Periodic Reporting for period 4 - TENSION (Efficacy and safety of thrombectomy in stroke with extended lesion and extended time window: a randomized, controlled trial)
Reporting period: 2022-07-01 to 2023-12-31
TENSION (efficacy and safety of ThrombEctomy iN Stroke with extended leSION and extended time window: a randomized, controlled trial) strives at providing innovative treatment to patients with severe stroke to reduce the individual and societal burden of death and dependency from stroke. To this end, TENSION is a randomized, controlled, prospective, open label, blinded endpoint (PROBE) trial of thrombectomy in stroke patients with extended ischemic stroke lesions and patients presenting in a late time window, who are excluded from available effective treatment approaches based on current knowledge and guidelines. The aim of TENSION is to provide evidence to guide effective treatment in these patients. The trial will enroll up to 665 subjects in eight European countries. Outcome evaluation will involve a comprehensive array of clinical and safety parameters, health and socio-economic outcomes including patient reported outcome measures (PROM) for evaluation according to the principles of value-based healthcare. Health economic evaluation with cost-effectiveness analysis will be performed and gender-effects on treatment and outcome will be studied. Stroke is a major cause of death and disability in Europe with a large social and economic impact on patients, families, and society. The burden of stroke is in large parts determined by severe strokes resulting from the occlusion of large brain-supplying arteries. About 1.5 million people suffer from stroke in the EU each year with 10-20% severe strokes that might be candidates for thrombectomy, but in whom the benefit of treatment is uncertain. Based on current knowledge, no effective treatment is available for these patients, if brain lesions resulting from stroke are already extended and if patients arrive late in hospital, i.e. up to 12 hours of symptom onset. The central objective of TENSION is to assess whether stroke treatment using an existing currently available intervention, i.e. thrombectomy, improves clinical outcome, survival and quality of life in severe stroke patients with extended lesions and in an extended time window, as well. By this, TENSION will increase the population of stroke patients that may effectively be treated with thrombectomy. The larger demand for stroke thrombectomy together with the unequivocal demonstration of clinical benefit in a randomized controlled trial will foster area-wide implementation of thrombectomy and support establishment of interventional stroke in all European countries.
During the final reporting period, the main tasks were related to completion of the clinical trial, data analysis, publication, and dissemination. In February 2023, a pre-planned interim analysis of the trial was performed including primary outcome data of 222 patients. In this analysis, pre-defined thresholds for overwhelming efficacy were met. Based on these results, the independent Members of the data safety and monitoring board (DSMB) unanimously recommended permanent closure of enrolment in the trial with continued follow-up of existing patients and analysis of final data in due course. On May 12th 2023, the last patient underwent the ninety day follow up visit for primary outcome evaluation. Subsequent monitoring visits and data cleaning allowed for the export of the trial data on July 7th 2023. Statistical analysis according to the proposed statistical analysis plan was performed effectively and the manuscript and supplementary materials were prepared for submission. The manuscript was submitted to The Lancet accepted for publication (https://doi.org/10.1016/S0140-6736(23)02032-9(opens in new window)) and published simultaneously to presentation of the results at the World Stroke Congress 2023 in Toronto.
The study was conducted in 40 hospitals in Europe and one site in Canada. All trial-related boards and committees are working effectively. The image core lab continuously evaluated all images acquired within the trial, and the quality of image judgement by local investigators was deemed good. The primary analysis was done in the intention-to-treat population, i.e. all patients were analysed according to the randomized assignment. Primary outcome was functional status at 90 days. Safety endpoints included mortality and rates of symptomatic intracranial haemorrhage.
The trial results demonstrated a clear benefit of thrombectomy together with best medical treatment over best medical treatment alone: At 90 days, endovascular thrombectomy was associated with a shift in the distribution of scores on the modified Rankin Scale towards better outcome (adjusted common odds ratio 2·58 [95% confidence interval 1·60–4·15]; p=0·0001). Thrombectomy was also associated with a lower mortality (hazard ratio 0·67 [95% confidence interval 0·46–0·98]; p=0·038). There were no safety concerns.
We also completed health-economic analyses, which demonstrated that thrombectomy for acute ischemic stroke with established large infarct is likely to be cost-effective compared with best medical treatment alone, assuming that an additional investment of €17,158/QALY is deemed acceptable by the healthcare payer.
Dissemination, communication and exploitation activities were intensified and are continued beyond the end of the project including plans for scientific data sharing with the other completed trials of thrombectomy in patients with low ASPECTS.
The study was conducted in 40 hospitals in Europe and one site in Canada. All trial-related boards and committees are working effectively. The image core lab continuously evaluated all images acquired within the trial, and the quality of image judgement by local investigators was deemed good. The primary analysis was done in the intention-to-treat population, i.e. all patients were analysed according to the randomized assignment. Primary outcome was functional status at 90 days. Safety endpoints included mortality and rates of symptomatic intracranial haemorrhage.
The trial results demonstrated a clear benefit of thrombectomy together with best medical treatment over best medical treatment alone: At 90 days, endovascular thrombectomy was associated with a shift in the distribution of scores on the modified Rankin Scale towards better outcome (adjusted common odds ratio 2·58 [95% confidence interval 1·60–4·15]; p=0·0001). Thrombectomy was also associated with a lower mortality (hazard ratio 0·67 [95% confidence interval 0·46–0·98]; p=0·038). There were no safety concerns.
We also completed health-economic analyses, which demonstrated that thrombectomy for acute ischemic stroke with established large infarct is likely to be cost-effective compared with best medical treatment alone, assuming that an additional investment of €17,158/QALY is deemed acceptable by the healthcare payer.
Dissemination, communication and exploitation activities were intensified and are continued beyond the end of the project including plans for scientific data sharing with the other completed trials of thrombectomy in patients with low ASPECTS.
TENSION has fulfilled his overall ambition, which was to make effective treatment available for severe stroke patients and by this to improve functional outcome and quality of life of thousands of stroke patients in Europe, and to reduce the individual, societal and economic burden of death and disability resulting from severe stroke. In the clinical trial, endovascular thrombectomy was associated with improved functional outcome and lower mortality in patients with acute ischaemic stroke from large vessel occlusion with established large infarct in a setting using non-contrast CT as the predominant imaging modality for patient selection. These findings are novel and carry important implications for clinical practice worldwide.
In a so-called thrombectomy, blood clots are removed from the arteries of the brain with the help of a catheter in the event of a stroke to restore blood flow to the brain. Until recently, this thrombectomy has only been used regularly if a stroke had not yet caused major brain damage. The TENSION research project demonstrated that catheter treatment is also effective for severe strokes. This treatment method can help patients to develop less secondary damage and lead a more independent life. On this basis, standard therapy for severe strokes can be expanded and patient care can be improved. By this, TENSION will help reduce the amount of 4 million DALYs lost each year due to stroke in the EU, and also the estimated more than € 64 billion health-care cost for stroke in Europe.
In a so-called thrombectomy, blood clots are removed from the arteries of the brain with the help of a catheter in the event of a stroke to restore blood flow to the brain. Until recently, this thrombectomy has only been used regularly if a stroke had not yet caused major brain damage. The TENSION research project demonstrated that catheter treatment is also effective for severe strokes. This treatment method can help patients to develop less secondary damage and lead a more independent life. On this basis, standard therapy for severe strokes can be expanded and patient care can be improved. By this, TENSION will help reduce the amount of 4 million DALYs lost each year due to stroke in the EU, and also the estimated more than € 64 billion health-care cost for stroke in Europe.