The Safety of Intravenous Thrombolysis for Ischemic Stroke in Patients With Pre-Existing Cerebral Aneurysms
A Case Series and Review of the Literature
Background and Purpose—Unruptured cerebral aneurysms are currently considered a contraindication to intravenous tissue-type plasminogen activator for acute ischemic stroke. This is due to a theoretical increase in the risk of hemorrhage from aneurysm rupture, although it is unknown whether this risk is a significant one. We sought to determine the safety of intravenous tissue-type plasminogen activator administration in a cohort of patients with pre-existing aneurysms.
Methods—We reviewed the medical records of patients treated for acute ischemic stroke with intravenous tissue-type plasminogen activator during an 11-year period at 2 academic medical centers. We identified a subset of patients with unruptured cerebral aneurysms present on prethrombolysis vascular imaging. Our outcomes of interest were any intracranial hemorrhage, symptomatic intracranial hemorrhage, and subarachnoid hemorrhage. Fisher exact test was used to compare the rates of hemorrhage among patients with and without aneurysms.
Results—We identified 236 eligible patients, of whom 22 had unruptured cerebral aneurysms. The rate of intracranial hemorrhage among patients with aneurysms (14%; 95% CI, 3%–35%) did not significantly differ from the rate among patients without aneurysms (19%; 95% CI, 14%–25%). None of the patients with aneurysms developed symptomatic intracranial hemorrhage (0%; 95% CI, 0%–15%) compared with 10 of 214 patients without aneurysms (5%; 95% CI, 2%–8%). Similar proportions of patients developed subarachnoid hemorrhage (5%; 95% CI, 0%–23% versus 6%; 95% CI, 3%–10%).
Conclusions—Our findings suggest that intravenous tissue-type plasminogen activator for acute ischemic stroke is safe to administer in patients with pre-existing cerebral aneurysms because the risk of aneurysm rupture and symptomatic intracranial hemorrhage is low.
The use of intravenous (IV) tissue-type plasminogen activator (tPA) early in the course of ischemic stroke can considerably decrease its morbidity.1 At present, the national use of IV thrombolytics for acute ischemic stroke is relatively infrequent, occurring in approximately 3% to 5% of patients.2,3 In the hopes of increasing the frequency of IV tPA use, several groups are re-evaluating whether certain exclusion criteria for tPA, established before initial trials, are valid.4 Patients with vascular malformations such as unruptured cerebral aneurysms are traditionally deemed ineligible for tPA. This exclusion is due to a theoretical increase in the risk of intracranial hemorrhage (ICH) from aneurysm rupture postthrombolysis. Many centers are using cerebrovascular imaging as part of their standard evaluation of acute ischemic stroke; this has led to an increase in incidentally discovered aneurysms in patients otherwise eligible for tPA.5 In a previous review of off-label thrombolytic use, 2 patients with pre-existing cerebral aneurysms developed subarachnoid hemorrhage (SAH) after the administration of tPA; in 1 case, the tPA was administered intra-arterially rather than intravenously and in the other case, cardiac doses of tPA were used for myocardial infarction rather than ischemic stroke.6,7 Because there are minimal data regarding the consequences of intravenous tPA use for acute ischemic stroke in patients with asymptomatic cerebral aneurysms, we sought to determine the safety of IV tPA administration in this particular patient population through a retrospective, hospital-based study along with a review of the previously published literature.
We retrospectively reviewed the medical records of patients who received the standard 0.9-mg/kg dose of IV tPA within 4.5 hours of ischemic stroke onset at the University of California at San Francisco. We included patients treated at either Moffitt-Long Hospital or San Francisco General Hospital (both affiliated with the University of California at San Diego), between January 2000 and April 2011. The study was approved by our Institutional Review Board. Patients were identified through a computerized database of hospital discharge diagnoses using the International Classification of Diseases, 9th Revision, procedure code for tPA administration (99.1; injection or infusion of thrombolytic agent) as well as by searching hospital billing codes for tPA use in those patients admitted to the neurology service.
The medical records and neuroimaging of all potential matches were reviewed to confirm the diagnosis of IV tPA administration for acute ischemic stroke. We included only those patients who underwent (1) a prethrombolysis noncontrast head CT or brain MRI along with either a CT angiogram or MR angiogram; and (2) follow-up neuroimaging with either CT or MRI within 24 to 36 hours of tPA administration. We reviewed the formal report of each patient's cerebrovascular imaging, as attested to by an attending neuroradiologist within 24 hours of being obtained. We thereby identified a subset of patients with unruptured cerebral aneurysms present on their prethrombolysis CT angiogram or MR angiogram. We did not have data in regard to whether these aneurysms were detected on the preliminary radiology reads, before the administration of tPA, or whether these aneurysms were noted incidentally by the attending neuroradiologist in the ensuing hours.
We reviewed medical charts and post-tPA neuroimaging to identify those patients with our primary outcome: the development of any ICH subsequent to the administration of tPA. Secondary outcomes included: (1) symptomatic ICH, defined as intracranial hemorrhage with clinical decompensation as measured by an increase in the National Institutes of Health Stroke Scale of at least 4 points8; and (2) SAH (including SAH attributable to aneurysm rupture).
