Karissa Arthur, MD
European Stroke Organisation Conference
September 1–3, 2021
Dual Antiplatelet Therapy for Minor Acute Ischemic Stroke: Clopidogrel vs Ticagrelor: Pierre Amarenco, Paris University
In this session, Dr. Amarenco compared clopidogrel versus ticagrelor for minor acute ischemic stroke. He first summarized data for aspirin monotherapy showing that it reduces the risk of ischemic stroke by 60%, and the 6-week risk of disabling stroke by 70%. He then called to attention the CHANCE and POINT trials, as well as a pooled analysis of both, showing that dual antiplatelet therapy with aspirin plus clopidogrel after a minor stroke or TIA is 34% superior to aspirin alone in preventing stroke in the first 21 days. Dr. Amarenco went on to discuss the shortcomings of clopidogrel, with specific regard to CYP2C19 loss of function carriers in which there is less efficacy for stroke prevention. In contrast to clopidogrel, ticagrelor is a direct acting drug which does not require biotransformation, binds reversibly to platelets, has faster onset, higher platelet inhibition, and faster offset and therefore has a more attractive profile than clopidogrel.
In the SOCRATES trial, ticagrelor was not superior to aspirin in reducing stroke, MI, or vascular death, but perhaps was superior in preventing stroke in patients with ipsilateral atherosclerotic stenosis of the cervico-cranial vasculature. In the THALES trial, ticagrelor plus aspirin was superior to aspirin alone in reducing stroke or death. THALES also found a number needed to treat of 34 when ticagrelor plus aspirin is used in patients with ipsilateral atherosclerotic stenosis compared to aspirin alone. Current AHA guidelines give class 2A recommendations for clopidogrel plus aspirin for 21 days, and 2B evidence for ticagrelor plus aspirin. However, if patients are CYP2C19 loss of function carriers (or cannot be tested quickly), it may be reasonable to treat with ticagrelor. The upcoming CHANCE-2 trial will compare aspirin plus clopidogrel with aspirin plus ticagrelor for 21 days, followed by antiplatelet monotherapy for 90 days.
Factor XIa Inhibitors for Minor Acute Ischemic Stroke: Fact or Fiction?: Mike Sharma, University of Ottowa
Dr. Sharma presented on the possible use of factor XIa inhibitors for minor acute ischemic stroke. He first discussed the goal to decouple antithrombotic effects from hemostasis. Factor XIa amplifies thrombin generation through the intrinsic pathway, leading to a stable clot which does not affect hemostasis. This is in contrast to other direct oral anticoagulants which work through the extrinsic pathway and affect hemostasis. In vitro, factor XIa inhibition reduces thrombin amplification. In mouse studies, it reduces thrombosis without affecting hemostasis.
Humans with factor XI deficiency, known as hemophilia C, have a mild bleeding type and often go undiagnosed. These patients also have lower risks of cardiovascular events, stroke, and venous thrombosis. There have been several trials looking at factor XIa inhibitors in orthopedic patients obtaining knee surgery, and it was found that there was almost a 10-fold reduction in risk of venous thrombosis without increase in clinically relevant bleeding. Two current trials (AXIOMATIC SSP and PACIFIC STROKE) are studying factor XI inhibition in patients with stroke.
Sphenopalatine Ganglion Stimulation for Ischemic Stroke: Fact or Fiction?: Maria Beridze, First University Clinic of Tbilisi State Medical University
Dr. Beridze discussed sphenopalatine ganglion (SPG) stimulation in treatment of acute ischemic stroke. In experimental models, SPG stimulation up to 24 hours after stroke onset augments cerebral blood flow, reduces infarct volume, and protects the blood brain barrier. Dr. Beridze went on to discuss results of the IMPACT trials (Implant for Augmentation of Cerebral Blood Flow Trials). The initial study was for feasibility of SPG stimulation in anterior circulation stroke. 84 patients were enrolled and had an mRS 0.76 lower than historical controls at 3 months. IMPACT-24A randomized 303 patients to SPG stimulation vs sham treatment, and there was no significant difference in outcome. However, patients with cortical stroke had significantly better outcome with SPG stimulation compared to patients with subcortical stroke. IMPACT-24B was a sham-controlled study of 1000 patients. In patients with cortical involvement, the SPG group had significantly better mRS, but again this effect was not seen in the entire group. When data from IMPACT-24A and -24B were pooled, there was a significantly improved mRS in patients with cortical strokes who were treated with SPG stimulation.
