A post hoc analysis from the randomized controlled trial (RCT) of Enhanced Control of Hypertension and Thrombolysis Stroke (ENCHANTED) Study (1) indicated a significant interaction between the different doses of intravenous thrombolysis (IVT) and pre-treatment of antiplatelet (2). Compared to the standard dose of IVT with alteplase, the low-dose group showed increased favorable functional outcome after the pre-treatment with antiplatelets (2). They found that, the pre-treatment of antiplatelets with IVT revealed borderline significance for increased Symptomatic Intracranial Hemorrhage (SICH) (2) according to terms of the Safe Implementation of Thrombolysis in Stroke- Monitoring Study (SITS-MOST) criteria (3).

Previous studies on patients with acute ischemic stroke who were treated with IVT found a 2-fold risk of increased SICH with a single antiplatelet pre-treatment (4–6), and 4- to 9-fold increased risk with dual antiplatelet pre-treatment (DAPP) (4–6). This extremely high risk of increased SICH with DAPP was likely caused by selection bias. Two recent studies by Tsivgoulis et al. (7, 8) employed propensity score matching (PSM) to control the imbalance of the confounders between both the groups, with and without DAPP. Their results suggest that DAPP caused no significant increase in SICH by most standards except of the SITS-MOST criteria, and no significant improvement in the Favorable Functional Outcome (FFO) (7, 8). A recent pooled analysis study showed similar findings at first (9); however, a recent letter to this study revealed that the pooled results were biased by duplicate data and disproved the major findings (10). They indicated that DAPP significantly increased SICH by deleting duplicate data (10). Thereafter, some issues remain to be answered. First, studies employing the PSM method focused on mild ischemic stroke severity with a National Institute of Health Stroke Scale (NIHSS) score of < 10 (7, 8). Second, there was a high heterogeneity in the definition of DAPP (including both aspirin + dipyridamole and aspirin + clopidogrel) and SICH standards in the pooled analysis (9). Third, we considered that older patients were more susceptible to bleeding with DAPP.

The aim of this study was to investigate whether pre-treatment with single antiplatelet, warfarin, and DAPP for acute ischemic stroke patients who were treated with IVT with the following characteristics: (1) older age, (2) moderate to high severity with high NIHSS score at baseline, and (3) the low-dose alteplase, imposed changed risk of SICH and the global functional outcomes.

In this study, we found a significant interaction between the dosage of alteplase and DAPP for the global functional outcome. In the DAPP group, low-dose alteplase had a higher proportion of unfavorable outcomes despite no significantly increased ordinal mRS. For the older adults, pre-treatment with ASA resulted in significant improvement of FFO but not FI. The DAPP group had lower proportions of better outcomes, but no significant difference in terms of FFO and FI compared to no AP/AC. However, DAPP was found to have a significantly increased 5-fold the risk of SICH with both NINDS and ECASS II standards. Mortality was found to be significantly increased by more than 4-fold in the DAPP group.

Our analysis was in line with most of the observational studies, which showed that prior dual antiplatelets increased the 4- to 9-fold risk of SICH (4–6). In contrast, our results showed some disagreement from two recent studies employing propensity score matching (PSM) adjustment (7, 8), which found that DAPP did not significantly increase SICH after adjustment for confounders. In fact, these studies employing PSM adjustment enrolled patients with mild severity of acute ischemic stroke (average NIHSS score of <10) (7, 8), while we included patients with higher severity (mean NIHSS score of 13–16). In addition, the control group showed different characteristics between these studies and ours (8). Their reference group included patients pre-treated with a single antiplatelet agent and no antiplatelets, whereas our reference group was treated without any AP/AC. Moreover, our patients were older. These characteristic differences between our enrolled patients and theirs, should cause the diverged results. On the other hand, the WAR group in our study showed no significant difference in comparison to no AP/AC. Since patients treated with warfarin with INR > 1.7 were excluded for IVT in our protocol, patients in the WAR group actually were below of their therapeutic range. This should explain the lower SICH rates in the WAR group.

