Cardiac Issues and Stroke Evidence Tables and Reference List
Patent foramen ovale (PFO)
Individuals with PFOs may be at increased risk of stroke and stroke recurrence, particularly in younger patients (<60 years of age) with stroke of unknown etiology. Although surgical closure has been used for patients with this condition, until recently, its effectiveness remained in question. Three earlier RCTs, CLOSURE 1 (Furlan et al. 2012), the PC Trial (Meier et al. 2013), and RESPECT (Carroll et al. 2013) investigated the effectiveness of PFO closure for reducing the risk of stroke recurrence and mortality following cryptogenic stroke, compared to medical management. Across the three trials, no significant reductions in the risk of the primary outcomes, which included recurrent stroke or TIA and death, were associated with closure in their respective intention-to-treat analyses. The associated hazard ratios (HR were: 0.78 (95% CI 0.45 to 1.35, p=0.37) in CLOSURE 1, during 2-years follow-up; 0.63, (95% CI 0.24 to 1.62, p=0.34) in the PC trial after a mean of 4.1 years of follow-up, and 0.49, (95% CI 0.22 to 1.11, p=0.08) in RESPECT after a mean follow-up of 2.6 years. Whereas the authors of CLOSURE 1 and the PC trials both observed similar findings in per protocol based analyses, the authors of RESPECT reported that in a per protocol analysis, PFO closure was associated with a significant reduction in the composite outcome of recurrent ischemic stroke or death, compared to medical therapy (HR= 0.37, 95% CI 0.14 to 0.96, p=0.03). There was no significant increase in the risk of serious adverse events in the intervention arm of any of the trials.
Results from more recent studies from the CLOSE (Mas et al. 2017) and REDUCE (Sondergaard et al. 2017) trials and long-term results of the RESPECT trial (Saver et al. 2017) have demonstrated that among carefully-selected patients, PFO closure was superior to medical therapy for prevention of stroke recurrence. In the CLOSE trial, Mas et al. (2017) recruited 633 young patients (mean age approximately 43 years) who had experienced a recent stroke with no identifiable cause other than a PFO, which had to be associated with either an atrial septal aneurysm (excursion >10 mm) or a large interatrial shunt (>30 microbubbles in the left atrium within three cardiac cycles after opacification of the right atrium). After a mean duration of follow-up of 5.3, there were no strokes in patients randomized to the PFO closure group compared with 6.0% in the antiplatelet-only group, who received mainly aspirin. (HR= 0.03; 95% CI 0-0.26; p<0.001; NNT=20 to prevent 1 stroke in 5 years; 95% CI 17-25). The rate of procedural complications in the PFO closure group was 5.9%. The frequency of atrial fibrillation was significantly higher in the PFO group (4.6% vs. 0.9%, p=0.02). The REDUCE trial (Sondergaard et al. 2017) enrolled 664 patients (mean age 45.2 years) with a PFO with a right-to-left shunt (spontaneous or during Valsalva maneuver), of whom 81% had moderate (6-25 microbubbles) or large (>25 microbubbles) interatrial shunts. The risk of ischemic stroke was significantly lower in the PFO closure group after a median duration of follow-up of 3.2 years (1.4% vs. 5.4%, HR=0.23, 95% CI 0.09-0.62; p=0.002; NNT=28 to prevent 1 stroke in 2 years). Serious device-related adverse events occurred in 1.4% of patients. The frequency of new-onset atrial fibrillation or flutter was significantly higher in the PFO closure group (6.6% vs 0.4%, p<0.01). Finally, in long-term follow-up of the RESPECT trial, after a median duration of follow-up of 5.9 years, the risk of recurrent ischemic stroke was significantly lower in the PFO closure group (3.6% vs. 5.8%; HR=0.55, 95% CI 0.31-0.999, p=0.046). In subgroup analysis, the benefit of closure appeared to be driven by those with an atrial septal aneurysm or a ‘substantial’ shunt size (grade 3).
