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Idarucizumab can reverse the effect of the direct thrombin inhibitor dabigatran,1 a non-vitamin K oral anticoagulant (NOAC) available for primary and secondary prevention of cardioembolic stroke due to non-valvular atrial fibrillation. Ischaemic stroke may happen despite ongoing anticoagulation, a contraindication to intravenous thrombolysis (IVT).2 Thus, patients with ischaemic stroke while on dabigatran might be eligible for anticoagulation reversal with idarucizumab to allow IVT. Here, we report our case series and provide a systematic review to define outcomes of such treatment algorithm.
Case series of patients undergoing IVT after dabigatran reversal was identified from our stroke registry (online supplementary file 1). Systematic review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines3 and specified protocol (PROSPERO: http://www.crd.york.ac.uk/PROSPERO, registration no. CRD42017060274) (online supplementary file 2). Search strategy, performed on Cochrane Library, MEDLINE, EMBASE and PubMed, can be found in online supplementary file 1.
Data extraction and outcome assessment
All available data were collected (online supplementary file 1). According to National Institute of Health Stroke Scale (NIHSS) total score, stroke were divided into mild (1–4), moderate (5–15), moderate to severe (16–20) and severe (21–42 4). Unfavourable outcome was defined as an increase in NIHSS score or death. Additional outcomes included modified Rankin Scale (mRS) at follow-up, symptomatic intracerebral haemorrhage, systemic bleeding, allergic reactions to idarucizumab, recurrent stroke and venous thrombosis during post-acute phase.
Statistical analysis was performed with R software using stats packages. Descriptive statistics are presented for continuous variables as means, SD, medians and IQRs. Categorical variables are presented as counts and percentages. Multivariate logistic regressions were used for modelling the functional outcome.
Searching our stroke registry, from October 2015, among 627 stroke cases we detected two cases that met the inclusions criteria (online supplementary file 1). Databases search identified 188 articles. Only 24 articles fulfilled inclusion criteria and were included for revision,4–26 all being case series or case reports (table 1).
Overall, including ours, 55 cases of ischaemic stroke treated with IVT after reversal of dabigatran with idarucizumab were collected (43.6% women; mean age 74.35±11.32 years) (table 1). Mean dabigatran dosage was 247.69±38.43 mg. Personal history revealed hypertension in 23.26%, diabetes in 13.95%, dyslipidaemia in 6.98% and previous stroke in 11.63%. All individuals received anticoagulation reversal with idarucizumab and subsequent IVT according to the prescribing information. Prolonged activated partial thromboplastin time (aPTT) (>35 s) was found in 75.0% of cases (36/48), while prolonged TT (>20 s) was detected in 96.3% of patients (26/27). No correlation was found between aPTT prolongation and dabigatran concentrations.
Clinical and neuroradiological outcomes
At admission, seven patients had mild (NIHSS 1–4, 12.96%), 34 moderate (NIHSS 5–15, 62.96%), six moderate to severe (NIHSS 16–20, 11.11%) and seven severe stroke (NIHSS 21–42, 12.96%). Mean time from symptoms onset to IVT was 174.82±53.76 min. Overall, 45 patients (81.9%) benefited from treatment, with median NIHSS improvement of 5 points (IQR 3–10). No NIHSS variation was detected for four patients, and an unfavourable outcome was recorded in only six patients: four died, and two had NIHSS worsening, one of them developing a further stroke after 30 hours from first IVT.5 Haemorrhagic transformation was asymptomatic in one patient, while three patients had clinical deterioration, leading to significant disability (n=1, mRS 5) or death (n=2, mRS 6). Overall, mRS score ≤2 at follow-up was reported in 56.76% of patients (n=21, available data for 37 patients). After stroke on dabigatran, 23 patients were prescribed the same drug (62.16%), while 8 patients increased dosage from 110 twice daily to 150 twice daily, and 13 patients changed prescription.
With univariate analysis, NIHSS at admission, mRS at admission and symptomatic intracranial haemorrhage all negatively impacted mRS at follow-up, but no factor was confirmed predictive of worse outcome with multivariate analysis (table 2).
We systematically reviewed data on IVT after dabigatran reversal with idarucizumab, defining clinical course and outcomes.
Overall, 55 patients have been reported.4–26 Moderate stroke prevailed (62.96% of patients), and IVT was performed within an early time window (mean 175 min). Blood clotting test, altered in up to 96% of patients, returned within limits soon after idarucizumab administration. Thus, IVT after dabigatran reversal with idarucizumab seems feasible in real-life setting and might then be considered for all patients suffering from a stroke while on dabigatran.
Moreover, the clinical improvement seen in 81.9% of patients, together with follow-up mRS <2 in 56% of patients, suggest that effectiveness IVT is preserved. An unfavourable outcome was registered for 10.9% of patients, all displaying known risk factors for worse outcome, including arterial occlusion of a major intracranial vessel, high NIHSS and haemorrhagic transformation.27 Time to last dabigatran intake, dabigatran serum concentration, blood clotting examinations and time to treatment did not affect outcome. Thus idarucizumab reversal might be taken into account in all patients eligible for IVT with last dabigatran assumption within 24 hours, as well as in those with unknown dose timing and altered aPTT or TT, which can be used as point-of care methods if dabigatran concentrations cannot be determined.28
Compared with the existing systematic review,4 we have been able to double included papers (24 vs 13) and enlarge the cohort of more than a third (55 patients vs 40). Moreover, in this systematic review, stroke severity increased, with moderate to severe stroke in 63% of cases (vs 10%4), and median time to IVT increasing to 173 min (vs 155 min4). Despite increasing stroke severity and time to IVT, the rate of favourable outcomes is higher than previously reported (81.9% vs 72%), suggesting that the treatment paradigm might be considered also for all patients with acute ischaemic stroke, including those with moderate to severe stroke and longer time windows for IVT. Since at least 1% of patients eligible for IVT will be on NOAC,28 the results of this systematic review, supporting safety and effectiveness of IVT after idarucizumab, might help clinicians in pursuing this treatment paradigm. Further data from patient registries, such as the Registry of Acute Stroke Under Novel Oral Anticoagulants-Prime (RASU-NOA-Prime, ClinicalTrials.gov: NCT02533960) will refine treatment paradigm and eligibility.⇑ ⇑
DG and MR contributed equally.
Contributors DG, SR and SC conceived the idea, planned and designed the study. DG, CC, AM and MR wrote the first draft. CM and AG evaluated and wrote the clinical cases. DG and SM designed the search strategy. DG, ES, AM and MR evaluated the literature and selected the papers. DG, SR and CC planned the data extraction. SM, AM and MR extracted and analysed data. DG and MR revised the draft and updated the manuscript. CP, SC, TM and SR provided critical insights. All authors have approved and contributed to the final version of the manuscript.
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests None declared.
Patient consent Not required.
Provenance and peer review Not commissioned; internally peer reviewed.
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