|Year : 2022 | Volume
| Issue : 6 | Page : 1036-1046
Safety of recanalization therapy in acute ischemic stroke patients on direct oral anticoagulant therapy: An updated systematic review and meta-analysis
Yanxing Zhang, Huan Tang, Xiaohong Gui, Ye Du, Chenglong Wu
Department of Neurology, Shaoxing People's Hospital, (Shaoxing Hospital, Zhejiang University School of Medicine), Shaoxing City, China
|Date of Submission||22-Mar-2022|
|Date of Decision||08-Sep-2022|
|Date of Acceptance||10-Sep-2022|
|Date of Web Publication||04-Nov-2022|
Department of Neurology, Shaoxing Peoplefs Hospital, (Shaoxing Hospital, Zhejiang University School of Medicine), North Road of Zhongxing No. 568 Shaoxing City, Zhejiang Province
Source of Support: None, Conflict of Interest: None
| Abstract|| |
This review provides an updated assessment of the safety of recanalization therapy for Acute Ischemic Stroke (AIS) patients receiving direct oral anticoagulants (DOAC) therapy. We checked the literature for published observational from 1st January 1950 to 31st March 2021. The rate of symptomatic intracerebral hemorrhage (sICH), arterial recanalization rate, good functional recovery, and mortality at 3 months were investigated, and data were expressed as Risk ratio (RR) with a 95% confidence interval (CI). Publication bias, sensitivity analysis, and meta-regression analyses were conducted utilizing STATA software. 17 articles [14 for endovascular therapy (EVT) and 3 intravenous thrombolysis for (IVT)] were finally included in the review. AIS patients with DOAC therapy showed a decreased rate of sICH (RR = 0.85, 95% CI = 0.72 to 1.00, P = 0.04), and lower probability of good functional recovery at three months (RR = 0.79, 95% CI = 0.73 to 0.85, P < 0.001) than patients without anticoagulation therapy post EVT. However, no significant differences in sICH rates in AIS patients with DOAC therapy after IVT (RR = 0.87, 95% CI = 0.48 to 1.58, P = 0.64) were observed. AIS patients not prescribed DOAC after EVT had a higher mortality risk (RR = 1.29, 95% CI = 1.15–1.44, P < 0.001). Patients with AIS on DOAC therapy were found to have a lower incidence of sICH following EVT. However, no evidence of an increased bleeding risk in patients previously treated with DOAC after IVT was observed. Therefore, more detailed studies with biological data to monitor compliance and details on the size and etiology/severity of the incident ischemic lesion is needed.
Keywords: Acute stroke, anticoagulation, endovascular treatment, intravenous thrombolysis, recanalization, symptomatic intracerebral hemorrhage
|How to cite this article:|
Zhang Y, Tang H, Gui X, Du Y, Wu C. Safety of recanalization therapy in acute ischemic stroke patients on direct oral anticoagulant therapy: An updated systematic review and meta-analysis. Ann Indian Acad Neurol 2022;25:1036-46
|How to cite this URL:|
Zhang Y, Tang H, Gui X, Du Y, Wu C. Safety of recanalization therapy in acute ischemic stroke patients on direct oral anticoagulant therapy: An updated systematic review and meta-analysis. Ann Indian Acad Neurol [serial online] 2022 [cited 2023 Feb 6];25:1036-46. Available from: https://www.annalsofian.org/text.asp?2022/25/6/1036/360460
| Introduction|| |
In routine clinical practice, atrial fibrillation (AF) is responsible for 25–40% of all acute ischemic strokes (AIS), caused by the occlusion of large vessels, Anticoagulants like vitamin K antagonists (VKAs) or direct oral anticoagulants (DOAC) are frequently prescribed for preventing stroke in individuals with AF.,,, Nevertheless, AIS is seen in around 2% of individuals who are under anticoagulant therapy., In addition, research has shown that around 10% of patients experiencing AIS are under anticoagulant therapy at the beginning of a stroke., It has also been found that the use of VKA and/or DOAC therapies correlate with decreased severity of stroke in the early period.,,,
Early recanalization strategies, such as intravenous thrombolysis (IVT) and endovascular treatment (EVT), are the primary methods of treating AIS, preventing major disability, and improving functional recovery after AIS. According to current recommendations, the use of anticoagulant drugs is a relative contradiction for IVT and the risk/benefit of carrying out a mechanical thrombectomy (MT) should be judged for every patient. Observational data indicate that IVT and EVT can be safely carried out in selective patients under VKAs provided that INR is under 1.7 along with DOAC.,,,,, However, baseline use of anticoagulation poses a major hinderance in hyper-acute settings due to a heightened chance of developing symptomatic intracranial hemorrhage (sICH). The incidence rate for developing sICH is 3.7% for IVT treatment, 4.3% for EVT, and 5.1% for both IVT and EVT.
