Warfarin for prevention of thromboembolism in atrial fibrillation: comparison of patient characteristics and outcomes of the "Real-World" Michigan Anticoagulation Quality Improvement Initiative (MAQI2) registry to the RE-LY, ROCKET-AF, and ARISTOTLE trials.

Randomized controlled trials (RCTs) examining warfarin use for stroke prevention in atrial fibrillation (AF) may not accurately reflect real-world populations. We aimed to determine the representativeness of the RCT populations to real-world patients and to describe differences in the characteristics of trial populations from trial eligible patients in a real-world setting. We hypothesized that a significant fraction of real-world patients would not qualify for the RE-LY, ROCKET-AF, and ARISTOTLE trials and that real-world patients qualifying for the studies may have more strokes and bleeding events. We compared the inclusion and exclusion criteria, patient characteristics, and clinical outcomes from RE-LY, ROCKET-AF, and ARISTOTLE against data from the Michigan Anticoagulation Quality Improvement Initiative (MAQI2), a regional network of six community- and academic-based anticoagulation clinics. Of the 1446 non-valvular AF patients in the MAQI2 registry taking warfarin, approximately 40-60% would meet the selection criteria used in RE-LY (788, 54.5%), ROCKET-AF (566, 39.1%), and ARISTOTLE (866, 59.9%). The most common reasons for exclusion from one or more trial were anemia (15.1%), other concurrent medications (11.2%), and chronic kidney disease (9.4%). Trial-eligible MAQI2 patients were older, more frequently female, with a higher rate of paroxysmal AF, and lower rates of congestive heart failure, previous stroke, and previous myocardial infarction than the trial populations. MAQI2 patients eligible for each trial had a lower rate of stroke and similar rate of major bleeding than was observed in the trials. A sizable proportion of real-world AF patients managed in anticoagulation clinics would not have been eligible for the RE-LY, ROCKET-AF, and ARISOTLE trials. The expected stroke risk reduction and bleeding risk among real-world AF patients on warfarin may not be congruent with published clinical trial data.

SAMe-TT2R2 predicts quality of anticoagulation in patients with acute venous thromboembolism: The MAQI2 experience.

A high SAMe-TT2R2 score predicted poor warfarin control and adverse events among atrial fibrillation patients. However, the SAMe-TT2R2 score has not been well validated in venous thromboembolism (VTE) patients. A cohort of 1943 warfarin-treated patients with acute VTE was analyzed to correlate the SAMe-TT2R2 score with time in therapeutic range (TTR) and clinical adverse events. A TTR <60% was more frequent among patients with a high (>2) versus low (0-1) SAMe-TT2R2 score (63.4% vs 52.3%, p<0.0001). A high SAMe-TT2R2 score (>2) correlated with increased overall adverse events (7.9 vs 4.5 overall adverse events/100 patient years, p=0.002), driven primarily by increased recurrent VTE rates (4.2 vs 1.5 recurrent VTE/100 patient years, p=0.0003). The SAMe-TT2R2 score had a modest predictive ability for international normalized ratio (INR) quality and adverse clinical events among warfarin-treated VTE patients. The utility of the SAMe-TT2R2 score to guide clinical decision-making remains to be investigated.

Prescribing trends of atrial fibrillation patients who switched from warfarin to a direct oral anticoagulant.

Direct oral anticoagulant (DOAC) agents offer several lifestyle and therapeutic advantages for patients relative to warfarin in the treatment of atrial fibrillation (AF). These alternative agents are increasingly used in the treatment of AF, however the adoption practices, patient profiles, and reasons for switching to a DOAC from warfarin have not been well studied. Through the Michigan Anticoagulation Quality Improvement Initiative, abstracted data from 3873 AF patients, enrolled between 2010 and 2015, were collected on demographics and comorbid conditions, stroke and bleeding risk scores, and reasons for anticoagulant switching. Over the study period, patients who switched from warfarin to a DOAC had similar baseline characteristics, risk scores, and insurance status but differed in baseline CrCl. The most common reasons for switching were patient related ease of use concerns (37.5%) as opposed to clinical reasons (16.5% of patients). Only 13% of patients that switched to a DOAC switched back to warfarin by the end of the study period.

