Abstract
Background and Purpose—Many patients receiving thrombolysis for acute ischemic stroke are on prior antiplatelet therapy (APT), which may increase symptomatic intracerebral hemorrhage risk. In a prespecified subgroup analysis, we report comparative effects of different doses of intravenous alteplase according to prior APT use among participants of the international multicenter ENCHANTED study (Enhanced Control of Hypertension and Thrombolysis Stroke Study).
Methods—Among 3285 alteplase-treated patients (mean age, 66.6 years; 38% women) randomly assigned to low-dose (0.6 mg/kg) or standard-dose (0.9 mg/kg) intravenous alteplase within 4.5 hours of symptom onset, 752 (22.9%) reported prior APT use. Primary outcome at 90 days was the combined end point of death or disability (modified Rankin Scale [mRS] scores, 2–6). Other outcomes included mRS scores 3 to 6, ordinal mRS shift, and symptomatic intracerebral hemorrhage by various standard criteria.
Results—There were no significant differences in outcome between patients with and without prior APT after adjustment for baseline characteristics and management factors during the first week; defined by mRS scores 2 to 6 (adjusted odds ratio [OR], 1.01; 95% confidence interval [CI], 0.81–1.26; P=0.953), 3 to 6 (OR, 0.95; 95% CI, 0.75–1.20; P=0.662), or ordinal mRS shift (OR, 1.03; 95% CI, 0.87–1.21; P=0.770). Alteplase-treated patients on prior APT had higher symptomatic intracerebral hemorrhage (OR, 1.82; 95% CI, 1.00–3.30; P=0.051) according to the safe implementation of thrombolysis in stroke-monitoring study definition. Although not significant (P-trend, 0.053), low-dose alteplase tended to have better outcomes than standard-dose alteplase in those on prior APT compared with those not using APT (mRS scores of 2–6; OR, 0.84; 95% CI, 0.62–1.12 versus OR, 1.16; 95% CI, 0.99–1.36).
Conclusions—Low-dose alteplase may improve outcomes in thrombolysis-treated acute ischemic stroke patients on prior APT, but this requires further evaluation in a randomized controlled trial.
Clinical Trial Registration—URL: http://www.clinicaltrials.gov. Unique identifier: NCT01422616.
Introduction
See related article, p 1720
Intravenous alteplase (recombinant tissue plasminogen activator) is the only approved medical reperfusion treatment in patients with acute ischemic stroke (AIS); and the earlier the treatment is given, the greater the proportional benefit.1 Because ≤40% of AIS patients have regularly taken antiplatelet therapy (APT), mainly aspirin, at the time of intravenous alteplase,2–4 a harmful interaction between these 2 agents may reduce the net benefit of thrombolysis treatment. Two recent meta-analyses of randomized controlled trials and cohort studies have both reported that APT use at the time of alteplase significantly increases the risk of symptomatic intracerebral hemorrhage (sICH).5,6 Pan et al6 reported that his was associated with a reduced probability of good outcome (odds ratio [OR], 0.86; 95% confidence interval [CI], 0.73–1.01; P=0.06), although others have not reported any clear attenuation of the clinical benefit.7 However, the ARTIS trial (APT in Combination With Recombinant Tissue Plasminogen Activator in Thrombolysis in Ischemic Stroke), the only randomized trial of de novo aspirin with standard-dose alteplase versus standard-dose alteplase alone, was terminated prematurely because of an excess sICH in the combination arm (absolute difference, 2.8%; 95% CI, 0.2–5.4; P=0.04).8
Concerns over the risk of sICH with intravenous alteplase have led to lower doses being used in many AIS patient groups, particularly Asians,9 after a dose of 0.6 mg/kg was approved for use in Japan. The ENCHANTED study (Enhanced Control of Hypertension and Thrombolysis Stroke Study) was designed to evaluate the effectiveness of low dose (0.6 mg/kg body weight) compared with a standard dose (0.9 mg/kg) of intravenous alteplase in patients with AIS who fulfill guideline-recommended criteria for thrombolysis treatment.10 Although the ENCHANTED trial failed to meet its primary noninferiority outcome, a prespecified subgroup analysis identified a borderline significant interaction (P=0.052) between prior APT use and alteplase dose on the primary outcome—the conventional binary separation of scores of 2 to 6 that define death or disability on the modified Rankin Scale (mRS).10 We report herein, more details of the balance of benefits and risks of alteplase according to prior APT use and potential modification of effects by use of low-dose alteplase.
