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.
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.
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.
To assess bleeding rates for ASA with DOACs vs warfarin and one another.
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.
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.
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.
•Aspirin (ASA) is sometimes combined with oral anticoagulation, but this is not always indicated.•We assessed outcomes of oral anticoagulation + ASA for venous thromboembolism and atrial fibrillation.•Direct oral anticoagulants led to more nonmajor bleeding but similar outcomes to warfarin.•Major bleeding was least with apixaban + ASA, followed by warfarin + ASA, and highest with rivaroxaban + ASA.
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.
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.
•Watchful waiting describes maintaining a warfarin dose after a slightly out-of-range INR and retesting within the following 2 weeks.•Although a warfarin dose change is more effective in producing a therapeutic INR, our study supports ACCP guidelines for watchful waiting.
Display omitted
▪
Introduction
The direct oral anticoagulants (DOACs) including apixaban, dabigatran, edoxaban, and rivaroxaban are increasingly utilized for the management of venous thromboembolic disease (VTE) ...and/or non-valvular atrial fibrillation (NVAF). Adding aspirin (ASA) to warfarin or DOAC therapy increases bleeding risk. Patients on combination therapy with ASA and an anticoagulant were not well represented in clinical trials comparing DOACs to warfarin. We sought to compare bleeding and thrombotic outcomes with DOACs and ASA compared to warfarin and ASA in a non-trial setting.
Methods
We conducted a retrospective registry-based cohort study of adults on DOAC or warfarin therapy for VTE and/or NVAF. Warfarin treated patients were followed by six anticoagulation clinics. Four out of the six clinics contributed data on their patients that were on DOACs in the Michigan Anticoagulation Quality Improvement Initiative (MAQI 2) from January 2009 to June 2021. Patients were excluded if they had a history of heart valve replacement, recent myocardial infarction, or less than 3 months of follow-up. Two propensity matched cohorts (warfarin+ASA vs DOAC+ASA) of patients were analyzed based on ASA use at the time of study enrollment. The primary outcome was any new bleeding event. Secondary outcomes included new episodes of arterial or venous thrombosis, bleeding event type (major, fatal, life threatening, central nervous system, and non-major bleeding), emergency room visits, hospitalizations, transfusions, and death. Random chart audits were done to confirm the accuracy of the abstracted data. Event rates were compared using Poisson regression.
Results
We identified a total of 1,139 patients on DOACs plus ASA and 4,422 patients on warfarin plus ASA. After propensity matching, we compared two groups of 1,114 matched patients. DOAC treated patients were predominately on apixaban (62.3%) and rivaroxaban (30.4%), most often at therapeutic doses (Table 1). Patients were largely (90.5%) on low dose ASA (≤ 100 mg). Patient demographics, co-morbidities, indication for anticoagulation, history of bleeding or clotting, medications, and duration of follow-up were well-balanced after matching. Patients were followed for a median of 11.7 months (interquartile range 4.4 and 34 months). Patients treated with DOAC+ASA had 2.4 thrombotic events per 100 patient years compared to 2.2 thrombotic events per 100 patient years with warfarin+ASA (P=0.78). There were no significant differences observed between groups by thrombotic subtype (stroke, transient ischemic attack, pulmonary embolism, deep vein thrombosis, table 1). Bleeding was also similar with 30.1 bleeding events per 100 patient years with DOAC+ASA compared to 27.8 bleeds per 100 patient years with warfarin+ASA (P=0.24). There were no significant differences by bleeding subtype (table 1). Hospitalizations for clotting occurred less frequently with DOAC+ASA (0.9 hospitalizations per 100 patient years) compared to warfarin+ASA (1.7 hospitalizations per 100 patient years, P=0.03). Mortality, transfusions, and healthcare utilization were otherwise similar between the two groups.
Conclusions
For patients on a DOAC versus warfarin with ASA for atrial fibrillation and/or venous thromboembolic disease without a recent myocardial infarction or heart valve replacement, bleeding and thrombotic outcomes were similar.
