Original research article European Stroke Journal Effect of atrial fibrillation on 2020, Vol. 5(3) 245–251 ! European Stroke Organisation endovascular thrombectomy for acute 2020 ischemic stroke. A meta-analysis Article reuse guidelines: sagepub.com/journals-permissions of individual patient data from six DOI: 10.1177/2396987320923447 journals.sagepub.com/home/eso randomised trials: Results from the HERMES collaboration JA Smaal1 , IR de Ridder1, A Heshmatollah2 , WH van Zwam1 , DWJ Dippel2, CB Majoie3, S Brown4, M Goyal5, BCV Campbell6, KW Muir7, AM Demchuck8, A Davalos9, TG Jovin10, PJ Mitchell11, P White12, JL Saver13, MD Hill8 , YB Roos14, A van der Lugt15 and RJ van Oostenbrugge1; For the HERMES collaboration Abstract Background: Atrial fibrillation is an important risk factor for ischemic stroke, and is associated with an increased risk of poor outcome after ischemic stroke. Endovascular thrombectomy is safe and effective in acute ischemic stroke patients with large vessel occlusion of the anterior circulation. This meta-analysis aims to investigate whether there is an interaction between atrial fibrillation and treatment effect of endovascular thrombectomy, and secondarily whether atrial fibrillation is associated with worse outcome in patients with ischemic stroke due to large vessel occlusion. Methods: Individual patient data were from six of the recent randomised clinical trials (MR CLEAN, EXTEND-IA, REVASCAT, SWIFT PRIME, ESCAPE, PISTE) in which endovascular thrombectomy plus standard care was compared to standard care alone. Primary outcome measure was the shift on the modified Rankin scale (mRS) at 90 days. Secondary outcomes were functional independence (mRS 0–2) at 90 days, National Institutes of Health Stroke Scale score at 24 h, symptomatic intracranial hemorrhage and mortality at 90 days. The primary effect parameter was the adjusted common odds ratio, estimated with ordinal logistic regression (shift analysis); treatment effect modification of atrial fibrillation was assessed with a multiplicative interaction term. Results: Among 1351 patients, 447 patients had atrial fibrillation, 224 of whom were treated with endovascular thrombectomy. We found no interaction of atrial fibrillation with treatment effect of endovascular thrombectomy for 10 Stroke Institute, Department of Neurology, University of Pittsburgh 1 Maastricht University Medical Center, Cardiovascular Research Institute Medical Center, Pittsburgh, PA, USA 11 Maastricht (CARIM), Maastricht, The Netherlands Department of Radiology, Royal Melbourne Hospital, University of 2 Department of Neurology, Erasmus MC University Medical Center, Melbourne, Melbourne, VIC, Australia 12 Rotterdam, The Netherlands Institute of Neuroscience, Newcastle University, Newcastle upon Tyne, 3 Department of Radiology & Nuclear Medicine, Amsterdam University UK 13 Medical Centers, location AMC, Amsterdam, the Netherlands Department of Neurology, Amsterdam University Medical Centers, 4 Altair Biostatistics, St Louis Park, MN, USA location AMC, Amsterdam, the Netherlands 5 14 Department of Radiology, University of Calgary, Foothills Hospital, Department of Neurology, Amsterdam University Medical Centers, Calgary, AB, Canada location AMC, Amsterdam, the Netherlands 6 15 Department of Medicine and Neurology, Melbourne Brain Centre, Royal Department of Radiology and Nuclear Medicine, Erasmus MC Melbourne Hospital, University of Melbourne, Parkville, VIC, Australia University Medical Center, Rotterdam, The Netherlands 7 Institute of Neuroscience and Psychology, University of Glasgow, Queen Elizabeth University Hospital, Glasgow, UK Corresponding author: 8 Department of Clinical Neurosciences, Hotchkiss Brain Institute, JA Smaal, Department of Neurology, Maastricht University Medical Cumming School of Medicine, University of Calgary, Foothills Hospital, Center, Maastricht, P. Debyelaan 25, 6229 HX Maastricht, Calgary, AB, Canada The Netherlands. 