By Santosh Murthy, MD

Assistant Professor of Neurology, Weill Cornell Medical College

Dr. Murthy reports no financial relationships relevant to this field of study.

SYNOPSIS: In this meta-analysis of multiple observational studies, clinical outcomes after oral anticoagulant-associated intracerebral
hematoma were similar for those associated with vitamin K antagonists or the new class of direct oral anticoagulants.

SOURCE: Tsivgoulis G, Wilson D, Katsanos AH, et al. Neuroimaging and clinical outcomes of oral anticoagulant-associated intracerebral hemorrhage. Ann Neurol 2018;84:694-704.

In about one-fifth of patients with primary intracerebral hemorrhage (ICH), the condition has been found to be related to anticoagulant use. Historically, vitamin K antagonists (VKAs), such as warfarin (once widely accepted as the oral medication of choice), were associated independently with higher admission hematoma volumes, hematoma expansion, higher mortality, and more severe disability compared to patients not on anticoagulant medications. The advent of nonvitamin K antagonists, direct oral anticoagulants (DOACs) has added a new dimension to the field of anticoagulation.

The authors of randomized, clinical trials in patients with atrial fibrillation have demonstrated conclusively that the risk of ICH is significantly lower with DOACs compared to VKAs, while the antithromboembolic benefit is similar. However, head-to-head comparisons of ICH outcomes in patients on these medications have yielded conflicting results, given limitations of low power, retrospective design, and mostly single-center data.

Tsivgoulis et al presented an individual patient data meta-analysis in which they compared 219 patients with DOAC-associated ICH with 831 with VKA-related ICHs across seven published, international, observational studies. The primary outcome was 30-day all-cause mortality, while thesecondary outcomes included clinical ICH severity, hematoma expansion, and functional outcomes at prespecified time points. The authors showed that DOAC use was associated with milder ICH clinical severity, as evidenced by lower National Institutes of Health Stroke Scale scores and smaller admission hematoma volumes, compared to VKA use. However, there were no differences in 30-day mortality (24.3% vs. 26.5%; hazard ratio, 0.94; 95% confidence interval [CI], 0.67-1.31), functional outcomes between the two groups at hospital discharge (common odds ratio, 0.78; 95% CI, 0.57-1.07), or functional status at three months (common OR, 1.03; 95% CI, 0.75-1.43) after adjusting for potential confounders, such as demographics and clinical and radiological characteristics of ICH.

COMMENTARY

This individual patient data meta-analysis highlights important baseline clinical and radiological characteristics of DOAC-ICH compared to VKA-ICH. These results are in stark contrast to those reported in a large retrospective cohort study using the American Heart Association’s Get With the Guidelines registry of nearly 150,000 ICH patients, which revealed that DOAC-ICH led to lower inpatient mortality and favorable discharge disposition compared to VKA-ICH. However, the results were not adjusted for baseline clinical or radiological ICH severity, which likely confounded the multivariable analyses. One may surmise that selective inhibition of the extrinsic coagulation pathway and shorter half-life of DOACs confer a pharmacologic advantage over VKAs. With emerging data tipping the balance in favor of DOACs as the oral anticoagulant medication of choice, studies with longer follow-ups of six months to one year are warranted, since the trajectory for recovery after ICH often is slower than that of ischemic stroke.

Current data suggest that rates of mortality and disability are relatively similar between VKA- and DOAC-associated ICH. Emerging data suggest that DOACs have smaller baseline hematoma volumes. As for the risk of ICH, DOACs appear to carry a significantly lower risk compared to VKAs. However, the antithromboembolic benefit is similar between the two groups. Although the prothrombin complex concentrates are used widely to reverse coagulopathy associated with warfarin use, specific medications, such as idarucizumab and andexanet, are now available as reversal agents for DOACs.