Cerebral microbleeds post-ESUS may up recurrent stroke, mortality risk

Cerebral microbleeds (CMBs) may increase the risk of recurrent stroke and mortality in patients who have recently experienced an embolic stroke of undetermined source (ESUS), according to subgroup analyses of the phase III NAVIGATE ESUS* trial.

This multinational trial involved 7,213 patients aged ≥50 years who had neuroimaging-confirmed ESUS 7 days to 6 months pre-screening. They were randomized to receive once-daily doses of rivaroxaban (15 mg) or aspirin (100 mg). The subgroup analyses comprised the 51 percent (n=3,699) who had documented information on CMBs on baseline MRI, of whom 11 percent (n=395) had CMBs (mean age 69.5 years, 61 percent male, 51 percent White).

Over the median follow-up of 11 months, 190 of the 3,699 patients experienced a recurrent stroke, 29 of which occurred in patients with CMBs.

There was a trend toward an increased risk of recurrent stroke in patients with CMBs compared with those without CMBs (hazard ratio [HR], 1.51, 95 percent confidence interval [CI], 1.02–2.25; p=0.36). [JAMA Neurol 2020;doi:10.1001/jamaneurol.2020.3836]

This risk increased with increasing CMB burden (5.0, 5.6, and 8.5 per 100 person-years for none, mild, and moderate-severe CMB burden, respectively), with the greatest risk in patients with strictly lobar CMBs (12.1 per 100 person-years; HR, 2.42).

Strictly lobar CMBs were also associated with an increased risk of ischaemic stroke (11.1 per 100 person-years; HR, 2.33, 95 percent CI, 1.26–4.30). However, overall presence of CMBs was not tied to an increased risk of ischaemic stroke.

Patients with CMBs also had a significantly increased risk of intracerebral haemorrhage (ICH; HR, 4.18, 95 percent CI, 1.26–13.90; p<0.001), which increased with increasing CMB burden (0.2, 0.5, and 3.0 per 100 person-years for none, mild, and moderate-severe CMB burden, respectively), but did not differ by CMB type (strictly lobar or deep/mixed CMBs).

Presence of CMBs was also tied to an increased risk of all-cause mortality (HR, 2.13, 95 percent CI, 1.06–4.26; p=0.005), the greatest risk observed with strictly lobar CMB (HR, 3.22).

Certain factors were tied to an increased risk of CMBs namely increasing age (odds ratio [OR], 1.03 per year, 95 percent CI, 1.01–1.04), East Asian race/ethnicity (OR, 1.57, 95 percent CI, 1.04–2.37), hypertension (OR, 2.20, 95 percent CI, 1.54–3.15), multiterritorial ESUS (OR, 1.95, 95 percent CI, 1.42–2.67), chronic infarcts (OR, 1.78, 95 percent CI, 1.42–2.23), and occult ICH (OR, 5.23, 95 percent CI, 2.76–9.90).

Presence of CMBs did not appear to affect the impact of rivaroxaban on any of the treatment outcomes. Comparing patients assigned to rivaroxaban or aspirin, recurrent stroke risk did not significantly differ between patients with or without CMBs (HRs, 1.68 and 0.99, respectively; p_interaction=0.33). Among patients on rivaroxaban, the risk of ICH was similar among patients with and without CMBs (HRs, 3.12 and 2.96, respectively; p_interaction>0.99).

Concerns about bleeding unfounded?

“CMBs have been historically associated with a risk of ICH [which] has led to concerns about the safety of anticoagulation use in [these patients],” said Drs Laurent Puy and Charlotte Cordonnier from Université Lille, Inserm, CHU Lille, France, in an editorial. [JAMA Neurol 2020;10.1001/jamaneurol.2020.3847]

“[W]e found no indication of interaction between the effects of rivaroxaban and CMBs, including multiple or strictly lobar CMBs, for the outcome of ICH,” said the researchers. “[O]ur results and the existing literature … do not support the clinical concern regarding antithrombotic therapy in patients with ischaemic stroke and CMBs,” they noted.

“In patients at high risk of ischaemic stroke, clinicians should stop worrying about a possible bleed and start a solid evidence-based prevention of future ischaemic events,” added Puy and Cordonnier. “CMBs are markers of the severity of the underlying vessel disease, but they are just one among others,” they added.

The association between multiterritorial ESUS and CMBs, which appeared to increase with increasing CMB burden, is of particular interest, they continued. “It may suggest that multiterritorial ESUS, considered until now to be embolic, could be associated with small vessel disease.”