9 Department of Neuroscience, University Autònoma de Barcelona, Spain Email: anne.smaal@mumc.nl 246 European Stroke Journal 5(3) both primary (p-value for interaction: 0.58) and secondary outcomes. Regardless of treatment allocation, we found no difference in primary outcome (mRS at 90 days: aOR 1.11 (95% CI 0.89–1.38) and secondary outcomes between patients with and without atrial fibrillation. Conclusion: We found no interaction of atrial fibrillation on treatment effect of endovascular thrombectomy, and no difference in outcome between large vessel occlusion stroke patients with and without atrial fibrillation. Keywords Ischemic stroke, endovascular thrombectomy, atrial fibrillation, large vessel occlusion Date received: 19 November 2019; accepted: 3 April 2020 Introduction PRIME, REVASCAT, PISTE, and THRACE trials were pooled.5 The HERMES executive committee Patients with acute ischemic stroke and atrial fibrilla- (comprising representatives of each trial) confirmed tion (AF) present with a higher score on the National that all eligible trials were included and contributed Institute of Health Stroke Scale (NIHSS) more fre- their trial data and the data were collated by an inde- quently have intracranial arterial occlusion(s) and pendent biostatistician (SB). All participants or their have a worse functional outcome than patients without legal representatives provided informed consent AF.1,2 Furthermore, in patients with AF, treatment according to each trial protocol and each study was with intravenous thrombolysis (IVT) is less effective approved by the local ethics board. The meta-analysis on both recanalisation and clinical outcome.3,4 was prospectively designed by the HERMES executive Possible explanations are that emboli in AF are committee, but not registered. AF status was known in larger and show a different pattern of occlusion than all of the aforementioned trials but the THRACE trial emboli due to other causes. Endovascular thrombec- whose data were therefore excluded. tomy (EVT) is effective and safe in acute ischemic stroke due to proximal intracranial large vessel occlu- Outcome measures sion (LVO) of the anterior circulation.5–7 A post hoc subgroup analysis of the MR CLEAN trial was com- The primary outcome was the shift on the modified patible with decreased treatment effect in patients with Rankin Scale (mRS) score at 90 days. The mRS is a AF.8 However, as only a small number of patients was score indicating the level of disability ranked between included in this analysis, the uncertainty of this finding 0–6, with a score of 0–2 associated with functional was high. Our aim was to investigate whether AF independence, an increased level of disability with a modifies treatment effect of EVT for acute ischemic score of 3–5, and a score of 6 indicating death. stroke due to LVO. Secondarily, we sought to deter- Secondary outcome measures were functional indepen- mine whether AF was associated with worse outcome dence, defined as mRS 0–2 at 90 days, and stroke sever- in patients with ischemic stroke due to LVO. ity, measured with the NIHSS score, at 24 h after stroke onset. Safety outcomes were symptomatic intra- cranial hemorrhage (sICH) and mortality at 90 days. Methods The endpoints in the individual studies were measured in person or by (telephone) interview; raters were Data collection blinded to the study arm. Data are from the “highly effective reperfusion using multiple endovascular devices” (HERMES) collabora- Clinical definitions tion. The HERMES collaboration combined patient The diagnosis of AF was made when patient history level data available from clinical trials that used was positive for AF, or when AF was diagnosed during second-generation mechanical devices (primarily stent hospital stay. retrievers) to test if additional mechanical thrombec- tomy (intervention group) is better than standard care (control group) in patients with acute ischemic Statistical analysis stroke. For this purpose, individual patient data from We performed an individual patient-level meta-analysis the MR CLEAN, ESCAPE, EXTEND-IA, SWIFT based on the intention-to-treat principle. The primary Smaal et al. 247 effect parameter was the adjusted common odds ratio no definite conclusion could be drawn. A meta-analysis (acOR), estimated with ordinal logistic regression (shift of 11 randomised controlled trials (RCT) comparing analysis). We assessed treatment effect modification by EVT versus standard care found that good functional AF with a multiplicative interaction variable on both outcome (mRS 0–2 at 90 days) after EVT occurred the primary and secondary outcomes. We adjusted the more often in patients with AF.9 These meta- primary and secondary effect parameters for potential analyses, however, also included several older, neutral imbalances