoagulants (DOACs), but it is unknown whether DOAC therapy management services improve outcomes for patients with atrial fibrillation (AF). Objective: To compare outcomes associated with 3 DOAC care models for preventing adverse anticoagulation-related outcomes among patients with AF. Design, Setting, and Participants: This retrospective cohort study included 44 746 adult patients with a diagnosis of AF who initiated oral anticoagulation (DOAC or warfarin) between August 1, 2016, and December 31, 2019, in 3 Kaiser Permanente (KP) regions. Statistical analysis was conducted from August 2021 through May 2023. Exposures: Each KP region used an AMS to manage warfarin but used distinct approaches to DOAC care: (1) usual care (UC) by the prescribing clinician, (2) UC plus an automated population management tool (PMT), or (3) pharmacist-managed AMS care. Propensity scores and inverse probability of treatment weights (IPTWs) were estimated. Direct oral anticoagulant care models were first indirectly compared using warfarin as a common comparator within each region and then directly compared across regions. Main Outcomes and Measures: Patients were followed up until the first occurrence of an outcome (composite of thromboembolic stroke, intracranial hemorrhage, other major bleeding, or death), discontinuation of KP membership, or December 31, 2020. Results: Overall, 44 746 patients were included: 6182 in the UC care model (3297 DOAC; 2885 warfarin), 33 625 in the UC plus PMT care model (21 891 DOAC; 11 734 warfarin), and 4939 in the AMS care model (2089 DOAC; 2850 warfarin). Baseline characteristics (mean [SD] age, 73.1 [10.6] years, 56.1% male, 67.2% non-Hispanic White, median CHA2DS2-VASc [congestive heart failure, hypertension, age ≥75 years, diabetes, stroke, vascular disease, age 65-74 years, female sex] score of 3 [IQR, 2-5]) were well balanced after IPTW. Over a median follow-up of 2 years, patients who received the UC plus PMT or AMS care model did not have significantly better outcomes than those who received UC. The incidence rate of the composite outcome was 5.4% per year for DOAC and 9.1% per year for warfarin for those in the UC group, 6.1% per year for DOAC and 10.5% per year for those in the UC plus PMT group, and 5.1% per year for DOAC and 8.0% per year for those in the AMS group. The IPTW-adjusted hazard ratios (HRs) for the composite outcome comparing DOAC vs warfarin were 0.91 (95% CI, 0.79-1.05) in the UC group, 0.85 (95% CI, 0.79-0.90) in the UC plus PMT group, and 0.84 (95% CI, 0.72-0.99) in the AMS group (P = .62 for heterogeneity across care models). When directly comparing patients receiving DOAC, the IPTW-adjusted HR was 1.06 (95% CI, 0.85-1.34) for the UC plus PMT group vs the UC group and 0.85 (95% CI, 0.71-1.02) for the AMS group vs the UC group. Conclusions and Relevance: This cohort study did not find appreciably better outcomes for patients receiving DOAC who were managed by either a UC plus PMT or AMS care model compared with UC.

Effectiveness and safety of Dabigatran 110 mg versus 150 mg for Stroke Prevention in Patients with Atrial Fibrillation at High Bleeding Risk.

PURPOSE: The effectiveness and tolerability of a reduced dose (110 mg) of dabigatran versus the standard dose (150 mg) were evaluated in subgroups of patients with atrial fibrillation (AF) at high bleeding risk. METHODS: Eligible patients were adults with AF and a creatinine clearance rate ≥30 mL/min who were initiated on treatment with dabigatran (index) between 2016 and 2018. High-bleeding-risk subgroups were identified: (1) age ≥80 years; (2) moderate renal impairment (creatinine clearance rate 30-<50 mL/min); and (3) recent bleeding or a HAS-BLED score of ≥3. Fine-Gray subdistribution hazard regression models with inverse probability of treatment weights were used to investigate associations between dabigatran dose and three outcomes: stroke or systemic embolism, major bleeding requiring hospitalization, and all-cause mortality. FINDINGS: Among 7858 patients with AF and a high bleeding risk (age ≥80 years, 3472; moderate renal impairment, 1574; recent bleeding or HAS-BLED score ≥3, 2812), 32.3% received reduced-dose dabigatran. Compared with the standard dose, use of the reduced dose of dabigatran was not associated with an increased risk for stroke or systemic embolism but was associated with a lower risk for major bleeding (HR = 0.65; 95% CI, 0.44-0.95) and all-cause mortality (HR = 0.78; 95% CI, 0.65-0.92) in patients aged ≥80 years. The use of reduced-dose dabigatran was associated with a lower risk for major bleeding (HR = 0.54; 95% CI, 0.30-0.95) and all-cause mortality among patients with moderate renal impairment (HR = 0.53; 95% CI, 0.40-0.71). IMPLICATIONS: Lower risks for bleed and mortality associated with reduced- versus standard-dose dabigatran in patients with AF and a high bleeding risk suggest a better dosing strategy.

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.

Warfarin Management and Outcomes in Patients with Nonvalvular Atrial Fibrillation Within an Integrated Health Care System.

