Safety Outcomes After Thrombolysis for Acute Ischemic Stroke in Patients With Recent Stroke
Background and Purpose—It is uncertain whether previous ischemic stroke within 3 months of receiving intravenous thrombolysis (tPA [tissue-type plasminogen activator]) for acute ischemic stroke (AIS) is associated with an increased risk of adverse outcomes.
Methods—Using administrative claims data, we identified adults with AIS who received intravenous tPA at California, New York, and Florida hospitals from 2005 to 2013. Our primary outcome was intracerebral hemorrhage, and our secondary outcomes were unfavorable discharge disposition and inpatient mortality. We used logistic regression to compare rates of outcomes in patients with and without previous ischemic stroke within 3 months of intravenous tPA for AIS.
Results—We identified 36 599 AIS patients treated with intravenous tPA, of whom 568 (1.6%) had a previous ischemic stroke in the past 3 months. Of all patients who received intravenous tPA, the rate of intracerebral hemorrhage was 4.9% (95% confidence interval [CI], 4.7%–5.1%), and death occurred in 10.7% (95% CI, 10.4%–11.0%). After adjusting for demographics, vascular risk factors, and the Elixhauser Comorbidity Index, previous ischemic stroke within 3 months of thrombolysis for AIS was not associated with an increased risk of intracerebral hemorrhage (odds ratio, 0.9; 95% CI, 0.6–1.4; P=0.62), but was associated with an increased risk of death (odds ratio, 1.5; 95% CI, 1.2–1.9; P=0.001) and unfavorable discharge disposition (odds ratio, 1.3; 95% CI, 1.0–1.7; P=0.04).
Conclusions—Among patients who receive intravenous tPA for AIS, recent ischemic stroke is not associated with an increased risk of intracerebral hemorrhage but is associated with a higher risk of death and unfavorable discharge disposition.
Although the updated Food and Drug Administration label no longer considers recent stroke to be a contraindication to intravenous tPA (tissue-type plasminogen activator) use, the American Heart Association/American Stroke Association continues to recommend against intravenous tPA use in acute ischemic stroke (AIS) patients with a history of stroke within the previous 3 months.1,2 An enhanced understanding of the risk of thrombolysis in patients with AIS with recent stroke is crucial as ≈20% of ischemic strokes are recurrences, and up to 20% of these recurrences occur within 3 months of the initial event.3,4 Therefore, we evaluated whether a history of ischemic stroke within the previous 3 months of thrombolysis for AIS is associated with a heightened risk of intracerebral hemorrhage (ICH), unfavorable discharge disposition, or death in a large, heterogeneous group of patients.
We performed a retrospective cohort study of AIS patients treated with intravenous tPA using publically available data from the Agency of Healthcare Research and Quality, extracted from administrative claims from California, New York, and Florida (Methods in the online-only Data Supplement). The Weill Cornell Medicine institutional review board approved our analysis of these data.
We included adults with AIS treated for the first time with intravenous tPA between 2005 and 2011 in California, 2005 and 2013 in Florida, and 2006 and 2013 in New York. We defined AIS using International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes 433.x1, 434.x1, or 436 in any diagnosis code position in the absence of a primary discharge code for rehabilitation (V57) or any codes for subarachnoid hemorrhage (430), or trauma (800–804, 850–854). Use of intravenous tPA was defined by the ICD-9-CM procedure code (99.10) in any procedure code position.
Our exposure variable was a previous ischemic stroke within 3 months of intravenous tPA for AIS. For every case, we identified the presence or absence of a separate hospitalization for ischemic stroke in the 3 months before thrombolysis for AIS. The primary outcome was the development of ICH within the index visit for AIS during which the patient received intravenous tPA. ICH was defined by the presence of the ICD-9-CM code 431 in any diagnosis position, in the absence of a present on admission ICD-9-CM code for ICH. Secondary outcomes were inpatient mortality and unfavorable discharge disposition. Discharge disposition has been shown to correlate with 90-day and 1-year functional outcomes based on the modified Rankin Scale.5 Discharge disposition was categorized as either unfavorable (discharge to skilled nursing facility, subacute care center, chronic rehabilitation center, hospice, or death) or favorable (discharged home), as in previous analyses.5
Descriptive statistics were used to calculate crude rates of patient characteristics and outcomes. Multivariable logistic regression was used to examine the association between recent previous ischemic stroke and our outcomes of interest while adjusting for potential confounders: demographics, stroke risk factors (Methods in the online-only Data Supplement), and the Elixhauser Comorbidity Index. As our goal was to isolate the relationship between exposures and outcomes, all variables were left in the model regardless of statistical significance. In a prespecified secondary analysis, we divided the 3-month time period before intravenous tPA administration into 1-month intervals to determine whether the length of time between previous stroke and thrombolysis for AIS modifies the risk of outcomes. We performed 4 sensitivity analyses to test the validity of our results (Methods in the online-only Data Supplement). In a post hoc exploratory analysis, we assessed the risk of ICH, death, and unfavorable discharge disposition in patients with claims for AIS not treated with intravenous tPA stratified by history of ischemic stroke hospitalization in the past 3 months. Statistical significance was set at α=0.05.
We identified 36 599 patients who were treated with intravenous tPA for AIS, among whom mechanical thrombectomy was performed in 2093 (5.7%). History of ischemic stroke within 3 months was present in 568 cases (1.6%). Patients with previous stroke were younger (mean age, 69.0 [±14.1] versus 70.9 [±14.6] years), more likely to have peripheral vascular disease and had more Elixhauser comorbidities (3.4 versus 3.2, P=0.01; Table I in the online-only Data Supplement).