Besides, this study revealed the real-world dosing patterns of IVT for eligible patients with acute ischemic stroke in Taiwan and other east Asian countries. In 2006, the Japan Alteplase Clinical Trial (J-ACT) showed equivalent efficacy and higher safety results of IV thrombolysis using alteplase at a dose of 0.6 mg/kg (16). Thereafter, the Japanese drug safety authority approved the dose. In 2010, an observational study in Taiwan (TTT-AIS) showed the standard dose of 0.9 mg/kg alteplase may not be optimal for aged population (11). In 2014, another study in Taiwan (TTT-AIS II) showed a lower dose of 0.6 mg/kg was associated with a better outcome for elderly (age group of 71–80 years) as well (12). In the background, most of the neurologists in Taiwan tended to adopt a lower dose of alteplase for IV thrombolysis during our enrollment. On the other hand, in 2018, an another analysis for Taiwanese octogenarian stroke patients with higher severity (high NIHSS score of ≥ 14 at initial presentation) showed a standard dose of 0.9 mg/kg with higher rates of the FFO in comparison to lower dose of 0.6 mg/kg (17). For mild stroke (NIHSS score of 4–8), both standard-dose and low-dose alteplase showed comparable rates of favorable functional outcomes, but low-dose alteplase for mild stroke showed much reduced mortality on day 90 for octogenarians (17). In our study, the stroke patient characteristics (Table 1) showed higher baseline severity (mean NIHSS score of 13–15 for all pre-treatment groups). We considered a lower dose should be inadequate for the stroke patients with higher severity patients and the results showed higher death rates.

Our inclusion of stroke patients of >60 years for IVT should be representative of the majority stroke patients in Taiwan. The demographic data in Taiwan showed the incidence rates of first stroke for age below 60 years were extremely low (18, 19). Among the largest cohort of 8,562 stroke-free people in Taiwan followed for 4 years, the incidence rate of first stroke for age groups of 36–44 and 45–54 years were 2 per 100,000 and 12 per 100,000 person-years, respectively (18). The incidence rate of first stroke throughout all age groups was 104 per 100,000 person-years (18). In contrast, the incidence rate of first stroke for age groups of 55–64, 65–74, and over 75 years were, respectively, 41 per 100,000, 29 per 100,000 and 20 per 100,000 years (18). The proportion of first stroke incidence rate for age below 55 years in Taiwanese population was 13.5%.

The propensity score matching was not conducted in our study due to our multiple pre-treatment groups (five groups). Currently, methods of binary treatment (two groups) propensity scoring are well-developed and established completely (20–22). Methods of multinomial treatment (>2 groups) propensity scoring have been in the developing status and were increasing unstable with expanding the comparison groups since the current distance-based matching approach cannot be extended to more than three groups (21, 23–25). Since we had five pre-treatment groups of ASA, P2Y12, DAPP, WAR, and any AP/AC, using the method of binary treatment propensity score matching would produce five reference groups of No AP/AC. The demographic and characteristic composition among the new five reference groups for those ASA, P2Y12, DAPP, WAR, and any AP/AC were totally different. The efficacy and safety outcome among the five pre-treatment groups were not comparable. To reasonably comparing with the five pre-treatment groups, we preferred to use method of multivariate logistic regression since they shared the same reference group.

Our studies have robust strengths and offer distinctive information. First, the patients enrolled were homogenous for the baseline demographic and medical characteristics among the six groups, such as age, sex, laboratory tests, alteplase dose, and the onset to needle time. Second, patients who were enrolled in the study had moderate to high baseline severity of acute ischemic stroke. Third, we found significant interactions between different doses of alteplase and DAPP. Fourth, we focused on older patients. This should offer the evidence that DAPP should still be cautious for older adults with acute ischemic stroke treated with IVT. Lastly, TTT-AIS was a multicenter study across all regions in Taiwan, and the representative nationwide cohort was used for analysis (11–13). This study investigated the efficacy and safety of antithrombotic pre-treatment in real-life study model.