Display omitted
Kaatz: Gilead: Consultancy; CSL Behring: Consultancy; Novartis: Consultancy; Bristol Myer Squibb: Consultancy, Research Funding; Pfizer: Consultancy; Alexion: Consultancy; Janssen: Consultancy, Research Funding; Osmosis Research: Research Funding. Kline-Rogers: Janssen: Consultancy; American College of Physicians: Consultancy. Sood: Bayer: Consultancy. Froehlich: Merck: Consultancy; Janssen: Consultancy; Novartis: Consultancy; Boehringer-Ingelheim: Consultancy; Pfizer: Consultancy; Blue Cross Blue Shield of Michigan: Research Funding; Fibromuscular Disease Society of America: Research Funding. Barnes: National Certification Board of Anticoagulation Providers: Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy; Acelis: Consultancy; AMAG Pharmaceuticals: Consultancy; Connected Health: Consultancy; Blue Cross Blue Shield of Michigan: Research Funding; AC Forum: Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy; Bristol-Myers Squibb: Consultancy.
Abstract only Introduction: For some patients on chronic warfarin anticoagulation for atrial fibrillation and/or venous thromboembolic disease, the addition of aspirin (ASA) may increase bleeding ...with uncertain therapeutic benefit. Between 2017 and 2018, the six-center Michigan Anticoagulation Quality Improvement Initiative implemented a multi-center quality improvement project to reduce excess aspirin use. Hypothesis: We anticipated reductions in overall ASA use and bleeding. Methods: Warfarin treated patients taking ASA without a clear indication (eg. coronary artery disease) were identified. Their primary care provider was contacted to advise if ongoing ASA+warfarin was recommended. ASA was discontinued if suggested by their doctor. Data was abstracted by trained abstractors using predefined forms. In December 2019, we evaluated monthly rates of excess ASA use, bleeding, and thrombotic outcomes. Data were analyzed using piecewise linear regression. Results: We followed 6,738 patients for a median (interquartile range) of 6.7 months (3.2-19.3 months). Aspirin use declined significantly over the 24 months before our intervention (P<0.001) with an accelerated decline post intervention (p=0.001, Figure 1). Our intervention was associated with a non-significant decline in bleeding (p=0.12), emergency room (ER) visits for bleeding (p=0.35), admissions for bleeding (p=0.97), a significant decline in major bleeding (p=0.029), and no significant change in thrombotic outcomes (p=0.34). Including the decline in ASA use starting 24 months pre-intervention, reducing ASA use resulted in significant declines in any bleeding, major bleeding, and ER visits for bleeding (p=0.021, p=0.001, p=0.038 respectively). There remained no change in thrombotic outcomes (p=0.36). Conclusions: Our quality improvement intervention reduced aspirin use. Reductions in aspirin use were associated with reduced bleeding outcomes without increased thrombotic outcomes.
▪
Introduction: For warfarin-treated patients with atrial fibrillation (AF) or venous thromboembolism (VTE), concomitant use of aspirin and warfarin increases the risk of major bleeding 1.5-1.8 fold ...without an apparent reduction in thrombotic events when there is no clear indication for combination therapy. As a result, each of six anticoagulation clinics in the Michigan Anticoagulation Quality Improvement Initiative (MAQI2) consortium implemented a common intervention between late 2017 and mid 2018 aiming to reduce inappropriate aspirin use. The intervention consisted of a screening process to identify possible inappropriate aspirin use and then contacting the patient's provider to discuss the need for ongoing aspirin therapy. Site-level implementation variation included the personnel carrying out the intervention, the use of technology, and the means of provider communication. Treatment decisions were deferred to the treating provider but facilitated by the anticoagulation clinic staff.
We sought to assess the impact of this intervention on the rate of inappropriate aspirin use over time and compare patient characteristics based on aspirin use post intervention.
Methods: First, we compared the overall rate of inappropriate aspirin use among the six center MAQI2 anticoagulation clinic cohort immediately before and after the intervention. All patients in MAQI2 were treated with warfarin. Then, we identified a sub-cohort of warfarin-treated patients with AF and/or VTE enrolled between January 2010 to June 2019. Within that sub-cohort, we assessed aspirin use pre and post the site-specific date of implementation of the intervention. Patients with a potential indication for aspirin use were excluded (e.g., any history of coronary artery disease, myocardial infarction, percutaneous coronary intervention, mechanical heart valve replacement, left ventricular assist device placement, peripheral arterial disease, or coronary artery bypass grafting). Each site was able to further restrict who was targeted for intervention (for example, excluding patients with a history of antiphospholipid syndrome or stroke).
