Resumption of Anticoagulant Therapy Following Ischemic and Hemorrhagic Strokes: Indications and Timing

Despite the publication of meta-analyses and review articles reporting on anticoagulant resumption after ischemic stroke or intracranial hemorrhage,^1,2 there is no consensus on the optimal timing of anticoagulation initiation or resumption after these events. Because hemorrhagic transformation is correlated with larger infarct, previous intracranial hemorrhage, thrombocytopenia, and reperfusion treatment, practitioners have used anticoagulation indication, National Institutes of Health Stroke Scale score, size of the stroke, HAS-BLED score, and various other clinical data to guide their decisions.^2,3 We discuss indications for anticoagulation and the timing of initiation or resumption.

Atrial Fibrillation

Atrial fibrillation (AF) increases stroke risk by 5-fold and is one of the major causes of cardioembolic stroke, which accounts for about 20% of ischemic strokes.⁴ Left atrial appendage (LAA) thrombus formation secondary to hemostasis from atrial arrhythmia is the generally accepted explanation for cause of stroke in people with AF. Anticoagulation with either vitamin K antagonist (VKA) or a direct oral anticoagulant (DOAC) significantly reduces the risk of stroke in people with AF. Therefore, anticoagulation is considered the first-line therapy for thromboembolism prevention in people with AF based on their CHA2DS2-VASc score, and people who have a history of stroke or transient ischemic attack (TIA) automatically meet the indication.

Comparing DOACs with VKA, several randomized trials have shown noninferiority of DOACs, and one meta-analysis showed that DOACs had 11% lower stroke or embolic risk with reduced major bleeding (4% vs 5%) and intracranial hemorrhage (0.6% vs 1.3%).⁵ Therefore, American Heart Association (AHA) guidelines recommended DOAC treatment for nonvalvular AF without mechanical heart valve after acute ischemic stroke (AIS) or TIA to reduce the risk of stroke recurrence.⁶ For people with valvular AF or mechanical heart valve, VKA is the choice of anticoagulation. Among DOACs, apixaban seems to have less bleeding risk compared with rivaroxaban.5 In people with contraindications to long-term anticoagulation, LAA closure has been shown to be effective and safe to reduce stroke risk in people with AF and high risk of bleeding, and should be considered as a feasible alternative.⁷ On the other hand, AF ablation, an endovascular procedure that restores sinus rhythm, failed to decrease stroke risk. This raises the question whether atrial dysfunction or “cardiopathy” in the setting of AF may be a more important pathway to ischemic stroke than AF itself.

Cardiac Thrombus

Left ventricular (LV) thrombus is an important complication in the setting of myocardial infarction and subsequent low ejection fraction cardiac dysfunction. Meta-analyses have revealed that the risk of stroke or systemic embolism was significantly increased in the presence of left ventricular thrombi (odds ratio, 5.45; 95% CI, 3.02–9.83).⁸

Following formation of the LV thrombus, the myocardium gradually undergoes remodeling to incorporate the thrombi into the akinetic wall segment. Although the exact time frame over which this process occurs is unknown, studies have revealed decreased systemic embolism or stroke risk around 3 months following diagnosis. The use of oral anticoagulation (specifically with VKA) has been associated with a significant reduction in the risk of embolism (odds ratio, 0.14; 95% CI, 0.04–0.52).⁸

Although DOACs have been shown to be as effective as VKA at preventing embolic complications in AF and venous thromboembolism (VTE), with lower hemorrhagic complications and increased convenience, the data are conflicting for their use in LV thrombus. The most recent AHA/American Stroke Association (ASA) guidelines (from 2021) recommend anticoagulation with therapeutic VKA for at least 3 months in people with stroke or TIA and LV thrombus (strong recommendation supported by level B nonrandomized evidence).

The LAA is the source of thrombus ≈90% of the time in the setting of nonvalvular AF. Akin to LV thrombus treatment, a paucity of data specific to the use of DOACs for treatment of LAA thrombus exists. The recommendation remains anticoagulation with VKA for at least 3 months in the setting of LAA thrombus.

Mechanical Heart Valve

In people with a mechanical heart valve, VKA with an international normalized ratio range of 2.5 to 3.5 is recommended to reduce the risk of recurrent stroke.⁹ Mitral valve replacement confers a higher risk compared with aortic valve replacement. Addition of aspirin to VKA has been recommended in the particularly high-risk subgroup of people with a history of stroke or TIA and mechanical valve replacement in certain clinical contexts.⁹ With regards to the use of DOACs, dabigatran has been specifically shown to be associated with worse outcomes as compared with VKA in people with mechanical heart valves, resulting in higher thromboembolic and hemorrhagic complications.¹⁰ Other DOACs have not been specifically studied for this indication and are thus not recommended.

