Antithrombotic medications, which include both antiplatelet agents and anticoagulants, have had a large impact in the reduction of first-ever and recurrent ischemic stroke in patients with atrial fibrillation, prior ischemic stroke or transient ischemic attack, prior myocardial infarction, and other subpopulations at higher risk for ischemic events.11–13
Yet, the effectiveness and safety of AT medications depend upon patient compliance as well as their appropriately prescribed use in various clinical situations in which bleeding risks of these medications may be temporarily or chronically increased. Decisions regarding perioperative management of AT medication are among the most common and complex treatment decisions that physicians face.
Our population-based study indicates that about 5% of ischemic strokes are associated with withdrawal of AT medications within 60 days of onset. In our study, strokes associated with discontinuation of AT medication had significantly greater mortality and morbidity than strokes occurring while on AT medication, even after controlling for higher rates of atrial fibrillation and other variables associated with poorer outcome. This observation is consistent with a Kaiser Permanente study of patients with atrial fibrillation in which stroke patients who had an INR of less than 2.0 at admission had significantly more severe strokes and higher mortality as compared with patients with an INR of ≥ 2.0.14
Acute stroke patients are often aphasic or cognitively impaired, ascertainment of medication history may be incomplete, particularly in those patients on medications that are purchased over-the-counter and may not be listed in pharmacy records. Thus, our estimated percent of strokes (5.2%) after stopping AT may be an underestimate. In a prospective survey of discontinuation of antiplatelet medication in stroke patients, Sibon and colleagues reported that 5% of 289 ischemic stroke patients at a single University Hospital in Bordeaux, France had stopped an antiplatelet agent within 30 days of stroke onset.1
All of the strokes occurred within 6–10 days after stoppage of medication, and 54% of patients had medication held by a physician for surgical procedures (6) or another cause (1). Maulaz and colleagues reported a case-control study from Centre Hospitalier Universitaire Vaudois in Lausanne in which 4.2% of ischemic stroke patients had discontinued aspirin within the prior month; all strokes occurred within 25 days of discontinuation.3
Neither of these studies included anticoagulant medications.
Our data suggest that the risk of AT medication withdrawal is related to time since withdrawal as well as to reinstitution of an effective AT medication. Stroke events were clustered mostly in the first two weeks after stoppage of medications, which was particularly the case for medications stopped for procedures or for supratherapeutic anticoagulation. Strokes for other categories of medication withdrawal also occurred more frequently in the first several weeks after stoppage of medication, but strokes continued to occur up to 60 days after stoppage. This is illustrated by events associated with medication stoppage due to bleeding complications in which AT medications would be less likely to be restarted quickly, if at all. Our data are potentially susceptible to recall and documentation biases given our methodology. However, given that the time period prior to stroke was only 60 days, recall bias is probably small.
Our data also suggest that withdrawal of warfarin is associated with a greater risk of ischemic stroke than withdrawal of antiplatelet agents, which likely reflects in part the higher risk of ischemic events in subjects on warfarin. In a 2005 telephone survey of a random population sample from the same Greater Cincinnati study region, 40% of whites (mean age 62) and 36% of blacks (mean age 59) reported regular aspirin use.15
Questions regarding use of warfarin and other antiplatelet agents were not part of the 2005 survey. Other recent population studies provide useful comparison of relative use of AT agents. The REGARDS cohort study includes 30,166 community dwelling adults over the age of 45 who were enrolled throughout the U.S. during 2003–2006. Of this cohort (mean age 66.1, s.d. 9.0 years), 47.5% were on aspirin, 5.0% were on a thienopyridine or dipyridamole, and 3.6% were on warfarin (personal written communication, Suzanne Judd, George Howard, 8/9/10). Using the United Kingdom General Practice Research Database from 2000 through 2005, Delaney and colleagues reported a case-control study of gastointentinal bleeding that included matched 40,171 controls (mean age 69.1 years, s.d. 17.7); 3.2% of these controls were on warfarin and 1.8% were on a thienopyridine.16
In contrast to the much greater use of antiplatelet agents than warfarin in the general population, over half of ischemic strokes in our study population occurred in patients who had withdrawal of warfarin. The majority of these patients are on warfarin for atrial fibrillation which represents a group at higher risk of thromboembolic event, particularly those with prior strokes or high CHAD2 scores. 2, 17
To calculate an accurate risk of thrombotic events associated with stoppage of AT medication, one would need to know the prevalence of AT medication in the general population, the frequency and duration of medication stoppage, the number of ischemic and hemorrhagic events on and off AT medication, and the use of bridging therapy during the same time period. Such data are currently not available in our population nor in any larger population of which we are aware. In addition, determination of the risk of ischemic events following stoppage of AT medication can be confounded in part by the reason for stoppage (e.g. cardiac surgery which has a known risk of ischemic stroke). Several smaller cohort studies of subjects who had interruption of AT therapy indicate the absolute risk of thrombotic events associated with interruption of warfarin for procedures is about 1% but is higher in those subjects with atrial fibrillation and prior stroke. 8, 9, 17–19
The effect of bridging therapy on reduction of thrombo-embolic events in these cohort studies is unclear since subjects who receive bridging therapies are at higher baseline risk of thrombo-embolic events.19
The ongoing BRIDGE Study, a randomized trial funded by the National Heart, Lung and Blood Institute, and the PERIOP 2 Study, a randomized trial sponsored by the Lawson Health Research Institute, will hopefully provide more clarity about the role of bridging therapy in patients with atrial fibrillation and/or mechanical valves with a higher risk of thromboembolic events. Nonetheless, our data support current guidelines recommending minimization of the time off AT medication, particularly in those patients with prior stroke, mechanical heart valves, or atrial fibrillation with higher CHAD2 scores, and continuation of antiplatelet medication in those patients undergoing cardiac and carotid artery procedures.2
In addition, the specific properties of new oral AT medications like dabigatran (half-life, measurement of biologic effect, etc.) will need to be considered in these ongoing studies and in clinical practice.20
The ACCP Guidelines for perioperative management of AT therapy provide a stratification of risk as well as recommendations for continuation or bridging of AT therapy based upon the underlying indication for AT medication and the risk of bleeding for a given surgery.2
For example, for minor dental, ophthalmic, and dermatologic procedures, maintainence of anticoagulation or antiplatelet therapy throughout the perioperative period is recommended by the ACCP. However, the ACCP Guidelines do not address all minor procedures such as lumbar punctures. Lumbar punctures have a very low risk of epidural hematomas in the setting of antiplatelet agents, yet national guidelines recommend stoppage of thienopyridines for seven days prior to performance of a lumbar puncture, one of the most common procedures in neurologic practice, without stratification of risk.21
Local institutions or physicians may be even more rigid and require stoppage of any antiplatelet agents, including aspirin, for minor procedures even in those patients with higher risk of thrombo-embolic events.22
The financial burden of medication also impacts patient compliance. We found that 8.4% of infarcts that occurred within 60 days of medication withdrawal were associated with patient-directed cessation of medication as a result of financial burden. This may underestimate the true burden represented by financial constraints in that 16.7% of patients with infarcts within 60 days of medication withdrawal were categorized as noncompliant with medications, yet the reasons for their non-compliance were not always available.