in major pre-specified confounding varia- trials and did not adjust for treatment with IVT and bles (age, stroke severity (NIHSS) at baseline, treat- other potential confounders. ment with IVT, localisation of occlusion and time Our finding that in stroke patients with LVO of the from onset to randomisation). We reported adjusted anterior circulation there is no difference in functional and unadjusted common odds ratios with 95% confi- outcome between patients with and without AF, is in dence interval (CI). We analysed binary outcomes with contrast with results of earlier studies in patients with logistic and linear regression respectively, and reported ischemic stroke in general, which found that patients as adjusted and unadjusted odds ratios or betas with with AF had a worse clinical outcome, even after 95% CIs, where applicable. All reported p-values are IVT.3,4 However, in these studies populations with two-sided. We performed all statistical analyses SAS other stroke types such as atherothrombotic or lacunar software, version 9.3, and R, version 3.2. strokes were included. Patients with AF more frequent- ly suffer from proximal arterial occlusions, which over- all leads to a poorer outcome than other types of Results ischemic stroke. A likely explanation for our finding In the six trials (MR CLEAN, EXTEND-IA, is that we only looked at the subset of patients with REVASCAT, SWIFT PRIME, ESCAPE, PISTE), LVO, and that the underlying mechanism has less influ- 1351 patients were included. Data on 90-day follow- ence on stroke severity and outcome than the LVO up were missing in 10 patients (Figure S1). AF was itself. The finding that baseline NIHSS does not signif- present in 447 patients (33.1%) of whom 224 (50%) icantly differ between patients with AF and those with- were treated with EVT. At baseline, patients with AF out supports this notion. were older, less often treated with IVT, had a higher We found a trend towards a lower rate of intracra- ASPECTS score and more frequently suffered from nial hemorrhage in patients with AF (4.5% in patients hypertension (Table 1, Table S1). without AF vs 3.4% in patients with AF). However, There was no significant difference in the treatment this difference did not reach significance (aOR 0.57; effect size of EVT (acOR 2.39 (95% CI 1.47, 3.88) in 95% CI 0.3–1.07). A significantly lower percentage of AF patients, acOR 2.34 (95% CI 1.66, 3.31) in patients AF subjects received IVT compared to patients without without AF) and no interaction of AF with treatment AF (76.3% vs 90.6%). At baseline, patients with AF effect of EVT (p-value for interaction 0.58) (Table 2, were treated with tPA significantly less frequent than Table S2). We also found no difference in functional patients without AF. This is likely due to the fact that outcome between patients with and without AF (aOR patients with AF are more likely to use oral anticoagu- 1.11 (95% CI 0.89, 1.38) (Table 3). For the secondary lation, which is a contra-indication for the administra- outcomes, there was a trend towards a lower rate of tion of tPA. symptomatic intracranial hemorrhage in patients with Our results could imply that the lower percentage of AF (aOR 0.57 (95% CI 0.3, 1.07)) (Table 3). sICH in the AF group might be related to the lower percentage of pre-treatment with IVT. The percentage of sICH after treatment with IVT is around 5%.10 Discussion Considering this finding, the question arises whether In this individual patient data meta-analysis, we found in patients with a proximal arterial occlusion treatment no significant modification of the effect of EVT by AF with IVT prior to EVT is beneficial. Recent observa- on functional outcome, and secondary outcomes (func- tional studies report conflicting results, some reporting tional independence at 90 days, NIHSS score at 24 h, that pre-treatment with IVT before EVT is beneficial symptomatic intracranial hemorrhage and mortality at for outcome,7,11,12 while others note there is no clear 90 days). Additionally, in these patients with LVO, benefit of pre-treatment while the risk of intracranial the risk of poor outcome was not increased in patients hemorrhage is higher.13,14 Another issue is the delay with AF. pre-treatment with IVT causes in patients also treated A subgroup analysis of the MR CLEAN trial with EVT. The main limitation of these studies is the showed a