It’s the thing to do in stroke – wedge new treatments into practice with a narrow time window and strict eligibility requirements, then expand, expand, expand.
This latest publication/advertising supplement in the Journal of the American Medical Association pools together the endovascular trials MR CLEAN, ESCAPE, EXTEND-IA, REVASCAT, and SWIFT-PRIME for an individual-patient meta-analysis to explore the various nuances of the treatment effect. After much cleaning and tweaking, the authors come around and say “Whoa! We found a benefit out to 7.3 hours from symptom onset, not just the 6 hour limit recommended by the American Heart Association!”
These were all positive trials, so it’s no surprise the overall outcome is positive – nor is these authors ability to drag out favorable outcomes beyond the 6-hour cut-off, considering some of these trials enrolled patients out to twelve hours. However, in their clumsy calisthenics to marry these data to the time-based hypothesis of acute stroke practice, these authors are clearly dancing around the most important bit of evidence emerging from these trials: imaging selection. They spend a handful of sentences discussing the imaging selection eligibility criteria of the included trials, but one benefit of meta-analyses is its use as a tool to obfuscate such inconvenient aspects in favor of words, words, words relating to the methods of their statistical analysis.
As I described in my #smaccDUB talk, you need two things for stroke therapy to be effective: viable tissue and effective reperfusion. These trials – ESCAPE, EXTEND-IA, and SWIFT-PRIME – finally hit that sweet spot with small infarct cores and safe, effective recanalization. Some of that viable tissue absolutely decays over time, so the time-based hypothesis is not entirely untrue, but it’s a low-value oversimplification. As many of use in Comprehensive Stroke Centers have seen, perfusion imaging can direct therapy for patients far outside the general AHA recommendations. The obvious corollary to this, however, is that perfusion imaging similarly identifies patients for whom intervention is futile, regardless of time window. This second point runs contrary, however, to the financial interests at stake here.
The authors do mention imaging-based criteria is being investigated in multiple clinical trials, e.g.: NCT02142283, NCT02586415. However, these trials are carefully designed not to enroach upon established time-based criteria, and to use imaging only to further extend the treatment windows.
Other fun tidbits:
- A few patients randomized to endovascular intervention did not receive one. After all, most received pre-intervention tPA – some would be expected to recanalize with medical therapy alone. However, this publication gives another lovely window into our clot-buster that doesn’t bust clots: only 6.8% could be reasonably concluded to have had clot thrombolysis after medical therapy alone. We probably should not be giving tPA to patients for whom endovascular intervention is planned.
- All five studies cited here were published in the New England Journal of Medicine. This meta-analysis is in JAMA. Presented without comment.
“Time to Treatment With Endovascular Thrombectomy and Outcomes From Ischemic Stroke: A Meta-analysis”
Coda – there were just a couple relevant conflict of interest disclosures:
Dr Saver reports being an employee of the University of California; serving as an unpaid site investigator in multicenter trials run by Medtronic and Stryker for which the UC Regents received payments on the basis of clinical trial contracts for the number of subjects enrolled; receiving stock options for services as a scientific consultant regarding trial design and conduct to Cognition Medical; receiving funding for services as a scientific consultant regarding trial design and conduct to Covidien/Medtronic, Stryker, Neuravi, BrainsGate, Pfizer, Bristol Myers-Squibb, Boehringer Ingelheim (prevention only), ZZ Biotech, and St Jude Medical; serving as an unpaid consultant to Genentech advising on the design and conduct of the PRISMS trial; neither the University of California nor Dr Saver received any payments for this voluntary service. The University of California has patent rights in retrieval devices for stroke. Dr Goyal reports receiving grants from Covidien/Medtronic, consulting payments from Covidien/Medtronic, and having patent rights in systems and methods for diagnosing strokes (PCT/ CA2013/000761) licensed to GE Healthcare. Dr van der Lugt reports grant funding from the Dutch Heart Foundation, AgioCare BV, Medtronic/Covidien/EV3, MEDAC Gmbh/LAMEPRO/Penumbra, Stryker, and Top Medical/Concentric. Dr Menon reports