Benefit and risk of early intravenous heparin after thrombolysis in patients with acute ischemic stroke

Abstract Background and purpose We performed a retrospective analysis of the “Thrombolysis Implementation and Monitor of Acute Ischemic Stroke in China (TIMS‐China)” registry to explore the benefit and risk of intravenous thrombolysis (IVT) followed by intravenous heparin (IVH) in acute ischemic stroke (AIS) patients. Methods In the TIMS‐China database, the patients who received IVH immediately after IVT (Early IVH group) and those who initiated antithrombotic therapy (ATT) until 24 hr after IVT (Standard ATT group) were screened for this comparison. Propensity score (PS) matching was performed between both groups. The logistic regression analysis was performed in the matched population to compare all the efficacy and safety outcomes. Results Of 1,437 patients in this study, 119 received early IVH and 1,318 cases initiated standard ATT. After PS matching (1:2), 117 pairs were identified. The early IVH group had higher proportions of neurological improvement at 24 hr (OR = 2.24, 95% CI = 1.42–3.53) and 7 days (OR = 1.92, 95% CI = 1.22–3.03), better chance of excellent recovery (OR = 1.69, 95% CI = 1.07–2.67) and functional independence (OR = 1.77, 95% CI = 1.13–2.78) at 90 days, and a lower 90‐day mortality (OR = 0.44, 95% CI = 0.21–0.92) than standard ATT group. Additionally, early IVH did not increase the risk of symptomatic intracranial hemorrhage (OR = 0.92, 95% CI = 0.34–2.48). Conclusions IVH immediately after thrombolysis seems to be safe and potentially more effective as compared with standard ATT delay of 24 hr for a subset of AIS patients.

In this study, we conducted a retrospective analysis of AIS patients who had received such combination treatment from the data in the Thrombolysis Implementation and Monitor of Acute Ischemic Stroke in China (TIMS-China) in older to examine the efficacy and safety outcomes of intravenous heparin (IVH) immediately following IVT.

| Study population
TIMS-China was a national prospective consecutive stroke registry of IVT for AIS patients in 67 major stroke centers in China. (Liao et al., 2014) None of the patients received bridging mechanical thrombectomy or other emergency endovascular treatment. The study protocol was approved by the Ethics Committee of Beijing Tiantan Hospital. The registry was regularly monitored independently by the Quality Monitoring Committee of TIMS-China and a Contract Research Organization. For a patient with AIS eligible for enrollment, the patient or patient's legally authorized representative would be given the written informed consent of TIMS-China study before enrollment, and all patients received IVT in the dose range between 0.5-0.9 mg/kg, with 10% of the total dose given as a bolus over 1 min and the remainder infused over 60 min. The National Institutes of Health Stroke Scale (NIHSS) score was measured at baseline, 2 hr, 24 hr, 7 days (or at discharge, whichever occurs first) and any time of neurological deterioration. The modified Rankin Scale (mRS) score was assessed at 7 days (or at discharge, whichever occurs first) and 90 days. Only the neurologists who were trained and qualified for using NIHSS and mRS recorded the scores. Brain imaging (CT or MR) was performed at baseline, 24 hr, 7 days (or at discharge, whichever occurs first) and any time of neurological deterioration. The imaging findings were interpreted by two independent trained radiologists blinded to clinical data in each participating hospital. A third experienced senior radiologist was involved to resolve any disagreement.
In the TIMS-China registry, antithrombotic regimens after IVT were decided by an individual clinical decision. The patients who received IVH immediately after IVT (early IVH group) and those who initiated ATT until 24 hr after IVT based on the current guidelines' recommendation (standard ATT group) were screened for this comparison. For safety reasons, patients were re-examined for head CT after completion of 1-hr tPA infusion and before initiation of IVH.
Heparin was administered only if the patient had no intracranial or major extracranial hemorrhage. An informed consent was signed prior to initiation of IVH, and then, IVH was started as a bolus of 30 U/kg (maximum dose: 3,000 U) within a minute, followed by a continuous infusion at 500-1000 U per hour for at least 24 hr, up to 72 hr. The goal of the activated partial thromboplastin time (APTT) was 1.5-2 times of the baseline. It was monitored at baseline, 2 hr, 6 hr, 12 hr, and every 12 hr thereafter during heparin infusion and within 2 hr of any dosage adjustment. IVH was discontinued immediately when major extracranial or any intracranial bleeding was suspected.