The primary outcome of post-thrombolysis ICH occurred in 1792 (4.9%; 95% confidence interval [CI], 4.7%–5.1%) patients, including 24 (4.2%; 95% CI, 2.6%–5.9%) patients with recent previous ischemic stroke and 1768 (4.9%; 95% CI, 4.7%–5.1%) patients without. Patients with ICH were older (mean age, 74.6 [±12.4] versus 70.7 [±14.6] years) and more likely to have medical comorbidities (Table II in the online-only Data Supplement). In-hospital death occurred in 10.7% (95% CI, 10.4%–11.0%) of all AIS patients, including 84 (14.8%; 95% CI, 11.9%–17.7%) patients with recent previous stroke and 3839 (10.6%; 95% CI, 10.3%–11.0%) patients without. Among the 34 715 (94.9%) patients with available discharge disposition data, unfavorable discharge disposition occurred in 73.4% (95% CI, 72.9%–73.9%) of patients, including 349 (78.3%; 95% CI, 74.4%–82.1%) patients with recent previous stroke and 25 139 (73.4%; 95% CI, 72.9%–73.8%) patients without.
After adjusting for demographics, stroke risk factors, and the Elixhauser Comorbidity Index, a previous ischemic stroke within 3 months of thrombolysis for AIS was not associated with an increased risk of ICH (odds ratio [OR], 0.9; 95% CI, 0.6–1.4; P=0.62), but was associated with an increased risk of death (OR, 1.5; 95% CI, 1.2–1.9; P=0.001) and unfavorable discharge disposition (OR, 1.3; 95% CI, 1.0–1.7; P=0.04). The risk of ICH in patients with a recent ischemic stroke was unchanged in 4 sensitivity analyses (Results in the online-only Data Supplement). In secondary analysis, ICH risk did not vary when stratified by 1-month time intervals from the time of previous stroke (Table III in the online-only Data Supplement).
Post Hoc Analysis
Recent ischemic stroke in patients with claims for AIS who did not receive intravenous tPA was not associated with an increased risk of ICH (OR, 1.0; 95% CI, 0.8–1.2; P=0.86), but was associated with an increased risk of death (OR, 2.1; 95% CI, 2.0–2.2; P<0.001) and unfavorable discharge disposition (OR, 1.4; 95% CI, 1.3–1.4; P<0.001; Table IV in the online-only Data Supplement).
In a large, heterogeneous sample of patients with AIS treated with intravenous tPA, history of recent stroke was not associated with an increased risk of ICH, but was associated with an increased risk of inpatient death and unfavorable discharge disposition. These findings are consistent with and build on those reported in previous, smaller studies.6,7 The higher risk of death and unfavorable discharge disposition may be because of recurrent strokes generally being more severe and disabling, as well as more limitations of care in patients who have a second stroke. Furthermore, in an exploratory analysis in patients with claims for AIS not treated with intravenous tPA, recent ischemic stroke remained associated with an increased risk of unfavorable discharge disposition and inpatient death, suggesting that recurrent ischemic stroke rather than treatment with intravenous tPA portends poor outcome.
This study has several limitations. First, data on stroke severity, size, location, onset-to-treatment time, and patients’ baseline neurological status were unavailable. Second, patients who received intravenous tPA despite a recent historical stroke may have been a closely selected, lower-risk population as practitioners administered intravenous tPA in light of the American Heart Association/American Stroke Association recommendation to not administer intravenous tPA to such patients. Third, because we restricted our cohort to patients with AIS treated with intravenous tPA for the first time, our results may not generalize to patients with previous intravenous tPA use. Fourth, we lacked data on long-term functional outcomes, which are typically used to evaluate the effect of stroke interventions in randomized trials. Fifth, our use of administrative data may have led to a misclassification of stroke or ICH events, and we lacked a well-validated algorithm to identify recurrent ischemic stroke, particularly for cases not treated with intravenous tPA as in our post hoc exploratory analysis. In addition, there is no specific ICD-9-CM code for hemorrhagic conversion after intravenous tPA for AIS. We aimed to increase our accuracy by including only those patients who had ICD-9-CM codes for ICH (not present on admission), AIS, and intravenous tPA during the same hospitalization. Nonetheless, some ICHs may have occurred later in the AIS hospitalization and therefore might not have been a direct consequence of intravenous tPA, although this would be expected to occur with similar frequency in patients with and without recent previous stroke. Last, we lack data on whether the ICH was symptomatic or asymptomatic.
Our results, in conjunction with previously published studies, suggest that select use of intravenous tPA in patients with previous ischemic stroke in the past 3 months is not associated with an increased risk of ICH.
We thank Monica Chen for clerical assistance.
Sources of Funding
Dr Navi was supported by K23NS091395 (National Institutes of Health); Florence Gould Endowment for Discovery in Stroke. Dr Gialdini was supported by Feil Family Foundation.
Presented in part at the International Stroke Conference, Houston, TX, February 23, 2017, and at the American Academy of Neurology, Boston, MA, April 25, 2017.
The online-only Data Supplement is available with this article at http://stroke.ahajournals.org/lookup/suppl/doi:10.1161/STROKEAHA.117.018119/-/DC1.
- Received March 11, 2017.
- Revision received June 7, 2017.
- Accepted June 9, 2017.
- © 2017 American Heart Association, Inc.
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