Frequency and Predictors of Major Bleeding in Patients With Embolic Strokes of Undetermined Source
Journal
Stroke
ISSN
0039-2499
1524-4628
Date Issued
2020
Author(s)
Robert Mikulík
Jens Eckstein
Lesly A. Pearce
Hardi Mundl
Salvatore Rudilosso
Veroníca V. Olavarría
Ashkan Shoamanesh
Ángel Chamorro
Joan Martí-Fàbregas
Roland Veltkamp
Şerefnur Öztürk
Turgut Tatlisumak
W. Frank Peacock
Scott D. Berkowitz
Stuart J. Connolly
Robert G. Hart
Type
Resource Types::text::journal::journal article
URL Institutional Repository
Abstract
<jats:sec>
<jats:title>Background and Purpose:</jats:title>
<jats:p>Risks, sites, and predictors of major bleeding during antithrombotic therapies have not been well defined for patients with recent embolic stroke of undetermined source.</jats:p>
</jats:sec>
<jats:sec>
<jats:title>Methods:</jats:title>
<jats:p>Exploratory analysis of major bleeds defined by International Society of Thrombosis and Hemostasis criteria occurring among 7213 participants in international NAVIGATE (New Approach Rivaroxaban Inhibition of Factor Xa in a Global Trial) embolic stroke of undetermined source randomized trial comparing rivaroxaban 15 mg daily with aspirin 100 mg daily.</jats:p>
</jats:sec>
<jats:sec>
<jats:title>Results:</jats:title>
<jats:p>
During a median follow-up of 11 months, 85 major bleeds occurred. The most frequent site was gastrointestinal (38%), followed by intracranial (29%). Assignment to rivaroxaban (hazard ratio [HR], 2.7 [95% CI, 1.7–4.3]), East Asia region (HR, 2.5 [95% CI, 1.6–3.9]), systolic blood pressure ≥160 mm Hg (HR, 2.2 [95% CI, 1.2–3.8]), and reduced estimated glomerular filtration rate (HR, 1.2 per 10 mL/min per 1.73 m
<jats:sup>2</jats:sup>
decrease, [95% CI, 1.0–1.3]) were independently associated with presence of major bleeds. Five (6%) were fatal. Among 15 patients with intracerebral hemorrhage, 2 (13%) were fatal. There was no evidence of an early high-risk period following initiation of rivaroxaban. The annualized rate of intracerebral hemorrhage was 6-fold higher among East Asian participants (0.67%) versus all other regions (0.11%; HR, 6.3 [95% CI, 2.2–18.0]). Distribution of bleeding sites was similar for rivaroxaban and aspirin.
</jats:p>
</jats:sec>
<jats:sec>
<jats:title>Conclusions:</jats:title>
<jats:p>Among embolic stroke of undetermined source patients participating in an international randomized trial, independent predictors of major bleeding were assignment to rivaroxaban, East Asia region, increased systolic blood pressure, and impaired renal function. East Asia as a region was strongly associated with risk of intracerebral hemorrhage. Estimated glomerular filtration rate should be a consideration for stratifying bleeding risk.</jats:p>
</jats:sec>
<jats:sec>
<jats:title>Registration:</jats:title>
<jats:p>
URL:
<jats:ext-link xmlns:xlink="http://www.w3.org/1999/xlink" ext-link-type="uri" xlink:href="https://www.clinicaltrials.gov">https://www.clinicaltrials.gov</jats:ext-link>
. Unique identifier: NCT02313909.
</jats:p>
</jats:sec>
<jats:title>Background and Purpose:</jats:title>
<jats:p>Risks, sites, and predictors of major bleeding during antithrombotic therapies have not been well defined for patients with recent embolic stroke of undetermined source.</jats:p>
</jats:sec>
<jats:sec>
<jats:title>Methods:</jats:title>
<jats:p>Exploratory analysis of major bleeds defined by International Society of Thrombosis and Hemostasis criteria occurring among 7213 participants in international NAVIGATE (New Approach Rivaroxaban Inhibition of Factor Xa in a Global Trial) embolic stroke of undetermined source randomized trial comparing rivaroxaban 15 mg daily with aspirin 100 mg daily.</jats:p>
</jats:sec>
<jats:sec>
<jats:title>Results:</jats:title>
<jats:p>
During a median follow-up of 11 months, 85 major bleeds occurred. The most frequent site was gastrointestinal (38%), followed by intracranial (29%). Assignment to rivaroxaban (hazard ratio [HR], 2.7 [95% CI, 1.7–4.3]), East Asia region (HR, 2.5 [95% CI, 1.6–3.9]), systolic blood pressure ≥160 mm Hg (HR, 2.2 [95% CI, 1.2–3.8]), and reduced estimated glomerular filtration rate (HR, 1.2 per 10 mL/min per 1.73 m
<jats:sup>2</jats:sup>
decrease, [95% CI, 1.0–1.3]) were independently associated with presence of major bleeds. Five (6%) were fatal. Among 15 patients with intracerebral hemorrhage, 2 (13%) were fatal. There was no evidence of an early high-risk period following initiation of rivaroxaban. The annualized rate of intracerebral hemorrhage was 6-fold higher among East Asian participants (0.67%) versus all other regions (0.11%; HR, 6.3 [95% CI, 2.2–18.0]). Distribution of bleeding sites was similar for rivaroxaban and aspirin.
</jats:p>
</jats:sec>
<jats:sec>
<jats:title>Conclusions:</jats:title>
<jats:p>Among embolic stroke of undetermined source patients participating in an international randomized trial, independent predictors of major bleeding were assignment to rivaroxaban, East Asia region, increased systolic blood pressure, and impaired renal function. East Asia as a region was strongly associated with risk of intracerebral hemorrhage. Estimated glomerular filtration rate should be a consideration for stratifying bleeding risk.</jats:p>
</jats:sec>
<jats:sec>
<jats:title>Registration:</jats:title>
<jats:p>
URL:
<jats:ext-link xmlns:xlink="http://www.w3.org/1999/xlink" ext-link-type="uri" xlink:href="https://www.clinicaltrials.gov">https://www.clinicaltrials.gov</jats:ext-link>
. Unique identifier: NCT02313909.
</jats:p>
</jats:sec>
Subjects
blood pressure
;
embolism
;
glomerular filtration rate
;
infarction
;
rivaroxaban
;
adult
;
aged
;
asian continental ancestry group
;
cerebral hemorrhage
;
double-blind method
;
factor xa inhibitors
;
far east
;
female
;
glomerular filtration rate
;
hemorrhage
;
humans
;
intracranial embolism
;
male
;
middle aged
;
risk factors
;
rivaroxaban
;
stroke
;
blood clotting factor 10a inhibitor
;
rivaroxaban
;
adult
;
aged
;
asian continental ancestry group
;
bleeding
;
brain embolism
;
brain hemorrhage
;
cerebrovascular accident
;
clinical trial
;
complication
;
controlled study
;
double blind procedure
;
far east
;
female
;
glomerulus filtration rate
;
human
;
male
;
middle aged
;
multicenter study
;
phase 3 clinical trial
;
randomized controlled trial
;
risk factor