Whether prior anticoagulant medication increases the risk of symptomatic intracranial hemorrhage, recanalization, good clinical recovery, and mortality on clinical follow-up after EVT in AIS patients is still unclear. Despite the aforementioned uncertainties, there has been only a single meta-analysis assessing the impact of recanalization therapy in terms of incidence of sICH in patients with AIS receiving or not receiving DOAC following EVT or IVT. However, this previous meta-analysis consisted of a small sample size pooling data from 9 studies. Since then, several additional research articles have been published assessing if recanalization is safe in stroke patients with and without DOAC following EVT or IVT. This systematic review and meta-analysis aims to determine if recanalization therapy is safe for AIS patients receiving DOAC therapy.
| Material and Methods|| |
Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) criteria were used for the analysis. Electronic search engines including PubMed, Cochrane Library, Scopus, Google Scholar, and TRIP database were used to examine for a thorough literature search for observational studies published between 1st January 1950 to 31st March 2021: “Endovascular treatment” OR “EVT” OR “Mechanical Thrombectomy” OR “MT” AND “Intravenous thrombolysis” OR “IVT” AND “Acute Ischemic stroke” OR “Stroke” OR “cerebrovascular Disease” AND “Oral Anticoagulants” OR “OAC” OR “vitamin K antagonists” OR “VKAs” or “New Oral Anticoagulants” OR “NOAC” OR “Direct oral anticoagulants” OR “DOACs” AND “International normalized ratio” OR “INR” AND “Recanalization” were used as keywords. The bibliography of the selected papers was then checked for any new articles on human subjects that were eligible. The search was conducted without any restrictions on publication language.
Study eligibility criteria
(a) Prospective, retrospective, or ambispective observational cohort studies investigating the safety of recanalization therapy (EVT or IVT) in AIS patients with and without DOAC following; (b) Studies including cases of AIS that were clinically confirmed by medical imaging; (c) Age over 18 years (adult population); (d) Studies with raw data for clinical outcomes such as sICH, mortality, recanalization, and functional recovery in AIS patients with and without anticoagulation after EVT or IVT.
(1) Single arm studies, review articles, abstracts, pre-prints, editorials, and duplicate studies; (2) Studies not reporting relevant outcomes and (3) Those studies wherein full texts were unavailable.
Data collection and analysis
Two reviewers autonomously used previously described selection criteria to screen all eligible studies. After the initial review of the abstract, full text of the studies were reviewed. Any disagreements were resolved by a third reviewer. Information including author's name, country, study type, period of assessment, year of publication, number of patients, types of anticoagulants used, sICH criteria, recanalization rate, mortality, and good clinical recovery at 3-month follow-up was retrieved from each included study.
The incidence of symptomatic intracranial hemorrhage following EVT or IVT based on prior use of DOAC was selected as a primary outcome. The secondary outcome measures included recanalization rate, good functional recovery, and mortality at 3 months. Recanalization rates were defined based on a Thrombolysis in Myocardial Infarction (TIMI) score of 2b or 3 on CT, digital subtraction angiography (DSA) imaging, or MRI. Modified Rankin Score (mRS) between 0 and 2 indicated good functional recovery at 3 months follow-up after EVT or IVT.
Quality assessments to investigate the bias risk was done via the Newcastle-Ottawa Scale (NOS). Selection, comparability, and exposure are the three broad factors used in NOS assessment, with scores from 0 (worst quality) to 9 (best quality). Two reviewers separately rated the study's quality. Any discrepancies between the reviewer were resolved by discussion with the corresponding author.
Publication bias was assessed by funnel plot and Egger's regression test.
Pooled Risk Ratio (RR) and 95% confidence interval (CI) were calculated by combining fixed or random effect model data. Heterogeneity was measured by I2 statistics. If I2 was more than 50%, it was considered significant, and a random-effects model was utilized; if I2 was less than 50%, we preferred a fixed-effect model. The effect of individual cohorts was assessed by a sensitivity analysis that eliminates individual studies in a sequential manner. STATA, version 12.0 (Stata Statistical Software, Release 12; StataCorp LP, College Station, TX) was used, and P < 0.05 was determined as significant.