trend towards a lower treatment effect of observational and retrospective design. Therefore, EVT in patients with AF.8 However, the number of more research into the benefit of IVT in patients with patients with AF in this study was rather low, therefore proven LVO eligible for EVT is needed. Currently, 248 Table 1. Baseline characteristics by AF status and treatment allocation. AF No AF Control EVT Control EVT Mean  SD (N) Mean  SD (N) Mean  SD (N) Mean  SD (N) [Median] [Median] [Median] [Median] (IQR) (IQR) (IQR) (IQR) Characteristic OR % (n/N) OR % (n/N) OR % (n/N) OR % (n/N) Age (years) 72.8  9.4 (223) 72.8  10.1 (224) 63.6  13.6 (459) 63.1  13.7 (443) [74.0] (67.0, 79.0) [73.0] (67.0, 80.1) [64.7] (55.0, 74.0) [63.0] (54.0, 74.0) Female gender 49.8% (111/223) 47.8% (107/224) 44.8% (206/460) 49.0% (217/443) NIHSS at baseline 16.8  5.4 (223) 17.5  4.8 (223) 16.9  5.7 (457) 16.5  5.2 (440) [17.0] (14.0, 20.5) [18.0] (14.5, 21.0) [17.0] (13.0, 21.0) [17.0] (13.0, 20.0) tPA delivered 79.4% (177/223) 73.2% (164/224) 92.0% (424/461) 89.2% (395/443) Diabetes mellitus 17.9% (40/223) 21.0% (47/224) 17.6% (81/461) 15.1% (67/443) Hypertension 74.9% (167/223) 68.8% (154/224) 51.6% (238/461) 48.5% (215/443) ASPECTS at baseline 8.1  1.7 (219) 8.0  1.7 (222) 7.6  1.9 (452) 7.7  1.7 (439) [8.0] (7.0, 9.0) [8.0] (7.0, 9.0) [8.0] (7.0, 9.0) [8.0] (7.0, 9.0) Occlusion location Not available 7.2% (16/223) 6.3% (14/224) 5.6% (26/461) 4.7% (21/443) ICA 24.2% (54/223) 27.2% (61/224) 29.3% (135/461) 27.8% (123/443) M1 61.0% (136/223) 55.8% (125/224) 55.7% (257/461) 58.5% (259/443) M2 7.6% (17/223) 10.7% (24/224) 9.3% (43/461) 8.8% (39/443) Other 0.0% (0/223) 0.0% (0/224) 0.0% (0/461) 0.2% (1/443) Onset of tPA 125.0  66.4 (178) 115.7  50.8 (162) 116.1  60.9 (424) 111.5  47.3 (395) [110.0] (80.0, 147.8) [105.0] (75.3, 139.3) [100.0] (75.0, 145.0) [102.0] (75.0, 135.0) Onset of randomisation 213.4  96.1 (223) 212.7  104.9 (224) 208.4  88.7 (458) 210.4  99.3 (441) [196.0] (139.0, 277.0) [191.0] (137.8, 257.5) [191.5] (141.3, 264.0) [193.0] (142.0, 253.0) AF: atrial fibrillation; NIHSS: National Institutes of Health Stroke Scale; tPA: tissue plasminogen activator; ASPECTS: Alberta Stroke Program Early CT Score; ICA: internal carotid artery; SD: standard deviation; AF: atrial fibrillation; EVT: endovascular thrombectomy. European Stroke Journal 5(3) Smaal et al. 249 P inter-action there are several ongoing trials investigating this issue (MR CLEAN NO-IV, DIRECT-MT, SWIFT DIRECT, and DIRECT SAFE). 0.581 0.544 0.536 0.686 0.900 Strengths of this meta-analysis are the large number of included of patients and the high prevalence of AF (1351, 33% AF), leading to more reliable estimations. ( 5.82, 1.54) Also, the uniform documentation of baseline character- (1.66, 3.31) (1.96, 3.56) (0.55, 1.96) (0.55, 1.45) istics and outcome measures is a strength. A limitation of this meta-analysis is that the pres- ence of AF was documented in a binary way, meaning No AF it is not certain whether the patients were known with 2.34 2.64 3.68 1.04 0.89 AF before EVT, and whether it was paroxysmal or chronic. Also, the duration of cardiac monitoring was Adjusted value (95% CI) not recorded; therefore it cannot be excluded that the (–5.74, –1.26) monitoring varied between studies and individual (1.47, 3.88) (1.50, 3.85) (0.36, 3.30) (0.41, 1.17) mRS; modified Rankin scale; AF: atrial fibrillation; NIHSS: National Institutes of Health Stroke Scale; sICH: symptomatic intracranial hemorrhage. patients resulting in a diagnosis bias. Another limita- tion is that data on anticoagulation status were not available for all subjects, as there was no standardised 2.39 2.41 1.09 0.69 –3.50 Results are unadjusted and adjusted for age, NIHSS at baseline, IVT, localisation of occlusion and time from onset to randomisation. collection of such data across the studies that were Table 2. Primary outcome, secondary outcomes, and p-value for interaction by AF status and treatment allocation. AF included in this meta-analysis. However, the fact that fewer patients with AF were concurrently treated with P inter-action intravenous thrombolysis may suggest that many AF patients were anticoagulated and therefore ineligible 0.848 0.350 0.729 0.848 0.812 for intravenous thrombolysis treatment. Furthermore, no information on recurrent strokes following the ini- tial event was recorded. This would