Using site specific definitions for inappropriate aspirin use we identified four groups at the end of the study period: 1) patients not on aspirin, 2) aspirin-using patients without an apparent indication who stopped aspirin following implementation, 3) aspirin-using patients without an apparent indication who remained on aspirin following implementation, and 4) aspirin-using patients who developed an indication for aspirin during the study period. To assess inappropriate aspirin use in our cohort, the characteristics of the first three groups were compared.
Results:
Between August 2017 and May 2019, a total of 3,766 warfarin-treated patients enrolled in MAQI2. Following implementation, inappropriate aspirin use was reduced by 34% (from 27.9% 401/1437 to 18.5% 251/1356). A sub-cohort of 1,007 patients who met the inclusion criteria had clinical follow-up pre and post intervention and were followed for an average of 40.1 months from enrollment to their first follow-up post-intervention. Of this sub-cohort, 226 (22.4%) were inappropriately on aspirin, with 50 (22.1%) stopping aspirin. A small number of patients 37 (3.7%) developed an indication for aspirin (e.g., myocardial infarction) during the study period and were removed from this analysis.
As compared to patients not taking aspirin, patients on inappropriate aspirin were more often taking warfarin for AF, had congestive heart failure, chronic kidney disease, diabetes mellitus, hypertension, and had a higher Charlson Comorbidity index; they were less likely to have VTE or a history of VTE. As compared to patients continuing on aspirin following implementation, patients stopping inappropriate aspirin were more likely to have chronic kidney disease (p=0.02) or a history of falls (p=0.03).
Conclusion:
Among warfarin-treated patients with AF or VTE, inappropriate aspirin usage can be identified and significantly reduced using a simple intervention in the anticoagulation clinic. Patients at higher risk of bleeding may be more likely to have their aspirin discontinued. Further studies are needed to see if reducing inappropriate aspirin usage translates to improved clinical outcomes and to determine the reasons for patient persistence on inappropriate aspirin.
Display omitted
Kaatz:Janssen: Honoraria, Research Funding; Pfizer: Honoraria; Bristol Myers Squibb: Honoraria; Portola: Honoraria. Kline-Rogers:AC Forum: Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria; QUANTUM-AF: Membership on an entity's Board of Directors or advisory committees. Sood:Bayer: Research Funding. Froehlich:Blue Cross Blue Shield of Michigan: Research Funding; Novartis: Honoraria; Boehringer-Ingelheim: Honoraria; Fibromuscular Dysplasia Society: Research Funding; Merck: Honoraria; Pfizer: Honoraria; Janssen: Honoraria. Barnes:Portola: Honoraria; Pfizer/Bristol Myers Squib: Research Funding; Pfizer: Honoraria; AMAG Pharmaceuticals: Honoraria; Bristol Myers Squib: Honoraria; Blue Cross Blue Shield of Michigan: Research Funding; Janssen: Honoraria.
▪
Introduction: The direct oral anticoagulants (DOACs: apixaban, dabigatran, edoxaban and rivaroxaban) may be used for the treatment and secondary prevention of venous thromboembolism (VTE) and for ...the prevention of stroke in the setting of non-valvular atrial fibrillation (NVAF). Adding aspirin (ASA) to a DOAC is often appropriate after acute coronary syndromes or percutaneous coronary intervention. However, many patients receive oral anticoagulation and ASA without a clear need for combination therapy. Current data, largely from patients treated with warfarin and ASA, suggest that the addition of ASA may increase bleeding risk without reducing thrombotic events. However, it is uncertain if this applies to patients on DOACs with ASA, and patients on combination DOAC+ASA therapy were not well represented in clinical trials. We sought to evaluate the impact of adding ASA to DOAC therapy for patients without an apparent indication for combination therapy.
