Acute ischemic stroke thrombolysis with tenecteplase: An institutional experience from South India.

OBJECTIVE: Outcome assessment of intravenous (IV) thrombolysis with tenecteplase in acute ischemic stroke.
MATERIALS AND METHODS: We consecutively enrolled acute ischemic stroke patients who underwent IV thrombolysis with tenecteplase from October 2016 to May 2017. Primary clinical efficacy outcome was defined as an improvement in the National Institute of Health Stroke Scale (NIHSS) score of ≥4 points at 24 h (h). Secondary clinical efficacy outcome was the favorable outcome on modified Rankin scale at 90 days defined as a score of 0 or 1. The safety endpoints were death rate at 90 days and symptomatic intracranial hemorrhage (SICH).
RESULTS: Mean NIHSS scores at baseline and 24 h were 13 (±3.81) and 9.29 (±5.74), respectively, the difference being statistically significant (P = 0.016). In this study, nine patients (64%) met the primary clinical efficacy outcome and eleven (78.5%) patients met the secondary clinical efficacy outcome. Only 1 (7%) patient developed SICH and additionally, aspiration pneumonia with subsequent death.
CONCLUSION: This study confirms the efficacy and safety of tenecteplase for stroke thrombolysis in our clinical setting. Tenecteplase appears to be a suitable option for stroke thrombolysis in resource-limited settings, considering its cost-effectiveness, and ease of administration.

INTRODUCTION

Intravenous (IV) thrombolysis with recombinant tissue plasminogen activator (rt-PA) has assumed vital importance in the successful treatment of acute ischemic stroke. Conventionally, alteplase infusion has proved to be efficacious in improving the functional outcomes when given within 4.5 h (h) of the stroke onset, and it is the only worldwide approved rt-PA agent for stroke thrombolysis.[12] However, recent randomized controlled trials (RCTs) have compared the results of alteplase and tenecteplase in stroke thrombolysis and observed tenecteplase to have an efficacy and safety at least, similar or superior to alteplase.[345] Besides, tenecteplase has some pharmacological advantages in comparison to alteplase. It has a longer duration of action and higher fibrin specificity. Further, it can be given as a single bolus injection, unlike alteplase which is given as a continuous infusion after the bolus dose, thus offering the advantage of a convenient administration. Based on these advantages and the results of above-mentioned RCTs, tenecteplase has been recently approved for ischemic stroke thrombolysis in India within 3 h of the stroke onset. Moreover, it offers the additional benefit of reasonable pricing, being available at a cost which is nearly half of the alteplase. A low-cost rt-PA agent with an ease of administration offers a great potential to tackle the stroke epidemic in developing countries like India. Thus, in consequence to its recent approval for stroke thrombolysis and owing to its free availability under hospital's medicines indenting scheme, we planned to start stroke thrombolysis with tenecteplase (Metalyse®) at our tertiary hospital. We report our observations from Kakatiya Medical College and associated Mahatma Gandhi Memorial Hospital (MGMH) at Warangal, which is a government-run tertiary care referral health center in Telangana region of South India. MGMH is served by well-established intensive and acute medical care units, along with a regular neurology outpatient department. The majority of patients attending our hospital belong to the rural population, who often cannot afford the high cost of alteplase. Hence, with the approval of tenecteplase for stroke thrombolysis, we hoped to realize the goal of improved stroke management for our impoverished patients.

MATERIALS AND METHODS

The present study was a prospective observational study which was conducted from October 2016 to May 2017. During the study, we enrolled all the ischemic stroke patients who underwent thrombolysis with tenecteplase.

Inclusion and exclusion criteria

We enrolled patients more than 18 years of age who were diagnosed with acute ischemic stroke, had the National Institute of Health Stroke Scale (NIHSS) score >4, and a modified Rankin scale (mRS) score of ≤2 before the stroke onset.[4] We used baseline computed tomography (CT) scan of the brain in all cases to rule out intracranial hemorrhage. Further, other classical contraindications for alteplase thrombolysis were used as exclusion criteria.[1]

Respecting the time window of its approval for stroke thrombolysis, we used tenecteplase within 3 h of the stroke onset. Informed consent was obtained in all cases after discussing benefits and the risk of a hemorrhagic event associated with thrombolytic therapy. Tenecteplase was administered as a single bolus IV injection at the dose of 0.2 mg/kg, with total dose not exceeding 20 mg.