have been interest- (–4.58, –2.41) ing data, considering the fact that in the initial period (1.66, 2.94) (1.88, 3.31) (0.54, 1.90) (0.53, 1.40) following an ischemic stroke patients might temporar- ily not be treated with anticoagulation, possibly leading to a higher recurrence of ischemic stroke in this patient No AF group. However, as we found no difference in outcome –3.50 2.21 2.50 1.01 0.86 between patients with and without AF in this study, we Unadjusted value (95% CI) can deduce that a possibly higher rate of recurrence in AF patients did not lead to an overall worse function- ( 5.12, 0.80) ing at three months, when compared to patients with- (1.33, 3.30) (1.32, 2.99) (0.40, 3.35) (0.47, 1.23) out AF. Lastly, the included data were derived from randomised controlled trials randomising for EVT plus standard treatment or standard treatment alone; there –2.96 2.10 1.99 1.15 0.76 was no stratification by AF status and therefore, AF unmeasured confounders cannot be ruled out. Effect cOR Beta OR OR OR Conclusion mRS score of 0–2 at 90 days We found no interaction of AF with effect of EVT in patients with AIS due to LVO. Furthermore, we found mRS score at 90 days Mortality at 90 days no difference in the functional outcome between patients with and without AF regardless of treatment, NIHSS at 24 h suggesting that the cause of proximal arterial occlusion does not influence outcome in AIS due to LVO. Altogether, our data implies AF status should not sICH influence the decision to proceed to EVT. 250 European Stroke Journal 5(3) Table 3. Primary outcome, secondary outcomes, and p-value for interaction by AF status, independent of treatment allocation. p-Value Unadjusted value Adjusted value (main effect Effect N (95% CI) AF vs no AF (95% CI) AF vs no AF of AF) Modified Rankin score cOR 1341 0.73 (0.59, 0.89) 1.11 (0.89, 1.38) 0.372 (mRS) at 90 days Functional independence OR 1341 0.82 (0.64, 1.05) 1.14 (0.87, 1.51) 0.337 (mRS 0–2) at 90 days NIHSS score at 24 h Beta 1309 0.46 (–0.47, 1.39) –0.36 (–1.23, 0.52) 0.423 Symptomatic ICH OR 1351 0.80 (0.44, 1.47) 0.57 (0.3, 1.07) 0.082 Mortality at 90 days OR 1341 1.86 (1.39, 2.49) 1.14 (0.83, 1.57) 0.410 Results are unadjusted, and adjusted for age, baseline NIHSS, treatment with IVT, treatment with EVT, localisation of occlusion and time from onset to randomisation. Results include a random effect to capture between-study variance. Odds ratios show results for AF versus non-AF, meaning that an odds ratio > 1 indicates greater probability of the outcome in AF subjects. AF: atrial fibrillation; NIHSS: National Institutes of Health Stroke Scale; OR: odds ratio; cOR: common odds ratio. Contributorship than other cardioembolic stroke subtypes. Stroke 2016; AS, IR, RvO authored the article. Primary statistical analysis 47: 1486–1492. was done by SB. All authors reviewed and edited the article 2. Sanák D, Herzig R, Král M, et al. Is atrial fibrillation and approved the final version of the article. associated with poor outcome after thrombolysis? J Neurol 2010; 257: 999–1003. 3. Kimura K, Iguchi Y, Yamashita S, et al. Atrial fibrilla- Declaration of Conflicting Interests tion as an independent predictor for no early recanaliza- The author(s) declared no potential conflicts of interest with tion after IV-t-PA in acute ischemic stroke. J Neurol Sci respect to the research, authorship, and/or publication of this 2008; 267: 57–61. article. 4. Seet RCS, Zhang Y, Wijdicks EF, et al. Relationship between chronic atrial fibrillation and worse outcomes Ethical approval in stroke patients after intravenous thrombolysis. Arch Each trial used in this meta-analysis was approved by the Neurol 2011; 68: 1454–1458. 5. Goyal M, Menon BK, van Zwam WH, et al. local medical ethical committee. Endovascular thrombectomy after large-vessel ischaemic stroke: a meta-analysis of individual patient data from Funding five randomised trials. Lancet 2016; 387: 1723–1731. The author(s) received no financial support for the research, 6. Muir KW, Ford GA, Messow C, et al. Endovascular authorship, and/or publication of this article. therapy for acute ischaemic stroke: the pragmatic ischae- mic stroke thrombectomy evaluation (PISTE) rando- Guarantor mised, controlled trial. J Neurol Neurosurg Psychiatry RvO. 2017; 88: 38–44. 7. Bracard S, Ducrocq X, Mas JL, et al. 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