Author: Emily Shor, Pharm.D.
Approximately 13% to 26% of ischemic strokes occur in the setting of a cerebral embolism associated with non-valvular atrial fibrillation.1 Initiation of anticoagulation has been shown to be efficacious in secondary prevention of stroke, but the appropriate timing of anticoagulation initiation requires balancing efficacy and safety. After an atrial fibrillation associated ischemic stroke, the risk of recurrence of ischemic stroke within the subsequent 14 days increases by 0.5% to 1.3% per day when anticoagulation is not initiated.2 However, early initiation of anticoagulation is also associated with an increased risk of hemorrhagic transformation. Therefore, optimizing the timing of anticoagulation initiation proves to be a complex, yet common, challenge after an atrial fibrillation associated ischemic stroke.
The risk of recurrent ischemic stroke and the risk of hemorrhagic transformation are two key considerations when determining the timing of anticoagulation initiation. To assess a patient’s risk of recurrent stroke, the CHA2DS2-VASc score can be utilized as a predictive model, particularly in patients with atrial fibrillation.3 Additionally, a larger ischemic lesion size at the time of the ischemic stroke is associated with an increased risk of recurrent stroke. Similarly, higher CHA2DS2-VASc score and large ischemic lesion size have been associated with an increased risk of hemorrhagic transformation, a common and serious complication of stroke that results in an ischemia-related brain hemorrhage.3 Risk factors for hemorrhagic transformation include massive cerebral infarction, area of infarction (grey matter), concurrent atrial fibrillation, higher National Institutes of Health Stroke Scale (NIHSS) score, hyperglycemia, low platelet count, poor collateral vessels, and use of thrombolytic therapy.4-5 Each of these factors should be assessed when determining when to initiate anticoagulation.
While warfarin has served as the mainstay anticoagulant for patients with atrial fibrillation, direct oral anticoagulants (DOACs) have also proven to be efficacious for secondary prevention of stroke in patients with atrial fibrillation. However, the landmark trials that established the role of DOACs in stroke prevention in patients with atrial fibrillation largely excluded patients with recent ischemic strokes (Table 1). In the ARISTOTLE and ROCKET-AF trials, all patients with a documented history of stroke were enrolled at least a year after the index stroke event.6-7 Therefore, these landmark trials do not offer data regarding the optimal time to initiate DOACs after an ischemic stroke.
Current guidelines addressing the management of patients with stroke offer varying strategies of initiating anticoagulation. The 2014 American Heart Association/American Stroke Association (AHA/ASA) Guidelines for Prevention of Stroke in Patients with Stroke and Transient Ischemic Attack state that it is reasonable to initiate oral anticoagulation within 14 days after symptom onset (Class IIa; Level of Evidence B). In patients at high risk for hemorrhagic conversion (ex. large infarct, hemorrhagic transformation on initial imaging, uncontrolled hypertension, or hemorrhagic tendency), it is reasonable to initiate oral anticoagulation after 14 days (Class IIa; Level of Evidence B).10 In contrast, the 2016 European Society of Cardiology (ESC) Guidelines for the Management of Atrial Fibrillation recommend initiating an oral anticoagulant based on severity of stroke. Patients who experience a transient ischemic attack (TIA) should start anticoagulation one day after the event. Patients with a mild stroke (NIHSS < 8), moderate stroke (NIHSS 8-15), or severe stroke (NIHSS >16) should start anticoagulation three, six, or 12 days after the acute event, respectively. Although the 2016 ESC guidelines provide more specific recommendations, the recommendations are based on expert opinion.11 However, the 2016 ESC guidelines reflect more recent data that has been published since the 2014 AHA/ASA guidelines. The 2018 European Heart Rhythm Association (EHRA) Practical Guide on the Use of Non-Vitamin K Antagonist Oral Anticoagulants in Patients with Atrial Fibrillation provide recommendations similar to the 2016 ESC guidelines. The EHRA recommends DOACs be continued or initiated one day after a TIA and exclusion of intracranial hemorrhage by imaging. If stroke size is not expected to increase risk of hemorrhagic transformation, oral anticoagulation should be initiated > 3 days, > 6-8 days, and > 12-14 days after a mild, moderate, or severe stroke, respectively.13
Randomized controlled trials assessing the optimal time frame to initiate anticoagulation in patients with atrial fibrillation associated ischemic stroke are lacking. The RAF study evaluated the risk of recurrent ischemic events and severe bleeding in patients with acute stroke and atrial fibrillation and sought to identify the risk factors for these events. This international, prospective, multicenter study enrolled 766 patients, including 284 (37%) receiving vitamin K antagonists (VKAs) alone, 276 (36%) receiving VKA after low molecular weight heparin (LMWH), 113 (15%) receiving LMWH alone, and 93 (12%) receiving a DOAC. Mean NIHSS score on admission was 11.9 among patients who received LMWH alone, 6.9 among patients who transitioned from LMWH to oral anticoagulation, and 8.3 among patients who received oral anticoagulation alone. Mean time to anticoagulation initiation after ischemic stroke onset was 8.5 days, 6.5 days, and 12.1 days in the DOAC, LMWH, and VKA groups, respectively. Overall, 123 patients experienced 128 outcome events, including ischemic stroke/TIA/systemic embolism (7.6%), symptomatic intracranial bleeding (3.6%), and major extracerebral bleeding (1.4%). An adjusted analysis determined that anticoagulation initiation between four to 14 days from stroke onset was associated with a significant decrease in all outcome events (HR: 0.53; 95% CI: 0.3-0.93; p=0.025) and ischemic outcome events (HR: 0.43; 95% CI: 0.19-0.97; p=0.043) and a nonsignificant decrease in symptomatic cerebral bleeding (HR: 0.39; 95% CI 0.12-1.19; p=0.09). Predictive factors for primary outcomes included increased CHA2DS2-VASc score, large lesion size, and type of anticoagulant used after stroke. Use of LMWH after stroke increased symptomatic intracranial bleeding incidence. Ultimately, the RAF study concluded that the safest time to initiate anticoagulation as secondary prevention is four to 14 days.3
