COMMENTARY

Important New Results in Stroke

Hans-Christoph Diener, MD, PhD

Disclosures

March 26, 2019

This transcript has been edited for clarity.

Dear colleagues, I'm Christoph Diener, a neurologist from the University of Duisburg-Essen in Germany. Today I want to inform you about the most important results from the International Stroke Conference, which was held in Hawaii at the beginning of February.

Let me start with three positive studies. The first one was the Australian EXTEND study.[1] This study investigated whether tissue plasminogen activator (tPA) is superior to placebo in the time window between 4.5 and 9 hours. This study included not only patients in this time window but also patients with wake-up stroke. The decision to randomize patients was based on perfusion imaging, using either CT or MRI perfusion.

The study randomized 225 patients, and the endpoint was modified Rankin 0 or 1, which is a good outcome. This was achieved in 35% of patients with tPA compared with 29% on placebo, and this translates to an adjusted risk ratio of 1.44 at 90 days. The mortality was 12% with tPA whereas it was 9% with placebo, which was not significantly different. As you would expect, the rate of symptomatic hemorrhage was higher with tPA, at 6% versus 1%.

If we take all of the evidence from the past 2 or 3 years, both on thrombectomy and tPA, we will no longer consider patients by a fixed time window. I think the decision about whether to choose tPA or thrombectomy basically depends on functional imaging, either with perfusion CT or perfusion and diffusion-weighted imaging on MRI.

The second study was a really exciting study from Japan that recruited patients with non-cardioembolic stroke.[2] They were randomized to either a monotherapy with aspirin or clopidogrel or the combination of cilostazol with aspirin and clopidogrel. The study recruited 1884 patients and the primary endpoint was recurrent stroke. This happened in 29 of 913 patients on combination therapy, which is 3.2%, compared with 64 out of 926 patients on monotherapy, which is 6.9%.

The combination therapy had a hazard ratio of 0.49, which means a 50% risk reduction, as there was no increased risk of bleeding with combination therapy. This study was done in Japan, and whether the results translate to patients outside of Asia or Japan is unknown at the moment. It would be really worthwhile to replicate this study, for example in North America and Europe.

We have a very effective reversal agent for dabigatran, which is idarucizumab, and we also now have a reversal agent for Xa inhibitors and heparin, which is andexanet alfa. The ANNEXA-4 study was reported and simultaneously published in the New England Journal of Medicine.[3] This study included 352 patients with acute major bleeding on either rivaroxaban or apixaban, and these patients were treated within 18 hours with andexanet alfa. The treatment is a bolus followed by 2 hours of infusion. The endpoint was a change in anti-Xa activity and good hemostatic activity at 12 hours.

Approximately two thirds of patients had intracranial hemorrhage and 26% had GI gastrointestinal bleeds. On average, the severely sick patients were 77 years old. There was a 92% reduction in anti-Xa activity at 2 hours and 34% at the end of infusion. Good hemostasis was achieved in 82% of patients. Mortality was 14% and thrombotic events occurred in 10% of patients, mostly in patients who could no longer be anticoagulated and still had a high risk for thrombotic events due to atrial fibrillation.

The study clearly shows that andexanet alfa is a highly effective reversal agent for anti-Xa inhibitors. The downside, I think, is the high cost, which is currently about $24,000 for the lower dose of andexanet alfa in the United States.

We also had quite a number of neutral trials. I would like to start with the most frustrating study, which was the SHINE study: Stroke Hyperglycemia Insulin Network Effort.[4] This study included patients with type 2 diabetes or glucose above 150 mg/dL and an acute stroke. The investigators compared intensive therapy with IV insulin and a target blood glucose between 80 and 130 mg/dL, whereas the standard subcutaneous therapy had a target below 180 mg/dL.

This study included 1151 patients and the endpoint was modified Rankin at 90 days. Patients treated with intensive glucose therapy achieved good control of glucose, but there was no difference in outcome. Hypoglycemia, as you would expect, was more frequent with IV insulin.

The RIGHT-2 study was designed to investigate the transdermal application of glyceryl trinitrate (GTN) in the ambulance by paramedics in people with acute stroke.[5] The inclusion criterion was a blood pressure above 120 mm Hg. The study in the UK recruited 1149 patients with either acute stroke or TIA, including 26% with stroke mimics. The GTN group achieved a 5.8–mm Hg lower blood pressure than control but there was no difference in functional outcome or mortality.

ENCHANTED was a factorial study, which was designed to compare a lower dose of tPA, 0.6 mg/kg body weight, with a dose of 0.9 mg/kg.[6] The study also had randomization between intensive versus mild blood pressure lowering in 2227 patients. There was no difference in functional status in terms of modified Rankin Scale at 90 days. There were fewer intracranial hemorrhages with the more aggressive blood pressure lowering.

The RESPECT study from Japan included 1263 patients and was designed to compare aggressive blood pressure lowering with a milder blood pressure lowering.[7] The endpoint was recurrent stroke, and again, there was no difference in recurrent stroke.

I think the second most important study after the insulin study was the MISTIE III study.[8] This is a study with patients who had moderate to large intracerebral bleeds, usually basal ganglia bleeds. The patients were randomized to a minimally invasive therapy where a catheter is placed into the bleeding and low-dose tPA is given every 8 hours, compared with control.

This study included 506 patients and the endpoint was modified Rankin after 1 year. Unfortunately, there was no difference. There was a reduced mortality in the surgical group, which was offset by a higher rate of people who are severely disabled. Unfortunately, we still do not have effective surgical therapy for people with moderate to large intracerebral bleeds.

Ladies and gentlemen, there is a balance between a few positive trials, and as usual, more neutral or negative trials reported at the International Stroke Conference in Hawaii.

I am Christoph Diener from Germany. Thank you very much for listening and watching.

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