Rehabilitation Outcomes of Stroke Patients Treated With Tissue Plasminogen Activator

Original Research

Rehabilitation Outcomes of Stroke Patients Treated With Tissue Plasminogen Activator Zeev Meiner, MD, Anna Sajin, MD, Isabella Schwartz, MD, Jeanna Tsenter, MD, Ivelin Yovchev, MD, Roni Eichel, MD, Tamir Ben-Hur, MD, PhD, Ronen R. Leker, MD Objective: To investigate the influence of thrombolysis on functional outcomes after rehabilitation. Background: Systemic thrombolysis with tissue plasminogen activator (tPA) is considered the mainstay of acute stroke therapy and was found to improve short-term outcome. Design: Matched case-controlled design. Setting: Inpatient neurology and rehabilitation departments. Participants: Thirty-seven patients given tPA and 37 control patients not treated with lytics because of protocol limits. Methods: We retrospectively analyzed data from a cohort of stroke patients who were treated with systemic tPA. The rehabilitation outcome of thrombolysis-treated patients was compared with that observed for tPA-ineligible and age- and stroke severity-matched patients treated at the same neurology and rehabilitation departments. Main Outcome Measure: Neurological evaluation was assessed with the National Institutes of Health stroke scale (NIHSS). Activity of daily living was measured using the Functional Independence Measure (FIM) instrument. Functional outcome was measured using the modified Rankin scale (mRS). Results: The treatment group included 37 patients given tPA; 37 tPA-ineligible patients served as controls. On admission to rehabilitation, there were no significant differences in functional, neurological, and rehabilitation parameters between the groups. At the end of the rehabilitation period, NIHSS scores were significantly lower in the thrombolysis group (P ⫽ .036). More patients in the thrombolysis group reached functional independence defined as mRS ⱕ2 (20/37 versus 10/37; P ⫽ .03). At the end of rehabilitation, total FIM score (mean 102.8 versus 93.9; P ⫽ .039), total FIM gain (mean 27.8 versus 21.4; P ⫽ .09), and total FIM efficiency scores (0.8 versus 0.43; P ⫽ .013) were higher in the thrombolysis group and more patients in this group were discharged home. Conclusions: Although the bulk of neurological improvement occurred before the inpatient rehabilitation, thrombolysis-treated patients continue to improve faster and to a larger extent during the rehabilitation period suggesting that the beneficial effects of thrombolysis continue beyond the acute phase. PM R 2010;2:698-702

INTRODUCTION Stroke is a leading cause of chronic disability in Western societies and is associated with enormous socioeconomic burdens. Tissue plasminogen activator (tPA) is the only U.S. Food and Drug Administration–approved therapy for acute ischemic stroke [1,2]. tPA lyses the occluding clots and restores blood flow to the ischemic tissue, leading to potential salvage of ischemic tissue and gain of function that would be otherwise lost [1,2]. In most cases, neurological improvements are seen early after tPA administration [3]; earlier therapy results in better outcome [2,4]. Nevertheless, stroke survivors are often left with significant motor, sensory, or cognitive impairments even after treatment with tPA, and these sequelae are usually treated in a rehabilitation department [5-11]. However, the impact of previous treatment with tPA on the rate of successful rehabilitation remains unclear. Therefore, we set out to compare the results of standardized rehabilitation therapy between patients treated PM&R

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Z.M. Departments of Physical Medicine and Rehabilitation and Neurology, POB 24035, Hadassah-Hebrew University Medical Center, Jerusalem, 91240 Israel. Address correspondence to: Z.M.; e-mail: meiner@hadassah. org.il Disclosure: nothing to disclose A.S. Department of Physical Medicine and Rehabilitation, Hadassah-Hebrew University Medical Center, Jerusalem, Israel Disclosure: nothing to disclose I.S. Department of Physical Medicine and Rehabilitation, Hadassah-Hebrew University Medical Center, Jerusalem, Israel Disclosure: nothing to disclose J.T. Department of Physical Medicine and Rehabilitation, Hadassah-Hebrew University Medical Center, Jerusalem, Israel Disclosure: nothing to disclose I.Y. Department of Physical Medicine and Rehabilitation, Hadassah-Hebrew University Medical Center, Jerusalem, Israel Disclosure: nothing to disclose R.E. Department of Neurology, HadassahHebrew University Medical Center Jerusalem, Israel Disclosure: nothing to disclose T.B.-H. Department of Neurology, HadassahHebrew University Medical Center Jerusalem, Israel Disclosure: nothing to disclose R.R.L. Department of Neurology, HadassahHebrew University Medical Center Jerusalem, Israel Disclosure: nothing to disclose Disclosure Key can be found on the Table of Contents and at www.pmrjournal.org Supported by the Peritz and Chantal Sheinberg Cerebrovascular Research Fund and by the Sol Irwin Juni Trust Fund. Submitted for publication March 26, 2010; accepted May 18, 2010.