Venous Thromboembolism

VTE remains an underdiagnosed and undertreated problem in hospitalized patients with stroke. In the patient with acute hemiplegic stroke, incidence of deep vein thrombosis (DVT) reaches nearly 50% within 2 weeks if not treated with appropriate chemoprophylaxis. This risk continues into the stroke rehabilitation phase, where DVT risk continues to be increased up to 9 weeks after stroke.¹¹ Within the stroke subpopulation, it is thought that untreated proximal subclinical DVT results in mortality rates of 15% and that pulmonary embolism accounts for 13% to 25% of early deaths following stroke. Although mortality from pulmonary embolism can arise within first few days of stroke, typically it is more common between the second and fourth week after stroke. In addition to mortality concerns, nonlethal pulmonary embolism can adversely affect cardiopulmonary reserves and severely impair stroke rehabilitation, limiting functional recovery.¹¹

As compared with the high fatality rates in untreated VTE, in the presence of appropriate full-dose anticoagulation, recurrent fatal pulmonary embolism only occurred in 1.5% of people with pulmonary embolism and 0.4% of people with DVT. Therefore, initiating appropriate anticoagulation in an expedient manner is of vital importance in acute stroke.¹¹ DOACs have become the mainstay of treatment of VTE, with the American College of Chest Physicians 2016 guidelines and European Society of Cardiology 2017 guidelines supporting their use. Compared with low-molecular-weight heparin (LMWH) bridging with subsequent VKA treatment, numerous DOACs have been shown to be noninferior for recurrent VTE and associated with a lower risk of major bleeding, including intracranial bleeding.¹² All-cause mortality rates are comparable between DOACs and LMWH or VKA.¹³ Additional favorable characteristics supporting DOAC use include rapid onset of action, predictable pharmacokinetics, and lack of monitoring requirements. However, in the setting of substantial renal impairment or cost barriers, VKA use is recommended.¹⁴ Inferior vena cava filters are an important treatment alternative to consider when the perceived risk of hemorrhage from anticoagulation use is too high in people with VTE.

Chemoprophylaxis is of vital importance during hospitalization for acute stroke. A meta-analysis of clinical trials demonstrated ≈80% reduction in incidence of DVT with appropriate chemoprophylaxis using unfractionated heparin or LMWH.¹¹

Antiphospholipid Syndrome

Antiphospholipid syndrome (APS) is an autoimmune condition with a wide range of clinical manifestations, including systemic thromboembolism, mainly DVT and stroke. The diagnosis of APS is based on history of thrombosis or pregnancy complications in people with persistent antiphospholipid antibodies. APS-related stroke represents up to 20% of stroke events in people under 45 years of age. In APS, recurrent arterial events most frequently follow initial arterial events and, similarly, initial venous events tend to recur as venous events afterwards.¹⁵ The risk of recurrent thromboembolic events is as high as 69% in 6 years of follow-up in people with APS¹⁶; hence indefinite anticoagulation is necessary in this patient population.

In people with APS treated with DOACs compared with those treated with VKA, there was no evidence of higher risk of recurrent VTE, but significantly increased risk of recurrent arterial thrombosis.¹⁷ Therefore, for people who meet the criteria for APS, moderate-intensity anticoagulation with VKA (international normalized ratio 2 to 3) is reasonable.

Cancer-Related Stroke

Active cancer is an established risk factor for ischemic stroke. Multiple large studies, including prospective ones, have demonstrated an increased risk of stroke and other arterial thromboembolic events in people with incident cancer versus matched controls.¹⁸ Cancer-mediated hypercoagulability could cause embolic stroke of undetermined source (ESUS) through in situ thrombus formation within the cerebral vasculature. Another mechanism tied to hypercoagulability that could cause ESUS with cancer is paradoxical embolization. Up to 20% of people with cancer develop VTE during their lifetime and ≈25% of the population harbors a patent foramen ovale.¹⁹ Hypercoagulability is associated with poor survival after stroke in people with active cancer. OASIS-CANCER (Optimal Anticoagulation Strategy in Stroke related to Cancer) showed that treatment with anticoagulant corrected the hypercoagulable status, improving the 1-year survival among people with cancer.²⁰

There is limited evidence to guide whether people with cancer who experience a stroke should be treated with anticoagulation or antiplatelet therapy and this decision should be individualized based on the individual’s profile and the etiology of stroke. The Canadian Stroke Best Practice Guidelines recommend that people with active malignancy who experience an arterial ischemic stroke or TIA secondary to a presumed cancer-associated hypercoagulable state be considered for anticoagulation therapy over antiplatelet therapy.²¹ The potential benefits and harms of LMWH in people with cancer within the stroke population are unknown. Upcoming trials such as TEACH 2 will compare DOAC with antiplatelet monotherapy in people with cancer with AIS and another pilot trial in Korea is comparing edoxaban with LMWH in people with cancer and stroke.²²

