Feil Professor and Chairman, Department of Neurology, and Assistant Dean of Clinical Affairs, Weill Cornell Medical College; Neurologist-in-Chief, New York Presbyterian Hospital
Dr. Fink reports no financial relationships relevant to this field of study.
Message from the editor: The following reviews of studies presented at the 2019 International Stroke Conference were written after my personal attendance at the presentations, followed by review of the simultaneous publications in The New England Journal of Medicine and The Lancet. All comments and opinions are solely those of this editor.
Treatment of Factor Xa Inhibitor-Related Major Bleeding With Andexanet (LB7)
SOURCE: Connolly SJ, Crowther M, Eikelboom JW, et al. Full study report of andexanet alfa for bleeding associated with Factor Xa inhibitors. Concurrently published in N Engl J Med 2019; Feb 7. doi:10.1056/NEJMoa1814051.
Factor Xa inhibitors, such as apixaban and rivaroxaban, are used widely for preventing thromboembolism in patients with atrial fibrillation, deep venous thrombosis, and pulmonary embolism. However, when there is a serious bleeding complication, particularly intracranial hemorrhage, there have been limited treatments available to reverse the anticoagulant effects of these medications.
Andexanet is a recombinant coagulation Factor Xa and is designed to rapidly neutralize Factor Xa inhibitors at times of acute bleeding. Connolly and colleagues from the University of Texas studied an adult population presenting with major bleeding occurring within 18 hours of their last dose of apixaban, enoxiban, enoxaparin, or rivaroxaban. Patients received either a low dose (400 mg bolus plus 4 mg/min infusion for two hours) or high dose (800 mg bolus plus 8 mg/min infusion for two hours) of andexanet, depending on the timing and dose of the specific anticoagulant agent that the patient was taking. The primary outcomes were change from baseline in anti-Xa activity and the rate of effective hemostasis within 12 hours. Hemostasis was determined in each patient through evaluation by an independent committee that reviewed the clinical case records. Patients were included in the evaluation if the committee considered the bleeding serious and if baseline anti-Xa activity was greater than 75 ng/mL. Safety outcomes included death and thrombotic events at 30 days following treatment with andexanet.
The investigators enrolled 352 patients from 76 sites worldwide from 2015 through 2018. The mean time from last dose taken of a Factor Xa inhibitor to andexanet administration was 12 hours. Serious bleeding was localized to the intracranial compartment in 64% of patients — intraparenchymal bleeding into the brain (ICH) comprised 46%, subdural bleeding 28%, and subarachnoid bleeding in 15%. Serious gastrointestinal (GI) bleeding occurred in 26% of patients. Mean age was 77 years. Indications for treatment with Factor Xa inhibitors were atrial fibrillation in 80% and venous thromboembolism in 17%. In the study, 194 patients were taking apixaban, 128 were taking rivaroxaban, 20 were taking enoxaparin, and 10 were taking edoxaban.
A total of 249 cases of bleeding were adjudicated, and treatment with andexanet resulted in excellent or good hemostasis in 204 patients (82%). In 71 patients with nontraumatic, intraparenchymal brain hemorrhages, 56 had volume expansion of < 35% from baseline in one hour. Of these, 55 of 56 had no additional hematoma expansion at 12 hours. The safety profile was excellent, but 34 patients (9.7%) had at least one thrombotic event within 30 days — seven patients had myocardial infarction, 14 had ischemic stroke, and 13 had deep vein thrombosis. All thrombotic events occurred before anticoagulation was restarted. Thirty-day mortality was 15% for patients with intracranial hemorrhage and 11.1% for patients with GI hemorrhage.
Andexanet rapidly reversed anti-Factor Xa activity and resulted in effective hemostasis and a 30-day mortality from ICH of 15%, well below what has occurred in historical control groups.
Dual Antiplatelet Therapy With Cilostazol for Secondary Stroke Prevention (LB3)
SOURCE: Toyoda K, et al. Dual antiplatelet therapy using cilostazol for high-risk ischemic stroke: The cilostazol stroke prevention study for antiplatelet combination (CSPS.com). ISC 2019.
In previous studies, dual antiplatelet therapy with aspirin and clopidogrel was shown to reduce early recurrence of ischemic stroke, with short-term benefit and a long-term risk of major bleeding. Cilostazol has been used to reduce the risk of recurrent stroke with a low bleeding risk and is safe for long-term use. Toyoda and colleagues from Osaka, Japan, reported on a multicenter, open-label trial in which high-risk patients with benign cardioembolic ischemic stroke identified on MRI were assigned to receive aspirin or clopidogrel alone, or a combination of cilostazol 100 mg twice a day with aspirin or clopidogrel for secondary stroke prevention. High-risk patients were defined as meeting one or more of the following criteria: greater than 50% stenosis of a major intracranial or extracranial artery and two or more vascular risk factors. The primary outcome was the first recurrence of an ischemic stroke. Safety outcomes included severe or life-threatening bleeding.
