Direct-Acting Oral Anticoagulant Dabigatran as a Bridging Therapy while Optimizing Warfarin Dosage for Cardioembolic Stroke

Among the feared complications of stroke is recurrence, which occurs in 5.7%–51.3% [1]. Current clinical practice guidelines recommend that in patients with stroke or transient ischaemic attack (TIA) with atrial fibrillation (AF), in view of efficacy and safety, oral anticoagulation (OAC) with apixaban, dabigatran, edoxaban, or rivaroxaban (collectively known as direct-acting oral anticoagulants [DOACs]) or vitamin K antagonists (e.g., warfarin) be prescribed to reduce the risk of recurrent stroke [2]. In patients with stroke or TIA and AF who do not have moderate to severe mitral stenosis or a mechanical heart valve, DOACs are recommended in preference to warfarin [2]. DOACs carry additional advantages over warfarin, including rapid therapeutic onset, fewer drug-drug and drug-food interactions, no need for frequent blood drawings, and may be especially suited for patients with labile International Normalized Ratio (INR) and resultant reduced time-in-therapeutic range that would lead to an increased risk of stroke [3‒5].

The drawbacks of DOACS include the need for dose adjustment in renal impairment and thus regular renal monitoring, and contraindication in severe liver disease. In addition, there may be an issue of cost [3, 5]. The price of DOACs is not similar globally and is higher in some countries, e.g., the USA, Puerto Rico, and Thailand [6]. The costs borne by patients can be considerably higher when they are on DOAC compared to warfarin if they are paid out-of-pocket, even after considering medication [7], monitoring, consultation, hospitalization [8, 9], and varying reimbursement [10, 11]. This may lead to patients preferring warfarin over DOACs [12] on the long term, especially if they need only infrequent INR monitoring due to stability, or are close to INR monitoring stations [13]. Cost issues have led to chronic care facilities preferring warfarin over DOACs [14]. The real-world clinical concern is that those who are unable to afford DOACs are more likely to be non-adherent to treatment [15], increasing their risk for recurrent stroke or systemic embolism, and the resultant consequences.

Warfarin, the most widely used OAC, acts by inhibiting the hepatic synthesis of vitamin K-dependent factors, a process that takes several days and even weeks before the therapeutic target as measured by the INR is achieved [16]. During the time of sub-therapeutic dosing, the patient remains at risk of ischaemic events. This has led to the use of bridging treatments such as heparin-unfractionated (UFH) or low molecular weight (LMWH) – to provide anticoagulant cover until the therapeutic dose of OAC is reached [17, 18]. However, the use of UFH and LWWH for bridging for cardioembolic stroke is associated with higher bleeding risk compared with no bridging [19]; studies suggest that LMWH carries a lower bleeding risk than UFH [20, 21].

The use of heparin carries some disadvantages. These include the need for hospitalization for intravenous (IV) infusion of UFH, pain at sites of subcutaneous (SC) injection or IV infusion, bruising at SC injection sites, infection of IV sites, inconvenience of continuous IV or repeated SC injections, costs of drug and equipment and administration by nurses; more important are unreliable anticoagulation due to irregular absorption from SC sites or fluctuating levels of anticoagulation from IV infusions; there is also the risk of heparin-induced thrombocytopaenia [22, 23]. Thus, there is a need for an alternative to heparin as a bridging therapy while optimizing OAC with warfarin.

A distinct advantage of DOACs over warfarin is their rapid onset of action and short time to attain therapeutic effect [24‒26]. We therefore sought to use a DOAC in place of heparin during warfarin dose optimization among patients with acute ischaemic stroke (AIS) and non-valvular AF needing long-term OAC who after discussion preferred warfarin over DOAC. In these patients, we simultaneously administered warfarin and DOAC, and discontinued DOAC when INR >2 [27]. Warfarin was administered once daily in accordance with our hospital’s anticoagulation protocol. Dabigatran was chosen as it was the only DOAC available in the hospital. Dabigatran 110 mg 2 times daily was simultaneously administered orally to cases until INR ≥2, at which time it was discontinued and the patient remained only on warfarin. This dose of dabigatran was chosen as it was found to be as efficacious as warfarin and safer [28]. The coagulation parameters INR, prothrombin time, activated partial thromboplastin time (aPTT) were monitored daily as long as the patient remained in hospital, and frequently in the outpatient setting till INR was stable. Target INR was 2.0–3.0. All patients were evaluated for adverse events such as recurrent stroke, allergic reactions and overt bleeding (e.g., gross haematuria, symptomatic intracranial haemorrhage). We report our experience in the use of dabigatran as bridging therapy during warfarin optimization for cardioembolic stroke of 2 patients who opted to receive warfarin for long-term anticoagulation for secondary stroke prevention.

