Rivaroxaban for Prevention of Covert Brain Infarcts and Cognitive Decline

The COMPASS MRI Substudy

Mukul Sharma, MD, MSc; Robert G. Hart, MD; Eric E. Smith, MD, MPH; Jacqueline Bosch, MSc, PhD; John W. Eikelboom, MBBS, MSc; Stuart J. Connolly, MD; Leanne Dyal, MSc; Kevin W Reeh, MSc; Amparo Casanova, PhD; Rafael Diaz, MD; Patricio Lopez-Jaramillo, MD, PhD; Georg Ertl, MD; Stefan Störk, MD, PhD; Gilles R. Dagenais, MD, MSc; Eva M. Lonn, MD, MSc; Lars Ryden, MD; Andrew M. Tonkin, MD, MBBS; John D. Varigos, BSc (Hon); Deepak L. Bhatt, MD, MPH; Kelley R.H. Branch, MD, MSc; Jeffrey L. Probstfield, MD; Jae-Hyung Kim, MD, PhD; Martin O'Donnell, MBBS, PhD; Dragos Vinereanu, MD, PhD; Keith A.A. Fox, MB, ChB; Yan Liang, MD; Lisheng Liu, MD; Jun Zhu, MD; Nana Pogosova, MD, PhD; Aldo P. Maggioni, MD; Alvaro Avezum, MD, PhD; Leopoldo S. Piegas, MD, PhD; Katalin Keltai, MD; Matyas Keltai, MD; Scott D. Berkowitz, MD; Salim Yusuf, MBBS, DPhil


Stroke. 2020;51(10):2901-2909. 

In This Article

Abstract and Introduction


Background and Purpose: Covert brain infarcts are associated with cognitive decline. It is not known whether therapies that prevent symptomatic stroke prevent covert infarcts. COMPASS compared rivaroxaban with and without aspirin with aspirin for the prevention of stroke, myocardial infarction, and vascular death in participants with stable vascular disease and was terminated early because of benefits of rivaroxaban 2.5 mg twice daily plus aspirin over aspirin. We obtained serial magnetic resonance imagings and cognitive tests in a consenting subgroup of COMPASS patients to examine treatment effects on infarcts, cerebral microbleeds, and white matter hyperintensities.

Methods: Baseline and follow-up magnetic resonance imagings were completed in 1445 participants with a mean (SD) interval of 2.0 (0.7) years. Whole-brain T1, T2 fluid-attenuated inversion recovery, T2* sequences were centrally interpreted by blinded, trained readers. Participants had serial measurements of cognition and function. The primary end point was the proportion of participants with incident covert infarcts. Secondary end points were the composite of clinical stroke and covert brain infarcts, cerebral microbleeds, and white matter hyperintensities.

Results: At baseline, 493 (34.1%) participants had infarcts. Incident covert infarcts occurred in 55 (3.8%) participants. In the overall trial rivaroxaban plus aspirin reduced ischemic stroke by 49% (0.7% versus 1.4%; hazard ratio [95% CI], 0.51 [0.38–0.68]). In the magnetic resonance imaging substudy the effects of rivaroxaban+aspirin versus aspirin were: covert infarcts: 2.7% versus 3.5% (odds ratio [95% CI], 0.77 [0.37–1.60]); Covert infarcts or ischemic stroke: 2.9% versus 5.3% (odds ratio [95% CI], 0.53 [0.27–1.03]). Incident microbleeds occurred in 6.6% of participants and 65.7% of participants had an increase in white matter hyperintensities volume with no effect of treatment for either end point. There was no effect on cognitive tests.

Conclusions: Covert infarcts were not significantly reduced by treatment with rivaroxaban and aspirin but estimates for the combination of ischemic stroke and covert infarcts were consistent with the effect on ischemic stroke in the overall trial.

Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01776424.


Covert brain infarcts detected on magnetic resonance imaging (MRI) are frequent findings in the aging brain with a prevalence of 10% at age 65 rising to 25% at age of 80 years in population-based studies.[1] Covert infarcts are 5× to 10× more common than symptomatic stroke and occur in an estimated 9 million people in the United States annually.[2] These lesions are noted on cerebral imaging or pathological examination of the brain and are neither asymptomatic nor benign being associated with cognitive decline, gait impairment and psychiatric manifestations.[3–5] Covert vascular disease of the brain includes covert infarcts, white matter hyperintensities (WMH), and cerebral microbleeds (CMBs). Incident asymptomatic infarcts contribute to the accumulation of WMH.[6] CMBs are small round hypointense lesions seen on MRI sequences sensitive to paramagnetic effects and represent focal deposits of iron-containing blood breakdown products.[7] Although often thought of as a marker of hemorrhagic risk, the presence of CMBs is a marker of vascular disease and is associated with an increased risk of ischemic stroke, myocardial infarction, and vascular death.[8]

Vascular disease and Alzheimer disease represent the most common pathologies underlying cognitive compromise and an interaction between these processes results in an accelerated decline and earlier clinical manifestations.[9] A combination of Alzheimer and vascular pathology is the most common pathological finding in individuals with cognitive decline and dementia.[9] A reduction in the occurrence of covert cerebral infarcts has the potential to delay or reduce dementia and the accompanying human and societal burden. Evidence for interventions for the prevention of covert brain infarcts is lacking, particularly in asymptomatic populations where preventive strategies may be most effective.[10]

Rivaroxaban is a selective, direct factor Xa inhibitor used for venous thromboembolism and stroke prevention in the setting of atrial fibrillation. The COMPASS trial (Cardiovascular Outcomes for People Using Anticoagulation Strategies) compared rivaroxaban with and without aspirin against aspirin and demonstrated a significant reduction in the composite end point of vascular death, myocardial infarction, and stroke with the combination of rivaroxaban and aspirin. Importantly, there was a major reduction in ischemic stroke with combined therapy.[11,12] We present here the primary results of the MRI substudy of COMPASS (Cardiovascular Outcomes for People Using Anticoagulation Strategies MRI and Neurocogntive Deterioration Substudy: COMPASS MIND). In COMPASS MIND, we aimed to examine the effect of rivaroxaban with and without aspirin on covert cerebral infarcts, WMH volumes, CMBs, cognitive and functional status. Here, we report results for the comparison of rivaroxaban plus aspirin versus aspirin, as this treatment was more effective than aspirin for the COMPASS primary end point. Results for the rivaroxaban alone comparison are included in tables where appropriate but are not the focus of this report as this treatment did not show efficacy for the primary end point.