Treatment with combination warfarin and aspirin therapy compared with warfarin monotherapy was associated with a significant increase in bleeding, major bleeding, ED visits, and hospitalizations. These results persisted for at least 3 years of follow-up, without any observed added benefit regarding thrombotic events. The rates of combination warfarin and aspirin use did not significantly change over time, reflecting the limited data available to guide clinical decisions for this patient population.
The publication of the American College of Chest Physicians guidelines 10 about the management of atrial fibrillation did not seem to have any influence regarding aspirin use in this population. The observed rate of aspirin use among patients without clear therapeutic indication is consistent with what has been reported previously. Patients with substantial vascular or thrombotic risk factors may be intentionally maintained on combination warfarin and aspirin therapy.
Prospective studies are needed, especially for high-risk patients, to determine the optimal patient selection for and duration of combination therapy. Potential need of patients to require multiple antithrombotic medications is a common clinical scenario. Our nonrandomized data suggested that the number needed to harm 26 , 27 may only have been 36 persons for major bleeding and 29 persons for hospital admission among patients receiving combination warfarin and aspirin therapy compared with those receiving warfarin monotherapy.
An intervention targeted at reducing aspirin use in this population could have profound public health impact if these estimates are confirmed in prospective studies. Antiplatelet therapy use is dynamic for many patients. The clinicians at the anticoagulation clinics in this study routinely assessed the use of antiplatelet medications, which was a notable strength of this study.
Removing matched patients who initiated or discontinued aspirin therapy during the study period in our first sensitivity analysis gave very similar results eTable 1 in the Supplement. Major bleeding was significantly different only for the first year but not for the duration of follow-up. Differences in bleeding after the first year may have been affected by bleeding events during the first year or by the lower power of the study to detect a difference.
Our second sensitivity analysis focused on patients without atherosclerotic comorbidity found higher bleeding complications with combination warfarin and aspirin therapy compared with warfarin monotherapy. The observed rate of any bleeding reported in our study was high compared with other studies, resulting from the thoroughness of our manual data collection. Any bleeding in this study was by patient report only.
The rate of major bleeding events for unmatched patients eTable 4 in the Supplement is consistent with the published literature. Our study results may advance the field, with a long duration of follow-up in a real-world setting. The detailed propensity score match of numerous variables significantly limited potential confounders.
Furthermore, sensitivity analyses showing similar results increased confidence in our results. Our results were supported by the findings of similar studies about this topic. That study differed because it included dabigatran 6. In , Johnson et al 33 published a similar study through Kaiser Permanente Colorado Anticoagulation Service with 6 months of follow-up. In that study of more than patients, combination therapy was similarly associated with increased bleeding events but not with coronary events after adjustment for confounding factors.
Our study results, a decade later, were striking because excess aspirin use among patients treated with warfarin continued at high rates. Whereas this study did not randomize aspirin use between the 2 groups, strong propensity score matching using numerous covariates enabled us to reduce selection biases and allowed for the comparison of 2 well-matched groups that would mimic a randomized clinical trial, as closely as a nonrandomized study design will allow. While our propensity score matching was comprehensive for potential confounding variables, it is always possible that some unknown confounders were present that could have influenced the results eFigure 2 in the Supplement.
In addition, our analysis did not adjust for the severity of the comorbid conditions, and it was conceivable that a patient with, for example, uncontrolled diabetes or hypertension, may have benefited more from the addition of aspirin therapy than a patient with well-managed comorbid conditions.
Strengths of the study were that patients were closely followed up while enrolled in the anticoagulation clinics, with data collected using predefined forms that included relevant clinical outcomes. Random medical record audits validated the accuracy of the data. The population-based cohort may have been more likely to reflect real-world practice compared with patients in a clinical trial.
Despite being part of a quality improvement collaborative, all patients received standard anticoagulation care, and their findings likely are generalizable to other settings including anticoagulation clinics and high-quality care outside of anticoagulation clinics. By controlling for warfarin management through the use of the TTR variable, we tried to limit variation between groups to the receiving of aspirin alone.
We caution against extrapolating these findings to patients receiving direct oral anticoagulants with aspirin because the outcomes may be significantly different. Potential limitations to the study included issues surrounding generalizability because of the geographically limited patient population followed up at the anticoagulation clinics.
In addition, any medication changes, especially nonprescription aspirin use, may not have been well captured. However, given that data in this registry were abstracted from the medical record and that nurses and pharmacists in the anticoagulation clinic routinely reviewed any new or changed medications especially antithrombotic medications, such as aspirin , we believe our findings are reliable and robust.