| Outcome measurement
The efficacy outcome measures included neurological improvement at 24 hr and 7 days, excellent recovery and functional independence at 90 days. Neurological improvement was defined as NIHSS score decrease of ≥4 points from the baseline (National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group, 1995).
The mRS was used to assess functional outcome at 90 days. A central follow-up blinded to baseline information was carried out by telephone interview by trained neurologists based on a standardized interview protocol. Excellent recovery was defined as having a mRS score of 0-1, and functional independence was defined as having a mRS score of 0-2 (Hacke et al., 2008).
The safety outcome measures included post-IVT symptomatic intracranial hemorrhage (sICH) and any intracranial hemorrhage (aICH) within 7 days, and mortality within 90 days. sICH was evaluated by using the European Cooperative Acute Stroke Study (ECASS) definition, (Hacke et al., 2008) which was defined as any intracranial K E Y W O R D S anticoagulation, heparin, ischemic stroke, thrombolysis, tissue plasminogen activator hemorrhage associated with 4 or more points of worsening on NIHSS. aICH was verified by follow-up imaging studies regardless of any clinical deterioration.

| Statistical analysis
The baseline variables were compared between both groups by using a univariate analysis. The t test or Mann-Whitney U test was used to compare means or medians for continuous variables. The Pearson chi-square test or Fisher's exact test was used to compare the proportions for categorical variables. In order to improve the baseline comparability between both groups in this study, we performed a propensity score (PS) matching (1:2). The probabilities of receiving early IVH were calculated by using a logistic regression model. Fourteen potential confounding covariates were used to generate PS. They were age, sex, hypertension, diabetes mellitus, atrial fibrillation, prior stroke, prestroke mRS score, cigarette smoking, systolic blood pressure, admission NIHSS score, onset-to-needle time, tPA dose, stroke territory, and stroke subtype by Trial of Org 10172 in Acute Stroke Treatment (TOAST) criteria. The C-statistic was calculated to evaluate the goodness-of-fit for the model. After PS generation, the patients treated with early IVH and those treated with standard ATT delay of 24 hr were performed with the use of a 1:2 matching protocol without replacement (greedy-matching algorithm), with a caliper width ≤0.2 of the standard deviation of the logit of the PS. (Bangalore et al., 2015) In the matched population, for comparing the outcomes between the two groups, the odds ratios (OR) with their 95% confidence intervals (CI) were analyzed by a binary logistic regression model. In addition, we assessed whether the effects of the two antithrombotic regimens after IVT on the mRS scores at 90 days differed in certain subgroups by testing the treatment-by-subgroup interaction effect with the use of an ordinal logistic regression model. Statistical significance was set at p < .05.
All statistical analyses were performed with the statistical software package R (http://www.R-proje ct.org, The R Foundation) and Empowerstats (http://www.empow ersta ts.com, X&Y Solutions, Inc).    sICH was evaluated by using the European Cooperative Acute Stroke Study (ECASS) definition, which was defined as any intracranial hemorrhage associated with 4 or more points of worsening on NIHSS. aICH was verified by follow-up imaging studies regardless of any clinical deterioration.