BACKGROUND: Warfarin is a common treatment option to manage patients with nonvalvular atrial fibrillation (NVAF) in clinical practice. Understanding current pharmacist-led anticoagulation clinic management patterns and associated outcomes is important for quality improvement; however, currently little evidence associating outcomes with management patterns exists. OBJECTIVES: To (a) describe warfarin management patterns and (b) evaluate associations between warfarin treatment and clinical outcomes for patients with NVAF in an integrated health care system. METHODS: A retrospective cohort study was conducted among NVAF patients with warfarin therapy between January 1, 2006, and December 31, 2011, using Kaiser Permanente Southern California data, and followed until December 31, 2013. Management patterns related to international normalized ratio (INR) monitoring, anticoagulation clinic pharmacist intervention (consultation), and warfarin dose adjustments were investigated along with yearly attrition rates, time-in-therapeutic ranges (TTRs), and clinical outcomes (stroke or systemic embolism and major bleeding). Descriptive statistics and multivariable Cox proportional hazard models were used to determine associations between TTR and clinical outcomes. RESULTS: A total of 32,074 NVAF patients on warfarin treatment were identified and followed for a median of 3.8 years. About half (49%) of the patients were newly initiating warfarin therapy. INR monitoring and pharmacist interventions were conducted roughly every 3 weeks after 6 months of warfarin treatment. Sixty-three percent of the study population had ≥ 1 warfarin dose adjustments with a mean (SD) of 6.7 (6.3) annual dose adjustments. Warfarin dose adjustments occurred at a median of 1 day (interquartile ranges [IQR] 1-3) after the INR measurement. Yearly attrition rate was from 3.3% to 6.3% during the follow-up, and median (IQR) TTR was 61% (46%-73%). Patients who received frequent INR monitoring (≥ 27 times per year), pharmacist interventions (≥ 24 times per year), or frequently adjusted warfarin dose (≥ 11 times per year) consistently showed poor TTRs (mean TTR for the highest quartiles was 45.3%-48.3%). A higher TTR was associated with a lower risk of clinical outcomes regardless of frequency of INR monitoring, pharmacist interventions, or number of dose adjustments. Patients whose TTRs were < 65%, even with frequent pharmacist interventions, had similar stroke or systemic embolism event rates, as compared with patients with TTRs < 65% and less frequent interventions (1.88 vs. 1.54 stroke or systemic embolism rates per 100 person-years, respectively, P = 0.78). The lowest TTR quartile (< 46%) was associated with a 3 times higher risk of stroke or systemic embolism (hazard ratio [HR] = 3.19, 95% CI = 2.71-3.77) and a 2 times higher risk of major bleeding (HR = 2.10, 95% CI = 1.96-2.24) compared with the highest TTR quartile (≥ 73%). CONCLUSIONS: Despite close monitoring with timely warfarin dose adjustments, there were still a substantial number of challenging patients whose TTRs were suboptimal despite a higher number of pharmacist interventions. These patients eventually experienced more stroke or systemic embolism and bleeding events among NVAF patients managed by anticoagulation clinics. New individualized treatment or management strategies for patients who are not able to reach optimal therapeutic ranges are necessary to improve outcomes. DISCLOSURES: This research and manuscript were funded by Bristol-Myers Squibb Company and Pfizer. Authors from Bristol-Myers Squibb Company and Pfizer participated in the design of the study, interpretation of the data, review/revision of the manuscript, and approval of the final version of the manuscript. An received a grant for research support from Bristol-Myers Squibb/Pfizer. Niu, Rashid, and Zheng received a grant from Bristol-Myers Squibb/Pfizer to their institutions for salary reimbursement. Vo, Singh, and Aranda are employed by Bristol-Myers Squibb; Bruno was employed by Bristol-Myers Squibb at the time of this study. Mendes and Dills are employed by Pfizer, and Mendes was a member of the Pfizer Cardiovascular and Metabolic Field Medical Team during the time of this study. Lang, Jazdzewski, and Le have no known conflicts of interest to report. Study concept and design were contributed primarily by An and Rashid, along with the other authors. Niu took the lead in data collection, along with Zheng, and data interpretation was performed by An, along with Mendes and Dills, with assistance from the other authors. The manuscript was written by An and revised by Mendes, Dills, Vo, Singh, Bruno, and Aranda, along with Lang, Le, and Jazdezewski. Part of this study's findings was presented at the CHEST 2015 Annual Meeting in Montreal, Canada, on October 28, 2015.

Stroke and Bleeding Risk Associated With Antithrombotic Therapy for Patients With Nonvalvular Atrial Fibrillation in Clinical Practice.

BACKGROUND: The quality of antithrombotic therapy for patients with nonvalvular atrial fibrillation during routine medical care is often suboptimal. Evidence linking stroke and bleeding risk with antithrombotic treatment is limited. The purpose of this study was to evaluate the associations between antithrombotic treatment episodes and outcomes. METHODS AND RESULTS: A retrospective longitudinal observational cohort study was conducted using patients newly diagnosed with nonvalvular atrial fibrillation with 1 or more stroke risk factors (CHADS2 ≥1) in Kaiser Permanente Southern California between January 1, 2006 and December 31, 2011. A total of 1782 stroke and systemic embolism (SE) and 3528 major bleed events were identified from 23 297 patients during the 60 021 person-years of follow-up. The lowest stroke/SE rates and major bleed rates were observed in warfarin time in therapeutic range (TTR) ≥55% episodes (stroke/SE: 0.87 [0.71 to 1.04]; major bleed: 4.91 [4.53 to 5.28] per 100 person-years), which was similar to the bleed rate in aspirin episodes (4.95 [4.58 to 5.32] per 100 person-years). The warfarin TTR ≥55% episodes were associated with a 77% lower risk of stroke/SE (relative risk=0.23 [0.18 to 0.28]) compared to never on therapy; and the warfarin TTR <55% and on-aspirin episodes were associated with a 20% lower and with a 26% lower risk of stroke/SE compared to never on therapy, respectively. The warfarin TTR <55% episodes were associated with nearly double the risk of a major bleed compared to never on therapy (relative risk=1.93 [1.74 to 2.14]). CONCLUSIONS: Continuation of antithrombotic therapy as well as maintaining an adequate level of TTR is beneficial to prevent strokes while minimizing bleeding events.