The need for a population-based, dose optimization study for recombinant tissue plasminogen activator in acute ischemic stroke: A study from a tertiary care teaching hospital from South India.

CONTEXT: The guideline recommended dose of intravenous (i.v) recombinant tissue-type plasminogen activator (rt-PA) for acute ischemic stroke is 0.9 mg/kg in the European and American populations. In Asiatic population, some studies have shown that a lower dose of i.v rt-PA is equally efficacious. AIMS: To assess if there is a need for a dose optimization for i.v rt-PA study among Indians. SETTING AND
DESIGN: A prospective, observational database of acute stroke cases that presented to a tertiary care institute over a period of 1 year was made.
METHODS: The data procured using a prestructured elaborate pro forma. Based on the dose of rt-PA received, the individuals were divided into three groups; Group 1 (0.6-0.7 mg/kg), Group 2 (0.7-0.8 mg/kg), and Group 3 (0.8-0.9 mg/kg). Improvement was assessed in each group and between the thrombolysed and nonthrombolysed individuals. STATISTICAL ANALYSIS USED: The nonparametric Mann-Whitney U-test (Wilcoxon rank-sum test) was applied for assessing improvement of National Institutes of Health Stroke Scale score with significance level of α < 0.05 (P < 0.012) and compliance level at 95%.
RESULTS: Between the thrombolysed (n = 46) and nonthrombolysed (n = 113) group, there was a statistically significant neurological improvement in the thrombolysed group. Clinical improvement was noted in 75%, 85.7%, and 66.7% of individuals receiving rt-PA in Groups 1, 2, and 3, respectively. Four out of the five who developed a clinically significant intracranial hemorrhage were thrombolysed at a dose of 0.8-0.9 mg/kg rt-PA (Group 3).
CONCLUSION: There is a need for a properly randomized, dose optimization study of i.v rt-PA in the Indian subcontinent.

Introduction

Variable dose regimens of intravenous (i.v) recombinant tissue-plasminogen activator (rt-PA) are used across Asia without any reliable or established evidence.[1] The guideline recommended dose of i.v rt-PA for acute ischemic stroke is 0.9 mg/kg in the European and American populations.[2] In Asiatic population, some studies have shown that a lower dose of rt-PA is equally efficacious.[3] In China, a study of the different doses of rt-PA for acute stroke concluded that they did not support the dose of 0.9 mg/kg being optimal for all patients in the East Asian population.[4] Another study in acute ischemic stroke patients in China demonstrated that i.v rt-PA regimen, 0.9 mg/kg, with a maximum dose of 50 mg had a favorable outcome.[5]

Our study was conducted at a single tertiary care institute, where the institutional policy is to administer a maximum dose of 50 mg of rt-PA. The rationale behind this dosing is that, Asian studies have shown that low-dose i.v rt-PA is equally efficacious as the standard dose (0.9 mg/kg).[456] The evidence for the rationalization among the Indian population is minimal, which warrants further research. The fact that this is a more financially feasible option for individuals where the health-care expenditure of the average Indian is mostly out of one's own pocket (OOP)[7] also plays an important part in the country.

Methods

A prospective, observational database of acute stroke cases that presented to a tertiary care institute over a period of 1 year was made after approval from the Institutes Research Board and Ethics Committee. The data were procured using an elaborate prestructured pro forma. This included the clinco-bio-ethno-geographical data of the individuals, their serial National Institutes of Health Stroke Scale (NIHSS) score for 7 days, and modified Rankin Score (mRS) for every hospital visit till the end of 3 years.[8] It was noted that the dosage of rt-PA used in this institute was a maximum of 50 mg. This led to the research question whether the dose of rt-PA used was adequate in the individuals.

For the purpose of this study, the efficacy end-point assessed was the neurological improvement at 7 days and safety end-points were clinically significant intracerebral hemorrhage (ICH) and death. Improvement in neurological status was defined as a drop in the NIHSS score by 4 or more points or a score of zero at 7 days.[9] The stroke scale was completed by the investigators who were usually unaware of previous scores for an individual patient. Functional outcome of the individuals was followed up for 3 years. In the event, they did not show up for a follow-up; they were telephonically interviewed and mRS scored.

Descriptive and inferential statistical analyses were carried out in the present study. The statistical software namely IBM, SPSS 22.0, R environment version 3.1.1 was used for the analysis of the data. The results of categorical measurements are presented in number (%). The nonparametric Mann–Whitney U-test (Wilcoxon rank-sum test) was applied for assessing for improvement of NIHSS score among the thrombolysed and nonthrombolysed individuals with significance level of α < 0.05 (P < 0.012) and compliance level at 95%.

Based on the dose of rt-PA received, the individuals were divided into three groups.

Group 1 (0.6–0.7 mg/kg), Group 2 (0.7–0.8 mg/kg), and Group 3 (0.8–0.9 mg/kg), and improvement was assessed in each group [Figure 1].

Figure 1

Flow Chart: Stratifying suspected stroke patients

Results

Three hundred and sixty-one clinically suspected stroke patients presented to the emergency department of the institute, of which 229 (63.4%) reached within 270 min of onset of symptoms. One hundred and fifty-nine of the 229 had an ischemic stroke [Figure 1]. Sixty-two of the 159 were thrombolytic candidates, but only 46 got thrombolysed. This was because 11 (17.7%) could not afford the treatment and five declined consent due to fear of risk of hemorrhage.

When the thrombolysed (n = 46) and nonthrombolysed (n = 113) group were compared, it was noted that there was a statistically significant neurological improvement in the thrombolysed group (P < 0.012) [Figure 2].

Figure 2

7 day National Institutes of Health Stroke Scale improvementa postlysis

73.9% (34/46) patients in the thrombolysed group had improvement, whereas among the nonthrombolysed individuals, 45.1% improved (51/113).

