Off-Label Thrombolysis Is Not Associated With Poor Outcome in Patients With Stroke
Background and Purpose— Numerous contraindications included in the license of alteplase, most of which are not based on scientific evidence, restrict the portion of patients with acute ischemic stroke eligible for treatment with alteplase. We studied whether off-label thrombolysis was associated with poorer outcome or increased rates of symptomatic intracerebral hemorrhage compared with on-label use.
Methods— All consecutive patients with stroke treated with intravenous thrombolysis from 1995 to 2008 at the Helsinki University Central Hospital were registered (n=1104). After excluding basilar artery occlusions (n=119), the study population included 985 patients. Clinical outcome (modified Rankin Scale 0 to 2 versus 3 to 6) and symptomatic intracerebral hemorrhage according to 3 earlier published criteria were analyzed with a logistic regression model adjusting for 21 baseline variables.
Results— One or more license contraindications to thrombolysis was present in 51% of our patients (n=499). The most common of these were age >80 years (n=159), mild stroke National Institutes of Health Stroke Scale score <5 (n=129), use of intravenous antihypertensives prior to treatment (n=112), symptom-to-needle time >3 hours (n=95), blood pressure >185/110 mm Hg (n=47), and oral anticoagulation (n=39). Age >80 years was the only contraindication independently associated with poor outcome (OR, 2.18; 95% CI, 1.27 to 3.73) in the multivariate model. None of the contraindications were associated with an increased risk of symptomatic intracerebral hemorrhage.
Conclusions— Off-license thrombolysis was not associated with poorer clinical outcome, except for age >80 years, nor with increased rates of symptomatic intracerebral hemorrhage. The current extensive list of contraindications should be re-evaluated when data from ongoing randomized trials and observational studies become available.
The safety and efficacy of thrombolytic therapy with intravenous (IV) alteplase for acute ischemic stroke is well established,1–7 but only a small fraction of patients receive treatment.8 There are many reasons for this, late arrival being the most important one.9 Even when patients arrive on time, most of them are not treated.10 Numerous contraindications for thrombolysis in acute ischemic stroke listed in the license of alteplase arise from the study protocols of the randomized controlled trials (RCT). The RCTs aimed at enrolling patients likely to recover well if the occluded artery is recanalized, whereas patients with an assumed risk of hemorrhage were excluded. Most of the contraindications are based on expert opinion, not scientific evidence. The more restrictive indications and contraindications of the European Cooperative Acute Stroke Study (ECASS) trials2,3 ended up in the European product license, whereas the American license is more liberal due to the protocol of the National Institute of Neurological Disorders and Stroke (NINDS) trial.1 The only contraindication that so far has been tested in a RCT is the time window expansion from 3 to 4.5 hours.11
The aim of this observational study was to evaluate whether treating patients with acute ischemic stroke with thrombolytic therapy outside the European product license (off-label) is associated with poor clinical outcome or increased rates of symptomatic intracerebral hemorrhage (sICH) compared with patients treated according to the European license (on-label).
The Helsinki Stroke Thrombolysis Registry is an observational register of all thrombolytic therapies given for acute ischemic stroke at the Helsinki University Central Hospital, which is the only comprehensive stroke center in the region of Helsinki, Finland, and serves a population of 1.5 million.
Thrombolytic therapy for patients with stroke became familiar to us over the years 1992 to 1998 with the ECASS studies (ECASS and ECASS II)2,3 in which Helsinki was one of the highest recruiting centers. We have administered intravenous alteplase outside of clinical trials for basilar artery occlusion (BAO) since 199512 and for non-BAO ischemic stroke since March 1, 1998,13 promptly after ECASS II ended. Treatment is based on our department’s written guidelines for acute stroke, which have included guidelines for non-BAO thrombolysis since March 1, 1998. The guidelines are updated biannually and any time new scientific evidence becomes available. The Food and Drug Administration (FDA) licensed alteplase for acute ischemic stroke in 1996, whereas the European Medicines Agency (EMEA) waited until 2002 and then granted only a provisional license. Our department guidelines are less restrictive than the EMEA license and are closer to the FDA license (Supplemental Table I⇓; available at http://stroke.ahajournals.org). Mild stroke is not clearly defined in any of the licenses or guidelines and for this study, we used the ECASS III criteria of National Institutes of Health Stroke Scale (NIHSS) score 0 to 4.11 Rapid improvement in our protocol was defined as a general impression of significant improvement of initial symptoms before treatment.