Renal function in atrial fibrillation patients switched from warfarin to a direct oral anticoagulant.

All available direct oral anticoagulants (DOACs) are at least partially eliminated by the kidneys. These agents are increasingly being used as alternatives to warfarin for stroke prevention in patients with atrial fibrillation. The aim of this study was to identify changes in renal function and associated DOAC dosing implications in a multicenter cohort of atrial fibrillation patients switched from warfarin to DOAC treatment. We included all patients in the Michigan Anticoagulation Quality Improvement Initiative cohort who switched from warfarin to a DOAC with atrial fibrillation as their anticoagulant indication between 2009 and 2014, and who had at least two creatinine values. Compliance with FDA-recommended dosing based on renal function was assessed. Of the 189 patients switched from warfarin to a DOAC, 34 (18.0 %) had a baseline creatinine clearance <50 mL/min and 23 (12.2 %) experienced important fluctuations in renal function. Of these 23 patients, 6 (26.1 %) should have impacted the DOAC dosing, but only 1 patient actually received an appropriate dose adjustment. Additionally, 15 (7.9 %) of patients on DOACs had a dose change performed, but only one patient demonstrated a change in renal function to justify the dose adjustment. Most atrial fibrillation patients who switched from warfarin to a DOAC had stable renal function. However, the majority of patients who had a change in renal function did not receive the indicated dose change. As the use of DOACs expands, monitoring of renal function and appropriate dose adjustments are critical.

The changing characteristics of atrial fibrillation patients treated with warfarin.

It has been suggested that direct oral anticoagulants are being preferentially used in low risk atrial fibrillation (AF) patients. Understanding the changing risk profile of new AF patients treated with warfarin is important for interpreting the quality of warfarin delivery through an anticoagulation clinic. Six anticoagulation clinics participating in the Michigan Anticoagulation Quality Improvement Initiative enrolled 1293 AF patients between 2010 and 2014 as an inception cohort. Abstracted data included demographics, comorbidities, medication use and all INR values. Risk scores including CHADS2, CHA2DS2-VASc, HAS-BLED, SAMe-TT2R2, and Charlson comorbidity index (CCI) were calculated for each patient at the time of warfarin initiation. The quality of anticoagulation was assessed using the Rosendaal time in the therapeutic range (TTR) during the first 6 months of treatment. Between 2010 and 2014, patients initiating warfarin therapy for AF had an increasing mean CHADS2 (2.0 ± 1.1 to 2.2 ± 1.4, p = 0.02) and CCI (4.7 ± 1.8 to 5.1 ± 2.0, p = 0.03), and a trend towards increasing mean CHA2DS2-VASc, HAS-BLED, and SAMe-TT2R2 scores. The actual TTR remained unchanged over the study period (62.6 ± 18.2 to 62.7 ± 17.0, p = 0.98), and the number of INR checks did not change (18.9 ± 5.2 to 18.5 ± 5.1, p = 0.06). Between 2010 and 2014, AF patients newly starting warfarin had mild increases in risk for stroke and death with sustained quality of warfarin therapy.

Outcomes of direct oral anticoagulants with aspirin vs warfarin with aspirin: a registry-based cohort study.

