Hyperacute thrombolysis with recombinant tissue plasminogen activator of acute ischemic stroke: Feasibility and effectivity from an Indian perspective

Given the constraints of resources, thrombolysis for acute ischemic stroke (AIS) is under evaluation in developing countries like India, especially in areas such as western Utter Pradesh, where it is overly crowded and there is poor affordability. Aim: This study was done to evaluate recombinant tissue plasminogen activator r-tpa in acute ischemic stroke in hyper acute phase, in selected patients of western Utter Pradesh, in terms of feasibility and effectivity. Design: Open, non randomized study. Materials and Methods: Thirty two patients were classified using Trial of ORG 10172 in Acute Stroke treatment (TOAST) criteria (large artery atherosclerotic = 8; cardio embolic = 6; small vessel occlusion = 14; other determined etiology = 2; undetermined etiology = 2). The mean time to reach the hospital was 2 h (1.15-3.0), the mean door to CT scan 20 min (10-40) and door to r-tpa injection was 30 min (24-68). The National Institute of Health Stroke Scale (NIHSS) scores ranged from 11-22 (mean 15.5 +2.7). The dose of r-tpa administered was 0.9 mg/kg. Results: Twenty one patients (65.6%) showed significant improvement on the NIHSS score, at 48 h (4 points). (Mean change = 10; range = 4-17). At one month, 25 (78%) recorded improvement on the Barthel index (mean change = 45%). One developed frontal lobe hemorrhage and another developed recurrent stroke; one died of aspiration; and four showed no improvement. Modified Rankin score (m RS) was administered at the end of three months to 28 patients (90%); however, the rest could not be directly observed. The average modified Rankin Score was 1.2 (0-2). Conclusions: Hyperacute thrombolysis was found feasible and effective in selected patients with AIS from western Utter Pradesh and who had poor affordability.


Introduction
Acute ischemic stroke (AIS) is an area in neurological clinical practice, which has probably seen the greatest strides as far as an understanding of pathogenesis is concerned. This has led to advancement in the treatment options available for patients suff ering from ischemic stroke. Plenty of nihilism that surrounded strokes is gradually being lift ed along with the ignorance related to the condition, from both the minds of patients and the treating physicians. Most therapeutic options for AIS have one common feature; they generally have to be administered within a very narrow and speciÞ c time window. This is extremely pertinent, if the drug related adverse eff ects have to be minimized and therapeutic beneÞ ts maximized.
A study done by the National Institute of Neurological Disorders and Stroke (NINDS) on the intravenous use of recombinant tissue plasminogen activator (r-tpa), within three hours of AIS, has shown the beneÞ ts of this form of treatment. [1] In order to be eff ective, the protocol for institution of r-tpa therapy must be strictly followed. The level of this form of therapy is level I. [2] When all accumulated evidence for r-tpa therapy is considered, the relative risk reduction by the therapy is 44%, absolute risk reduction is 13% and the number needed to treat to save one person from death or disability is seven. [3] Many countries now routinely thrombolyse all patients of AIS, who present within the three-hour window period and do not have any contraindication. However, many stroke units, especially those in the developing nations like India, especially in western Utt er Pradesh, are hampered by constraints of resources and lack of awareness and aff ordability. The feasibility of thrombolysis is still being evaluated at these centers, as is being done in our study. Hyperacute thrombolysis for stroke was started in the year 1995-96 in India and in March 2002 at the All Institute of Medical Sciences (AIIMS). [4] Our study was slightly delayed by one to two years. We assessed the outcomes of the patients treated with IV r-tpa, including Intra Cerebral Hemorrhage (ICH) and Annals of Indian Academy of Neurology -October-December 2008 other events, especially aff ordability in the population of western Utt ar Pradesh. The overall purpose of this study is to report the current clinical practice of IV r-tpa for AIS in North India, especially western Utt er Pradesh.

Materials and Methods
We present the detailed data of the 32 patients treated at SRMS Institute of Medical Sciences (SRMSIMS), in whom an adequate follow-up of six months is available. All the patients were studied prospectively.
The variables that were speciÞ cally recorded for each patient treated with r-tpa included time of onset of symptoms, time of arrival at the emergency department, time of CT scan examination and the time of r-tpa administration. An extensive neurological examination, including the baseline NIH stroke scale (NIHSS) was performed in all the patients. Other parameters noted were the demographic proÞ le, stroke risk factors, baseline CT scan Þ ndings and blood pressure measurements [ Table 1].
Potential benefits and significant risks, specifically the fourfold greater risk of symptomatic intracerebral hemorrhage [5] after thrombolytic treatment were discussed with all the patients and/or their families and informed consent was obtained. The r-tpa protocol was based on the protocol published by the American Heart Association and the American Academy of Neurology. [6,7] Inclusion and exclusion criteria are shown in Table 2. All patients had pretreatment CT scans that were read by the att ending neurologist together with the radiologist. Each of our patients received 0.9 mg/kg of intravenous r-tpa, up to a maximum of 90 mg, based on the estimated or actual body weight. Ten per cent of this calculated dose was injected as a bolus and the remainder infused over an hour. Heparin and aspirin were withheld for the Þ rst 24 h aft er r-tpa administration in all our patients. Hypertension was treated using intravenous labetolol or intravenous enalapril. Occasionally, injection nitroglycerine or nitroprusside was required.
The results of follow-up CT scans or MRI scans were recorded in all the patients thrombolysed. The use of aspirin, clopidogrel, heparin, actirom and antihypertensive during the hospital stay was noted (see table 3). The peak blood pressure during r-tpa administration as well as during the Þ rst 24 th hour aft er the infusion was recorded. Using TOAST criteria, stroke subtype was determined by the following classiÞ cation: 1) Large artery atherosclerosis 2) Cardio-embolic 3) Small vessels occlusion 4) Stroke of other determined etiology and 5) Stroke of undermined etiology. We obtained telephone or clinic follow-up with the patient and the caregiver in all the 32 cases and assessed the Barthel Activities of Daily Living Index. For analysis, we deÞ ned good outcome as an improved NIHSS of >4 and a Barthel Index of >75%. At three months, 25 patients (78%) showed improvement on the Barthel index (mean change = 55%), one developed symptomatic ICH improved on conservative management. One patient died due to fatal ICH, with aspiration pneumonia. One of the three patients who had hemorrhagic conversion improved but the other two did not improve.