We have gathered a consecutive series of all thrombolytic therapies administered for acute ischemic stroke at our emergency room. Before the Safe Implementation of Thrombolysis in Stroke-Monitoring Study (SITS-MOST) register, we prospectively included in our register only the social security number, date of thrombolysis, and whether the patient had a BAO (years 1995 to 2002, n=163 of which 49 had BAO). Since January 2003, the data set of the SITS register14 was collected prospectively. In 2009, the medical records of all patients treated from 1995 up to December 31, 2008, were retrieved from the archive of our hospital with no missing records. The SITS data set was compiled for the first 163 patients and audited and corrected if needed for the rest of the patients. Additional detailed information on baseline characteristics, physiological parameters, diagnostic workup, medical and nonmedical treatments, rehabilitation, and outcome were collected for all of our patients. All head CT and MRI scans up to 14 days after thrombolytic therapy were interpreted and evaluated by neuroradiologists. Hemorrhages were classified according to SITS-MOST classification (HI1, HI2, PH1, PH2, PHr1, PHr2).14
In the present study, we included all consecutive patients without BAO treated at our emergency room with IV alteplase for acute ischemic stroke from 1995 until December 31, 2008. Patients with BAO were excluded because their natural history and treatment protocol differ considerably, for example, it always includes concomitant IV heparin and allows for symptom-to-needle times of up to 48 hours in cases with progressing symptoms.12
The primary outcome measure was clinical outcome at 3 months assessed by the modified Rankin Scale (mRS) dichotomized at 0 to 2 versus 3 to 6. Safety analyses were done with regard to sICH as defined by NINDS,1 ECASS,2 and SITS14 (for detailed criteria, see footnote of Table 3), and 3-month mortality.
To evaluate the independent effect of each European license contraindication on poor outcome (mRS 3 to 6) and sICH (ECASS criteria), a multivariate logistic regression model was estimated adjusting for 21 baseline variables: age, sex, arterial hypertension, hyperlipidemia, diabetes, atrial fibrillation, congestive heart failure, previous stroke, use of medication before stroke (acetylsalicylic acid), any non-acetylsalicylic acid antiplatelet, statin, oral antihypertensive), functional status before stroke dichotomized at mRS 0 to 1 versus 2 to 5, systolic and diastolic blood pressure, admission NIHSS score, blood glucose before thrombolysis, infarct on baseline imaging, artery occlusion or dense artery sign on baseline imaging, symptom-to-needle time, and year of stroke. We report the OR with 95% CIs for all the contraindications with >20 occurrences and the observed numbers of events only for the less common contraindications.
The statistical analyses were done on R 2.10.0 software package (The R Foundation for Statistical Computing, Vienna, Austria) and SPSS 17.0 (SPSS Inc, Chicago, Ill).
Between June 8, 1995, and December 31, 2008, a total of 1104 patients received thrombolysis at the neurological emergency room of Helsinki University Central Hospital. The 119 patients with BAO are excluded from the present analysis. Our study population consists of 985 patients.
The most important predictors of outcome, patient age and baseline NIHSS score, remained stable over time. Treatment delays were constantly reduced over the years with median door-to-needle time of 34 minutes for the whole study period and 22 minutes for the year 2008.
Only CT imaging was performed on 982 patients, 1 patient had only MRI, and 2 patients had both at baseline. CT perfusion was performed on 153 patients and CT or MR angiography on 128 patients before thrombolysis.
In our series 499 patients (51%) had ≥1 European license contraindications to thrombolytic therapy. Most frequent were age >80 years (n=159 [16%]), mild stroke (n=129 [13%]), use of IV antihypertensives before treatment (n=112 [11%]), symptom-to-needle time >3 hours (n=95 [10%]), blood pressure >185/110 mm Hg (n=47 [5%]), and oral anticoagulation (n=39 [4%]). Two concomitant contraindications were observed in 114 patients (12%), 3 in 33 patients (3%), and 4 in 3 patients (0.3%).
Three patients had a mild ischemic stroke within 3 months before thrombolysis. Eight patients had one of the following operations within 3 months: inguinal hernia operation, gynecological tumor resection; coronary bypass, femoropopliteal bypass, ankle fracture operation, colon resection with splenectomy, uvulectomy with functional endoscopic sinus surgery, or pyelostomy revision. One patient had a history of spontaneous intracerebral hemorrhage and 2 had a history of unoperated subarachnoid hemorrhage. Thirteen patients had a history of central nervous system pathology, a history of operation or trepanation of traumatic subdural hematoma or major cerebral contusion (8), meningioma operations (3), or normal pressure hydrocephalus shunting (2). Two patients were classified as having other risks for bleeding, 1 due to active hepatitis and 1 due to hematuria 1 week before treatment.
At 3 months, 28 patients (2.8%) were lost to follow-up; 4 of them were foreign tourists, 8 from other regions of Finland, and 3 had severe alcohol abuse. Of the remaining 13 patients, 2 were discharged home at Days 12 and 19 and the rest discharged to a rehabilitation hospital with no available follow-up data. The outcome of the rest of the patients is shown in Figure 1.