Patient A was a 60-year-old right-handed Chinese gentleman with a history of hypertension, hyperlipidaemia, and gout who was admitted with a sudden onset of left-sided weakness. Clinically, he was alert, but had right gaze preference and left-sided hemiplegia. The clinical diagnosis was of a right cortical stroke. He underwent IV tPA augmented with sonothrombolysis with some recanalization of the artery and a concomitant rapidly shrinking deficit (National Institute of Health Stroke Scale [NIHSS] 7 to 0). Subsequent brain scan showed infarcts in the right frontal and parietal lobes, corresponding to the territory of the right middle cerebral artery. He was found to have AF and advised starting anticoagulation. He opted for warfarin with dabigatran bridging which was started on day 2 of his hospital admission. His INR exceeded 2 by day 6 of anticoagulation, at which time the bridging dabigatran was stopped, fixed-dose warfarin was continued, and he was discharged well (Table 1). On subsequent close reviews in the clinic, his INR was in the therapeutic range of 2.0–3.0. He had no bleeding or recurrent ischaemic events during the month of follow-up. Modified Rankin Score was 0 on days 7 and 90 post-stroke.

Patient B was a 78-year-old right-handed Malay gentleman with a history of hypertension, hyperlipidaemia, and diabetes mellitus. He was admitted after he developed difficulty talking and mild right-sided weakness. Clinically, he was alert but had expressive aphasia and mild right-sided upper limb weakness (NIHSS 6). The clinical diagnosis was of a left cortical stroke. The brain scan showed a left posterior frontal and parietal infarct. He was out of the time window for recanalization therapy and was treated conservatively. He was found to have AF and advised starting anticoagulation. He opted for warfarin with dabigatran bridging which was started on day 1 of his hospital admission. His INR was almost 2 by day 5 of anticoagulation, at which time the bridging dabigatran was stopped and fixed-dose warfarin continued (Table 1). He declined daily blood taking – his INR 4 days later was in the therapeutic range of 2.0–3.0. He had no bleeding or recurrent ischaemic events. He underwent rehabilitation uneventfully and was discharged well. Modified Rankin Score was 4 on day 7 and 0 on day 90 post-stroke.

We present here two cases with AIS and AF needing long-term secondary stroke prevention with OAC who preferred warfarin over DOAC, where we used a DOAC dabigatran as bridge therapy for a short period while optimizing warfarin dosage. Target INR was achieved in less than a week, without adverse events, e.g., bleeding recurrent ischaemic event. One patient could be discharged as soon as INR was therapeutic; the other was able to actively participate in rehabilitation without being restricted by IV lines.

Stroke is a major cause of death and disability globally, with 12.2 million (95% UI 11.0–13.6) incident cases, 101 million (93.2–111) prevalent cases, 143 million (133–153) DALYs lost, and 6.55 million (6.00–7.02) deaths in 2019. Globally, stroke remained the second-leading cause of death (11.6% [10.8–12.2] of total deaths) and the third-leading cause of death and disability combined (5.7% [5.1–6.2] of total DALYs) in 2019 [29]. In a systematic review and meta-analysis of recent interventional studies (n = 14,889), the pooled risk of stroke after a TIA was 1.36% (95% CI: 1.15–1.59) at 2 days, 2.06% (95% CI: 1.83–2.33) at 7 days, 2.78% (95% CI: 2.47–3.12) at 30 days, and 3.42% (95% CI: 3.14–3.74) at 90 days [30]. A systematic review and meta-analysis of the cumulative risk of stroke recurrence over the last 10 years (37 studies, n = 1,075,014, the pooled stroke recurrence rate was 7.7% at 3 months, 9.5% at 6 months, 10.4% at 1 year, 16.1% at 2 years, 16.7% at 3 years, 14.8% at 5 years, 12.9% at 10 years, and 39.7% at 12 years after the initial stroke [31].

The presumed causative mechanism for IS has been classified using the Trial of Org 10,172 in Acute Stroke Treatment (TOAST) criteria as large artery atherosclerosis (LAA), cardioembolism (CE), small artery occlusion (SAO), stroke of other determined aetiology, or stroke of undetermined aetiology [32]. Recurrent stroke is most frequent in CE and LAA compared to SAO [1]. CE accounts for 20% of cases of ischaemic strokes, half of which are due to non-valvular AF, 1/4 due to valvular heart disease and 1/3 due to LV clot [33]. The risk of stroke recurrence is significantly higher when the patient has AF (OR = 1.88, 95% CI: 1.56–2.25, p < 0.00001) [34].

