Intravenous alteplase for stroke with unknown time of onset guided by advanced imaging: systematic review and meta-analysis of individual patient data

Background: Patients who have had a stroke with unknown time of onset have been previously excluded from thrombolysis. We aimed to establish whether intravenous alteplase is safe and effective in such patients when salvageable tissue has been identified with imaging biomarkers. Methods: We did a systematic review and meta-analysis of individual patient data for trials published before Sept 21, 2020. Randomised trials of intravenous alteplase versus standard of care or placebo in adults with stroke with unknown time of onset with perfusion-diffusion MRI, perfusion CT, or MRI with diffusion weighted imaging-fluid attenuated inversion recovery (DWI-FLAIR) mismatch were eligible. The primary outcome was favourable functional outcome (score of 0–1 on the modified Rankin Scale [mRS]) at 90 days indicating no disability using an unconditional mixed-effect logistic-regression model fitted to estimate the treatment effect. Secondary outcomes were mRS shift towards a better functional outcome and independent outcome (mRS 0–2) at 90 days. Safety outcomes included death, severe disability or death (mRS score 4–6), and symptomatic intracranial haemorrhage. This study is registered with PROSPERO, CRD42020166903. Findings: Of 249 identified abstracts, four trials met our eligibility criteria for inclusion: WAKE-UP, EXTEND, THAWS, and ECASS-4. The four trials provided individual patient data for 843 individuals, of whom 429 (51%) were assigned to alteplase and 414 (49%) to placebo or standard care. A favourable outcome occurred in 199 (47%) of 420 patients with alteplase and in 160 (39%) of 409 patients among controls (adjusted odds ratio [OR] 1·49 [95% CI 1·10–2·03]; p=0·011), with low heterogeneity across studies (I2=27%). Alteplase was associated with a significant shift towards better functional outcome (adjusted common OR 1·38 [95% CI 1·05–1·80]; p=0·019), and a higher odds of independent outcome (adjusted OR 1·50 [1·06–2·12]; p=0·022). In the alteplase group, 90 (21%) patients were severely disabled or died (mRS score 4–6), compared with 102 (25%) patients in the control group (adjusted OR 0·76 [0·52–1·11]; p=0·15). 27 (6%) patients died in the alteplase group and 14 (3%) patients died among controls (adjusted OR 2·06 [1·03–4·09]; p=0·040). The prevalence of symptomatic intracranial haemorrhage was higher in the alteplase group than among controls (11 [3%] vs two [<1%], adjusted OR 5·58 [1·22–25·50]; p=0·024). Interpretation: In patients who have had a stroke with unknown time of onset with a DWI-FLAIR or perfusion mismatch, intravenous alteplase resulted in better functional outcome at 90 days than placebo or standard care. A net benefit was observed for all functional outcomes despite an increased risk of symptomatic intracranial haemorrhage. Although there were more deaths with alteplase than placebo, there were fewer cases of severe disability or death. Funding: None

Patient, Relative and Staff Experiences of Clinical Trial Participation in Neurooncology: “Maybe You Can Also Show the Positive, No Matter How It Ends”

Ronja Thallner,1 Christoph Gumbinger,1 Anja Hohmann,1 Antje Wick,1 Wolfgang Wick,1 Loraine Busetto1,2 1Department of Neurology, Heidelberg University Hospital, Heidelberg, Germany; 2Institute for Medical Virology, Goethe University Frankfurt, University Hospital, Frankfurt am Main, GermanyCorrespondence: Loraine Busetto, Institute for Medical Virology, Goethe University Frankfurt, University Hospital, Paul-Ehrlich-Straße 40, Frankfurt am Main, 60590, Germany, Tel/Fax +49 69 6301-86103, Email [email protected]: There is a lack of evidence regarding how patients with malignant brain tumor and their relatives experience participation in neurooncological clinical trials. Similarly, insights from the perspective of trial staff caring for this group of patients are missing. This study aims to investigate patient, relative and trial staff experiences regarding participation in clinical neurooncological trials.Methods: Within a qualitative exploratory study, 29 semi-structured interviews with brain tumor patients, relatives and trial staff were conducted and analyzed using reflexive thematic analysis (RTA) by Braun and Clarke. A patient researcher and patient council were involved in data analysis and interpretation.Results: Four themes were developed reflecting significant aspects of the trial experience: 1. “It all revolves around hope”; 2. “Trial participation: experiencing unique medical care”; 3. “Everyone’s roles are changing”; 4. “Communication as a possible area of conflict”. Experiencing trial participation and general medical treatment were found to be interconnected to such a degree that they were often not meaningfully distinguished by patients and relatives.Conclusion: In addition to assessing traditional endpoints for patient outcomes, we recommend increased emphasis on investigating the impact of the “soft” components constituting trial participation. Due to the interconnectedness of medical treatment and trial participation, we recommend further investigation in comparison to experiences in regular care. A deeper understanding of trial participation is needed to inform improvements for patient experiences and staff satisfaction alongside medical and scientific progress.Plain Language Summary: The treatment options available to patients with (malignant) brain tumors are currently very limited. Therefore, patients are sometimes offered to participate in a clinical trial. This means that they receive an experimental treatment (eg new medicine) for which it is not yet clear whether it works better than regular medical care. Currently, little is known about how this group of patients, their relatives and the hospital staff who care for them experience the participation in these clinical trials – which is what we aimed to explore in our study reported here.Based on interviews with patients, relatives and staff, we found that:trial participation mainly revolves around hope;trial participation entails experiencing unique medical care;trial participation significantly changes the previous roles of patients, relatives and staff;trial participation intensifies communication as a possible area of conflict.By providing information on how patients, relatives and staff make sense of their trial experiences, this study constitutes an important addition to the traditional focus of clinical trials on medical and scientific endpoints (eg progression-free survival). This may help clinicians and researchers involved in cancer research and treatment to understand why “unsuccessful” trials can still be perceived as positive by patients or how hopeful communication may support their patients even when perceived as “unrealistic” from the clinicians’ perspective. An in depth understanding of trial participation from the perspective of those affected is needed for improved care experiences alongside medical and scientific progress for cancer treatment.Keywords: cancer research, brain tumor, qualitative research, care experience