Methods: We conducted a registry-based cohort study of adults on DOAC therapy for NVAF or VTE followed at 6 anticoagulation clinics in Michigan between January 2009 to June 2019, recruited through the Michigan Anticoagulation Quality Improvement Initiative (MAQI2). Patients were excluded if they had a history of heart valve replacement, recent myocardial infarction, or less than 3 months of follow-up. Two propensity matched cohorts (DOACs vs. DOAC+ASA) of patients were analyzed based on aspirin use at the time of study enrollment. The primary outcome was any new bleeding event. Secondary outcomes included new episodes of arterial or VTE, bleeding event type (fatal, life threatening, major, clinically relevant non-major, non-major bleeding (CRNMB), and intracranial or intraspinal), and death. Random chart audits were done to confirm the accuracy of the abstracted data.
Results:
Of the study cohort of 2,045 patients, 647 (31.6%) patients without a clear indication for ASA received ASA with a DOAC. We compared two groups of 639 matched patients. Patient demographics, co-morbidities, and concurrent medications were well-balanced after propensity score matching. After an average of 15.2 months of follow-up we found that patients on combination therapy (DOAC+ASA) had a significantly higher rate of bleeding compared to patients on DOAC monotherapy (319 bleeding events vs. 261 bleeding events, P=0.02; 0.41 bleeds per patient vs. 0.33 bleeds per patient). This difference was largely driven by CRNMB events (151 with DOAC+ASA vs. 109 with DOAC monotherapy, P=0.01), with the only 2 fatal bleeding events observed with DOAC monotherapy. We did not observe a significant difference between the groups in other bleeding event classifications. Bleeding sites were most commonly cutaneous, gastrointestinal, and genitourinary. Observed rates of thrombosis (stroke, VTE, myocardial infarction, or other) were similar between the groups (19 events with DOAC+ASA vs. 18 events for DOAC monotherapy, P=NS). Patients on combination therapy had more emergency room visits and hospitalizations but these differences were not statistically significant.
Conclusion:
Patients on oral anticoagulation for VTE or NVAF with a DOAC, without a clear need for ASA, experienced more bleeding events with the addition of ASA compared to DOAC monotherapy, without an apparent improvement in the incidence of thrombosis. Further study is needed to assess if DOAC+ASA is safer than warfarin+ASA, to compare the outcomes of the individual DOACs, and to confirm these findings in a larger cohort. Until such assessment is complete, clinicians should carefully consider the need to add aspirin in patients on DOAC therapy.
Display omitted
Kaatz:Portola: Honoraria; Pfizer: Honoraria; Janssen: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria. Kline-Rogers:AC Forum: Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria; QUANTUM-AF: Membership on an entity's Board of Directors or advisory committees. Sood:Bayer: Research Funding. Froehlich:Fibromuscular Dysplasia Society: Research Funding; Janssen: Honoraria; Pfizer: Honoraria; Boehringer-Ingelheim: Honoraria; Merck: Honoraria; Blue Cross Blue Shield of Michigan: Research Funding; Novartis: Honoraria. Barnes:Portola: Honoraria; Janssen: Honoraria; Blue Cross Blue Shield of Michigan: Research Funding; Bristol Myers Squib: Honoraria; AMAG Pharmaceuticals: Honoraria; Pfizer/Bristol Myers Squib: Research Funding; Pfizer: Honoraria.
▪
Introduction: Warfarin and aspirin (ASA) are widely used to prevent or treat thromboembolic and atherosclerotic diseases. The most common indications for warfarin use are stroke prevention in ...atrial fibrillation (AF) and for the treatment of venous thromboembolic disease (VTE). When patients are started on warfarin, many are already taking ASA or they are subsequently placed on ASA due to other co-morbidities. There are limited indications for the combination of warfarin plus ASA, including mechanical heart valves, after percutaneous coronary intervention (PCI), or after acute coronary syndromes. Evidence suggests combination warfarin-ASA may offer no benefit, but place patients at increased bleeding risk outside of these indications.
We sought to assess the patient characteristics and outcomes of patients on warfarin for AF or VTE, comparing those who were on concurrent ASA without a strong indication (myocardial infarction MI within 6 months, mechanical heart valve or PCI) to those not on ASA. We hypothesized that combination therapy (warfarin-ASA) would result in increased bleeding rates with similar rates of MI, recurrent VTE, stroke, or death.