| Results|| |
The PRISMA flow chart illustrates specific points for studies being excluded and included in our review [Figure 1]. After searching five distinct databases, a total of 3585 studies were delineated. We deleted duplicate articles after which 1094 full-text articles remained. Out of 1094, 1012 articles were further excluded due to irrelevant studies (n = 960); case reports (n = 31); case series (n = 4) and reviews (n = 7). The remaining 82 full text articles were reviewed and 65 studies owing to insufficient data to report (n = 43), no comparator group (n = 17) and no outcome of interest (n = 5) were additionally excluded. Finally, 17 studies (14 for EVT; 3 for IVT) were included in our review.,,,,,,,,,,,,,,,,
|Figure 1: Flow diagram for the selection of studies and specific reasons for exclusion from the present meta-analysis|
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Of the 17 included studies,,,,,,,,,,,,,,,,, 10 studies were of prospective cohort and 7 were of retrospective cohort design [Table 1]. Studies were published between 2009 and 2021, with individual study samples ranging from 99 to 6173. Fourteen studies assessed the EVT outcomes in AIS patients with and without anticoagulation therapy, while the other 3 studies investigated the incidence of sICH following IVT in AIS patients depending on the use of DOAC. Eleven studies were performed in Europe, 4 studies in North America, and 2 studies were performed in others countries. Alone, VKA therapy before stroke was investigated in five studies, whereas the remaining eight studies included AIS patients on different types of DOAC. All included studies represent low risk of bias owing to a high score on the NOS [Table 2].
|Table 2: Quality assessment of included studies based on Newcastle-Ottawa Scale (NOS)|
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| Clinical Outcomes|| |
Endovascular therapy (EVT) studies
A combined analysis of 13 cohorts revealed that AIS patients receiving DOAC therapy after EVT had a significantly lower rate of symptomatic intracranial hemorrhage compared to AIS patients not receiving DOAC (RR = 0.85, 95 percent CI = 0.72–1.00, P = 0.04). As heterogeneity was not high (I2 = 0%, P = 0.76), we used a fixed effects model. On subgroup analysis based on study design, we noted that analysis of only prospective cohort studies,,,,,, suggested a reduced incidence of sICH in patients under DOAC after EVT (RR = 0.82, 95% CI = 0.69–0.97, P = 0.02). There was no significant difference for only retrospective studies,,,,, (RR = 1.07, 95% CI = 0.70–1.64, P = 0.74) [Figure 2].
|Figure 2: Forest plot for the association of sICH between group with and without anti-coagulant therapy of AIS patients undergoing EVT|
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Additionally, subgroup analysis depending on the study location, type of study center, anticoagulants type, sICH definition and INR criteria in patients taking VKA was performed. A significant lower incidence of sICH in studies that were conducted in European countries (RR = 0.83, 95% CI = 0.70–0.98, P = 0.03) and studies performed at multi-centric sites (RR = 0.80, 95% CI = 0.68–0.95, P = 0.02) was found. In other subgroups, our analysis did not reveal any significant association [Table 3].
|Table 3: Summary of estimates based on Subgroup analysis for sICH events in EVT group of included studies in our meta-analysis|
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Good functional recovery based on mRS (0–2) at 3 months follow up
Our findings, involving thirteen studies, suggest a lower probability of gaining good functional recovery after EVT in AIS patients under DOAC as compared to those not taking DOAC (RR = 0.79, 95% CI = 0.73–0.85, P < 0.001). We did not find any heterogeneity (I2 = 0%, P = 0.62) in the meta-analysis, which suggest good reliability of our findings. Subgroup analysis of only prospective cohort studies also revealed significantly lower chance of gaining good functional recovery based on mRS score (0–2) at 3 months follow up (RR = 0.76, 95% CI = 0.69–0.83, P < 0.001) [Figure 3].
|Figure 3: Forest plot for the association of good functional outcome (mRS ≤2) at 3 months between group with and without anti-coagulant therapy of AIS patients undergoing EVT|
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Mortality at 3 months
Three months following EVT, eleven studies reported mortality data. AIS patients who were not receiving DOAC prior to EVT had higher mortality risk (RR = 1.29, 95% CI = 1.15–1.44, P < 0.001) with no heterogeneity (I2 = 0%, P = 0.84). Although the difference found in retrospective studies was not statistically significant (RR = 1.14, 95% CI = 0.91–1.42, P = 0.25), subgroup analysis of only prospective cohort studies suggested a similar trend for higher mortality in AIS patients not under DOAC prior to EVT (RR = 1.35, 95% CI = 1.18–1.53, P = 0.001) [Figure 4].
|Figure 4: Forest plot for the association of mortality at 3 months between group with and without anti-coagulant therapy of AIS patients undergoing EVT|
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Based on prior usage of DOAC, arterial recanalization rates following endovascular therapy did not differ significantly (RR = 1.00, 95% CI = 0.96–1.05, P = 0.93) according to a pooled analysis of 8 studies. Neither prospective cohort studies nor retrospective cohort studies found a significant difference in the recanalization rate [Supplementary Figure S1].