A nonrandomized cohort analysis of the Virtual International Stroke Trials Archive (VISTA) described contrasting results compared to the RAF study. The VISTA analysis enrolled 1644 patients, including patients receiving VKA alone (31%), VKA and antiplatelets (48%), or antiplatelets alone (10%). Median time to anticoagulation initiation was two days, and median NIHSS score among patients receiving anticoagulants was 14. Among patients receiving antithrombotics, 10% experienced an ischemic stroke, and 3% experienced a symptomatic intracerebral hemorrhage at 90 days. The VISTA analysis concluded that initiation of anticoagulation within two to three days post-stroke decreased risk of recurrent stroke without a significant increase in bleeding events. While the differences in findings as compared to the RAF study can be attributed to differences in populations (ex. baseline NIHSS score), concomitant medications, and study design, the VISTA analysis suggests that there may be a population that may benefit from earlier initiation of anticoagulation as compared to the four to 14 day recommendation derived from the RAF study.13
DOACs are being utilized more frequently as they are associated with a lower risk of bleeding events as compared to VKAs in the general population. Overall, in the RAF study, 93 patients received a DOAC, and six of these patients experienced an outcome event at 90 days. The RAF-NOACs study subsequently evaluated the rates of recurrent ischemic embolic or severe bleeding events and their timing in patients with atrial fibrillation who develop an ischemic stroke and are initiated on a DOAC. This international, prospective, observational, multicenter study enrolled 395 patients receiving dabigatran, 376 patients receiving rivaroxaban, and 390 patients receiving apixaban. Median time to anticoagulant initiation after ischemic stroke was eight days for dabigatran and rivaroxaban groups and seven days for the apixaban group. Overall mean NIHSS score on admission was 7.7. At 90 days, ischemic stroke occurred in 2% of all patients (dabigatran group: 1.3%; apixaban group: 2.6%; rivaroxaban: 1.9%). The combined endpoint of ischemic stroke, symptomatic hemorrhagic transformation, or serious extracranial bleeding occurred in 5.2% of all patients (dabigatran group: 2.9%; apixaban group: 7.4%; rivaroxaban: 5.5%). These event rates were significantly lower than those reported in the RAF study, indicating this may be a lower risk population or suggesting an overall decreased rate of events in patients receiving DOACs as compared to warfarin. Initiation of anticoagulation within three to 14 days of stroke event was associated with a composite event rate of 2.1% as compared to 12.4% among patients who initiated anticoagulation within two days and 9.1% among patients who initiated anticoagulation after 14 days. However, timing of DOAC initiation was not found to be directly correlated to event rates, so the optimal timing of anticoagulation initiation cannot be inferred from this data. Similar to the RAF study, bridging with therapeutic LMWH preceding an oral anticoagulant was associated with an increased risk of primary composite events (OR: 4.13; 95% CI: 1.73-8.96; p=0.0003), ischemic outcome events (OR: 3.73; 95% CI: 0.95-10.63; p=0.01); and hemorrhagic outcome events (OR: 4.75; 95% CI: 1.60-12.32; p=0.0009). However, confounding variables, such as baseline NIHSS score, thrombotic risk, and bleed risk, may contribute to these patients’ increased risk of outcome events.14
The CROMIS-2 study was a post-hoc analysis of a prospective, multicenter, observational cohort study that evaluated oral anticoagulant timing in relation to 90-day clinical outcomes (composite of ischemic stroke, TIA, intracranial hemorrhage, or death due to any cause). Seven of 358 patients (2%) who received anticoagulation early (within four days of ischemic event) experienced an event as compared to 48 of 997 patients (5%) who initiated anticoagulation five days or later after an ischemic event. However, patients who were initiated on anticoagulation within four days of an ischemic event had a lower NIHSS score, smaller infarcts, and less frequent incidence of hemorrhagic transformation on index imaging. The CROMIS-2 study concluded that starting anticoagulation within four days, particularly in patients with milder strokes, no thrombolysis, and better pre-stroke functioning as defined by modified Rankin Scale, could be considered for initiation of anticoagulation within four days of ischemic stroke.15
Overall, while these observational studies provide guidance regarding anticoagulation initiation after an atrial fibrillation associated ischemic stroke, there are numerous limitations regarding their study designs and the generalizability of their results. For example, the observational study designs introduce selection bias from the provider, introducing confounding that cannot be controlled. Additionally, the dosing of anticoagulation was not included in these studies, which may contribute to differences in outcomes. While baseline thrombotic risk and stroke severity were reported, baseline bleeding risk was not assessed, which may be a valuable tool in determining which patients are at an increased risk of hemorrhagic transformation.3,13-15
Recent European guidelines recommend determining the appropriate timing of anticoagulation initiation based on stroke severity as compared to the 2014 AHA/ASA guidelines. However, guidelines generally recommend initiation of anticoagulation within 14 days of stroke symptom onset and delaying initiation of anticoagulation in patients with risk factors for hemorrhagic transformation. Patient specific factors, including size of lesion, NIHSS score upon presentation, CHA2DS2-VASc score, and risk of bleeding should be considered when deciding when to initiate anticoagulation within the three to 14 day window. Earlier initiation within this window (closer to four days after ischemic event) can be considered in patients with lower NIHSS score (<8), no thrombolysis, better pre-stroke functioning, smaller lesion size, and low bleeding/hemorrhagic conversion risk.
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