Vascular Disorders (Partially Occlusive Thrombus or Dissection)

Cervical artery dissection is a common cause of stroke in the young population. According to AHA guidelines, antithrombotics are recommended for at least 3 months to prevent recurrent stroke or TIA.⁶ However, which antithrombotic agent is preferred remains a subject of debate. VKA traditionally has been used for cervical artery dissection treatment, but with the convenience and safety profile of DOAC, this treatment also has been used.²³

The prevalence of intraluminal thrombus ranges from 1.6% to 3.2% in people with AIS. Intraluminal thrombus occurs in the setting of large artery atherosclerotic disease and concurrent local hemostasis and inflammation, embolism, or hypercoagulability.²⁴ There is a perceived high risk of stroke recurrence in patients with intraluminal thrombus. Therefore, medical management with anticoagulation has been proposed. The most common antithrombotic regimen is intravenous unfractionated heparin with or without a single antiplatelet such as aspirin.²⁴ However, evidence of short-term anticoagulation benefit for nonocclusive, extracranial intraluminal thrombus is not well-established and recent AHA guidelines had a IIb level recommendation.⁶ Dual antiplatelet therapy may be a reasonable treatment option in these cases, particularly given that most intraluminal thrombi occur in the setting of atherosclerosis.

Anticoagulation and Timing in AIS

An important consideration with regard to timing of anticoagulation initiation is the risk of hemorrhagic transformation in ischemic stroke. The risk of recurrent stroke appears to be highest in the days following the index AIS event,²⁵ but the benefit of anticoagulation can be offset by the risk of hemorrhagic transformation. Previous literature has noted the maximal risk of hemorrhagic transformation occurs ≈4 days after onset of stroke.²⁶ Thus, the risk of recurrent stroke from various causes or thrombus formation vs the risk of hemorrhagic transformation must be balanced carefully for the individual patient, incorporating the clinical factors mentioned previously.

Anticoagulation can be restarted earlier in high embolism or thrombosis risk situations, such as mechanical heart valve, hypercoagulability associated with malignancy, left ventricular thrombus, left ventricular assist device, left atrial thrombus, acute deep VTE, or recent myocardial infarction.²⁰

Recent evidence suggests that restarting anticoagulant within 4 days for AF-related ischemic stroke does not carry higher risk of major bleeding but reduces risks of early recurrent ischemic stroke.³ Some experts recommend resumption of anticoagulant after 2 days for people with small ischemic strokes, 7 to 10 days with moderate-sized ischemic strokes, and 10 to 14 days in those with large ischemic strokes.¹ Multiple observational and randomized studies have shown that early initiation of DOAC (within 3 days from ischemic stroke) was associated with similar ischemic and hemorrhagic complications compared with delayed DOAC initiation.²⁷ Thus the decision of when to start anticoagulation when indicated after ischemic stroke is nuanced and based on the risk of ischemic recurrence and hemorrhagic complications, which is thought to be driven by infarct size and presence of hemorrhagic transformation.

Anticoagulant Type and Timing Anticoagulant in ICH

In the intracerebral hemorrhage (ICH) setting, it is challenging to determine the optimal time to initiate anticoagulation for various indications. In a retrospective study from South Korea, resuming anticoagulation 6 to 8 weeks after ICH has been shown to lower all-cause mortality risk with lower risk of severe thrombotic and hemorrhagic events.²⁸ In one study, restarting therapeutic anticoagulation less than 2 weeks after ICH in people with a mechanical heart valve was associated with increased hemorrhagic complications.²⁹ However, given the retrospective design and limited patient population, it is unclear whether the findings would apply to people with other etiologies of ICH. The most recent AHA/ASA ICH guideline recommends factoring in the size of the hematoma and the person’s age in determining the optimal timing for anticoagulation initiation. It is important to weigh the risks of rebleeding and benefits of preventing thromboembolic events after ICH. Delaying anticoagulant initiation for less than 2 weeks is reasonable in people with low-risk ICH who have a higher risk of thromboembolism and for more than 4 weeks in those with high-risk ICH.³⁰

Conclusion

Resumption of anticoagulants in either ischemic stroke or intracranial hemorrhage is a decision that should be individualized on a case-by-case basis, considering severity of hemorrhage or infarct, systemic risk of bleeding, and the risk of thromboembolism while off anticoagulation. Patient and family involvement in decision-making is essential and people should be made aware that delayed anticoagulation does not fully prevent hemorrhage and early anticoagulation does not fully prevent stroke.¹