Materials and Methods
Patients
The ENCHANTED trial is an international, multicenter, prospective, randomized, open-label, blinded-end point trial that used a 2×2 quasi-factorial design to assess the effectiveness of low- versus standard-dose alteplase in the completed arm and more intensive versus guideline-recommended control of blood pressure in the ongoing arm, full details of which are outlined elsewhere.10 This analysis considers the alteplase dose arm where 3310 patients with a clinical diagnosis of AIS confirmed on brain imaging and fulfilling local criteria for thrombolysis treatment administered within 4.5 hours of symptom onset were randomly assigned to receive low-dose (0.6 mg/kg; 15% as bolus, 85% as infusion during 1 hour) or standard-dose (0.9 mg/kg; 10% as bolus, 90% as infusion during 1 hour) intravenous alteplase. The study protocol was approved by the appropriate ethics committee at each participating center, and written informed consent was obtained from the patient or an appropriate surrogate.
Procedures
Key demographic and clinical characteristics, including the prior use of aspirin or another APT agent, were recorded at the time of enrollment. Stroke severity was measured using the National Institutes of Health stroke scale at baseline, 24 hours, and at day 7 (or earlier, on discharge from hospital). Uncompressed digital images of all baseline and follow-up digital computed tomography, magnetic resonance imaging, and angiogram images were collected in DICOM format (Digital Imaging and Communications in Medicine) on a CD-ROM identified only with the patient’s unique study number and analyzed centrally for any intracranial hemorrhage by independent assessors blinded to clinical data, treatment, and date and sequence of scan. Assessors graded any identified hemorrhage as intracerebral using a range of standard definitions (Materials section in the online-only Data Supplement) and subarachnoid, intraventricular, subdural, or other.
The primary clinical outcome was the combined end point of death or disability at 90 days, defined by scores of 2 to 6 on the mRS. Other efficacy outcomes included an ordinal mRS shift and the combined end point of death or major disability (mRS scores of 3–6) at 90 days. The secondary (safety) outcome was sICH, defined according to several criteria from other studies (Materials section in the online-only Data Supplement).
Statistical Analysis
The association of prior APT on global functional outcome was estimated using ordinal logistic regression after the assumption of proportionality of the odds was confirmed from a likelihood ratio test. Logistic regression models were used to estimate associations for all the other outcomes. Adjustments were made for the prespecified minimization and baseline covariates and additionally for aspects of management during the first 7 days after hospital admission. In patients with and without prior APT, the heterogeneity of alteplase treatment effects was tested by adding interaction terms to the statistical models. 2-sided P values were reported, and P<0.05 was considered statistically significant. The SAS, version 9.3, (SAS Institute, Cary, NC) was used for the analysis.
Results
Baseline Characteristics
These analyses included 3285 patients (38% women; mean age, 66.6 years) in whom the presence or absence of prior APT use was recorded (Figure I in the online-only Data Supplement); 752 (22.9%) patients reporting the use of prior APT at baseline. Those with prior APT were older, and more likely to be of non-Asian ethnicity, had baseline imaging changes indicative of more severe cerebral infarction, and were diagnosed with a presumed cardioembolic or other stroke pathology (Table I in the online-only Data Supplement). Patients on prior APT were also more likely to have associated comorbidity (including hypertension, previous stroke, coronary artery or other cardiac disease, or risk factors, including atrial fibrillation, diabetes mellitus, and hypercholesterolemia) and to be on statin therapy (Table I in the online-only Data Supplement). However, with the exception of a history of hypercholesterolemia and use of statins, there were no baseline imbalances between the use of low-dose or standard-dose alteplase in patients on prior APT (Table). Overall, patients with prior APT were treated more quickly after the onset of symptoms and received a higher bolus alteplase dose, but there were no other significant differences in thrombolysis-associated management (Table II in the online-only Data Supplement).