IMPACT-24M enrolled 50 patients and showed that SPG stimulation significantly increased common carotid artery peak systolic and end-diastolic blood flow and improved pinch strength and grasp strength. The degree of NIHSS recovery was also higher in the SPG group compared to controls. IMPACT-P is an ongoing trial to test if SPG stimulation may “freeze” the volume of penumbra in patients with anterior circulation stroke with salvageable penumbra. In conclusion, SPG stimulation up to 24 hours after stroke can become effective treatment for anterior circulation independently from thrombolysis and thrombectomy.
Intravenous Glyburide for Cerebral Edema Complicating Acute Ischemic Stroke, and Other Approaches: Fact or Fiction?: Hanne Christensen, Bispebjerg Hospital and University of Copenhagen
The blood brain barrier (BBB) refers to cells that separate the insterstitium from the luminal contents of the cerebral vasculature. Any damage to the brain that disrupts the BBB will lead to edema. 1-10% of MCA strokes without reperfusion develop space-occupying infarction and malignant edema. Mortality is about 80%, with death usually caused by cerebral herniation. Early reperfusion is preventative. Treatment of malignant cerebral edema includes surgical decompression, which decreases risk of death. Medication options include mannitol and hypertonic saline, although they have no effect on outcome and are usually used as a bridge to surgery.
Glyburide is a sulfonurea drug which inhibits SUR1-TRMP4 channel complexes. SUR1-TRMP4 are expressed in injured brain tissue, and activation leads to ATP depletion and sodium influx generating ionic edema and vasogenic edema. GAMES-SP was a trial which studied IV glyburide in 86 patients with large anterior circulation stroke. Primary endpoint was not met due to the trial stopping early, but there was a trend towards reduction in 30-day mortality and median mid-line shift. The intervention group also suffered less clinical deterioration.
In summary, glyburide has a well-described mode of action, is pathophysiologically plausible, and has a good safety profile, but data for everyday current practice is lacking. The CHARM Phase 3 Study to Evaluate the Efficacy and Safety of IV Glyburide for Severe Cerebral Edema Following Large Hemispheric Infarction is currently enrolling. This is a randomized, controlled, blinded trial assessing improvement in functional outcome at day 90 in patients with large MCA stroke (NIHSS>10) treated with IV glyburide. Other candidate drugs to reduce cerebral edema include vaptans to prevent and treat hyponatremia, fingolimod which is an anti-inflammatory that reduces vascular permeability, and celecoxib which reduces inflammation.
Nerinetide for LVO Neuroprotection: Fact or Fiction?: Michael D. Hill, University of Calgary
Dr. Hill discussed nerinetide for LVO neuroprotection, though as he stated, a better term is cytoprotection. Nerinetide is thought to offer neuroprotection by “freezing” ischemic penumbra evolution without cerebral blood flow augementation. In a primate model, monkeys given MCA ischemia via a clip were administered nerinetide 30 minutes prior to reperfusion. Compared to monkeys who did not receive nerinetide, treated monkeys had less infarct volume and performed better on behavioral tests.
In humans, in a population of patients with LVO undergoing mechanical thrombectomy, nerinetide did not significantly improve functional independence compared to placebo, but safety events were similar between groups. This study showed an effect modification such that the patients who did not receive alteplase did have a mortality reduction with nerinetide, and the patients who received alteplase had lower levels of nerinetide in the blood. It is thought that alteplase has an indirect effect on plasma volume and therefore plasmin, which cleaves nerinetide, making it less effective. The d-enantiomer of neritenide can block this effect and retain its cytoprotective effect in a rat model. The ESCAPE-NEXT trial is a phase 3 randomized, controlled, blinded trial studying outcomes in patients with LVO undergoing mechanical thrombectomy treated with nerinetide versus placebo.