© 2010 by the American Academy of Physical Medicine and Rehabilitation Vol. 2, 698-702, August 2010 DOI: 10.1016/j.pmrj.2010.04.029

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with tPA before arrival at rehabilitation and similar patients who were not eligible for thrombolysis.

METHODS Subjects All patients with acute ischemic stroke treated at our tertiary care center were included in a prospective stroke registry. The institutional review board granted a general permission to collect routine research data on all stroke patients. We excluded patients with intracerebral, subarachnoid, and subdural hemorrhages. Detailed medical history was obtained from patients and spouses.

Procedures Patients that were acutely treated with intravenous thrombolytic agents were identified and their demographic clinical and radiological parameters were accrued. We compared the outcomes in these patients with those observed in age- and gender-matched control patients selected from a cohort of consecutive stroke patients entered in the same stroke database during the same period but who were not treated with thrombolytic drugs because of symptom onset or contraindications to therapy such as an international normalized ratio (INR) ⬎1.7 after 3 hours. Controls were selected according to a similar National Institutes of Health stroke scale (NIHSS) score on admission to neurology. All patients and controls were treated at the same rehabilitation center and received similar standard multidisciplinary rehabilitation treatment (120-180 minutes per day, according to the patient’s tolerance) 5 days per week by rehabilitation teams that were blinded to whether the patient received thrombolysis.

Outcome Measures All patients underwent a complete neurological examination, and neurological deficits were graded with the NIHSS on hospital admission [12]. NIHSS scores were also documented at discharge from the department of neurology and at discharge from the rehabilitation department; the degree of neurological improvement was measured as delta in NIHSS score between admission and end of inpatient rehabilitation treatment. Functional outcome was graded with the modified Rankin score (mRS) [13] administered at discharge from neurology and at discharge from rehabilitation. Good outcome was defined as a mRS score of 0-2 at discharge from rehabilitation. The daily living functions were evaluated using the Functional Independence Measure (FIM) [14] measured at entry and discharge from rehabilitation and the degree of functional improvement was measured as the delta in FIM scores.

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Statistical Analysis Statistical analysis was preformed with the Sigma-Stat package (SYSTAT, San Jose, CA). ␹2 and Student t-test were used for comparisons between patients treated or untreated with tPA and multiple logistic regression analyses were used to determine the impact of tPA treatment on functional outcome. Specifically, we implemented a logistic regression model that included all variables that yielded a between groups difference with a significance of less than 0.2. This model controlled for possible confounders including age and NIHSS scores at admission to neurology and to rehabilitation.

RESULTS Demographics Overall, 37 of 104 patients treated with IV tPA at our center were later referred to a single rehabilitation center and compared with 37 control patients referred to the same rehabilitation center. Patients referred to other rehabilitation facilities were excluded to avoid bias stemming from variable rehabilitation protocols implemented at different centers. The baseline characteristics of patients and controls did not differ significantly and are presented in Table 1. Of note, premorbid status was similar in both groups. The rates of any intracerebral hemorrhage or symptomatic intracerebral hemorrhage were extremely low in both groups. Noteworthy is that the rehabilitation admission time expressed as time in the neurological department was similar in both groups.

Baseline Data At entry to rehabilitation tPA patients had slightly less neurological disability shown by lower NIHSS scores (median scores 8 versus 10, P ⬍ .001). The percentage of patients with aphasia was slightly higher in the tPA group, although this difference was not statistically significant. The initial FIM scores at entry to rehabilitation were similar in both groups (Table 2).