Baseline Characteristics by Randomized Treatment Among Patients on Prior Antiplatelet Therapy
Prior APT and Outcome
Prior APT was associated with a worse 90-day clinical outcome, whether defined by mRS scores of 2 to 6 (unadjusted OR, 1.38; 95% CI, 1.17–1.63; P<0.001), 3 to 6 (OR, 1.33; 95% CI, 1.13–1.58; P<0.001), or ordinal shift (OR, 1.41; 95% CI, 1.22–1.63; P<0.001), or mortality alone (OR, 1.46; 95% CI, 1.12–1.89; P=0.005; Table III in the online-only Data Supplement). However, after adjustment for the minimization criteria and important baseline variables at the time of randomization, and subsequently for imbalances in management during the first 7 days of hospital admission, there were no significant differences in these outcomes between patients with and without prior APT (Table III in the online-only Data Supplement). Prior APT was also associated with an increased risk of sICH across most definitions (Table IV in the online-only Data Supplement).
Prior APT and Alteplase Dose
Although not significant, low-dose alteplase tended to have more favorable 90-day outcomes in patients on prior APT compared with those without prior APT, defined by mRS scores of 2 to 6 (unadjusted OR, 0.84; 95% CI, 0.62–1.12 versus OR, 1.16; 95% CI, 0.99–1.36, respectively; P-trend, 0.053), 3 to 6 (OR, 0.80; 95% CI, 0.60–1.08 versus OR, 1.10; 95% CI, 0.93–1.30]; P-trend, 0.065; Table V in the online-only Data Supplement), or as an ordinal mRS shift analysis (OR, 0.76; 95% CI, 0.59–0.88 versus OR, 1.07; 95% CI, 0.93–1.23; P interaction, 0.023; Figure 1). Conversely, for those patients without prior APT—77% of the ENCHANTED population—standard-dose alteplase was associated in a trend toward more favorable outcome (Table V in the online-only Data Supplement). Importantly, there was reduced mortality by 5.0% (−0.05 to 9.95) and 1.1% (−1.13 to 3.40) in patients with and without prior APT (P interaction, 0.23) treated with low-dose compared with standard-dose alteplase, but no significant differences in sICH across a broad range of definitions (Figure 2; Table VI in the online-only Data Supplement).
Global functional outcome at 90 days in patients with and without prior antiplatelet therapy by randomized treatment. The figure shows the raw distribution of scores on the modified Rankin Scale (mRS) at 90 days. Scores on the mRS range from 0 to 6, with 0 indicating no symptoms; 1, symptoms without clinical significant disability; 2, slight disability; 3, moderate disability; 4, moderately severe disability; 5, severe disability; and 6, death. Unadjusted odds ratios (ORs; and 95% confidence intervals [CIs]) are provided for ordinal shift of mRS between low- and standard-dose intravenous alteplase by patients with and without prior use of antiplatelet therapy and acute ischemic stroke.
Symptomatic intracerebral hemorrhage in patients with and without prior antiplatelet use, by randomized treatment. The figure shows the rates of symptomatic intracerebral hemorrhage (sICH) on follow-up neuroimaging for patients treated with low-dose and standard-dose intravenous alteplase for acute ischemic stroke, overall and for patients with and without prior antiplatelet therapy (APT). Definitions of sICH shown include SITS-MOST (Safe Implementation of Thrombolysis in Stroke Monitoring Study), NINDS (National Institute of Neurological Disorders and Stroke), ECASS2 and ECASS3 (European Cooperative Acute Stroke Study 2 and 3), and fatal. The overall effect is represented by the open diamond for each sICH definition. For subcategories, black diamonds represent point estimates and horizontal lines represent 95% confidence intervals (CIs).