The factors associated with poor outcome in the multivariate model were older age (OR, 1.04 per year of age; 95% CI, 1.02 to 1.07), higher baseline blood glucose (OR, 1.19 per mmol/L; 1.04 to 1.20), higher baseline NIHSS (OR 1.19 per point; 1.15 to 1.24), dense artery sign or artery occlusion on baseline imaging (OR, 1.71; 1.15 to 2.56), and mRS >1 before stroke (OR, 2.19; 1.12 to 4.26).
However, of all the license contraindications, only age >80 years (OR, 2.18; 1.27 to 3.73) was independently associated with poor outcome (Table 2).
As a secondary analysis, mRS was dichotomized at 0 to 1 versus 2 to 6. Age >80 years (OR, 3.19; 1.76 to 5.77) and symptom-to-needle-time >3 hours (OR, 2.18; 1.01 to 4.71) were the only contraindications independently associated with poor outcome in this post hoc multivariate analysis.
All but 6 patients had a control scan, 918 with CT only, 44 with MRI only, and 17 with both. The nonscanned patients did not show any clinical signs or symptoms of intracerebral hemorrhage.
The rates of sICH with various contraindications are shown in Table 3. In the multivariate model, higher baseline blood glucose (OR, 1.13 per mmol/L; 1.02 to 1.25), early infarct signs (OR, 2.00; 1.06 to 3.79), and dense artery sign or an occluded artery on baseline imaging (OR, 2.14; 1.17 to 3.96) were associated with increased risk of sICH according to the ECASS criteria.
None of the analyzed off-label patient groups were associated with increased rates of sICH in the multivariate model. Smaller groups that were not analyzable in multivariate models such as having a history of central nervous system pathology, intracranial hemorrhage, subarachnoid hemorrhage, or recent ischemic stroke did not experience high rates of sICH.
Extracranial hemorrhage, mostly presenting as subcutaneous bleeding or hematuria, with single cases of nasal, esophageal, and vaginal hemorrhages, were uncommon and never fatal. None of the patients with recent surgery or otherwise considered to have an increased risk of extracranial hemorrhage experienced one.
When compared with the patients in the SITS-MOST study, which only included on-label patients, and with the patients of the RCTs, the outcome of our off-label patients was not poorer, and our on-label patients showed a trend toward a better outcome (Figure 2).
Our results show that patients aged >80 years are the only off-label group associated with a poorer outcome than is achievable with on-label thrombolysis. None of the label contraindications are associated with increased rates of sICH. Half of our patients would not have been treated if all European label contraindications would have been followed.
Patients aged >80 years were the largest off-label group in our series. Although the NINDS study1 also included patients >80 years of age, their outcome has not been reported separately. No other randomized trial has been published on this age group. The American license does not include an upper age limit. Previous observational studies16 have reported 3-month mortality between 20% and 40% and sICH rates between 3% and 13% in this patient group, which are comparable to our results (27% and 11% accordingly). Selection of patients >80 years with MRI instead of CT has been associated with less intracranial hemorrhage but no difference in clinical outcome.17
Increasing age is an independent predictor of poor outcome in all the patients and also in those <80 years. Our results show that the risk is not linear, but rather increases exponentially in the oldest patients. The same association between age and outcome probably is true also without thrombolytic therapy. We cannot provide any data on how these patients would have fared without thrombolytic treatment. Ongoing trials such as the Italian multicenter trial randomizing patients to IV alteplase or placebo within 3 hours of symptom onset and the Third International Stroke Trial (IST-3) randomizing patients to IV alteplase or placebo within 6 hours will address this question in due time.18
We seem to treat more mild strokes (NIHSS <5) than most centers have reported. The European license states that mild stroke is a contraindication for thrombolysis but does not define mild stroke with NIHSS points or otherwise. A clear upper limit of 25 NIHSS points is, however, given. The NIHSS has the problem of nonlinearity. Having 3 points for dysarthria and facial palsy is not equivalent to having them for aphasia or cortical blindness. Discretion on what is a mild stroke is therefore left in the license and in our own protocol to the treating physicians. Two of our patients with resolving initial symptoms were treated without any NIHSS points based on an acute middle cerebral artery occlusion together with a large perfusion deficit on CT scan. The NINDS study included patients with only 1 point on NIHSS, and these patients with mild stroke did benefit from treatment.1,19 Our patients with mild baseline symptoms (n=129) did generally well, and the 2 patients who died did not have an intracerebral hemorrhage, but died of ischemic stroke and myocardial infarction.
