Authors (including presenting author) :
Lo WT (1), Fong WC (1), Cheung YF (1), Fong KW (1), Chan LT (1), Chan HF (1), Ismail M (1), Li TC (1), Chan CC (1), Chan CH (1), Luk CO (1), Chau SK (1), Ho YT (1), Lui CM (1), Kwok WY (1), Yuen MK (1), Chan ST(1), Fong CS(1), Or HF (1).
Affiliation :
(1) Department of Medicine, Queen Elizabeth Hospital.
Introduction :
Approximately 20-30% of all strokes are due to large vessel occlusions (LVO). The efficacy of recanalization by intravenous (IV) thrombolysis by the 2nd generation thrombolytic Alteplase is about 50%, but is lower for strokes with high clot burden, such as LVOs.
Tenecteplase (TNK) is a 3rd generation thrombolytic. It has the advantages of higher fibrin affinity, greater resistance to inactivation by plasminogen activator inhibitor, translating into higher efficacy in clot lysis and potentially lower haemorrhagic complications. Tenecteplase has a longer half-life, and can be administered as a single IV bolus, this being an advantage over the one-hour infusion that Alteplase needs, as the door-to-treatment time can be shortened.
Meta-analyses of randomized controlled trials had shown higher early recanalization rates in stroke patients given Tenecteplase than Alteplase, and some studies had shown a higher chance of early neurological improvement, with comparable safety profile. The Extend IA-TNK trial studied LVO patients given either IV Tenecteplase (0.25mg/kg) or Alteplase before mechanical thrombectomy. A significantly higher proportion of patients had recanalization achieved by IV Tenecteplase alone (22%) when compared to IV Alteplase alone (10%), without an increase in intracerebral haemorrhage (ICH). The functional outcome (3-month modified Rankin scale (mRS)) was more favourable. The EXTEND IA-TNK part 2 trial confirmed the dosage of 0.25 mg/kg to be the optimal dose for LVO strokes. A meta-analysis of randomized controlled trials of LVO patients suggested an estimate of an additional 173 more patients per 1000 treated patients to be non-disabled at 3 months if they were treated with Tenecteplase than if given Alteplase, International guidelines have now included the option of IV Tenecteplase 0.25 mg/kg for patients with LVO eligible to undergo mechanical thrombectomy. Real world registry studies of Tenecteplase showed comparable safety and efficacy profile.
Objectives :
The aim of this study was to review the safety and efficacy outcomes of Tenecteplase versus Alteplase (standard dose) for suspected anterior circulation LVO strokes in our hospital. The Tenecteplase treatment protocol was started in our hospital since May 2020 to include IV Tenecteplase as an option for LVO patients, in view of current evidence with corresponding changes in guidelines. Acute ischaemic stroke patients within the 4.5 hour time window eligible for IV thrombolytic use would be candidates for Tenecteplase (0.25 mg/kg) if they have clinically suspected or angiographically proven LVOs. “Angiographically proven LVO” patients are those with confirmation on computed tomography angiography (CTA). “Suspected LVO” patients are those with National Institute of Health Stroke scale (NIHSS) score >= 6 points, plus cortical signs or have hyperdense vessel sign on plain computed tomography (CT) of the brain, but CT angiography (CTA) and endovascular intervention service are not available or not suitable. Whether Tenecteplase was used instead of Alteplase was the discretion of the treating neurologist.
The EXTEND IA-TNK trials and subsequent trials in this era of mechanical thrombectomy select patients by angiography or perfusion, or would have mechanical thrombectomy performed for LVO patients who failed intravenous thrombolysis. This study specifically reviewed clinically suspected LVOs, (that is, without sophisticated imaging selection apart from CT brain, and without availability of endovascular therapy irrespective of recanalization success), to see how the safety and efficacy outcomes would be when compared to Alteplase. Such scenario is still common locally when provision of mechanical thrombectomy is only available in office hours in some hospitals. In view of low recanalization rates of Alteplase in LVOs, alternative thrombolytics of expected higher efficacy should be considered especially when mechanical thrombectomy cannot be offered. In this study, only anterior circulation strokes were included as we wanted to compare our outcomes with LVO patients given thrombolysis in international trials (HERMES collaboration), and for easier comparison between the groups of the pre-thrombolysis CT brain using the Alberta Stroke Program Early CT score (ASPECTS) for anterior circulation strokes.
Methodology :
This study is a retrospective comparison study of patients who received Tenecteplase (0.25 mg/kg) versus Standard dose Alteplase (0.9 mg/kg) within the 4.5 hour time window in our hospital. Data was retrieved from our stroke thrombolysis registry and from the electronic patient record system.