Intravenous thrombolysis (IVT) studies
No discernible change in sICH rates was found in AIS patients getting IVT based on prior use of DOAC in the pooled analysis comprising three large-multicenter studies ((RR = 0.87, 95% CI = 0.48–1.58, P = 0.64), with no heterogeneity (I2 = 0%, P = 0.85) [Figure 5].
|Figure 5: Forest plot for the association of sICH between group with and without anti-coagulant therapy of AIS patients undergoing IVT|
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Begg's funnel plot and Egger's test showed no publication bias for the association between (a) sICH rate (P = 0.90); (b) arterial recanalization rate (P = 0.80); (c) good functional recovery at 3 months (P = 0.13); and (d) mortality at 3 months (P = 0.93); in AIS patients with and without anticoagulation before EVT. Funnel plot shape was symmetrical [Supplementary Figure S2]a, [Supplementary Figure S2]b, [Supplementary Figure S2]c, [Supplementary Figure S2]d.
Single study removal had no general influence on the sICH rate in AIS patients depending on usage of DOAC prior to EVT. Only one study by Küpper et al. 2021 was identified as a major outlier [Supplementary Figure S3].
A meta-regression analysis carried out depending on the NOS quality score demonstrated non-significant result (P = 0.55) [Supplementary Figure S4].
| Discussion|| |
According to a previous meta-analysis by Liu et al. (2018), the rate of sICH, mortality, and arterial recanalization after EVT was the same as in AIS patients with and without the prior treatment with DOAC. Furthermore, the previous study reported no reason for an increase in sICH events in individuals with AIS under DOAC therapy prior to IVT. Our meta-analysis suggests that patients with AIS on DOAC therapy have a lower incidence of sICH following EVT but not after IVT. Both groups (with and without anticoagulation) in our study had similar recanalization rates, with anticoagulated patients having poorer functional recovery after EVT. The high mortality between the two groups could be due to the same severe bleeding events and recanalization.
Despite both groups having a similar recanalization rate, anticoagulant drugs were associated with poorer functional recovery in AIS patients at 3 months follow-up. This is mostly due to the anticoagulation group's older age, more frequent comorbidities, severe premorbid baseline, seeming higher incidence of AF, and more likely cardioembolic stroke. High infarct volume, AF and age related cardioembolic stroke have all been linked to a poorer clinical prognosis.,, Nonetheless, effective revascularization tends to be associated with a considerable recovery in terms of clinical outcome and decrease death in patients on anticoagulation. EVT may be a helpful choice for AIS patients with anticoagulants along with higher INR values. Majority studies in our review did not performed the adjusted analysis for the confounding factors such as age, risk factors, size of the ischemic lesion, etc., which may be probably a confondant effect explaining the lower incidence of sICH in the anticoagulated group.
Our findings confirm that prior stroke DOAC therapy does not lead to increased sICH events in patients undergoing IVT. Several possible mechanisms could shed light on the reasons behind this: (1) DOAC have a lower effect on post-ischemic BBB permeability than VKA; (2) DOAC decrease neurovascular dissociation by inhibiting matrix metalloproteinase-9 activation; (3) DOAC have no effect on factor-VII or VIIa plasma concentrations, whereas warfarin represses factor-VII production; and (4) even while receiving the appropriate anticoagulant prophylaxis, there is still reduced anticoagulant activity at stroke onset. Although DOAC plasma concentrations should theoretically decrease after one day, the detected plasma level of the agent do not correlate with the last dosing timepoint. Furthermore, IVT is not considered safe for AIS patients prescribed DOAC for more than 48 hours because the accurate drug concentrations vary based on the individuals renal function, age and other medical conditions.
Before applying the current findings, the following limitations should be highlighted. Firstly, the included studies were prospective and retrospective observational cohort studies, which are susceptible to selection bias. Our findings highly recommend conduct of larger prospective multicentric observational studies with adjusted multivariate analysis to confirm our conclusions. Second, many minor differences in sICH definitions were noted, which may have influenced the sICH rate. However, our analysis based on different sICH definitions yielded identical results. Third, due to the absence of baseline patient data in some EVT studies, we were unable to assess the influence of different confounders using meta-regression analysis.
| Conclusion|| |
Patients with AIS on DOAC therapy were found to have a lower incidence of sICH following EVT. However, no evidence of an increased bleeding risk in patients previously treated with DOAC after IVT was observed. However, more detailed studies with biological data to monitor compliance and details on the size and etiology/severity of the incident ischemic lesion are needed.
Financial support and sponsorship
Shaoxing Science and Technology Plan Project: 2020ZDSYS02 (Shaoxing Key Laboratory of Cardiovascular and Cerebrovascular Disease Rehabilitation Technology Innovation and Application).
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]
[Table 1], [Table 2], [Table 3]