Following enrollment, 1,839 patients were available for analysis, with 756 taking aspirin and 1,083 taking clopidogrel. Ischemic stroke occurred in 29 of 913 patients (3.2%) with dual therapy including cilostazol and in 64 of 926 patients (6.9%) on monotherapy during a median follow-up of 17 months (P = 0.001). Severe bleeding occurred in 0.9% of patients on dual therapy and 1.4% of patients on monotherapy (P = 0.354). The investigators concluded that patients treated with dual antiplatelet therapy combining cilostazol with either aspirin or clopidogrel had a lower risk of ischemic stroke recurrence and a similar risk of significant bleeding compared to patients treated with aspirin or clopidogrel alone.
Treatment of Intracerebral Hemorrhage With Deferoxamine (LB22)
SOURCE: Selim M. Intracerebral Hemorrhage Deferoxamine (iDEF) trial results. Presented at ISC 2019.
It is postulated that secondary neuronal injury following intracerebral hemorrhage (ICH) is caused by release of iron from hemolyzed erythrocytes. Deferoxamine is an iron chelator shown to have neuroprotective effects and improves recovery in animal models of ICH.
Selim and colleagues from Boston performed a Phase II clinical trial to determine if use of deferoxamine showed significant benefits to justify a Phase III trial. This was a multicenter, double-blind, randomized, placebo-controlled futility trial with an intention-to-treat analysis. The investigators randomized 294 patients with spontaneous supratentorial ICH to receive either deferoxamine 32 mg/kg/day or saline placebo given by intravenous infusion for three consecutive days. Treatment was started within 24 hours of ICH onset, and patients were followed for six months. Subjects were evaluated by the modified Rankin scale (mRS) and compared to the placebo group at three and six months. Safety endpoints included all adverse events until day 7 or discharge from the hospital. All other adverse events were recorded through 90 days.
A futility analysis was performed based on a primary hypothesis that the difference in good outcome proportions, as defined by the mRS at 90 days, is less than 12% in favor of deferoxamine treatment. At that point, it would be futile to move this treatment into Phase III evaluation. The primary results of the study showed that 34.3% of the deferoxamine-treated group and 32.9% of the placebo-treated group achieved an mRS score of 0-2, reaching an absolute risk difference of 0.6%. This result indicated that it would be futile to proceed with a Phase III trial. In addition, mortality at 180 days was 8.3% in the deferoxamine-treated group compared to 8.2% in the placebo group.
Intensive Control of Hypertension During and After Thrombolysis for Ischemic Stroke (LB6)
SOURCE: Anderson C, Robinson T; ENCHANTED Investigators. Main results of the enhanced control of hypertension and thrombolysis stroke study (enchanted) of the early intensive blood pressure control after thrombolysis. ISC 2019.
High systolic blood pressure > 185 mmHg is a contraindication to thrombolysis after acute ischemic stroke and is also avoided following successful thrombolysis to prevent intracerebral hemorrhage (ICH). Anderson and colleagues from Sydney, Australia, performed an international, multicenter, prospective, open-label, blinded trial. They randomly assigned thrombolysis-eligible patients with acute ischemic stroke < 6 hours of onset to intensive blood pressure management to attain a systolic blood pressure of 130-140 mmHg within one hour or to guideline-recommended blood pressure treatment to maintain systolic blood pressure < 180 mmHg, maintained over 72 hours. Choice of specific agents to treat hypertension were left to the discretion of the local treating physicians. The primary outcome was a comparison of modified Rankin scale (mRS) scores at 90 days, and safety outcomes were any intracranial hemorrhage diagnosed by standard criteria and central adjudication. Secondary outcomes included good recovery based on a mRS score of 0-1.
The investigators recruited and randomized 2,227 patients from 2012 until 2018, and 99% were followed and evaluated at 90 days. Median age of both groups was 67 years. Sixty-five percent of patients were Chinese, and 74% had Asian ethnicity. NIH stroke scores were similar in both groups. All patients were treated with alteplase, but at 67% of the standard dose, as part of a trial that also looked at modified dosage of thrombolysis. Comparison of the two groups showed an unadjusted ordinal shift of mRS scores with intensive blood pressure lowering, but the differences were not significant. There were no significant differences in functional outcome or mortality. There was a lower rate of intracranial hemorrhage in the intensive treatment group, 14.8% vs. 18.7% (P = 0.0137).