Discussion
These additional analyses of the ENCHANTED trial related to the patient subgroup on prior APT have shown that, albeit not significant, a trend toward more favorable clinical outcomes with low-dose as compared with standard-dose intravenous alteplase, warranting further evaluation in a randomized controlled trial. Patients on prior APT account for at least one quarter of the thrombolysis-eligible AIS population, as indicated by an international stroke thrombolysis registry,2 the United States Get With the Guidelines quality improvement registry,4 and participants in the ENCHANTED trial, and are at significantly higher risk of sICH3 and poor outcome11 compared with other patients who receive alteplase. This figure may increase further with the aging of population and data suggesting benefits of early use of aspirin in reducing the risk of secondary ischemic events after transient ischemic attack or minor ischemic stroke.12
Our findings are consistent with previous studies of patients on prior APT being at greater risk of thrombolysis-associated sICH, in part, related to the greater co-occurrence of other risk variables, such as older age, statin use, cardiac disease, atrial fibrillation, and diabetes mellitus.4,5 Although higher sICH with APT may explain much of the association with worse functional outcome after AIS, the presence of greater comorbidity is also likely to be particularly relevant.13 The Get With the Guidelines registry showed that aspirin monotherapy was associated with increased sICH after adjustment for baseline imbalances (adjusted OR, 1.18; 95% CI, 1.10–1.28).4
The ENCHANTED trial allowed for a randomized assessment of the comparative effects of low-dose versus standard-dose alteplase in patients on prior APT. Concerns of a higher risk of sICH have led to a wide range of doses of intravenous alteplase being used in many Asian countries in relation to perceived risks and affordability of the treatment.9 Although 3 studies—2 registries14,15 and 1 observational16—have specifically evaluated outcomes by dose of alteplase in Asian populations, only Chao et al16 reported a trend toward an adverse effect of prior APT on outcome. In particular, use of clopidogrel or ticlopidine, but not aspirin, was associated with an increased risk of sICH on multivariate analysis. However, only 3.4% and 4.0% of patients in the low- and standard-dose groups, respectively, were on these agents, and no beneficial effect of low-dose alteplase in patients on prior APT was observed.16 Nonetheless, as low-dose alteplase in the ENCHANTED trial was associated with lower sICH, this may be considered an important treatment option in such patients, despite the absence of any clear reduction in sICH in those patients on prior APT.
Some authors have suggested that prior APT may result in less severe strokes, by limiting the size of the occluding thrombus and subsequent risk of embolization,17 improving recanalization,18 or the microcirculation of the ischemic penumbra through inhibition of platelet-derived vasoconstrictors (eg, thromboxane A2),19 and of potential anti-inflammatory and neuroprotective effects.20 Most recently, a retrospective analysis of a large multicenter registry of 10 433 patients indicated better outcomes in those on prior APT after atherothrombotic stroke, but not after cardioembolism or small vessel occlusion, and only in patients without hemorrhagic transformation.21 However, Ricci et al22 found no association of previous aspirin use with baseline stroke severity in the third international stroke trial. Additionally, Pan et al6 did not demonstrate increased recanalization rate in patients on prior APT in their meta-analysis. In ENCHANTED trial, more patients in the prior APT group had atrial fibrillation and a final diagnosis of cardioembolic stroke, features which may suggest a lower efficacy of low-dose alteplase because of proximal vessel occlusion and greater clot burden. Nonetheless, low-dose alteplase was associated with better clinical outcome on shift analysis of 90-day mRS.
On the basis of these current data, many study protocols and guidelines have recommended that APT be avoided for at least 24 hours after the use of alteplase.23 Although higher sICH was seen with de novo use of aspirin at the time of thrombolysis in the ARTIS trial,8 only 3 (0.53%) episodes of sICH (according to the SITS-MOST definition [Safe Implementation of Thrombolysis in Stroke-Monitoring Study]) occurred among 571 patients who also received antithrombotic therapy (antiplatelet or heparin) within the first 24 hours after thrombolysis in the ENCHANTED trial. These numbers are too small to offer a reliable assessment of risk or to assess differences according to variable doses of alteplase. However, the Cochrane review of thrombolysis trials concluded that the odds of mortality increases with early administration of APT; the majority of this risk occurring in the first 24 hours.24
Another important aspect of APT in AIS relates to the type, number, and combination of prior agents for which the data are scarce, but a significant dose response in relation to the number of antiplatelet agents prescribed has been reported.5,6 A higher sICH risk was noted in thrombolysis-treated patients on combination therapy, in particular aspirin and clopidogrel, who were registered in the Virtual International Stroke Trials Archive database.25 Such an association was also noted in the SITS International Stroke Thrombolysis Register3 and the Get With the Guidelines registry cohort where the combination aspirin and clopidogrel were associated with a number needed to harm of 60 compared with 147 for aspirin monotherapy.4 Nonetheless, low number of patients and sICH in all these studies limits the reliability of these data and the recommendations that can be made for clinical practice. Moreover, uncertainty exists over the role of newer antiplatelet agents in the setting of thrombolysis for AIS, although a small pilot phase trial demonstrated the safety of a GP IIb/IIIa (glycoprotein IIb/IIIa) inhibitor with low-dose alteplase.26 Being a pragmatic academic study, ENCHANTED is unable to provide any information about the relation of type, dose, combination, duration, indication, and timing of the last dose of APT before thrombolysis to adverse outcomes, although it would seem reasonable to assume that aspirin monotherapy was the most commonly prescribed antiplatelet regimen used in participating countries.