This belief is supported by the results of the sensitivity analysis, in which patients with a known change in aspirin-use status were excluded eTable 1 in the Supplement. Recent MI, an exclusion criterion for the study, was defined on the MAQI 2 data collection form as an event that occurred fewer than 6 months before warfarin therapy initiation. Therefore, a low number of included patients may have been within a year of having a MI and had a stronger indication for concomitant aspirin use.
A total of patients 3. Given that such patients would likely receive inpatient care, this measure seemed appropriate. However, data for this outcome were only available for a portion of the study period and may not have been as well captured. Abstraction into the registry was limited to the data collected in the medical record at each anticoagulation clinic. Emergency department visits at outside hospitals that were not documented by the anticoagulation clinic would not be captured in our registry.
Therefore, the observed event rates may have underestimated true event rates if patients received care outside of our included facilities. Finally, there were few thrombotic events stroke, transient ischemic attack, or VTE during the study period, limiting our power to detect differences for this outcome. This study suggests that concurrent use of warfarin and aspirin therapy in patients without a heart valve replacement or recent ACS is associated with an increased risk of bleeding and related hospitalization.
Similar to other studies published for more than a decade, we did not observe any clinical benefit of aspirin being prescribed with warfarin therapy. Unfortunately, the rate of combined warfarin and aspirin use has not declined as a result of those findings, emphasizing the need for greater awareness of this issue and efforts to discontinue aspirin therapy in these patients, especially low-risk patients.
Further research is needed to help clinicians better stratify which patients should receive combination warfarin and aspirin therapy instead of warfarin monotherapy for VTE or AF. Corresponding Author: Geoffrey D. Published Online: March 4, Author Contributions: Drs Schaefer and Barnes had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.
No other disclosures were reported. Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy Continue.
Download PDF Comment. Figure 1. Cumulative Incidence of Major Bleeding by Treatment. View Large Download. Figure 2. Figure 3. Cumulative Incidence of Thrombosis by Treatment.
Supplemental Methods eTable 1. Outcomes of Unmatched Patient Cohorts eFigure 1. Study Schema eFigure 2. Standardized Difference Plot eFigure 3. Comparing direct oral anticoagulants and warfarin for atrial fibrillation, venous thromboembolism, and mechanical heart valves. Consult Pharm. Aspirin use for the primary prevention of cardiovascular disease and colorectal cancer: US Preventive Services Task Force recommendation statement.
Ann Intern Med. Guidelines for the prevention of stroke in patients with stroke and transient ischemic attack. Eur Heart J. Combined aspirin-oral anticoagulant therapy compared with oral anticoagulant therapy alone among patients at risk for cardiovascular disease: a meta-analysis of randomized trials. Arch Intern Med. The research involved adults taking direct oral anticoagulants DOACs , including apixaban, dabigatran, edoxaban, and rivaroxaban.
Some participants were transitioning to a DOAC from warfarin, another type of anticoagulant. All participants were undergoing treatment for atrial fibrillation or venous thromboembolic disease.
Of the 3, study participants, 1, took daily low-dose aspirin with their DOAC even though there was no clear indication for doing so. Another 2, participants took their DOAC alone.
After a minimum of 3 months follow-up, the researchers found an association between DOACs plus low-dose aspirin and increased bleeding events as well as hospital admissions related to bleeding. Blood thinners are typically prescribed to help prevent blood clots.
But researchers observed no clear benefit to taking daily aspirin with a DOAC. Clotting events between the two groups were similar. This was an observational study limited to people in Michigan. Study authors caution there are different subgroups and clinical scenarios where this has not been sufficiently studied. A study published in JAMA Internal Medicine suggests that the combination of daily aspirin and warfarin is also associated with excess bleeding.
Michael Chan is an interventional cardiologist with Providence St. Joseph Hospital in Orange County, California. The literature on this topic is limited, but it suggests that the decision to prescribe aspirin to patients already taking warfarin Coumadin should be individualized.
On one hand, the cardiovascular benefit of starting or continuing aspirin in patients already on warfarin outweighs the increased risk of bleeding in patients presenting with an acute coronary syndrome or those with mechanical heart valves or coronary stents.
However, for patients with stable coronary artery disease or at risk of coronary disease, the benefit of adding aspirin is not substantial, and continuing warfarin alone may be the preferred strategy. The decision whether to add aspirin to warfarin therapy should be individualized. In patients taking warfarin, the risk of major bleeding defined in most studies as hospitalization because of bleeding and requiring transfusion of at least two units of packed red cells, or an intracranial, intraperitoneal, or fatal bleeding episode is reported to be about 2.
The risk is low if the score is 0, moderate if the score is 1 or 2, and high if the score is 3 or more. In a validation study of the BRI, the rate of major bleeding was found to be 0.
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