Comparison of Functional Outcomes At the conclusion of rehabilitation, tPA patients had better functional outcomes as reflected by mRS scores ⱕ2 (20/37 versus 10/37, P ⫽ .03) and higher FIM scores (median 104.5 versus 98, P ⫽ .039) (Table 2). Furthermore, the delta of improvement in NIHSS scores was also significantly larger for tPA patients (median scores 6 versus 4, P ⫽ .001). The improvement in ADL functions according to FIM change was also higher in tPA patients, although it did not reach statistical significance (median 27.5 versus 18.5, P ⫽ .09). Overall, length of stay in rehabilitation was somewhat lower in tPAtreated patients, but the differences between the groups did

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Table 1. Baseline characteristics of tPA-treated stroke patients and controls Variable/Group

tPA (n ⴝ 37)

Age ⫾ SD (median) Gender (male %) Supratentorial (%) Vertebrobasilar (%) Hypertension (%) Ischemic heart disease (%) Atrial fibrillation (%) Diabetes mellitus (%) Hyperlipidemia (%) Smoking (%) Sedentary/overweight (%) Prior stroke/TIA (%) Use of antiplatelet agents (%) Use of anticoagulants (%) Use of statins (%) TOAST classification (%) Cardioembolic Large vessel Small vessel Other Unknown Involved left hemisphere (%) Aphasia present (%) Neglect present (%) Days in neurology (median)

66.2 ⫾ 10.4 (66) 28 (76) 35 (95) 2 (5) 29 (78) 13 (35) 12 (32) 13 (35) 26 (70) 13 (35) 22 (59) 8 (22) 22 (59) 11 (30) 28 (76)

No tPA (n ⴝ 37) 62.08 ⫾ 13.1 (66) 27 (73) 35 (95) 2 (5) 26 (70) 15 (40) 7 (19) 12 (32) 28 (76) 13 (35) 24 (65) 8 (22) 24 (66) 5 (14) 26 (70)

18 (49) 9 (24) 2 (5.5) 2 (5.5) 6 (16) 20 (54) 16 (43) 10 (27) 16.5 ⫾ 13.7 (13)

15 (41) 9 (24) 7 (19) 1 (3) 5 (13) 14 (38) 8 (22) 10 (27) 15.9 ⫾ 10.0 (13.5)

P .14 1 1 1 .38 .81 .29 1 .79 1 .225 1 .81 .16 .79 .48

.24 .08 1 .83

tPA ⫽ tissue plasminogen activator; TIA ⫽ transient ischemic attack; TOAST ⫽ Trial of Org 10172 in Acute Stroke Treatment. Values are mean ⫾ standard deviation (SD) (median) or number (percentage), P value: t-test/␹2 between tPA-treated and control.

not reach significance (median stay 49.5 days versus 55 days, P ⫽ .72). However, when the FIM efficiency score was calculated, it was significantly higher in the tPA-treated group (0.51 versus 0.30, P ⫽ .013). On logistic regression analysis, use of intravenous tPA significantly increased the odds ratio for good functional outcome defined as a mRS score of ⱕ2 by 4.19 (Table 3). Use of intravenous tPA was the only variable to be positively associated with increased chances of having a good outcome. Other variables that were associated with reduced chances for having good outcome

included increased age and higher NIHSS scores on admission to the department of rehabilitation.

DISCUSSION The findings of the current study indicate that the beneficial effects of tPA treatment on functional outcome after stroke continue during the rehabilitation period. Significantly larger improvements in neurological disability were observed in patients treated with tPA both at discharge from the neuro-

Table 2. Comparison of rehabilitation associated variables in tPA-treated patients and controls Variable/Group NIHSS at admission to neurology (median) NIHSS at admission to rehabilitation (median) NIHSS at discharge from rehabilitation (median) ⌬ NIHSS admission-discharge from neurology (median) ⌬ NIHSS admission-discharge from rehabilitation (median) mRS at discharge from rehabilitation (%) 0-2 3 4-5 FIM at admission to rehabilitation (median) FIM at discharge from rehabilitation (median) ⌬ FIM rehab admission-rehabilitation discharge (median) Length of stay in rehabilitation days (median) FIM efficiency score (median)

tPA (n ⴝ 37) 14.1 ⫾ 4.3 (13) 8.9 ⫾ 3.8 (8) 6.15 ⫾ 2.7 (6) 5.2 ⫾ 4.2 (4) 7.93 ⫾ 3.9 (6) 20 (54) 14 (38) 3 (8) 74.8 ⫾ 24.1 (68) 102.8 ⫾ 18.3 (104.5) 27.8 ⫾ 19.5 (27.5) 52.39 ⫾ 25.5 (49.5) 0.80 ⫾ 0.84 (0.51)

No tPA (n ⴝ 37) 12.45 ⫾ 5.4 (13) 10.1 ⫾ 4.2 (10) 7.9 ⫾ 3.9 (7) 2.29 ⫾ 2.98 (2) 4.6 ⫾ 3.5 (4) 10 (27) 17 (46) 10 (27) 73.4 ⫾ 21.7 (70) 93.95 ⫾ 18.2 (98) 21.4 ⫾ 12.6 (18.5) 54.45 ⫾ 24.9 (55) 0.40 ⫾ 0.24 (0.30)

P .078 .23 .04 .001 .001 .025

.299 .016 .16 .72 .05

tPA ⫽ tissue plasminogen activator; NIHSS ⫽ National Institute of Health Stroke Scale; mRS ⫽ Modified Rankin Scale; FIM ⫽ Functional Independence Measure. Values are mean ⫾ standard deviation (median) or number (percentage), P value: t-test/␹2 between tPA-treated and control.