Background: For patients anticoagulated with direct oral anticoagulants (DOACs) or warfarin and on aspirin (ASA) for nonvalvular atrial fibrillation and/or venous thromboembolism, it is unclear if bleeding outcomes differ. Objectives: To assess bleeding rates for ASA with DOACs vs warfarin and one another. Methods: Registry-based cohort study of patients followed by a 6-center quality improvement collaborative in Michigan using data from 2009 to 2022. The study included adults on ASA with warfarin or DOACs for atrial fibrillation and/or venous thromboembolism without a recent myocardial infarction or heart valve replacement. Results: After propensity matching by anticoagulant class, we compared 2 groups of 1467 patients followed for a median of 18.0 months. Any bleeding and nonmajor bleeding was increased with DOACs + ASA compared with warfarin + ASA (32.2 vs 27.8 and 27.1 vs 22.9 events/100 patient-years; relative risks [RRs], 1.1 and 1.2; 95% CIs, 1.1-1.2 and 1.1-1.3, respectively). After matching by drug, patients on apixaban + ASA vs warfarin + ASA had more bleeding (31.2 vs 27.8 events/100 patient-years; RR, 1.1; 95% CI, 1.0-1.2) and nonmajor bleeding but less major bleeding (3.8 vs 4.7 events/100 patient-years; RR, 0.8; 95% CI, 0.6-1.0) and emergency room visits for bleeding. Patients on rivaroxaban + ASA vs warfarin + ASA had more bleeding (39.3 vs 26.3 events/100 patient-years, RR, 1.5; 95% CI, 1.3-1.6), nonmajor bleeding, and thrombosis. Patients on apixaban + ASA vs rivaroxaban + ASA had significantly less bleeding (22.5 vs 39.3/100 patient-years; RR, 0.6; 95% CI, 0.5-0.7), nonmajor bleeding, major bleeding (2.1 vs 5.5 events/100 patient-years; RR, 0.4; 95% CI, 0.2-0.6), emergency room visits for bleeding, and thrombotic events. Conclusion: Patients on DOAC + ASA without a recent myocardial infarction or heart valve replacement had more nonmajor bleeding but otherwise similar outcomes compared with warfarin + ASA. Patients treated with rivaroxaban + ASA experienced more adverse clinical events compared with warfarin + ASA or apixaban + ASA.

Management strategies following slightly out-of-range INRs: watchful waiting vs dose changes.

Patients' international normalized ratios (INRs) often fall slightly out of range. In these cases, the American College of Chest Physicians (ACCP) guidelines suggest maintaining the current warfarin dose and retesting the INR within the following 2 weeks (watchful waiting). We sought to determine whether watchful waiting or dose changes for slightly out-of-range INRs is more effective in obtaining in-range INRs at follow-up. INRs and management strategies of warfarin-treated patients within the Michigan Anticoagulation Quality Improvement Initiative registry were analyzed. Management strategies included watchful waiting or dose changes. INRs slightly out of range (target range 2.0-3.0) and their associated management were identified. Multilevel mixed-effects logistic regression was used to estimate the probability of the next INR being in range, adjusted for clustering due to multiple out-of-range INRs per patient. A total of 45 351 slightly out-of-range INRs (ranging 1.50-1.99 and 3.01-3.49) from 8288 patients were identified. The next INR was slightly less likely to be in range with watchful waiting than with a dose change (predicted probabilities 58.9% vs 60.0%, P = 0.024). Although a significant statistical difference was detected in the probabilities of the next INR being back in range when managed by a dose change compared with watchful waiting following a slightly out-of-range INR, the magnitude of the difference was small and unlikely to represent clinical importance. Our study supports the current guideline recommendations for watchful waiting in cases of slightly out-of-range INRs values.

Assessment of an Intervention to Reduce Aspirin Prescribing for Patients Receiving Warfarin for Anticoagulation.