Outcomes

We defined the primary clinical efficacy outcome as improvement in NIHSS score of 4 or more points after 24 h.[6] Secondary clinical efficacy outcome was disability assessment at 90 days based on mRS score, dichotomized as a favorable outcome (with a score of 0 or 1) or an unfavorable outcome (a score of 2–6).[2] The safety endpoints were death rate at 90 days and symptomatic intracranial hemorrhage (SICH), which is defined as any fresh intracranial bleeding resulting in clinical worsening with a decline of >4 points in score on NIHSS or death, as per European Cooperative Acute Stroke Study III study protocol.[2]

Clinical assessment

All the acute ischemic stroke patients were assessed by an internal medicine resident in medical emergency on a priority basis. Those presenting in the window period for thrombolysis underwent a quick evaluation to rule out the contraindications to thrombolysis through medical history, blood pressure, premorbid mRS score and NIHSS score assessment. Simultaneously, capillary blood glucose estimation was done and blood samples were withdrawn for other standard laboratory tests as mentioned in the exclusion criteria for thrombolysis. Soon after, patients were shifted for an urgent CT scan of the brain. The patients having no evidence of intracranial hemorrhage were thrombolyzed according to above-mentioned protocol. All the patients receiving rt-PA were closely monitored for heart rate, blood pressure, and oxygen saturation for initial 24 h. NIHSS scores were calculated at baseline, 2 h, and 24 h post-thrombolysis while mRS scores assessment was done at baseline and 90-day post-thrombolysis.

Follow-up brain imaging

Any patient who showed neurological deterioration with an NIHSS score decline of ≥4 points was made to undergo an urgent CT scan to rule out SICH. In addition, all the patients receiving tPA underwent CT or magnetic resonance imaging of the brain within 24–48 h post-thrombolysis.

Variables and data entry

Variables including the time of stroke onset, onset-to-door time, door-to-imaging, and door-to-needle time were entered into well-structured case forms. Other data including demographic details, risk factors for stroke, vital signs, details of neurological examination including NIHSS and mRS scores, and laboratory parameters were also recorded. Data were entered into “Microsoft Excel” and “SPSS version 16.0” (SPSS Inc., Chicago, IL, USA) was used for statistical analysis.

RESULTS

During the study, a total of 14 patients underwent IV stroke thrombolysis with tenecteplase. Mean age was 60.7 years with 71% of the study subjects being males. Hypertension was the commonest risk factor present in 57% of the cases, followed by dyslipidemia in 50%. Most of the patients had large artery stroke subtype, with the infarct region belonging to the territory of middle cerebral artery in all the 14 cases. The mean time from onset of symptoms to arrival at the medical emergency was 116 (±24.11) minutes (min) while mean “door to needle” time was 57 (±18.47) min. The study subjects had a mean NIHSS score of 13 (±3.81) and a median mRS score of 5 (range: 3–5) at the baseline [Table 1].

Table 1

Baseline characteristics of 14 patients thrombolyzed with tenecteplase

Variables	Values (%)
Age (years, mean±SD)	60.71±9.21
Gender (male)	10 (71.4)
Risk factors
Hypertension	8 (57)
Dyslipidemia	7 (50)
Diabetes mellitus	3 (21)
Smoking	3 (21)
Stroke subtype
Large artery	10 (71)
Lacunar	4 (29)
Cerebral circulation
Anterior cerebral artery	0
Middle cerebral artery	100 (100)
Posterior cerebral artery	0
Laterality
Left hemisphere	8 (57)
Right hemisphere	6 (43)
Onset to door time (min, mean±SD)	116±24.11
Door to imaging time (min, mean±SD)	38±18.98
Door to needle time (min, mean±SD)	57±18.47
Baseline NIHSS score (mean±SD)	13±3.81
Baseline mRS score (median)	5

NIHSS=National Institute of Health Stroke Scale, mRS=Modified Rankin Scale, SD=Standard deviation

