Safety of Intravenous Thrombolysis Among Patients Taking Direct Oral Anticoagulants

A Systematic Review and Meta-Analysis

Shima Shahjouei, MD, MPH; Georgios Tsivgoulis, MD, PhD, MSc, FESO; Nitin Goyal, MD; Alireza Sadighi, MD; Ashkan Mowla, MD; Ming Wang, MS, PhD; David J. Seiffge, MD; Ramin Zand, MD, MPH

Disclosures

Stroke. 2020;51(2):533-541. 

In This Article

Results

Search Results

A total of 13 392 reports were retrieved by searching of 6 different resources—PubMed, Scopus, Embase, Clinicaltrial.gov, ICTRP (International Clinical Trials Registry Platform), and Cochrane library (Figure 1). After removing the duplicates and adding the manually tracked citations, 7680 title and abstracts were screened. Among the reviewed full texts, 73 case reports and 12 case series/original studies[7–12,15–17,25,31,32] were candidates of being included in this review.

Figure 1.

Summary of search results and study selection. DOAC indicates direct oral anticoagulant; ICTRP, International Clinical Trials Registry Platform; and IVT, intravenous thrombolysis.

Four studies[11,15,31,33] were excluded due to inadequate data or lack of control groups, despite contacting the corresponding authors (Materials in the online-only Data Supplement; Methods Document I). One study[16] was excluded because of additional endovascular interventions/intraatrial thrombolysis beside IVT. Another excluded study[17] was a review article without reporting new cases.

After personal communication to obtain the required data, 4 studies (Shahjouei et al,[10] Suzuki et al,[12] Seiffge et al,[8,9] and Mowla et al[25]) were included in the meta-analysis by limiting the interval between last DOAC intake and IVT to be less than 48 hours. The study by Shahjouei et al[10] presented a case series from our center. We retrospectively retrieved data for control groups in the same time interval from the same registry. Similarly, we requested the control data from Suzuki et al[8,9] and Mowla et al.[12,25] The 2 articles by Seiffge et al[8,9] were reports of a multicenter European study. We communicated with the corresponding author (Dr Seiffge) to be able to exclude the duplicate cases between these 2 reports and individual case reports that were separately published from this database, and treated data as one single study by this group.

We also used another report[7] for subgroup analysis. This study presented data from Get With The Guidelines-Stroke registry and could not provide the interval between last DOAC intake and IVT administration despite personal communication with the corresponding author.

Risk of Bias Assessment

Details of the risk of bias assessment according to ROBINS-E is available in the online-only Data Supplement (Methods, Document II). The overall bias was low in 3 studies (Shahjouei et al,[10] Seiffge et al,[8,9] and Mowla et al[25]) and medium in 2 studies (Suzuki et al[12] and Xian et al[7]). Risk of bias in confounding,[7,12] missing data,[12] and measurement of outcomes[7,25] were considered to be in medium scale Table. None of the case reports had a high risk of bias according to critical appraisal of case reports and small case series.[26,27]

Study Characteristics

Eligible Studies for Meta-analysis. Three studies reported the sICH according to both ECASS-II and NINDS guideline (Shahjouei et al,[10] Seiffge et al,[8,9] and Suzuki et al[12]), while Mowla et al[25] reported the outcome based on ECASS-II and Xian et al[7] reported sICH based on NINDS. Considering the NINDS definition, 13 of 2133 patients on warfarin and 2151 of 49 667 patients without prior anticoagulation therapy had sICH following IVT. When using the ECASS-II definition, 37 of 634 patients on warfarin and 441 of 4188 individuals without prior anticoagulant administration had sICH following IVT. In patients treated with DOACs, 15 of 366 patient had sICH (Seiffge et al: 3/51 and Xian et al: 12/251).

One study[12] used 0.6 mg/kg alteplase according to Japanese national guideline instead of the standard 0.9 mg/kg. The last intake dose of DOAC was reported to be less than 48 hours in one study,[12] 510 (240–1080) minutes in the report by Shahjouei et al,[10] 720 (270–1260) minutes in reports by Seiffge et al[8,9] and 820 (300–1440) minutes in the study by Mowla et al.[25] Accordingly, at least 53% of the patients received thrombolysis <24 hours following the last intake of DOACs.

Rivaroxaban—160/338 (47%)—and dabigatran—140/338 (41%)—were the most common DOACs in candidate studies for meta-analysis.

Outcome of Meta-analysis. A total of 52 823 stroke patients enrolled in meta-analysis—DOACs: 366 patients, warfarin: 2133 patients, and 503 241 patients without prior anticoagulation. Our analysis did not identify any additional risk of sICH after IVT in patients pretreated with DOACs during the last 48 hours before tPA-bolus in comparison with warfarin (OR for sICH according to NINDS definition: 0.55 [95% CI, 0.19–1.59]; OR for sICH according to ECASS-II definition: 0.77 [95% CI, 0.28–2.16]; Figure 2) or those without any prior anticoagulation (OR for sICH according to NINDS definition: 1.23 [95% CI, 0.46–3.31]; OR for sICH according to ECASS-II definition: 0.87 [95% CI, 0.32–2.41]; Figure 2). There was no evidence of heterogeneity across included studies (I 2=0%). Furthermore, we failed to detect any increased risk of sICH among patients pretreated with DOACs with no time limit between last intake of DOACs and tPA-bolus (OR for sICH according to NINDS definition: 0.85 [95% CI, 0.49–1.45]; OR for sICH according to ECASS-II definition: 1.11 [95% CI, 0.67–1.85]; Figure 3) or those without any prior anticoagulation (OR for sICH according to NINDS definition: 1.17 [95% CI, 0.43–3.15]; OR for sICH according to ECASS-II definition: 0.87 [95% CI, 0.33–2.41]; Figure 3). There was no evidence of heterogeneity across included studies (I 2=0%).

Figure 2.

Meta-analysis of symptomatic intracranial hemorrhage (sICH) in patients who received intravenous thrombolysis (IVT) in >48 h following the last intake dose of direct oral anticoagulants. Results are classified according to (1) the control groups (patients under warfarin with INR <1.7 or those without prior anticoagulant administration) and (2) the guideline for the definition of sICH (NINDS [National Institute of Neurological Disorders] or ECASS-II [European Cooperative Acute Stroke Study II]). DOAC indicates direct oral anticoagulants; and sHT, symptomatic hemorrhagic transformation.

Figure 3.

Meta-analysis of symptomatic intracranial hemorrhage (sICH) in patients who received intravenous thrombolysis (IVT) in unknown interval following the last intake dose of direct oral anticoagulants. Results are classified according to (1) the control groups (patients under warfarin with international normalized ratio <1.7 or those without prior anticoagulant administration) and (2) the guideline for the definition of sICH (NINDS [National Institute of Neurological Disorders] or ECASS-II [European Cooperative Acute Stroke Study II]). DOAC indicates direct oral anticoagulants; and sHT, symptomatic hemorrhagic transformation.

Individual Case Reports. Data from case reports were summarized but not used in the meta-analysis (in the online-only Data Supplement; Results). Details of individual cases who received IV in absence of reversal agent (Table I in the online-only Data Supplement), or presence of Idarucizumab (Table II in the online-only Data Supplement), and a summary of these 2 tables (Table III in the online-only Data Supplement) are also available.

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