Descriptive statistics were used to ascertain the proportion of patients with our outcomes of interest. We used a 2-sided Fisher exact test to compare the percentage of postthrombolysis ICH in patients with and without pre-existing aneurysms. All statistical analyses were performed using Stata (Version 10; College Station, TX).
Data Extraction of Previous Studies
Two of the authors independently searched PubMed and Embase databases for all previously published studies, in English, on the use of IV tPA for acute stroke in the presence of a pre-existing cerebral aneurysm. In the first extraction, we used the search terms: “ thrombolysis” and/or “tissue-type plasminogen activator” and/or “tPA” along with “aneurysm” and/or “malformation.” Reference lists in all relevant articles were perused to identify additional data sources. We included any case series or case report that discussed the use of IV tPA for ischemic stroke in patients with unruptured cerebral aneurysms.
Of the patients treated with IV tPA for acute ischemic stroke during our study period, 236 patients underwent prethrombolysis cerebrovascular imaging in addition to postthrombolysis follow-up neuroimaging. Pre-existing cerebral aneurysms were present in 22 of these 236 patients (9.3%). In Table 1, we outline the clinical characteristics of these 22 patients (mean age, 74 years; mean initial National Institutes of Health Stroke Scale score, 12). A total of 17 patients had saccular aneurysms, 3 patients had fusiform aneurysms, and 2 patients had multiple aneurysms. One aneurysm exhibited ring-like calcification; the other aneurysms were not calcified. Aneurysms were primarily located in the anterior circulation (73%). Seven aneurysms (27%) were ≥5 mm in diameter with the largest aneurysm found being 8 mm in diameter.
Of the patients with pre-existing cerebral aneurysms, 3 (14%) developed intracranial hemorrhage after IV tPA administration. All of these hemorrhages were asymptomatic. The ICHs were predominantly parenchymal and within the area of infarction. For 2 of these patients, hemorrhage occurred contralateral to the location of their aneurysm. One patient (5%) developed SAH in addition to parenchymal hemorrhage. This patient presented with a large right middle cerebral artery stroke; her prethrombolysis CT angiogram revealed an aneurysm arising from the right internal carotid artery, 5 mm in diameter. Twenty-four hours post-tPA, she developed patchy hemorrhage throughout the infarcted parenchyma of the right hemisphere; the SAH was of minimal extent, primarily within the right sylvian fissure (adjacent to the largest patch of parenchymal hemorrhage). Additional cerebrovascular imaging was not pursued.
The rate of postthrombolysis ICH among those individuals with pre-existing aneurysms was comparable to the rate of ICH among those without aneurysms (14%; 95% CI, 3%–35% versus 19%; 95% CI, 14%–25%; Table 2). None of the 22 patients with cerebral aneurysms developed a symptomatic ICH (0%; 95% CI, 0%–15%) compared with 10 of the 214 patients without aneurysms (5%; 95% CI, 2%–8%). The occurrence of postthrombolysis SAH was also similar in the 2 groups; 5% (95% CI, 0%–23%) in the patients with aneurysms versus 6% (95% CI, 3%–10%) in the patients without aneurysms.
During the course of our review, 2 patients with vascular lesions other than cerebral aneurysms were also identified. One patient had multiple pseudoaneurysms in association with dissections, including a 12-mm pseudoaneurysm of the left internal carotid artery and a 14-mm pseudoaneurysm of the right internal carotid artery. She did not sustain any intracranial hemorrhage post-tPA. The second patient had an arteriovenous malformation within the right basal ganglia; he also did not develop any hemorrhage after thrombolysis.
Eight relevant articles were extracted during the course of our literature review.6,9–15 All were case reports or case series describing the use of IV tPA (at a standard dose for ischemic stroke) in patients with asymptomatic cerebral aneurysms. In total, we identified 12 additional published cases of patients with unruptured aneurysms receiving IV tPA for acute stroke (Table 3). Seven of the 12 aneurysms were ≥5 mm in diameter with the largest aneurysm being 16 mm in diameter. Seventy-five percent of these aneurysms were located in the anterior circulation. Three patients (25%) developed ICH after tPA administration. The ICH was exclusively parenchymal; none of these patients developed SAH attributable to aneurysm rupture.