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Table 3. Multivariable analysis for prediction of good functional outcome (mRS ⱕ2) among patients with stroke who underwent rehabilitation Variable

OR (95% CI)

P

IV tPA given NIHSS at admission to neurology NIHSS at admission to rehabilitation Age

4.19 (1.05-16.71) 0.99 (0.84-1.18) 0.61 (0.45-0.81) 0.93 (0.88-0.98)

.04 .94 ⬍.001 .009

tPA ⫽ tissue plasminogen activator; NIHSS ⫽ National Institute of Health Stroke Scale; IV ⫽ intravenous.

logical department at entry into rehabilitation and the end of the in-patient rehabilitation period. This suggests that tPAtreated patients may benefit more from rehabilitation. Indeed, the proportion of patients entering rehabilitation with a moderate to severe degree of neurological disability that eventually reached functional independence was significantly larger in the tPA group compared with controls. In addition, larger increments in the FIM score were also noted in the tPA group. These better results in the tPA-treated group were achieved in spite of the fact that the percentage of patients with aphasia was slightly higher in the tPA group, although not statistically significant. The functional status of stroke patients improves with time from stroke onset. In fact, the largest impact on stroke recovery in patients treated in stroke units probably is due to early and more extensive rehabilitation efforts [15-17]. Furthermore, the benefit of early rehabilitation extends to long periods after stroke [18-21]. The benefits of tPA therapy also extends over long periods, and patients treated with tPA showed continued improvement in functional status up to 1 year after treatment [1,2,22]. However, it was not clear whether this effect is dependent on the fact that a larger proportion of tPA patients ultimately reach rehabilitation or whether this beneficial effect extends also into the rehabilitation period [23]. Our study is the first to show that this beneficial effect of tPA therapy continues while patients undergo rehabilitation and that these patients may benefit more from rehabilitation compared with patients not treated with lytic drugs. Neurological status as measured with the NIHSS improves to a larger extent early, whereas the patients are still admitted in neurology. Surprisingly, tPA-treated patients had FIM scores that were similar to those of controls on presentation to the rehabilitation department. However, this can be explained by the fact that only part of the tPA-treated patients reperfuse and some of them probably reoccluded the target artery [24,25]. The change in the observed neurological disability (⌬ NIHSS between admission to neurology and admission to rehabilitation) during the acute stay in the department of neurology was nevertheless larger in tPAtreated patients, suggesting that there is at least a tendency toward better short-term neurological (if not functional) outcome in these patients.

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As was shown by Nudo et al [26] and others, the scientific basis of functional improvement after intensive rehabilitation retraining after stroke included enlargement of brain areas that are activated by the physical activity. This process required the existence of a larger penumbra that is still viable. Thus, it is possible that patients subjected to tPA can benefit more from rehabilitation by virtue of better metabolic and functional state of the surviving neurons driven by tPAinduced tissue reperfusion that later contribute to better functional outcome. Delayed functional improvement after stroke could also result from several mechanisms that are augmented during rehabilitation, including neuronal plasticity [26,27], neurogenesis [28,29], and angiogenesis [30,31]. tPA can activate matrix metalloproteinases, which could have beneficial effects on recovery after stroke by promoting neurovascular repair [30]. Alternatively, the more robust functional improvement observed in tPA-treated patients may be explained by salvage of larger brain areas in these patients compared with controls. Empirical studies are required to investigate the mechanisms underlying the putative tPAinduced effects. This might provide information about devising novel rehabilitation approaches or stratification procedures for patients treated with or without lytics. Our study had several limitations: the number of patients in each group was small, patients could not be randomized to receive or not receive thrombolysis, and it was a retrospective trial. There was also a difference in the arrival time to the emergency room, which may influence the final outcome, although the initial impairment according to the NIHSS score was similar between the groups. Therefore larger prospective trials are needed to support our initial findings of beneficial effect of thrombolysis treatment in acute phase on the rehabilitation outcomes of stroke patients.

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