Results
Thirty two patients received IV r-tpa for AIS between September 2004 and July 2007. We observed 584 patients suspected of having an acute ischemic stroke during this period. The most common reasons for disqualiÞ cation from thrombolytic therapy were as follows: exceeding the window period 48%, ICH 20%, minor or rapidly resolving symptoms (10%), and non stroke diagnosis (10%). Of the patients who could qualify to receive thrombolysis, 40% could not be thrombolysed, since they could not aff ord r-tpa. Aff ordability is a major drawback in the use of r-tpa. The mean length of follow-up aft er discharge was 8.5 ± 3 months. ModiÞ ed Rankin score (m RS) was administered at the end of three months to 28 patients (90%); the rest could not be directly observed. The average modiÞ ed Rankin Score was 1.2 (0-2). One patient developed pneumonia and recovered with therapy.

Discussion
Despite the demonstration of beneÞ ts from thrombolytic treatment with intravenous r-tpa by the NINDS trial as early as in 1995, this form of therapy has been underused in developing countries like India and even in overly populated states such as Utt er Pradesh. The reluctance to aggressively thrombolyse patients of acute ischemic stroke has been att ributed to several factors including delay in arrival of patients to emergency, limited resources, ignorance or disbelief amongst neurologists with regard to the effi cacy of this mode of treatment and fear of serious r-tpa-related complications like hemorrhage. We succeeded in treating 32 patients of acute ischemic stroke with IV r-tpa, over a period of three years. Importantly, we were unable to thrombolyse 48% of otherwise eligible patients, due to delay in their arrival. Several studies have been tried to analyze the causes of such delays, but they been conducted in developed countries which are very diff erent from India. [8][9][10][11][12][13] The mean age of patients in our study was 66 years, whereas the mean age of patients in the NINDS trial was 67 years. Advanced age increases the odds of a poor outcome aft er thrombolysis. [14,15] However post hoc analysis of the NINDS data showed r-tpa to be beneÞ cial for patients in all strata of age. As the age of incidence of stroke increases, it becomes important to decide if older patients should be denied this potentially disability-avoiding therapy.
Our patients had a mean baseline NIHSS of 14, which is similar to that of patients in the NINDS r-tpa trial. The stroke sub types by Þ nal diagnosis was most oft en (35% patients) in small vessel disease. The NINDS trial and a few subsequent studies have shown that IV r-tpa within the three hours window is similar between diff erent stroke subtypes. It has been recommended that extensive diagnostic evaluation to determine stroke subtypes before thrombolysis is neither required nor justiÞ ed.
Patients arrived in the emergency department at an average of 120 min aft er symptom onset. A CT scan was performed within 20 minutes and IV r-tpa was administered within an average of 30 min from the time of arrival at the emergency department. A signiÞ cant diff erence between our study and the NINDS trial is that half of the randomized patients in the NINDS trial were treated within 90 min of stroke onset. However, the response to the treatment observed in the NINDS trial between patients treated under 90 min and between those treated between 90 and 180 min did not diff er future direction for widening the window period. This underlies the importance of not withholding treatment from patients, even if they present beyond 90 min of the onset of symptoms. We were able to treat patients within an average of 30 min from the time of arrival at the emergency department. This is contrary to the popular perception that it is generally not possible to treat patients within the time window of 180 min in busy and constrained hospitals of India, like in our study, unless they arrive early. Recent NIH consensus guidelines recommend a "door to needle" time of 60 min or less for acute stroke patients.
An improvement of four points or more on the NIHSS at 48 h was seen in 65.6% of our patients, while a Barthel Index of 75 or more at one month was present in 78% patients. It is important to note here that long term beneÞ ts as observed from the Barthel Index is significantly more impressive than the immediate beneÞ ts as reß ected from the 48 h NIHSS. The reluctance of many neurologists to treat patients is based on this premise of insufficient immediate improvement in outcome. However, it is equally important not to lose sight of the delayed beneÞ ts, especially considering the tremendous impact that stroke morbidity has on the individual, caregivers and society as a whole.
The preliminary data from India, with reference to western Utt er Pradesh, shows that hyperacute thrombolysis in acute ischemic stroke is both feasible and eff ective but still not aff ordable to a large segment of the population, due to poverty and lack of awareness of its importance and usefulness. It also emphasizes the importance of increasing awareness about stroke and its acute management. More signiÞ cantly, until patients start presenting more promptly for treatment, it needs to be understood that thrombolysis can still be provided in hospitals if a dedicated team of neurologists endeavors to reduce the "door to needle" time to the minimum possible.
The limitation of the present study is the lack of control group, which will impede the assessment of the effi cacy of thrombolytic. However, since the study was conducted to essentially evaluate the feasibility and eff ectivity in western Utt er Pradesh (India) which is a poverty stricken pocket and hence aff ordability of r-tpa is a major issue, the limitation is the sample size. We accede that it is a small number to draw any deÞ nite conclusions. However, the observation does reveal that even in this small number of patients, hyperacute thrombolysis can be undertaken in carefully screened patients of AIS. A future large trial needs to be undertaken with a blinded, controlled and randomized design, to substantiate our Þ ndings.