In the SITS registry, higher baseline blood pressure was associated with worse clinical outcome and increased risk of hemorrhage in multivariate analysis.20 Increased sICH rates were associated with baseline blood pressure >185/110 mm Hg in another recent study.21 We were able to control for more confounders in our present analysis and could not detect such associations. Treatment of high blood pressure with IV medication before thrombolysis was not associated with poorer outcome in our series, a result akin to the NINDS trial.22
Our institutional thrombolysis protocol strongly focuses on shortening the door-to-needle time. Thus, laboratory parameters are not available at the time of the treatment decision with the exception of point-of-care international normalized ratio and finger-prick glucose. Other laboratory abnormalities occur very seldom; for example, only 7 of the 985 (0.7%) patients had platelet values <100 E9/L. Moreover, these abnormalities were not associated with an increased rate of sICH. The limit for platelets in the American and European licenses is derived from the exclusion criteria of the NINDS and ECASS II trial protocols.1,2 Based on our experience, there is no point in delaying treatment by waiting for laboratory results unless the patient has a history or clear clinical signs suggesting laboratory abnormalities, which may be a contraindication for treatment. Similar findings from Boston have been recently published.23
For many of the contraindications, the number of patients reported in our series, although small, are larger than reported in the 2007 literature review24 (seizures, previous neurosurgery, recent stroke). Several of our patient groups have not been previously reported in the literature (glucose level >22.2 mmol/L, extraventricular drainage, and genitourinary bleed). Yet, these situations occur very rarely in our series, which is comforting.
In the subgroup analyses of the NINDS trial, only 4 risk factors, age >70 years, baseline NIHSS score >20, serum glucose >16.7 mmol/L, and edema or mass effect on the initial CT scan, were associated with both increased risk of sICH and a lower likelihood of favorable outcome.25 These results are in line with ours.
Compared with SITS-MOST patients, our off-label patients did not have a poorer outcome and our on-label patients showed a trend toward better outcome. This may be explained by differences in case-mix. Our on-label patients were younger than the patients in SITS-MOST.
Our analysis includes only patients treated with thrombolysis. We do not have data on how many patients with each of the European label contraindications were not treated or how they fared. Thus, selection bias is possible. However, patients admitted to our neurological emergency room are discussed biweekly in meetings and it is our experience that deviations from our own thrombolysis protocol are uncommon.
Our results suggest that the European label contraindications may be too restrictive. Violating official license is not legally possible in many parts of the world, and thus the license indications and contraindications, although not necessarily evidence-based, do matter. Although experienced centers and physicians may find our results tally with their experience, with less experience and in countries with a high risk of legal consequences, it is wise to follow the license indications and contraindications. Ongoing RCTs will generate new data, which may lead to license revision and in this way will possibly allow more patients with stroke to benefit from thrombolysis.
Of all the license contraindications to thrombolysis in acute ischemic stroke, only age >80 years was independently associated with poor outcome in our observational consecutive single-center series. None of the observed license contraindications were independently associated with sICH, not even old age. Many of the current license contraindications, particularly in Europe, stem from the exclusion criteria of RCTs but are not supported by scientific evidence. They should probably be re-evaluated when new data from RCTs and other observational series become available. Until then, the safest way for inexperienced centers to give thrombolysis is to follow official license indications and contraindications.
Sources of Funding
This study was funded by the Helsinki University Central Hospital Research Fund (EVO). A.M. is supported by Yrjö Jahnsson Foundation and the Finnish Medical Foundation. P.J.L. is supported by the Finnish Academy and Sigrid Jusélius Foundation.
A.M. received honoraria from Boehringer Ingelheim (modest). T.T. received research grants from Concentric Medical, Mitsubishi Pharma, Lundbeck AS, Boehringer Ingelheim, Schering Plough, and SanofiAventis (significant) and is a consultant and on the Advisory Board of Boehringer Ingelheim (modest). S.A. is employed by SanofiAventis (significant). O.H. received honoraria from Boehringer Ingelheim (modest). P.J.L. is on the Speakers’ Bureaus of Boehringer Ingelheim and Orion Pharma (modest). K.R. received honoraria from Boehringer Ingelheim (modest). T.S. received honoraria from Boehringer Ingelheim (modest). L.S. received honoraria from Boehringer Ingelheim and Pfizer (modest) and is a consultant and on the Advisory Board of Boehringer Ingelheim (modest). M.K. received honoraria from Boehringer Ingelheim, PAION AG, Forest Research Laboratories Inc, and Lundbeck AS for participating in Steering Committee meetings of all ECASS and Desmoteplase in Acute Ischemic Stroke Trial (DIAS) trials (modest); and is a consultant and on the Advisory Boards of Boehringer Ingelheim, PAION AG, Forest Research Laboratories Inc, and Lundbeck AS (modest).
- Received January 12, 2010.
- Revision received February 3, 2010.
- Accepted February 8, 2010.
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