Other limitations of our study include those related to an open-label trial, despite our efforts to minimize reporting bias, concealment of treatment allocation, rigorous assessment of adverse events, and blinded evaluation of clinical outcomes using established criteria. Because the ENCHANTED trial included patients with generally milder stroke severity with a slightly longer treatment delay from onset than in previous trials1 or registries,27 there may be concerns over the generalizability of these data, whereas imprecision in the estimates of the treatment effect may have arisen from the timing and interobserver variability in scoring of the mRS.28
Conclusions
Our study suggests that the use of low-dose, as compared with standard-dose, intravenous alteplase may be associated with improved clinical outcome in patients who were on prior APT. Therefore, we consider a formal evaluation of low- versus standard-dose alteplase in a randomized controlled trial of patients on prior APT is warranted. In addition, the potential beneficial effects of low-dose alteplase in other patient groups considered at high risk of sICH could be considered.29
Sources of Funding
The study is supported by grants from the National Health and Medical Research Council of Australia, the Stroke Association of the United Kingdom, the Ministry of Health and the National Council for Scientific and Technological Development of Brazil (467322/2014–7 and 402388/2013–5), and the Ministry for Health, Welfare, and Family Affairs of the Republic of Korea (HI14C1985).
Disclosures
Dr Robinson is the Senior Investigator for National Institute for Health Research (NIHR). He receives speaking fees from Bayer and Boehringer Ingelheim and advisory panel fees from Bayer and Daiichi Sankyo. P.M. Bath is a stroke association professor of stroke medicine and NIHR Senior Investigator. He receives advisory panel fees from Athersys, Covidien, Nestle, Phagenesis, and ReNeuron and is an unpaid director of Platelet Solutions. Dr Donnan receives advisory board fees from Boehringer Ingelheim, Bayer, Pfizer, AstraZeneca, Servier, and Sanofi. Dr Lavados receives research funding from AstraZeneca, Bayer, and Boehringer Ingelheim and speaking fees from Bayer. Dr Lindley receives speaking fees from Boehringer Ingelheim, Covidien, and Pfizer. Dr Pontes-Neto receives research funding and speaking fees from Boehringer Ingelheim and Medtronic. Dr Olavarria receives research fees from Clinica Alemana de Santiago and George Institute for Global Health. Dr Ricci receives fees from Boehringer, Bracco, and Medtronic. Dr Woodward works as a consultant for Amgen. Dr Chalmers receives research grants and lecture fees from Servier, and Dr Anderson receives advisory panel fees from AstraZeneca and Medtronic, speaking at seminars for Takeda (China) and Boehringer Ingelheim, and research grant from Takeda (China).
Footnotes
Guest Editor for this article was Kazunori Toyoda, MD, PhD, FAHA.
↵* Drs Robinson and Wang are joint first authors.
Presented in part at the European Stroke Organisation Conference, Barcelona, Spain, May 10–12, 2016.
The sponsors had no role in the study design, data collection, data analysis, data interpretation, or writing of the report. All authors had full access to the study data. The corresponding author had final responsibility for the decision to submit the article for publication.
The online-only Data Supplement is available with this article at http://stroke.ahajournals.org/lookup/suppl/doi:10.1161/STROKEAHA.116.016274/-/DC1.
- Received December 3, 2016.
- Revision received March 1, 2017.
- Accepted March 13, 2017.
- © 2017 American Heart Association, Inc.
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