In patients with AF and stroke or TIA, OAC is indicated to reduce the risk of recurrent stroke [2]. Pooled data of five warfarin trials of primary and secondary prevention of stroke showed a 68% relative risk reduction for warfarin compared to placebo and absolute reduction from 4.5% to 1.4% with slightly higher bleeding risk of 1.3% compared to 1% for placebo/aspirin [35]. In the only secondary prevention trial included, the European Atrial Fibrillation Trial (EAFT), 1,007 patients with non-rheumatic AF with a recent TIA or minor ischaemic stroke were randomized to open anticoagulation or double-blind treatment with either 300 mg aspirin per day or placebo [36]. The primary outcome measure was death from vascular disease, any stroke, myocardial infarction, or systemic embolism. During mean follow-up of 2.3 years, the annual rate of outcome events was 8% in patients assigned to anticoagulants vs 17% in placebo-treated patients (hazard ratio [HR] 0.53; 95% CI: 0.36–0.79). The risk of stroke alone was reduced from 12% to 4% per year (HR 0.34; 95% CI: 0.20–0.57).

Clinical trials have shown that DOACs are equivalent or superior to warfarin for the prevention of stroke or systemic embolism in AF, and may be as safe or safer in this population [28, 37‒39]. Overall, there is a 19% reduction in stroke or systemic embolism, driven by a 51% reduction in haemorrhagic stroke and a 10% overall reduction in mortality [26]. Relative to warfarin, each of the DOACs was similar for the primary efficacy and safety outcome in patients with or without prior stroke or TIA [40]. A secondary analysis of patients with prior stroke in DOAC trials reported a similar reduced rate of all stroke or systemic embolism of 4.94% with NOACs vs. 5.73% with warfarin, and a rate of major bleeding of 5.7% with NOAC vs. 6.4% with warfarin across the 4 DOACs; data from registries confirmed the results from the randomized trials [41].

Dabigatran was used because it was the only DOAC available in the hospital at that time. Dabigatran, or dabigatran etexilate mesylate in full, is β-alanine, N-[[2-[[[4-[[[(hexyloxy)carbonyl]amino]iminomethyl] phenyl]amino]methyl]-1-methyl-1H-benzimidazol-5-yl]carbonyl]-N-2-pyridinyl-ethyl ester, methanesulfonate. The empirical formula is C34H41N7O5⋅CH4O3S, with a molecular weight of 723.86 (mesylate salt), 627.75 (free base) [42]. It is a direct competitive inhibitor of thrombin, a serine protease that enables the conversion of fibrinogen into fibrin during the coagulation cascade – its inhibition prevents the development of a thrombus. Dabigatran’s absolute bioavailability following oral administration is approximately 3%–7%. After oral administration of dabigatran in healthy volunteers, Cmax occurs at 1-h post-administration in the fasted state. The half-life in healthy adult subjects is 12–17 h and is thus taken twice daily.

At recommended therapeutic doses, dabigatran prolongs the coagulation markers such as aPTT, ecarin clotting time (ECT), thrombin time (TT), and dilute thrombin time (dTT) [42, 43]. The aPTT test provides an approximation of dabigatran’s anticoagulant effect. The degree of anticoagulant activity can also be assessed by the ECT. This test is a more specific measure of the effect of dabigatran than aPTT. INR is relatively insensitive to exposure to dabigatran and cannot be interpreted the same way as used for warfarin monitoring.

A recent systematic review and meta-analysis did not reveal an increased bleeding risk with early use of OAC [44]. It included 12 eligible articles (10 cohort studies and 2 RCT), involving 11,421 patients (n = 5,690 in the early-initiation group and n = 5,731 in the delayed-initiation group). Early-initiation patients had a lower incidence of ischaemic events (OR 0.68, 95% CI: 0.55–0.84, p = 0.0003) and combined outcomes (OR 0.74, 95% CI: 0.57–0.95, p = 0.02). There were no significant differences in the incidence of haemorrhagic events (p = 0.26) and all-cause mortality (p = 0.20). This suggests that early initiation of OAC lowers the incidence of ischaemic events and combined outcomes in AIS patients with AF, and is safe.