Risk of Recurrent Stroke Associated with Heart Failure
Heart failure is known to be associated with increased risk of recurrent stroke. Katsanos et al. (2016) included the results from 7 studies (n=9,173) that reported the recurrence of ischemic stroke in patients with heart failure. The definitions used for heart failure were based on medical history (n=3), ejection fraction (n=1), Framingham criteria (n=1) or were not reported (n=3). Within the included studies, the percentage of patients with heart failure ranged from 4.8% to 33.9%. The mean follow-up durations across the included studies ranged from 7 days to 5 years. The risk of recurrent stroke was significantly increased among patients with heart failure (RR=1.96, 95% CI 1.49 -2.60, p<0.0001). Using data from the Canadian Stroke Registry, Pongmoragot et al. (2016) compared the outcomes of 12,396 patients admitted to hospital following an ischemic stroke with heart failure versus those without. Heart failure was defined either as pre-existing, or pulmonary edema present at the time of arrival to hospital. While the number of patients with stroke recurrence at 30 days did not differ between groups (3.9% vs. 3.2%, p=0.194), stroke fatality at discharge, 30 days and 1 year was significantly higher for patients with heart failure. Heart failure was also an independent predictor of death or disability at discharge (OR=1.18, 95% CI 1.01-1.37), 30-day survival (HR=1.22, 95% CI 1.05-1.41) and 30-day readmission (OR=1.32, 95% CI 1.05-1.65), after adjusting for age, sex, stroke severity and medical comorbidities.
Stroke Prevention for Patients in Heart Failure
The effectiveness of anticoagulation compared with antiplatelet therapy for stroke prevention in patients with heart failure in sinus rhythm remains unclear. Although several trials have compared their relative effectiveness, the superiority of any one approach has not been demonstrated. The Warfarin versus Aspirin in Reduced Cardiac Ejection Fraction (WARCEF) trial included 2,305 patients with left ventricular ejection fraction (LVEF) ≤35% (Homma et al. 2012). Patients were randomized to receive 325 mg aspirin daily or warfarin with a target INR of 2.75 for the study duration. After an average of 3.5 years, the rates for the primary outcome, a composite outcome of time to first event of ischemic stroke, intracerebral hemorrhage or death from any cause, were similar between groups (7.47 and 7.93 events/100 patient years for warfarin and aspirin, respectively; HR for warfarin=0.93, 95% CI 0.79-1.10, p=0.40). Although warfarin was associated with a significantly reduced risk of ischemic stroke (HR=0.52, 95% CI 0.33-0.82, p=0.005), the risks of major and minor hemorrhages were significantly increased. A sub group analysis of the WARCEF trial (Homma et al. 2013) found that patients <60 years treated with warfarin had a significantly lower risk of the primary outcome (HR=0.63, 95% CI 0.48-0.84, p=0.003), compared with aspirin therapy, while there was no significant treatment effect for patients 60 years or older. Patients <60 years treated with warfarin had a significantly lower risk of the primary outcome plus any major hemorrhage (HR=0.68, 95% CI 0.52-0.89, p=0.005). Patients ≥60 years treated with warfarin had a higher risk (HR=1.25, 95% CI 1.02-1.53, p=0.03) compared with aspirin. Investigators of the Warfarin and Antiplatelet Therapy in Chronic Heart Failure (WATCH) Trial compared 162 mg aspirin daily versus 75 mg clopidogrel daily versus warfarin, with target INR of 2.5 to 3.0 in patients in heart failure with a LVEF ≤35% (Massie et al. 2009). The risk of the primary outcome was similar between groups (20.7% aspirin vs. 21.6% clopidogrel vs. 19.6% warfarin). While warfarin was associated with a decreased risk of nonfatal and total stroke compared with either antiplatelet agent, the risk of bleeding events was significantly higher among patients in the warfarin group compared with clopidogrel. In two trials, the treatment contrasts included a placebo or no treatment arm (Cokkinos et al., 2006 and Cleland et al. 2004). In neither study were there significant differences between study groups for the primary outcome, which included stroke and death.
Aortic Arch Atheroma
The definitive management of patients with aortic arch plaques is unclear. Typically, monotherapy with an antiplatelet agent or oral anticoagulation is used to prevent further events in patients with a prior ischemic stroke. Amarenco et al. (2014) tested the hypothesis that dual antiplatelet therapy would be superior to oral anticoagulation. The Aortic Arch Related Cerebral Hazard Trial (ARCH) included 351 patients with a previous ischemic stroke, TIA, or peripheral embolism with plaque in the thoracic aorta >4 mm and no other identified embolic source. Patients were randomized to receive 75 to 150 mg/d aspirin + 75 mg/d clopidogrel or dose-adjusted warfarin with a target INR of 2.5 (2-3) for the duration of the trial. After a median of 3.4 years of follow-up, the risk of the primary outcome, a composite of cerebral infarction, myocardial infarction, peripheral embolism, vascular death, or intracranial hemorrhage was not significantly lower in the dual therapy group (7.6% vs. 11.3%, HR=0.76, 95% CI 0.36-1.61, p=0.50). There was no significant difference in the occurrence of major hemorrhages between groups (2.3% for dual therapy vs. 3.4% for warfarin, p=0.2).