Importance: For some patients receiving warfarin, adding aspirin (acetylsalicylic acid) increases bleeding risk with unclear treatment benefit. Reducing excess aspirin use could be associated with improved clinical outcomes. Objective: To assess changes in aspirin use, bleeding, and thrombosis event rates among patients treated with warfarin. Design, Setting, and Participants: This pre-post observational quality improvement study was conducted from January 1, 2010, to December 31, 2019, at a 6-center quality improvement collaborative in Michigan among 6738 adults taking warfarin for atrial fibrillation and/or venous thromboembolism without an apparent indication for concomitant aspirin. Statistical analysis was conducted from November 26, 2020, to June 14, 2021. Intervention: Primary care professionals for patients taking aspirin were asked whether an ongoing combination aspirin and warfarin treatment was indicated. If not, then aspirin was discontinued with the approval of the managing clinician. Main Outcomes and Measures: Outcomes were assessed before and after intervention for the primary analysis and before and after 24 months before the intervention (when rates of aspirin use first began to decrease) for the secondary analysis. Outcomes included the rate of aspirin use, bleeding, and thrombotic outcomes. An interrupted time series analysis assessed cumulative monthly event rates over time. Results: A total of 6738 patients treated with warfarin (3160 men [46.9%]; mean [SD] age, 62.8 [16.2] years) were followed up for a median of 6.7 months (IQR, 3.2-19.3 months). Aspirin use decreased slightly from a baseline mean use of 29.4% (95% CI, 28.9%-29.9%) to 27.1% (95% CI, 26.1%-28.0%) during the 24 months before the intervention (P < .001 for slope before and after 24 months before the intervention) with an accelerated decrease after the intervention (mean aspirin use, 15.7%; 95% CI, 14.8%-16.8%; P = .001 for slope before and after intervention). In the primary analysis, the intervention was associated with a significant decrease in major bleeding events per month (preintervention, 0.31%; 95% CI, 0.27%-0.34%; postintervention, 0.21%; 95% CI, 0.14%-0.28%; P = .03 for difference in slope before and after intervention). No change was observed in mean percentage of patients having a thrombotic event from before to after the intervention (0.21% vs 0.24%; P = .34 for difference in slope). In the secondary analysis, reducing aspirin use (starting 24 months before the intervention) was associated with decreases in mean percentage of patients having any bleeding event (2.3% vs 1.5%; P = .02 for change in slope before and after 24 months before the intervention), mean percentage of patients having a major bleeding event (0.31% vs 0.25%; P = .001 for change in slope before and after 24 months before the intervention), and mean percentage of patients with an emergency department visit for bleeding (0.99% vs 0.67%; P = .04 for change in slope before and after 24 months before the intervention), with no change in mean percentage of patients with a thrombotic event (0.20% vs 0.23%; P = .36 for change in slope before and after 24 months before the intervention). Conclusions and Relevance: This quality improvement intervention was associated with an acceleration of a preexisting decrease in aspirin use among patients taking warfarin for atrial fibrillation and/or venous thromboembolism without a clear indication for aspirin therapy. Reductions in aspirin use were associated with reduced bleeding. This study suggests that an anticoagulation clinic-based aspirin deimplementation intervention can improve guideline-concordant aspirin use.

Adverse Events Associated With the Addition of Aspirin to Direct Oral Anticoagulant Therapy Without a Clear Indication.

Importance: It is unclear how many patients treated with a direct oral anticoagulant (DOAC) are using concomitant acetylsalicylic acid (ASA, or aspirin) and how this affects clinical outcomes. Objective: To evaluate the frequency and outcomes of prescription of concomitant ASA and DOAC therapy for patients with atrial fibrillation (AF) or venous thromboembolic disease (VTE). Design, Setting, and Participants: This registry-based cohort study took place at 4 anticoagulation clinics in Michigan from January 2015 to December 2019. Eligible participants were adults undergoing treatment with a DOAC for AF or VTE, without a recent myocardial infarction (MI) or history of heart valve replacement, with at least 3 months of follow-up. Exposures: Use of ASA concomitant with DOAC therapy. Main Outcomes and Measures: Rates of bleeding (any, nonmajor, major), rates of thrombosis (stroke, VTE, MI), emergency department visits, hospitalizations, and death. Results: Of the study cohort of 3280 patients (1673 [51.0%] men; mean [SD] age 68.2 [13.3] years), 1107 (33.8%) patients without a clear indication for ASA were being treated with DOACs and ASA. Two propensity score-matched cohorts, each with 1047 patients, were analyzed (DOAC plus ASA and DOAC only). Patients were followed up for a mean (SD) of 20.9 (19.0) months. Patients taking DOAC and ASA experienced more bleeding events compared with DOAC monotherapy (26.0 bleeds vs 31.6 bleeds per 100 patient years, P = .01). Specifically, patients undergoing combination therapy had significantly higher rates of nonmajor bleeding (26.1 bleeds vs 21.7 bleeds per 100 patient years, P = .02) compared with DOAC monotherapy. Major bleeding rates were similar between the 2 cohorts. Thrombotic event rates were also similar between the cohorts (2.5 events vs 2.3 events per 100 patient years for patients treated with DOAC and ASA compared with DOAC monotherapy, P = .80). Patients were more often hospitalized while undergoing combination therapy (9.1 vs 6.5 admissions per 100 patient years, P = .02). Conclusion and Relevance: Nearly one-third of patients with AF and/or VTE who were treated with a DOAC received ASA without a clear indication. Compared with DOAC monotherapy, concurrent DOAC and ASA use was associated with increased bleeding and hospitalizations but similar observed thrombosis rate. Future research should identify and deprescribe ASA for patients when the risk exceeds the anticipated benefit.