This study has some limitations. First, the prospective cohort study design in our study was still susceptible to residual confounding. Some unmeasured confounding effects were not controlled. In addition, the analysis in this study excluded patients aged <60 years, and these findings may not be applicable throughout all ages. Second, there were a small number of patients in the DAPP group (2.3%, n = 27) and therefore the outcomes of SICH per NINDS (three out of 27 patients, adjusted OR: 4.90, 95% CI 1.28–18.69) and per ECASS II (two out of 27 patients, adjusted OR: 5.09, 95% CI: 1.01–25.68) in the DAPP group showed wide confidence interval. Although the number of DAPP patients in this study was small, this low proportion reflects real-world conditions. Previous observational studies indicated that the proportion of DAPP ranged from 1.3 to 7.3% for all ischemic stroke patients treated with IVT. Third, warfarin group was not representative to those patients treated with sufficient dose of warfarin. Only stroke patients insufficiently treated with warfarin (INR <1.7) and IVT were included for this analysis. Lastly, some patients had incomplete follow-up at 90 days. In Taiwan, the prolonged hospital stay and readmission for stroke patients are serious problems. Since March 2014, the nationwide post-acute stroke care (PAC) program (26) was launched to improve the problems of shortage of acute beds, and overcrowded emergency departments. Stroke patients with stable neurological functional status for ≥72 h and no uncontrolled complications were transferred to regional hospitals. Some patients participating in the PAC program were unwilling to be contacted. While the follow-up rates for groups of ASA, P2Y12, DAPP, and WAR groups were 88.3% (188/213), 86.5% (32/37), 81.5% (22/27), and 81.8% (36/44), the follow-rate for no AP/AC group was 82.7% (682/825). Theoretically, no differential incomplete follow-up (27) were found between groups with and without AP/AC pre-treatment, and the validity in our analysis was still assured.

In clinical practice, physicians should be cautious for older patients receiving DAPP before IVT. Since a significant interaction for functional outcome was noted between the different dosage of alteplase and use of DAPP (Figure 1), standard-dose alteplase still could be considered for these stroke patients with high-risk and higher baseline severity. In our previous analysis for 249 old stroke patients over the age of 80 years, standard-dose alteplase was associated with an increased proportion of FI of mRS 0–2 (34.8 vs. 22.2%) and a little increased mortality (13.5 vs. 9.3%) at 90 days (17). Nevertheless, the previous subgroup analysis for a total of 128 octogenarian patients of high severity (NIHSS ≥ 14) showed an increased proportion of FI of mRS 0–2 (20.8 vs. 8.9%) and a near equivalent mortality (15.3 vs. 14.3%) (17). Although an early observational study of IVT in Japan showed similar functional outcomes and approved a low-dose IVT of 0.6 mg/kg (16), we did not recommend universal use of low-dose IVT for all older patients. Consequently, physicians should evaluate many factors of age, baseline stroke severity, comorbidities, and pre-treatment of antiplatelets and anticoagulants when prescribing the optimal dose of alteplase for acute ischemic stroke patients.

In conclusion, pre-treatment with ASA seems to improve functional outcomes in terms of FFO (mRS of 0–1), but not of FI (mRS 0–2). For older adults, DAPP increases the risk of SICH, especially for patients presenting themselves with moderate to high severity of acute ischemic stroke following IVT. In addition, DAPP increased the risk of mortality for older adults and showed no increase for the better outcomes in terms of FFO and FI. Nevertheless, DAPP still should not be the reason to hold IVT and to prescribe low-dose IVT in our analysis.

The datasets presented in this article are not readily available because distribution of dataset was restricted by Institutional Review Board of Kaohsiung Medical University. Requests to access the datasets should be directed to A-Ching Chao, achch@cc.kmu.edu.tw.

The studies involving human participants were reviewed and approved by Institutional Review Board of Kaohsiung Medical University. The patients/participants provided their written informed consent to participate in this study.

S-FL wrote the first draft of the manuscript. All authors contributed to the conception and design of the study, acquisition, analysis, and interpretation of data.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.