Study of Rivaroxaban for Cerebral Venous Thrombosis: A Randomized Controlled Feasibility Trial Comparing Anticoagulation With Rivaroxaban to Standard-of-Care in Symptomatic Cerebral Venous Thrombosis.

BACKGROUND: Emerging data suggest that direct oral anticoagulants may be a suitable choice for anticoagulation for cerebral venous thrombosis (CVT). However, conducting high-quality trials in CVT is challenging as it is a rare disease with low rates of adverse outcomes such as major bleeding and functional dependence. To facilitate the design of future CVT trials, SECRET (Study of Rivaroxaban for Cerebral Venous Thrombosis) assessed (1) the feasibility of recruitment, (2) the safety of rivaroxaban compared with standard-of-care anticoagulation, and (3) patient-centered functional outcomes. METHODS: This was a phase II, prospective, open-label blinded-end point 1:1 randomized trial conducted at 12 Canadian centers. Participants were aged ≥18 years, within 14 days of a new diagnosis of symptomatic CVT, and suitable for oral anticoagulation; they were randomized to receive rivaroxaban 20 mg daily, or standard-of-care anticoagulation (warfarin, target international normalized ratio, 2.0-3.0, or low-molecular-weight heparin) for 180 days, with optional extension up to 365 days. Primary outcomes were annual rate of recruitment (feasibility); and a composite of symptomatic intracranial hemorrhage, major extracranial hemorrhage, or mortality at 180 days (safety). Secondary outcomes included recurrent venous thromboembolism, recanalization, clinically relevant nonmajor bleeding, and functional and patient-reported outcomes (modified Rankin Scale, quality of life, headache, mood, fatigue, and cognition) at days 180 and 365. RESULTS: Fifty-five participants were randomized. The rate of recruitment was 21.3 participants/year; 57% of eligible candidates consented. Median age was 48.0 years (interquartile range, 38.5-73.2); 66% were female. There was 1 primary event (symptomatic intracranial hemorrhage), 2 clinically relevant nonmajor bleeding events, and 1 recurrent CVT by day 180, all in the rivaroxaban group. All participants in both arms had at least partial recanalization by day 180. At enrollment, both groups on average reported reduced quality of life, low mood, fatigue, and headache with impaired cognitive performance. All metrics improved markedly by day 180. CONCLUSIONS: Recruitment targets were reached, but many eligible participants declined randomization. There were numerically more bleeding events in patients taking rivaroxaban compared with control, but rates of bleeding and recurrent venous thromboembolism were low overall and in keeping with previous studies. Participants had symptoms affecting their well-being at enrollment but improved over time. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT03178864.

Identification and comparison of adverse events for preparations of IVIG in patients with neuromuscular diseases.

OBJECTIVE: Risk factors for adverse events in intravenous immunoglobulin (IVIG) therapy are uncertain. We sought to determine the associations of IVIG-related adverse events in patients with neuromuscular disorders. PATIENTS AND METHODS: We determined the prevalence of adverse events with the use of different forms of IVIG in a tertiary care patient population with neuromuscular diseases. A retrospective assessment for over two decades of patient care was performed. RESULTS: Adverse events occurred in 43% of patients over time and during 10% of infusions. Prevalence of adverse events, especially headache, was higher for lyophilized forms of IVIG, and increased with cumulative IVIG delivery. Fortunately, serious adverse events were rare for all IVIG preparations. Discontinuation of IVIG therapy occurred most commonly due to perceived inefficacy or adverse events with lyophilized forms of IVIG. CONCLUSION: IVIG is generally well tolerated and only rarely associated with serious adverse events, but lyophilized forms of IVIG may be associated with greater prevalence of adverse events in patients with neuromuscular diseases.

Intracerebral hemorrhage: outcomes and eligibility for factor VIIa treatment in a National Stroke Registry.