The presence of an unruptured cerebral aneurysm is considered by many an exclusion criterion for the administration of IV tPA, although it is unclear whether IV thrombolysis increases the likelihood of aneurysm rupture. The exclusion of this particular patient population is not trivial; in our study, 22 of 236 patients (9.3%) were noted to have incidental aneurysms. In 1 other single-center study, incidental aneurysms were discovered in 6.6% of patients presenting with symptoms of acute ischemic stroke.16 This is a relatively higher prevalence of aneurysms when compared with the general population17 and may reflect shared risk factors for the development of stroke and intracranial aneurysms (such as hypertension and tobacco abuse). To the best of our knowledge, previous case reports describe a total of 12 patients with unruptured cerebral aneurysms who received IV tPA for acute ischemic stroke11–15; none of these patients developed aneurysm rupture or SAH as a consequence. The findings in our cohort are comparable to the findings in these case reports: aneurysm rupture postthrombolysis is rare. None of our 22 patients with cerebral aneurysms developed symptomatic ICH as a consequence of IV tPA compared with 10 (5%) of the patients without aneurysms. In addition, the rate of postthrombolysis SAH did not statistically differ among those with and without cerebral aneurysms (5% versus 6%, respectively). Of the 22 patients in our cohort, 1 patient (5%) developed subarachnoid hemorrhage after tPA administration. The SAH, directly adjacent to parenchymal hemorrhage within the patient's infarct, was of minimal extent. Although we believe this patient's SAH was quite unlikely to be aneurysmal in etiology, we cannot definitively exclude aneurysm rupture. Combined with the previous case reports, our findings suggest that IV thrombolysis may lead to cerebral aneurysm rupture in 1 of every 34 patients (3%; 95% CI, 0%–16%).
Of note, there is 1 recently published case report of a patient who may have had a sentinel bleed from an intracranial aneurysm several days before the onset of ischemic stroke symptoms.18 This patient received IV tPA (because the history suggestive of a sentinel bleed was not obtained before the administration of thrombolytics) and subsequently developed symptomatic ICH including aneurysmal SAH. We did not include this case report in our review because, per the authors, IV thrombolysis may have resulted in rebleeding from a previously ruptured aneurysm rather than de novo aneurysm rupture. The case does highlight, however, the necessity of carefully excluding previous aneurysm rupture in this particular patient population before the administration of tPA.
Our study is the largest to date comparing the rates of postthrombolysis ICH among those with pre-existing cerebral aneurysms to those without. In addition, this is the first report to our knowledge of patients with multiple cerebral aneurysms receiving IV tPA. One patient had fusiform aneurysms of both the supraclinoid internal carotid artery and the basilar artery; the other patient had a total of 4 saccular aneurysms. Neither patient developed any postthrombolysis ICH or SAH. This is also the first report to our knowledge of a patient with a cerebral aneurysm who underwent both IV and intra-arterial thrombolysis. Shortly after the administration of IV tPA, intra-arterial tPA was instilled into an acute clot within the M2 segment of the right middle cerebral artery, immediately beside a 2.5-mm aneurysm arising from the distal right M1 segment. No postthrombolysis hemorrhage occurred in this case either.
This study should be interpreted in light of several limitations. First, and most importantly, given the low prevalence of unruptured aneurysms and the single-center nature of our study, we are limited by a small sample size. This is reflected in the width of our confidence intervals. However, because this is the largest case series of IV tPA administration in patients with unruptured aneurysms, our study can serve as an approximate guide to the risk of IV thrombolysis in this patient population. Second, of the aneurysms identified in our cohort, 73% were <5 mm in diameter. In several previously published studies of the natural history of unruptured cerebral aneurysms, rates of rupture were higher among patients with larger aneurysms.19–21 It may be that the low rate of aneurysm rupture observed in our study may simply be due to this paucity of large aneurysms. In addition, because our retrospective review captured only those patients who received IV tPA, rather than all patients screened for potential thrombolysis, patients with large intracranial aneurysms detected on their initial cerebrovascular imaging may have been explicitly excluded from receiving IV tPA, creating a potential source of bias. That being said, the size of aneurysms in our study is characteristic of unruptured aneurysms in general because various autopsy and angiography studies have revealed approximately 92% of patients with unruptured aneurysms have aneurysms <10 mm in size.17
In conclusion, our analysis suggests that IV tPA is safe to administer in patients with pre-existing cerebral aneurysms, because the rate of aneurysm rupture and symptomatic intracranial hemorrhage is low. Indeed, the rate of symptomatic intracranial hemorrhage is comparable to the rate observed with IV tPA administration in general. Additional studies with larger cohorts will be required to provide further reassurance regarding the safety of IV thrombolysis in this patient population.
- Received July 29, 2011.
- Revision received September 18, 2011.
- Accepted October 6, 2011.
- © 2012 American Heart Association, Inc.
- Adeoye O,
- Hornung R,
- Khatri Pooja,
- Kleindorfer D
- De Silva DA,
- Manzano J,
- Chang HM,
- Wong MC
- Hope JK,
- Wilson JL,
- Thomson FJ
- Aleu A,
- Mellado P,
- Lichy C,
- Kohrmann M,
- Schellinger P
- Hacke W,
- Kaste M,
- Fieschi C,
- von Kummer R,
- Davalos A,
- Meier D,
- et al
- De Keyser J,
- Gdovinova Z,
- Uyttenboogaart M,
- Vroomen PC,
- Luijckx GJ
- Kim J,
- Park M,
- Yoon W,
- Cho K
- Yoneda Y,
- Yamamoto S,
- Hara Y,
- Yamashita H
- Rinkel GJE,
- Djibuti M,
- Algra A,
- van Gijn J
- Rammos SK,
- Neils DM,
- Fraser K,
- Klopfenstein JD