The two cases reported here show that therapeutic INR could be safely achieved in a timely manner among male patients with acute stroke who require anticoagulation with warfarin using dabigatran instead of heparin as bridging therapy. There was an increase in aPTT with dabigatran administration as seen in earlier studies [43, 45], which then decreased when dabigatran was stopped. There was no reduction in INR after stopping dabigatran. None of the patients had repeat ischaemic events during the bridging period. One patient (patient A) could be discharged as soon as INR was in therapeutic range. The other patient (patient B) could actively participate in his rehabilitation without being restricted by IV lines and continuous infusion of heparin.

To date, early/urgent anticoagulation holds uncertainties, especially with the results of bridging with heparin/LMWH [19‒21]. Clinical practice guidelines for stroke from the USA [2], Canada [46] and Europe [47] do not make recommendations on bridging in non-valvular AF – there are no high-quality studies on who should undergo bridging. The just-published guidelines by the European Society of Cardiology 2024 recommend that we minimize duration of heparin-bridging therapy [48]. There remains an uncertainty on the timing of anticoagulation. Bridging anticoagulation may be beneficial in patients at high risk of ischaemic stroke and low risk of intracranial haemorrhage – it can be considered after weighing the benefits and risks of ischaemic and haemorrhagic complications [49].

Ours is a novel concept of bridging warfarin with dabigatran during initiation of anticoagulation, as opposed to the traditional method of using heparin. There are no previous similar studies to compare with. Our study provides preliminary evidence for a more convenient method for initiating OAC that will benefit patients as they do not need unpleasant injections, suffer irregular anticoagulation, and potentially prolonged hospital stay which increases healthcare costs. This can be performed in an outpatient setting. Recently published studies have shown the benefit of early anticoagulation for patients with stroke and AF [50, 51]. While we studied stroke patients, the use of bridging therapy though is recognized among those undergoing surgery [52], with mechanical prosthetic valves [53] and venous thromboembolism [54]. These are the situations in which this novel therapeutic approach can also be of use. It is crucial that patient preferences are considered in therapeutic decision making. Patients not currently using warfarin may choose warfarin over DOACs because of a preference for regular blood testing/dietary restrictions [55]. A structured narrative review of 47 publications of patients’ perspectives on, and patients’ adherence to, anticoagulant therapy showed that the need for regular therapeutic drug monitoring, dose adjustments, and dietary considerations lead to patient’s reluctance to take warfarin therapy; however, high cost, twice-daily dosing of some DOACs and gastrointestinal adverse effects present challenges for patients [56]. In a systematic review, warfarin may be less preferred over DOACs due to concerns about narrow therapeutic window, inconvenience of twice-daily dosing for some DOACs, and increased risk of adverse events; however, the lack of monitoring with DOACs and cost issues may negatively impact medication adherence [57]. Regular monitoring as required for warfarin may be perceived as an advantage [58]. Cost conversations are associated with patients’ considerations of treatment cost burden but not final treatment choice [59]. Patient decision aids have been shown in a systematic review of eight studies to increase AF knowledge and decisional confidence but had a variable impact on the choice of stroke prevention therapy [60].

Our study has several limitations. There were only two patients included. We did not evaluate dabigatran levels to exactly correlate its effect to prothrombin time/INR and aPTT levels. We did not monitor ECT, TT, or dTT. We did not study the other DOACs due to unavailability at the time. Both patients were male, which may affect the generalizability of our results to females.

We tested a novel idea of using a DOAC dabigatran as bridging therapy in place of heparin during warfarin dose optimization for patients with ischaemic stroke due to cardioembolism. We found no new ischaemic events during that period. After we administered dabigatran, the INR increased rapidly for a few days with no reduction with discontinuation of dabigatran. We believe larger prospective studies with head-to-head comparison of warfarin bridging with one of the newer anticoagulants or heparin will give us an answer to a long-awaited question on the best way for initiation of anticoagulation for stroke prevention as well as other illnesses where warfarin with bridging therapy is to be administered.

Ethical approval is not required for this study in accordance with local or national guidelines. Written informed consent was obtained from participants for publication of the details of their medical case and any accompanying images.

The authors have no conflicts of interest to declare.

This study was not supported by any sponsor or funder.

Y.K. conceptualized the project. N.V. and Y.K. wrote the manuscript. N.V., Y.K., L.L.L.Y., and B.C. were the clinicians in charge of the patients reported. L.L.L.Y. and B.C. critically reviewed the manuscript. N.V., Y.K., L.L.L.Y., and B.C. gave final approval for submission for publication.

The data that support the findings of this study are not publicly available due to their containing information that could compromise the privacy of research participants but are available from the corresponding author (N.V.) upon reasonable request.