The investigators concluded that intensive lowering of blood pressure to < 140 mmHg was not superior to guideline-recommended blood pressure lowering to < 180 mmHg for primary disability outcomes. Intensive lowering of blood pressure was found to be safe with respect to outcomes, and there was significant evidence for a lower risk of ICH following thrombolysis in patients treated with intensive blood pressure reduction. It is difficult to know if the findings can be generalized, since most participants in the study were from China and Asia, and the etiology of ischemic stroke and ICH may be different in this population compared to other ethnic groups.
Minimally Invasive Surgery for Intracerebral Hemorrhage – MISTIE III Results (LB4)
SOURCE: Hanley DF, Zuccarello M, Awad IA, et al; for the MISTIE 3 investigators. MISTIE 3 trial results. Concurrently published in Lancet 2019; Feb. 7.
The MISTIE (Minimally Invasive Surgery Plus Rt-PA for ICH Evacuation Phase III ) investigators used an experimental protocol that involves placement of a catheter into an intracerebral blood clot with enhanced removal by repeated infusion of alteplase into the clot followed by aspiration over a three-day period. After 20 years of early-phase studies, the results of a Phase III trial were reported by Hanley and colleagues from Johns Hopkins University. The primary outcome measure was a comparison of patients who had modified Rankin scale (mRS) score of 0-3 vs. mRS score of 4-6 at 365 days after ICH.
The investigators randomized 499 subjects from 74 sites to the catheter aspiration procedure followed by alteplase irrigation or best medical therapy. The population was 61% male with an average age of 61 years. Sixty-two percent of the hemorrhages were in the basal ganglia and 38% were lobar. At presentation, the clot sizes averaged 44 mL with 6 mL of intraventricular hemorrhage. Mean Glasgow Coma Scores were 11. Age, Glasgow Coma Score, clot size, intraventricular hemorrhage volume, and patients who underwent withdrawal-of-care were not different between the groups. The protocol-defined surgical goal was to reduce the volume of ICH to < 15 mL, and this occurred in 59% of MISTIE patients. MISTIE vs. medical treatment was safe, with 30-day mortality of 9% vs. 15%, rebleeding rates of 3% vs. 3%, and infection rates of 1% vs. 0%. The primary endpoint, mRS score of 0-3 vs. 4-6 at 365 days, demonstrated a 3% difference favoring MISTIE patients, but this difference was not statistically significant. A mortality difference at one year of 6% vs. 8% occurred in favor of MISTIE patients, with an adjusted hazard ratio of 0.70 (P = 0.03). Successful ICH removal correlated with improved outcomes.
The investigators concluded that minimally invasive surgery is safe compared to medical therapy. But the primary outcome result of the trial is neutral. There was a small benefit with reduced mortality, but no significant benefit regarding functional outcome. Investigators suggest that this procedure might be beneficial if replicable in other studies.
Extending the Time for Thrombolysis to 9 Hours for Acute Ischemic Stroke (LB21)
SOURCE: Ma H, Campbell B, Churilov L, et al. Extending the thrombolytic time window to 9 hours for acute ischemic stroke using perfusion imaging selection: The final result. ISC 2019.
Intravenous thrombolysis for acute ischemic stroke currently is restricted to 4.5 hours from onset of symptoms, although viable brain tissue is present beyond that time.
Ma and colleagues from Australia conducted a multicenter, randomized, double-blind, placebo-controlled trial of alteplase in ischemic stroke patients presenting within 4.5 to 9 hours from onset of symptoms or in patients who had a wake-up stroke. Selection of patients for treatment was based on an automated perfusion imaging software (RAPID) that revealed salvageable brain tissue. Primary outcome was excellent functional outcome as measured by a modified Rankin scale (mRS) score of 0-1 at three months. Other outcomes included independent functional outcome, early reperfusion, improvement of the NIH stroke scale, death, and symptomatic intracerebral hemorrhage (ICH).
After 225 patients were randomized, the study was terminated because of early loss of clinical equipoise. The intention-to-treat analysis showed that patients who received alteplase achieved better functional outcomes: for mRS score 0-1, 35% vs. 29%, with an adjusted risk ratio of 1.44 (P = 0.042) and for mRS score 0-2, 50% vs. 43%, risk ratio = 1.36 (P = 0.017) at three months, with increased early reperfusion and clinical improvement based on reduction of the NIH stroke scale at 24 hours. Mortality was similar in both groups (12% vs. 9%), while symptomatic ICH was higher in the thrombolysis group (6% vs. 1%), as would be expected.