Outcome analysis

In our study, nine patients (64%) met the primary clinical efficacy outcome with an improvement in NIHSS score of 4 or more points at 24 h. Mean NIHSS scores at 2 h and 24 h were 10.57 (±5.14) and 9.29 (±5.74), respectively. We used “one-way repeated measures analysis of variance” test and observed a significant difference between the NIHSS scores at baseline and 24 h (P = 0.016) [Table 2]. Further, 11 (78.5%) patients in our study achieved a favorable outcome on disability assessment at 90 days with an mRS score of 0 or 1, thus meeting the secondary clinical efficacy outcome of the study. Only 1 (7%) patient developed an adverse event in the form of SICH. The same patient also developed aspiration pneumonia and subsequently died.

Table 2

Outcome analysis after tenecteplase thrombolysis

Variables	Values	Significance of difference from baseline (P)
NIHSS score (mean±SD)
Baseline	12.93±3.81
2 h	10.57±5.14	0.061*
24 h	9.29±5.74	0.016*
mRS score (median)
Baseline	5
90 days	1	0.001†

*One-way repeated measures ANOVA, †Wilcoxon signed-rank test. NIHSS=National Institute of Health Stroke Scale, mRS=Modified Rankin scale, SD=Standard deviation

DISCUSSION

At present, the “incidence” and “case fatality rate” of stroke is higher in low- and middle-income countries according to the results of recently published Prospective Urban Rural Epidemiology study.[7] The stroke epidemic has recently arrived in India and is now a major health burden for our nation.[8] There are several barriers to acute stroke management in India including recognition of stroke symptoms, prehospital delays, inadequate ambulance services, and cost of tPA. Among these, the high cost of conventionally used tPA (alteplase) is the major hurdle for depriving the impoverished of getting a successful stroke treatment. The present study reconfirmed the efficacy and safety profile of tenecteplase in acute ischemic stroke, as observed in other recent studies. In our study, 64% (9/14) patients met the primary clinical efficacy outcome by achieving an improvement in NIHSS score of 4 or more points at 24 h and 78.5% (11/14) met the secondary clinical efficacy outcome by having an mRS score of 0 or 1 at 90 days. In another single arm study respecting tenecteplase in stroke, Belkouch et al. reported a 24 h improvement of NIHSS score by >4 points in 77% (10/13) cases.[6] Among Indian patients, none of the studies have reported the results of tenecteplase in stroke thrombolysis so far. However, our observations regarding the efficacy of Tenecteplase are similar to the results of previous Indian data regarding alteplase. Durai Pandian et al. from All India Institute of Medical Sciences reported 65% patients to have an improvement of 4 or more points in NIHSS score at 48 h with alteplase.[9] We observed highly significant difference between NIHSS scores at baseline and 24 h (P = 0.006) which is in agreement with the previously published studies on tenecteplase.[4] In the present study, 78.5% patients had an excellent recovery at 90 days with mRS score being 0 or 1, which is even better than the results of a recent RCT in which excellent recovery was observed in 54% subjects.[4] One patient (7%) in our study developed SICH and additionally, aspiration pneumonia with subsequent death. This rate of adverse event with tenecteplase thrombolysis is in line with the previous studies.

Thus, the results of our study reiterate the previous observations that tenecteplase is an effective and safe rt-PA agent for acute ischemic stroke thrombolysis.[410] However, the study has several limitations. First, we observed the results in a small number of patients and the findings need to be confirmed with a larger sample size. Second, ours was a single arm study with tenecteplase; however, a randomized comparison with alteplase is required to obtain a realistic data for our patients. Further, we performed IV thrombolysis with tenecteplase within 3 h of the symptoms onset, however, the benefits need to be confirmed in the extended time window of 4.5 h, as observed in other studies. Respecting these limitations, a matched comparative study of alteplase versus tenecteplase in acute ischemic stroke is underway at our hospital.

CONCLUSION

Tenecteplase appears to be a safe and efficacious agent for stroke thrombolysis. Considering its significantly low price and ease of administration, tenecteplase seems to be a suitable thrombolytic agent for stroke patients in developing countries.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.