Methods: We conducted a retrospective cohort study of adult patients, initiated on warfarin for AF or VTE between January 2009 and June 2017. Patients were recruited through the Michigan Anticoagulation Quality Improvement Initiative, a collaborative of six outpatient anticoagulation clinics throughout the state of Michigan. Patients with less than three months of follow-up, a MI within six months, and/or history of valve replacement were excluded. Patients were analyzed based on their aspirin use at the time of study enrollment. A HAS-BLED score, modified to exclude aspirin use, and a Charlson Co-morbidity Index was calculated for each patient at enrollment.
Analyses were performed using Student's t-tests, Wilcoxon Rank-sum tests, chi-square tests and Fisher's exact tests when appropriate. Survival and Poisson regression analyses were used to evaluate the effect of ASA use on various outcomes.
Results: A total of 6,572 patients met the inclusion criteria, with a mean duration of follow-up of 21.2 months; 38% were on warfarin-ASA compared to 62% on warfarin monotherapy. Patients on warfarin-ASA were older (mean 70.2±12.7 vs. 63.7±16.5, p<0.001), more often male (56.7% vs. 47.3%, p<0.001), and were more likely anticoagulated for AF (66.3% vs. 42.3%, p<0.001). Warfarin-ASA patients were more likely to have cardiovascular risk factors (diabetes mellitus, tobacco use, or hypertension), a history of stroke, heart failure, or a history of coronary artery disease (CAD). Patients on warfarin-ASA had a higher HAS-BLED score (mean 2.4±1.2 vs. 1.8±1.2, p<0.001), and Charlson Co-morbidity Index (mean 4.8±2.0 vs. 3.6±2.1, p<0.001).
Patients treated with warfarin-ASA vs. warfarin alone experienced less DVTs (0.7/100 patient years pt-yr vs. 1.3/100-pt-yr, p=0.002) and PE (0.1/100-pt-yr vs. 0.4/100-pt-yr, p=0.002), but had a higher rate of ischemic/embolic strokes (0.7/100-pt-yr vs. 0.4/100-pt-yr, p=0.02). Emergency department visits and hospitalizations for thromboembolic events were similar. Patients treated with warfarin-ASA vs. warfarin alone had a higher 1-year probability of having a major bleeding event (6.1% vs. 3.2%, p<0.001) or non-major bleeding event (22.9% vs. 18.7%, p=0.004). Warfarin-ASA treated patients had a higher rate of hospitalizations for bleeding (8.4/100-pt-yr vs. 5.7/100-pt-yr, p<0.001), blood transfusions (5.2/100-pt-yr vs. 4.1/100-pt-yr, p=0.009) and all-cause mortality relative to warfarin alone (4.1/100-pt-yr vs. 3.1/100-pt-yr, p=0.005). Kaplan-Meier curves for any clotting event, all bleeding events, major bleeding events, and death are shown (figure 1). A sensitivity analysis was performed that further excluded any history of MI, CAD, PCI, peripheral arterial disease, or coronary artery bypass grafting, and showed similar results.
Conclusion: Over one-third of patients in an unselected practice-based setting are treated with warfarin-ASA for AF and/or VTE without a clear indication. Compared to warfarin monotherapy, this was associated with minimally increased protection against VTE but with a significant increase in bleeding and perhaps mortality. Further research is needed to better stratify who should receive aspirin while on warfarin.
Display omitted
Sood:Bayer: Research Funding. Kline-Rogers:Janssen: Consultancy; ACP: Consultancy; AC Forum: Membership on an entity's Board of Directors or advisory committees. Almany:Trice Orthopedics: Consultancy; Micardia: Consultancy; Ablative Solutions: Equity Ownership; Kona: Consultancy; Biostar Ventures: Equity Ownership; Boston Scientific Watchman: Research Funding; Abbott Absorb Trial: Research Funding. Kaatz:Daiichi Sankyo: Consultancy, Honoraria; CSL Behring: Honoraria; Boehringer Ingelheim: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Portola: Consultancy. Froehlich:Merck: Consultancy; Fibromuscular Disease Society of America: Research Funding; Blue Cross/Blue Shield of Michigan: Research Funding; Boehringer Ingelheim: Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy; Novartis: Consultancy; Pfizer: Membership on an entity's Board of Directors or advisory committees. Barnes:Pfizer: Research Funding; Bristol Myers Squibb: Research Funding; Blue Cross/Blue Shield of Michigan: Research Funding; Aralez: Consultancy.
PDF