The weight of the patients was charted; subgroups were created based on the dose of rt-PA received and analyzed.

Five individuals who underwent thrombolysis developed a clinically significant intracranial hemorrhage (ICH) postthrombolysis. Four of those who developed a clinically significant ICH were thrombolysed at a dose of 0.8–0.9 mg/kg rt-PA and one at 0.6–0.7 mg/kg.

Six individuals passed away within 7 days of thrombolysis of which four deaths were due to ICH, one had a very large ischemic stroke, and one had an airway accident [Table 1]. Clinical improvement was noted in 75%, 85.7%, and 66.7% of the patients in the three groups, respectively [Table 2]. The thrombolysed candidates (n = 46) were followed up, and at the end of 3 years, eight (17.4%) were dead [Table 1], 19 (41.3%) had functionally good outcome with mRS of ≤1, no improvement was seen in six (13%), whereas 13 (28.3%) were lost to follow-up [Table 3]. Fifty percent of the individuals in Group 2, whereas 41.7% of the individuals in Group 3 had a functionally good outcome.

Table 1

Mortality data

Table 2

7 days National Institutes of Health Stroke Scale improvement across groups

Table 3

Follow-up data at the end of 3 years

Discussion

Thrombolytics in stroke is a relatively newer tool in the armamentarium, of a neurologist and emergency physician. rt-PA has been approved in the United States for treatment of acute ischemic stroke since 1996.[10]

Many controlled trials have demonstrated that thrombolysis with rt-PA is an effective treatment for acute stroke if given within first 3 h of onset of symptoms.[1112]

Subsequent research has confirmed benefits of rt-PA when used up to 4½ h after the onset of ischemic stroke.[12]

The standard dose of i.v rt-PA was determined after two pilot open-labeled studies.[1314] In the phase 1 pilot study, 74 patients were treated within 90 min of symptom onset over seven dose tiers of tissue plasminogen activator, ranging from 0.35 mg/kg to 1.08 mg/kg, and it was noted that intracranial hematoma did not occur in any of the 58 patients treated with <0.85 mg/kg.[13] A low-dose rt-PA (0.6 mg/kg) is the standard approved treatment for acute ischemic stroke in Japan after conducting many studies.[151617] No such trials have been conducted among the Indian population.

In our study, higher percentage of bleed and lesser clinical improvement were seen in the 0.8–0.9 mg/kg group compared to lower dose (0.7–0.8 mg/kg) group. The Taiwan Thrombolytic Therapy for Acute Ischemic Stroke study group compared low dose (0.65–0.79 mg/kg) and standard dose (0.88–0.92 mg/kg) of rt-PA in Chinese patients and their data showed that symptomatic ICH and mortality were higher in the standard-dose group.[18] There are different hypotheses put forward to explain this rationale. Studies have observed that there is a racial difference in sensitivity to rt-PA. Dark-skinned patients have been shown to have an enhanced sensitivity to rt-PA in patients with acute coronary syndrome.[19] The Japanese when compared to the Americans have been shown to have a higher concentration of plasma fibrinogen and fibrinogen activator inhibitor levels.[20] India is a melting pot of various races[21] and whether racial differences attribute to this varied response is yet to be studied among stroke victims in the Indian subcontinent.

In our study, improvement was seen in a higher percentage of individuals receiving lower dose of thrombolytic agent −0.7–0.8 mg/kg rather than the internationally recommended 0.9 mg/kg [Table 2]. It should be noted that this was not a statistically significant difference since the number of patients studied in each group was very low, but the noninferiority per se points out the necessity for further research on the subject.

About 17.7% of the individuals in this study could not afford the treatment modality in this urban tertiary care institute. In rural India, this number would be even more high. Lack of access to stroke care, financial constraints, and lack of infrastructure are of concern in developing nations.[222324] In India, rt-PA is available as 50 mg vials and 20 mg vials. A vial of 50 mg of the thrombolytic agent costs Rs. 40000 (594US$) which is almost double the monthly wages of a middle-class adult in India and this makes thrombolysis inaccessible to most were the health care expenditure is out of OOP.[725]

Fifty milligrams vial at 0.9 mg/kg would be sufficient to treat only someone up to the weight of 55.6 kg. Anything more than that would warrant additional vials of rt-PA which would add to the financial burden. A lower dose of thrombolytic agent, for instance 0.6 mg/kg, would mean that 50 mg vial would benefit an adult up to 83.3 kg, which, in the Indian subcontinent, would also be more affordable, making the option more accessible. If proven to be more efficacious or even noninferior than the regular 0.9 mg/kg dose, there would be significant financial gain for the patient, health-care providers including doctors, and stroke treatment government facilities responsible for health care. It is evident that further studies are needed in the subcontinent to optimize the dose required for the treatment of individuals.

Limitations

Although the database was made prospectively, the research question and subgroup formulation were done retrospectively. There was no proper randomization of the thrombolysed groups, and at the end of 3 years, 28% were lost to follow-up. Although all clinically suspected stroke cases (n = 361) were included in formulating the database, the thrombolysed limb constituted only a very small size (n = 46). The number in each individual subgroup was therefore too small to provide any statistically significant conclusion with regard to an optimal dose. It should also be noted that this study was done at a single center, and whether this is applicable in other parts of the country also needs to be further studied.

Conclusion

There are no proper randomized trials of rt-PA among the Indian population to date.

There exists a considerable variation in the dose of rt-PA in recent publications from Asia.

Although the low sample (n = 46), poorly randomized groups, studied in a single tertiary care teaching institute in South India, minimizes the scope for clinical translation of this research to clinical work, it does point toward the need for further research on dose optimization of i.v rt-PA in the Indian population.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.