Association of Adding Aspirin to Warfarin Therapy Without an Apparent Indication With Bleeding and Other Adverse Events.

Importance: It is not clear how often patients receive aspirin (acetylsalicylic acid) while receiving oral anticoagulation with warfarin sodium without a clear therapeutic indication for aspirin, such as a mechanical heart valve replacement, recent percutaneous coronary intervention, or acute coronary syndrome. The clinical outcomes of such patients treated with warfarin and aspirin therapy compared with warfarin monotherapy are not well defined to date. Objective: To evaluate the frequency and outcomes of adding aspirin to warfarin for patients without a clear therapeutic indication for combination therapy. Design, Setting, and Participants: A registry-based cohort study of adults enrolled at 6 anticoagulation clinics in Michigan (January 1, 2010, to December 31, 2017) who were receiving warfarin therapy for atrial fibrillation or venous thromboembolism without documentation of a recent myocardial infarction or history of valve replacement. Exposure: Aspirin use without therapeutic indication. Main Outcomes and Measures: Rates of any bleeding, major bleeding events, emergency department visits, hospitalizations, and thrombotic events at 1, 2, and 3 years. Results: Of the study cohort of 6539 patients (3326 men [50.9%]; mean [SD] age, 66.1 [15.5] years), 2453 patients (37.5%) without a clear therapeutic indication for aspirin were receiving combination warfarin and aspirin therapy. Data from 2 propensity score-matched cohorts of 1844 patients were analyzed (warfarin and aspirin vs warfarin only). At 1 year, patients receiving combination warfarin and aspirin compared with those receiving warfarin only had higher rates of overall bleeding (cumulative incidence, 26.0%; 95% CI, 23.8%-28.3% vs 20.3%; 95% CI, 18.3%-22.3%; P < .001), major bleeding (5.7%; 95% CI, 4.6%-7.1% vs 3.3%; 95% CI, 2.4%-4.3%; P < .001), emergency department visits for bleeding (13.3%; 95% CI, 11.6%-15.1% vs 9.8%; 95% CI, 8.4%-11.4%; P = .001), and hospitalizations for bleeding (8.1%; 6.8%-9.6% vs 5.2%; 4.1%-6.4%; P = .001). Rates of thrombosis were similar, with a 1-year cumulative incidence of 2.3% (95% CI, 1.6%-3.1%) for those receiving combination warfarin and aspirin therapy compared with 2.7% (95% CI, 2.0%-3.6%) for those receiving warfarin alone (P = .40). Similar findings persisted during 3 years of follow-up as well as in sensitivity analyses. Conclusions and Relevance: Compared with warfarin monotherapy, receipt of combination warfarin and aspirin therapy was associated with increased bleeding and similar observed rates of thrombosis. Further research is needed to better stratify which patients may benefit from aspirin while anticoagulated with warfarin for atrial fibrillation or venous thromboembolism; clinicians should be judicious in selecting patients for combination therapy.

Sociodemographic factors in patients continuing warfarin vs those transitioning to direct oral anticoagulants.