serving as an unpaid member of in the ESCAPE trial, which received support from Covidien/Medtronic, receiving grant support from AstraZeneca, honoraria from Penumbra, a submitted patent for triaging systems in ischemic stroke, and serving on the board of QuikFlo Health. Dr Majoie reports that his institution has received honoraria for his service on a Speaker’s Bureau from Stryker. Dr Dippel reports that his institution has received honoraria for his speaking from Stryker and grant funding from the Dutch Heart Foundation, AgioCare BV, Medtronic/Covidien/EV3, MEDAC Gmbh/ LAMEPRO, Penumbra, Stryker, and Top Medical/ Concentric. Dr Campbell reports that his institution received a grant to support the EXTEND-IA trial from Covidien/Medtronic. Dr Campbell reports grant funding from the National Health and Medical Research Council of Australia and Medtronic and fellowships from the National Heart Foundation of Australia, National Stroke Foundation of Australia, and Royal Australasian College of Physicians. Dr Nogueira reports receiving fees for service on steering and data safety monitoring committees to Medtronic, Stryker, Penumbra, and Rapid Medical. Dr Demchuk reports receiving grant support and personal fees from Covidien/Medtronic and personal fees from Pulse Therapeutics. Dr Devlin reports that his institutions received clinical trial payments for patients enrolled in clinical trials from Medtronic, clinical trial support from Brainsgate and Genervon, and holding a patent. Dr Frei reports personal fees from Penumbra, Stryker, Codman, MicroVention, and Siemens. Dr Jovin reports receiving fees for service on steering committees from Silk Road Medical, Covidien, Stryker Neurovascular, Air Liquide; personal fees from Neuravi and Johnson & Johnson; nonfinancial support from Fundacio Ictus; and serving on the advisory board for Anaconda. Dr Siddiqui reports personal fees from StimSox, Valor Medical, Neuro Technology Investors, Cardinal Health, Medina Medical Systems, Buffalo Technology Partners, International Medical Distribution Partners, Codman & Shurtleff, Medtronic, GuidePoint Global Consulting, Penumbra, Stryker, MicroVention, W. L. Gore & Associates, Three Rivers Medical, Corindus, Amnis Therapeutics, CereVasc, Pulsar Vascular, the Stroke Project, Cerebrotech Medical Systems, Rapid Medical, Lazarus, Medina Medical, Reverse Medical, Covidien, Neuravi, Silk Road Medical, Rebound Medical, Intersocietal Accreditation Committee; other fees from Penumbra, 3D Separator Trial, Covidien, SWIFT PRIME and SWIFT DIRECT trials, MicroVention, FRED trial, CONFIDENCE study, LARGE trial, POSITIVE trial, COMPASS trial, INVEST trial. Dr van Zwam reports that his institution has received honoraria for his speaking from Stryker and Codman. Dr Davis reports lecture fees and research support from Covidien/Medtronic; travel support from Bristol Myers-Squibb and Pfizer; and advisory board fees from Boehringer Ingelheim and Medtronic. Dr Silver reports personal fees from Boehringer Ingelheim. Dr Donnan reports nonfinancial support from Boehringer Ingelheim; grants from the Australian National Health and Medical Research Council; and fees for service on advisory boards for Boehringer Ingelheim, AstraZeneca, Bristol Myers-Squibb, Pfizer and Merck Sharp & Dohme. Dr Brown reports receiving consulting fees from Medtronic/Covidien and personal fees from the University of Calgary. Dr Mitchell reports that his institution received a grant to support the EXTEND-IA trial from Covidien/Medtronic; his institution has received unrestricted research funding and grants from Codman Johnson and Johnson, Medtronic, and Stryker; and serving as an unpaid consultant to Codman Johnson and Johnson. Dr Davalos reports receiving payments for serving on a multicenter study steering committee and grant funding from Medtronic. Dr Roos reports grant funding from Medtronic. Dr Hill reports unrestricted grant funding for the ESCAPE trial to University of Calgary from Covidien/Medtronic, and active/in-kind support consortium of public/charitable sources (Heart and Stroke Foundation, Alberta Innovates Health Solutions, Alberta Health Services) and the University of Calgary (Hotchkiss Brain Institute, Departments of Clinical Neurosciences and Radiology, and Calgary Stroke Program); personal fees from Merck, nonfinancial support from Hoffmann-La Roche Canada. In addition, Dr Hill has a submitted patent for triaging systems in ischemic stroke, and owns stock in Calgary Scientific, a company that focuses on medical imaging software. No other disclosures were reported.
Funding/Support: The HERMES pooled analysis project is supported by a grant from Medtronic to the University of Calgary.