The investigators concluded that patients presenting within nine hours or with a wake-up stroke, selected by perfusion imaging, can achieve a significantly higher rate of excellent functional outcome compared to patients treated with placebo. The increase in rate of ICH is consistent with other thrombolytic trials, but this was not associated with increased mortality and it did not negate the beneficial effects and improved rate of excellent functional outcome in patients treated with thrombolysis.
Nitroglycerin for Prehospital Treatment of Acute Ischemic Stroke (LB2)
SOURCE: Bath PM, Scutt P, Woodhouse LJ, et al. Glyceryl trinitrate for pre-hospital ultra-acute stroke: Main results from the Rapid Intervention with Glyceryl Trinitrate in Hypertensive Stroke Trial 2 (RIGHT-2). Concurrently published in Lancet 2019; Feb. 6.
Glycerol trinitrate, known as nitroglycerin in the United States, is a nitric oxide that lowers blood pressure and has been shown in previous small trials to improve functional outcome and reduced death in patients with ischemic stroke and intracerebral hemorrhage (ICH) when given within six hours. Bath and colleagues from the United Kingdom tested whether nitroglycerin is safe and effective in improving outcome when administered by paramedics before hospital admission.
This was an ambulance-based, multicenter prospective, randomized, outcomes-blinded trial of patients with presumed stroke, either ischemic stroke or hemorrhagic stroke, and a systolic blood pressure of 120 mmHg or higher. Patients were randomized to nitroglycerin patch or sham patch within four hours of symptom onset. Treatment was initiated by paramedics on an ambulance. The primary outcome was a shift in the modified Rankin scale (mRS) at three months. A total of 1,148 patients were enrolled by 516 paramedics from eight ambulance services from 2015 through 2018. Mean age was 73 years, 52% of patients were male, 57% had prior hypertension, 24% had prior stroke, 20% had diabetes, and 21% had atrial fibrillation. Mean blood pressure was 162/92 mmHg. Final diagnoses of the patients included ischemic stroke (51%), ICH (13%), transient ischemic attack (TIA; 9%), and stroke mimic (25%).
In patients treated with nitroglycerin, systolic blood pressure was lowered by 5.8 mm compared with the sham group. There was no difference in mRS score between the groups in participants with a final diagnosis of stroke or TIA. There were no significant differences in any of the mRS score groups. There were no differences in secondary outcomes, death, or serious adverse events between treatment groups. The investigators concluded that prehospital treatment with transdermal nitroglycerin does not seem to improve functional outcome in patients with presumed stroke.
Intensive Treatment of Hyperglycemia in Patients With Acute Stroke (LB1)
SOURCE: Johnston KC, Bruno A, Barrett KM, et al. Stroke Hyperglycemia Insulin Network Effort (SHINE) trial primary results.
Hyperglycemia is common in patients with acute stroke. Preclinical and clinical data show that hyperglycemia during acute cerebral ischemia is associated with worse outcome. At the same time, severe hypoglycemia increases injury to ischemic brain. In clinical studies, it is unclear if lowering glucose improves outcome. This study was designed to determine if intensive lowering of glucose with intravenous insulin will improve outcome in patients with acute ischemic stroke.
Johnston and colleagues from the University of Virginia randomized 1,151 patients enrolled at 63 sites across the United States between 2012 and 2018. Patients were randomized to treatment with intravenous insulin, targeting a blood sugar of 80-130 mg/dL vs. a standard subcutaneous sliding scale insulin treatment, with a target of 80-179 mg/dL. The primary outcome measure was 90-day modified Rankin scale (mRS), and the primary safety outcome was severe hypoglycemia, defined as < 40 mg/dL. Secondary outcomes included the 90-day NIH stroke scale, Barthel Index, and stroke-specific quality of life scale.
This study was stopped after 82% of patients had been enrolled after the fourth interim analysis determined futility. No safety Ballenger was crossed. There was no difference between the two groups in the primary efficacy outcome of mRS score. Although more incidents of severe hypoglycemia occurred in the intensive treatment group (2.6% vs. 0%), the episodes of hypoglycemia did not result in any negative or adverse outcomes. The investigators concluded that intensive glucose control does not improve 90-day functional outcome and increases the risk of severe hypoglycemia. Subcutaneous insulin with a target of < 180 mg/dL is the preferred treatment target.
The following reviews of studies presented at the 2019 International Stroke Conference were written after my personal attendance at the presentations, followed by review of the simultaneous publications in The New England Journal of Medicine and The Lancet. All comments and opinions are solely those of this editor. — Matthew E. Fink, MD
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