BACKGROUND: Intracerebral hemorrhage (ICH) is a devastating form of stroke for which the lack of treatment options, high mortality rate, and the tendency to severely disable result in high social and economic burden. METHODS: We analyzed data in the Registry of the Canadian Stroke Network (RCSN). We sought to: (1) provide a descriptive analysis of ICH; (2) determine the proportion of ICH patients that might have been eligible for treatment with recombinant activated factor VII (rFVIIa) using criteria from a recent phase II trial; (3) compare 6-month outcomes of ICH patients with those of ischemic stroke patients, matched for gender, age, and stroke severity. RESULTS: In the RCSN, 11% of all strokes were nontraumatic ICH. The median Canadian Neurological Scale score was 7. A minority (33%) of patients arrived to the emergency department in less than 3 h from onset. In this cohort, in-hospital mortality was 15%. At 6 months, a further 9% of patients had died and 58% had a slight to no disability (Stroke Impact Scale-16 score > or = 75). Approximately 20% of ICH patients would have been eligible for rFVIIa treatment. Compared to ischemic stroke, ICH showed a trend towards increased mortality at discharge (OR: 1.96, CI: 0.99-3.87). At 6-month follow-up, ICH showed increased mortality (OR: 2.27, CI: 1.29-3.97), yet functional outcomes were not significantly different. CONCLUSION: ICH patients had a higher case-fatality rate when compared to acute ischemic stroke, but survivors had similar functional outcomes. In Canada, about one fifth of ICH patients might potentially benefit from rFVIIa if it is approved, with the major exclusion factor being time.

Outcome after stroke upon awakening.

BACKGROUND: An estimated 20-25% of all strokes occur during sleep and these patients wake up with their deficits. This study evaluated outcomes among patients who woke up with stroke compared to those who were awake at stroke onset. METHODS: Using data from the Registry of the Canadian Stroke Network Phases 1 and 2, we compared demographics, clinical data and six-month outcomes between patients with stroke-on-awakening versus stroke-while-awake. Strokes of all types (ischemic stroke, transient ischemic attack, intracerebral hemorrhage and subarachnoid hemorrhage) were included. Standard descriptive statistics, multivariable logistic regression and general linear modeling were applied to the data to compare variables. RESULTS: Among 2585 stroke patients, 349 (13.5%) woke up with stroke and 2236 (86.5%) did not. Patients with stroke-on-awakening were more likely to have higher blood pressure and to suffer ischemic stroke, but stroke severity, measured by level of consciousness, did not differ. Mortality both at discharge and at six-month follow-up did not differ between the two cohorts. However, patients with stroke-on-awakening were less likely to return home, and their median Stroke Impact Scale-16 scores were 7.0 points lower compared to those with stroke-while-awake. CONCLUSIONS: There are minor demographic and clinical differences between patients with stroke-on-awakening and stroke-while-awake. Functional outcomes are slightly worse among patients with stroke-on-awakening, an effect which was driven by poor outcomes among patients with subarachnoid hemorrhage.

TPA use for stroke in the Registry of the Canadian Stroke Network.

BACKGROUND: Thrombolytic therapy with recombinant tissue plasminogen activator (tPA) has been shown to be cost-effective and safe. Thrombolysis for stroke with tPA is now a standard of care in North America. However, it is only used on a small percentage of patients. METHODS: The Registry of the Canadian Stroke Network was a consent-based stroke registry from 21 hospital sites across Canada. Using the thrombolysis data in phase 1 and 2 of the Registry, we sought to describe the use of stroke thrombolysis and its outcomes. RESULTS: A total of 4107 patients were diagnosed with ischemic stroke in phase 1 and 2 of the Registry, of which 8.9% were treated with tPA. In consented tPA patients, the method of tPA administration was 85.8% i.v. only, 9.0% ia only, and 5.2% i.v./i.a. combined. Patients had a median onset-to-treatment time of 167 minutes [IQR 140-188]. One quarter (25.5%) of eligible candidates (time from onset <150 minutes) were treated with tPA. Protocol violations occurred in 27.7% (67/242) of patients with 14.9% (10/67) mortality. Overall, in-hospital mortality was 11.6%. Lower Canadian Neurological Scale score and higher glucose level were predictive of mortality The symptomatic intracerebral hemorrhage (ICH) rate (phase 2 only) was 4.3%. The mean Stroke Impact Scale-16 score at six months was 73.2, approximately equivalent to a modified Rankin scale score of 2. CONCLUSIONS: At selected hospitals in Canada, thrombolysis use is higher than previously reported rates. Thrombolysis continues to be safe and effective in Canada.