Clinical factors and patient preferences are important for selecting oral anticoagulants for venous thromboembolism (VTE) and atrial fibrillation (AF). The relative association of sociodemographic factors with anticoagulant use is unknown. We evaluated a prospective cohort to compare sociodemographic variables in patients who continued on warfarin for AF or VTE to those who transitioned to 1 of the direct oral anticoagulants (DOACs). Adult patients, newly started on warfarin, were enrolled through 6 anticoagulation clinics across Michigan. Of 8468 patients, 53.3% had AF, 45.6% had VTE, and 1.1% had both. Of these, 696 (8.2%) switched from warfarin to a DOAC. There were no significant differences between switchers and nonswitchers for percentage of time with a therapeutic international normalized ratio on warfarin, urban-rural residence status, or health insurance. Switchers were more often white (83.3% vs 77.7%; P < .001), partnered (67.3% vs 59.2%; P < .001), or resided in a zip code with a higher median household income (P < .001). The results show that sociodemographic factors, such as race, partnered status, and income are associated with a patient's likelihood of switching to a DOAC vs remaining on warfarin therapy. Although clinical factors predominate, the reason for, and impact of, these observed variations in care requires further investigation.

The predictive ability of the CHADS2 and CHA2DS2-VASc scores for bleeding risk in atrial fibrillation: the MAQI(2) experience.

INTRODUCTION: Guidelines recommend the assessment of stroke and bleeding risk before initiating warfarin anticoagulation in patients with atrial fibrillation. Many of the elements used to predict stroke also overlap with bleeding risk in atrial fibrillation patients and it is tempting to use stroke risk scores to efficiently estimate bleeding risk. Comparison of stroke risk scores to bleeding risk scores to predict bleeding has not been thoroughly assessed. METHODS: 2600 patients followed at seven anticoagulation clinics were followed from October 2009-May 2013. Five risk models (CHADS2, CHA2DS2-VASc, HEMORR2HAGES, HAS-BLED and ATRIA) were retrospectively applied to each patient. The primary outcome was the first major bleeding event. Area under the ROC curves were compared with C statistic and net reclassification improvement (NRI) analysis was performed. RESULTS: 110 patients experienced a major bleeding event in 2581.6 patient-years (4.5%/year). Mean follow up was 1.0±0.8years. All of the formal bleeding risk scores had a modest predictive value for first major bleeding events (C statistic 0.66-0.69), performing better than CHADS2 and CHA2DS2-VASc scores (C statistic difference 0.10 - 0.16). NRI analysis demonstrated a 52-69% and 47-64% improvement of the formal bleeding risk scores over the CHADS2 score and CHA2DS2-VASc score, respectively. CONCLUSIONS: The CHADS2 and CHA2DS2-VASc scores did not perform as well as formal bleeding risk scores for prediction of major bleeding in non-valvular atrial fibrillation patients treated with warfarin. All three bleeding risk scores (HAS-BLED, ATRIA and HEMORR2HAGES) performed moderately well.

Clinical and safety impact of an inpatient pharmacist-directed anticoagulation service.

BACKGROUND: Warfarin is implicated in approximately 30% of reported anticoagulant-related errors. In order to improve anticoagulation management and safety, our institution implemented an inpatient Pharmacist-Directed Anticoagulation Service (PDAS). OBJECTIVE: To evaluate the impact of this service on both transition of care and safety of patients receiving warfarin anticoagulation. DESIGN: Cluster randomized trial. SETTING: Large, urban teaching hospital and level 1 trauma center. PATIENTS: All patients receiving warfarin on two medical and two cardiology units. INTERVENTION: A PDAS provided dosing, monitoring, and coordination of transition from the inpatient-to-outpatient setting. MEASUREMENTS: Endpoints were assessed during hospitalization and 30 days after discharge. Transition of care was considered effective if compliance with all of the transition of care metrics occurred. The transition of care metrics included: appropriate enrollment in the anticoagulation clinic, documented inpatient-to-outpatient provider contact, documented inpatient provider-to-anticoagulation clinic communication and patient follow-up with the anticoagulation clinic within five days of discharge. Safety was measured by the composite endpoint of thromboembolism, major bleeding, or international normalized ratio (INR) ≥5. RESULTS: This study included 500 patients. Transition of care metric compliance occurred in 73% more patients in the PDAS group (P < 0.001). There was also a 32% reduction in the composite safety endpoint in the PDAS group (P = 0.103). This finding was driven by a reduction in rate of INR ≥5 (P = 0.076). CONCLUSIONS: Implementation of a PDAS provides a net improvement in quality of care for the patient taking warfarin in the inpatient setting.