All consecutive patients treated with IV thrombolytics from 1st January till 30th September, 2020 were reviewed, retrieving data for patients given Tenecteplase and Standard dose Alteplase. (We have been informed in October 2020 that the stock of Tenecteplase worldwide may not be sufficient due to resource diversion during COVID, so we had cut down on the use of Tenecteplase then.) Only anterior circulation suspected LVO strokes were included. Excluded from the analysis were: 1) mechanical thrombectomy patients; 2) low dose Alteplase patients; 3) posterior circulation strokes, 4) final diagnosis of stroke mimics, or 5) poor premorbid patients (modified Rankin scale (mRS) >2) for fairer outcome comparison, as only good pre-morbid (mRS 0-2) patients were included for Tenecteplase use in this phase.
These Tenecteplase patients with suspected anterior circulation LVO were matched with Alteplase patients from our IV thrombolysis stroke registry dating back from 2008, using the same inclusion and exclusion criteria. The following parameters were used to match: age (+/- 5 years difference), onset-to-needle time (+/-10 mins difference), atrial fibrillation (AF) and NIHSS. Where possible, the side of weakness was matched, as the NIHSS score would be more comparable. The Alteplase patients with the closest NIHSS were recruited to be the matching patient. As AF related clots may be easier to lyse, we attempted to match the presence of AF.
Demographics, baseline stroke severity according to the NIHSS score, imaging features of early ischemia according to ASPECTS and treatment parameters (symptom onset-to-needle time, door-to-needle time) were compared (1) between Tenecteplase and Alteplase patients, and (2) with the non-interventional control arm of HERMES collaboration study of proximal anterior circulation LVO strokes endovascular trials. The non-interventional arm in HERMES has 653 patients in total, 87% of whom received intravenous Alteplase.
Safety outcomes were the symptomatic ICH rate, parenchymal haematoma-2 (PH-2) rate and 30-day all-cause mortality. Efficacy outcomes were an excellent (>= 8 points) NIHSS improvement at 24 hours post thrombolysis, a good (>= 4 points) NIHSS improvement at 24 hours post thrombolysis, and a good 3-month functional outcome (mRS 0-2).
Result & Outcome :
There were consecutively 91 patients treated with IV thrombolytics from 1st May till 30th September, 2020, out of which 35 were given Tenecteplase. Excluded in our analysis were 7 mechanical thrombectomy patients, 2 posterior circulation strokes, 3 not met the suspected LVO criteria, and 2 protocol violations. Three Tenecteplase patients could not be matched with the Alteplase patients from our IV thrombolysis registry. Finally there were 18 Tenecteplase patients included in our analysis for suspected anterior circulation LVO strokes without endovascular thrombectomy done to compare with 18 Standard-dose Alteplase patients.
Baseline parameters were similar. The mean age was 78 years, and the median ASPECTS was 9. The median NIHSS was 19 and 20 for the Tenecteplase and Alteplase patients respectively.
There was no significant difference in safety outcome, with a similarly low incidence of symptomatic intracerebral haemorrhage (none in the Tenecteplase group and 1 patient (5.6%) in the Alteplase group). The 30-day all-cause mortality was 11.1% (2 patients) in the Tenecteplase group, and 16.7% (3 patients) in the Alteplase group, none related to bleeding. No angioedema occurred. No significant differences in efficacy outcomes in terms of 24-hour NIHSS improvement or 3-month functional outcome were found. Both groups had 33% (6 patients) and 50% (9 patients) achieving an excellent and a good NIHSS improvement at 24 hours respectively. At 3 months, good functional outcome occurred in 33.3 % (6 patients) and 50% (9 patients) in the Tenecteplase and Alteplase group respectively. Two out of the 6 Tenecteplase patients with excellent 24-hour NIHSS improvement did not regain good 3-month functional outcome, one due to comorbidities, and the other had limited training in old care home. Some milder stroke patients in both groups had good functional outcome after rehabilitation despite no or only minor 24-hour NIHSS improvement.
In this study where clinically suspected anterior circulation large vessel occlusion patients selected for review are those without advanced imaging for case selection or thrombectomy, so outcome solely reflects the effects of Tenecteplase, Tenecteplase is safe and of similar efficacy when compared with Alteplase. Even a comparable efficacy and safety profile would mean that Tenecteplase can be considered, as it can be given as a bolus dose, this being important in the time critical stroke treatment where time is brain. Hence the use of Tenecteplase should be considered with monitoring of outcome.