| D ISCUSS I ON
Neurological improvement was defined as NIHSS score decrease of ≥ 4 points from the baseline. Excellent recovery was defined as having a mRS score of 0-1, and functional independence was defined as having a mRS score of 0-2.
Abbreviations: aICH, any intracranial hemorrhage, ATT, antithrombotic therapy, CI, confidence interval, IVH, intravenous heparin, OR, odds ratio, sICH, symptomatic intracranial hemorrhage. a At 7 d or discharge, whichever comes first. center case-control study demonstrated that thrombolysis followed by anticoagulation with IVH did not increase the risk of sICH. (Amaro et al., 2013;Grond et al., 1998;Schmülling et al., 2003) As for patients with acute basilar artery stroke, one study showed a higher rate of sICH and a shift toward worse outcome in thrombolyzed patients treated with IVH as compared to subcutaneous low-molecular TA B L E 4 Stratified analyses of 90-day mRS between heparin and standard ATT groups in the matched population weight heparin, (Ritvonen et al., 2019) while another study did not find that sICH after thrombolysis was related to adjuvant anticoagulation with IVH. (Sairanen et al., 2015)  Although previous studies from Japan found that the efficacy and safety of the low-dose tPA (0.6 mg/kg) was comparable to that of the full dose (0.9 mg/kg), (Minematsu et al., 2012) lower doses of tPA could weaken the potency of tPA (Anderson et al., 2016;Liao et al., 2014). By using an ordinal logistic analysis, the interaction of IVH with different doses of IVT was studied. Our analysis showed that there was no significant interaction effect on 90-day mRS between heparin and standard ATT groups when stratified by different tPA doses.
Our study had several limitations. Firstly, this study was a retrospective analysis of prospectively collected data and was thus vulnerable to selection bias, despite the fact that important baselines in both groups were well-balanced by using a PS matching.
However, the C-statistic for PS model was as low as 0.74, some unmeasured factors might affect physician's decision on the selection of early IVH. For example, clinical experience and research suggest that several potential factors could increase the risk of hemorrhagic transformation after thrombolysis include large infarcts, early ischemic changes, poor collaterals, multiple microbleeds, high glucose, renal impairment, and previous antiplatelet agents (Charidimou et al., 2017;Whiteley, Slot, Fernandes, Sandercock, & Wardlaw, 2012). All of these factors can be recognized by treating physicians before the initiation of IVH. By balancing the risks and benefits, IVH was likely to be administered to a certain subset of patients who might benefit more. In our analyzed cases, early heparin was often used in patients having received low-dose tPA, with more severe strokes or posterior circulation strokes. It is also possible that early use of IVH was decided by the unknown intermediate factors, presumably improving functional outcomes and decreasing bleeding risks. Moreover, the rate of intracranial hemorrhage in this analysis may be underestimated because the patients were excluded due to ultra-early hemorrhage after thrombolysis that withholds initial use of antithrombotics. Secondly, there was no follow-up imaging assessment in the database to support the notion of possible vessel recanalization. Last but not least, our results were obtained in a subgroup of Chinese AIS patients with moderate severity strokes (median NIHSS = 14), with low-dose tPA used in 40% and posterior circulation strokes in 43% of cases, and cannot be extrapolated to other population groups.

| CON CLUS IONS
In summary, this matched-control study aimed to investigate the effect of early IVH after IVT on the clinical outcomes in a certain subset of AIS patients, which is not recommended by the current guidelines. In this retrospective analysis from a prospective registry, such combination therapy with IVT followed by IVH might improve their functional outcomes and not increase their risk of hemorrhagic transformation. Nevertheless, future randomized placebo-controlled multicenter trials are needed to confirm our findings.

ACK N OWLED G EM ENTS
We thank all participating hospitals, relevant clinicians, statisticians, and imaging and laboratory technicians.

PEER R E V I E W
The peer review history for this article is available at https://publo ns.com/publo n/10.1002/brb3.1776.

DATA AVA I L A B I L I T Y S TAT E M E N T
The raw data supporting the conclusions of this manuscript will be made available by the author Yilong Wang (yilong528@gmail.com), without undue reservation, to any qualified researcher.