Aristeidis H. Katsanos, MD, PhD
NAVIGATE ESUS was a double-blinded, randomized, phase 3 clinical trial comparing rivaroxaban 15mg to aspirin 100mg in the secondary stroke prevention of patients with embolic strokes of undetermined source (ESUS). In the present pre-specified subgroup analysis, NAVIGATE ESUS Investigators assessed further the safety and efficacy of rivaroxaban 15mg to aspirin 100mg in ESUS patients with patent foramen ovale (PFO). PFO was uncovered in a total of 534 patients (7.4% of the total NAVIGATE ESUS trial population) after investigation with either transthoracic or transesophageal echocardiography.
After a mean follow-up of 11 months, ESUS patients with PFO randomized to rivaroxaban treatment were found to have a half, although non-statistically significant, risk for stroke recurrence compared to ESUS patients with PFO randomized to aspirin treatment (hazard ratio=0.54; 95%CI: 0.22–1.36). Interestingly, the treatment effect of rivaroxaban was found to be more pronounced in patients over 60 years of age, which were excluded from the majority of trials on PFO closure. However, rivaroxaban treatment was associated with a double, although again non-statistically significant, risk of major bleeding compared to aspirin (hazard ratio=2.05; 95% CI: 0.51–8.18).
As it became evident that the aforementioned analyses had limited power to detect any significant association, the authors pooled the data of NAVIGATE ESUS patients with PFO uncovered by transesophageal echocardiography together with data from two previous randomized clinical trials assessing the utility of oral anticoagulation (mainly with vitamin K antagonists) compared to aspirin on secondary prevention of cryptogenic stroke patients with PFO, namely the PFO in Cryptogenic Stroke Study (PICSS) and the Patent Foramen Ovale Closure or Anticoagulants versus Antiplatelet Therapy to Prevent Stroke Recurrence (CLOSE) trials. Combined data from the three trials yielded a marginally significant effect on recurrent stroke prevention (odds ratio=0.48, 95%CI: 0.24–0.96) in favor of oral anticoagulation, with no heterogeneity between effect sizes. The PFO subgroup uncovered by transesophageal echocardiography in the NAVIGATE ESUS trial was selected to be included in the meta-analysis since transesophageal echocardiography is currently the gold-standard method for PFO identification, as highlighted by the striking difference between the percentages of PFO patients detected by transesophageal compared to transthoracic echocardiography within the NAVIGATE ESUS trial (27.4% vs. 4.6%). Pooling data of major bleeding events reported in the NAVIGATE ESUS patients with PFO identified by transesophageal echocardiography and in patients from the CLOSE trial, the risk of major bleeding seems to be increased in patients receiving anticoagulants compared to antiplatelets (odds ratio=2.33, 95%CI: 0.88, 6.15).
Figure. Data derived from: Kasner SE, Swaminathan B, Lavados P, Sharma M, Muir K, Veltkamp R, et al. Rivaroxaban or aspirin for patent foramen ovale and embolic stroke of undetermined source: a prespecified subgroup analysis from the NAVIGATE ESUS trial. Lancet Neurol. 2018; and Mas J-L, Derumeaux G, Guillon B, Massardier E, Hosseini H, Mechtouff L, et al. Patent Foramen Ovale Closure or Anticoagulation vs. Antiplatelets after Stroke. N Engl J Med. 2017.
Taking into account the presumable favorable effect in prevention of recurrence, increased bleeding risk and the potential age-related therapeutic effect of oral anticoagulation in the secondary stroke prevention of patients with PFO, further research is needed to guide optimal treatment selection (closure, anticoagulation, antiplatelet) based on both patient clinical and PFO morphological characteristics.
