European Stroke Organisation Conference (ESOC)
May 16–18, 2017
May 16, 2017
The 3rd European Stroke Organization Conference (ESOC) session titled “Official Welcome and Large Clinical Trials” kicked off what was to be a spectacular conference with one of the most impactful 90 minutes I have ever witnessed. The session in the Grand Hall of the Prague Conference Center was standing room only and, after a warm introduction, incorporated 8 presentations from large clinical trials each lasting 8 minutes. The conference itself drew over 4,200 participants, challenging the International Stroke Conference in impact and attendance. This is a remarkable achievement for a conference in its third year of existence.
The session kicked off with the closure of patent foramen ovalle, oral anticoagulants or antiplatelet therapy to prevent stroke recurrence (CLOSE) clinical trial. In this study, over 600 patients with cryptogenic stroke were randomized to PFO closure versus antiplatelet therapy and anticoagulation. The number of events for the primary outcome of stroke was 14 in the antiplatelet arm versus zero in the closure arm, a highly statistically significant result. It was really out of the ordinary to have no events in the closure arm of the study, a reflection of some luck or excellent technique and timing in this French study. In general, the study investigators found that it would take 20 PFO closure procedures to prevent one stroke every five years. They did note 6% rate of atrial fibrillation in the PFO closure group compared to <1% in the medical arm.
The CLOSE presentation was followed by the Gore REDUCE clinical trial. This was a second study of PFO closure versus anti-thrombotic therapy and enrolled 664 patients in a 2-to-1 ratio of closure versus antiplatelet. No anticoagulation was allowed in this study. Of note, the study included MRI imaging for a novel co-primary outcome of brain infarction in addition to the standard clinical outcome of stroke. Half of the patients were recruited from the United States and half from Europe. Like the CLOSE study, patients in RECUE were young, aged 45, and 441 had closure of PFO with Gore device implant and 223 medical therapy. There was a significant 77% reduction in the primary endpoint with six events in the closure group and 12 events in the medical group; note that there were two times as many patients enrolled in the closure group. The MRI results were also interesting, with a new infarction found on 5.7% of closure versus 11.3% of medical therapy patients. Silent infarcts were two times more common in the medical therapy. The number needed to treat to prevent a stroke at two years with 28.
These two studies are sure to affect the current state of thought when it comes to PFO closure for cryptogenic stroke. Whereas the standard of care has been to only close PFO in the setting of recurrent stroke on best medical therapy, these results, when published, will affect practice. PFO closure may be considered as first-line therapy for well-selected true cryptogenic stroke in young individuals with no major stroke risk factors to address. These two studies appeared to be well conducted, and I look forward to their publication, and a larger meta-analysis of all clinical trials.
Next up in the session was the result of the DAWN clinical trial of thrombectomy in patients outside of the standard six-hour time window. DAWN utilized diffusion weighted imaging and CT perfusion imaging to select patients with clinical-core mismatch for thrombectomy versus medical therapy between six and 24 hours after last known while time. To get into the study, a patient needed to have an internal carotid artery or middle cerebral artery occlusion and an NIH stroke scale score of greater than or equal to 10. There has to be less than one third of the MCA territory demonstrating infarction on non-contrast CT or MRI. At that point, subjects received imaging with CT perfusion using the RAPID software to determine core volume based on prespecified threshold. In the MRI group, core was calculated off of the DWI and ADC images. In patients above the age of 80, there have to be less than 21 cc of core, whereas in patients less than 80, the size of core depended on the NIH stroke scale and could have been up to 50 cc. The primary outcome was a 90-day disability using a utility weighted modified ranking score. This study was stopped after 2 ½ years and 206 randomized patients by the DSMB due to overwhelming efficacy. The proportion of patients with independent function from 0 to 2 on the modified Rankin scale was 49% in the treated group versus 13% in the medical therapy group, a highly significant finding. There was no evidence of increase in symptomatic intracerebral hemorrhage and the study procedure was very well tolerated. The number needed to treat to shift the disability score on the modified Rankin scale was 2.
The results of DAWN are sure to impact the still care throughout the world when they are published and hopefully will be confirmed by the ongoing NIH-funded DEFUSE study. It would appear that the six-hour time window for thrombectomy applies to all ischemic stroke patients regardless of imaging characteristics; however, core-imaging guided thrombolysis may be independent of time. The magnitude of the effect should lead to further development and refinement of stroke systems of care with imaging to identify potential candidates in later windows. Notable in the study was the fact that many of these patients had wake up stroke and, therefore, the actual time of onset may have been far less than 24 hours; however, benefits were seen all the way out to 24 hours when imaging selection was used.
These three studies alone would have been more than enough; however, many other very important clinical trials were reported as well. The PICASSO study of Probucol, a CETP inhibitor, was also positive for its primary outcome. When Probucol was used on top of standard stroke therapy including statin in over 1,500 patients with the recent ischemic stroke, there was a significant reduction in the primary endpoint of stroke and intracerebral hemorrhage with a hazard ratio 0.69 and a p value of 0.03. The role of CETP inhibitors in stroke will need to be further evaluated, but the study authors thought the benefits were more likely pleotropic than necessarily having to do with dyslipidemia therapy.
Other studies of note included the RATS-3 study demonstrating that early cognitive linguistic therapy was not beneficial in improvement of daily verbal communication, and the T3 study demonstrating that trying to implement improved bundles of care in the ED for stroke is challenging. The ASTER trial showed that the adapt technique of using the aspiration catheter upfront versus stentriever upfront are compatible. Lastly, the Norwegian Tenecteplase place trial failed to show superiority of tenecteplase versus alteplase in patients with acute ischemic stroke. The study left open the intriguing possibility that the two treatments may be equivalent. This is a question that will need to be answered in future studies, including one currently ongoing in Australia.
Tenecteplase is a very important thrombolytic agent to explore because it is more thrombin-specific and requires a single injection rather than infusion over an hour. This may have an important role in stroke systems of care in the U.S., removing the barrier of needing infusion monitoring during transport. The days of “drip and ship” could be replaced by “squirt and ship.”
The city of Prague is beyond belief in its beauty. It is only the quality of the sessions at ESOC keeping me away from exploring the city further.
—Nerses Sanossian, MD