Table 3.
Summary of published randomized clinical trials evaluating antithrombotic treatment in heart failure with reduced ejection fraction and sinus rhythm.
| First author/trial | Population | Treatment/exposure | Primary outcome | Result(s) | Comments |
|---|---|---|---|---|---|
| Cleland/WASH (18) | 279 patients with left ventricular dysfunction* | No antithrombotic vs. warfarin vs. aspirin for primary prevention | Composite: Death, non-fatal myocardial infarction, or non-fatal stroke |
No difference between warfarin and aspirin or placebo groups 1.56 strokes/100 patient-years among all patients |
Trial terminated following concerns that “no antithrombotic” arm would impede recruitment |
| Cokkinos/HELAS (19) | 197 patients with LVEF < 35% and either IHD or DCM | Warfarin vs. aspirin for secondary prevention following myocardial infarction in IHD Warfarin vs. placebo for primary prevention in DCM |
Composite: Non-fatal stroke, peripheral or pulmonary embolism, myocardial (re)infarction, re-hospitalization, exacerbation of heart failure, or death |
No difference between warfarin and aspirin or placebo groups 15.7 events/100 patient-years for warfarin vs. 14.9 events/100 patient-years on aspirin with IHD 8.9 events/100 patient-years for warfarin vs. 14.8 events/100 patient-years on placebo with DCM 2.2 embolic events/100 patient-years among all patients |
|
| Massie/WATCH (20) | 1,587 patients with LVEF ≤ 35% and symptoms of heart failure | Open-label warfarin vs. randomized aspirin or clopidogrel for primary prevention | Composite: All-cause mortality, non-fatal MI, and non-fatal stroke |
No benefit of warfarin over aspirin HR 0.98, 95%CI 0.86–1.12 No benefit of warfarin over clopidogrel HR 0.89, 95%CI 0.68–1.16 No benefit of clopidogrel over aspirin HR 1.08, 95%CI 0.83–1.40 |
Study was terminated prematurely due to slow enrollment (target enrollment 4,500 not met). Power to detect the original 20% difference in primary outcome dropped from 90 to 41% One-fifth of study participants discontinued original study drug, or crossed over to other treatment arm |
| Homma/WARCEF (21) | 2,305 patients with LVEF ≤ 35% | Warfarin vs. aspirin for primary prevention | Composite: Ischemic stroke, intracerebral hemorrhage, or death |
No benefit of warfarin over aspirin HR 0.93, 95%CI 0.79–1.10 |
Among patients who survived 4 or more years after enrollment, there was a time-dependent benefit of warfarin over aspirin in the prevention of the primary outcome |
| Zannad/COMMANDER HF (3, 6) | 5,022 patients with CHF, LVEF ≤ 40% elevated plasma concentration of natriuretic peptides without atrial fibrillation | Rivaroxaban vs. aspirin for primary prevention | Efficacy: Composite outcome or death from any cause, myocardial infarction or stroke Safety: Fatal bleeding or bleeding into a critical space |
No benefit of rivaroxaban over aspirin for primary outcome HR 0.94, 95%CI 0.84–1.05 Rivaroxaban superior to aspirin for exploratory post hoc outcome of systemic embolism (3) HR 0.83, 95% CI 0.72–0.96 |
|
| Branch/COMPASS (22, 23) | Nested cohort/exploratory post hoc analysis of 4971 patients with coronary and/or peripheral artery disease and LVEF 31–40% from the COMPASS trial (N = 27,395) | Rivaroxaban with or without aspirin for primary prevention | Composite: Cardiovascular death, stroke, or myocardial infarction |
No benefit of rivaroxaban monotherapy over aspirin for primary outcome; benefit of low-dose rivaroxaban
+
aspirin was observed over aspirin HR for half-dose rivaroxaban + aspirin vs. aspirin alone 0.68, 95%CI 0.53–0.86 |
The COMPASS trial included 3 arms: rivaroxaban 2.5 mg twice daily plus aspirin 100mg once daily vs. rivaroxaban 5 mg twice daily vs. aspirin 100 mg once daily. In this analysis, only the combination of half-dose rivaroxaban + aspirin was found to be associated with lower risk of the primary outcome vs. aspirin alone |
| Merkler/NAVIGATE-ESUS (12, 24) | Nested cohort/exploratory post hoc analysis of 502 patients with stroke and left ventricular dysfunction† from the NAVIGATE-ESUS† trial (N = 7,213) | Rivaroxaban vs. aspirin for secondary prevention of ischemic stroke | Composite: Recurrent stroke or systemic embolism |
No benefit of rivaroxaban over aspirin for the primary outcome in the principal cohort Benefit of rivaroxaban over aspirin was observed for primary outcome in patients with left ventricular dysfunction HR 0.36; 95% CI, 0.14–0.93 |
Left ventricular ejection fraction not reported |
Left ventricular dysfunction from WASH was defined as increased left ventricular end-diastolic internal dimension (≥56 mm or ≥30 mm/m2 body surface area) combined with a fractional shortening of ≤ 28% or an echocardiographic ejection fraction ≤ 35%.
NAVIGATE-ESUS classified left ventricular dysfunction when regional wall motion abnormalities were noted or there was moderate to severely impaired left ventricular contractility with or without regional wall motion abnormalities.
WASH, Warfarin/Aspirin Study in Heart failure; HELAS, Heart failure Long-term Antithrombotic Study; IHD, ischemic heart disease; DCM, dilated cardiomyopathy; WARCEF, Warfarin vs. Aspirin in Reduced Cardiac Ejection Fraction; HR, hazard ratio; CI, confidence interval; WATCH, Warfarin and Antiplatelet Therapy in Chronic Heart failure; COMMANDER HF, A Study to Assess the Effectiveness and Safety of Rivaroxaban in Reducing the Risk of Death, Myocardial Infarction, or Stroke in Participants with Heart Failure and Coronary Artery Disease Following an Episode of Decompensated Heart Failure; COMPASS, Cardiovascular Outcomes for People Using Anticoagulation Strategies; NAVIGATE-ESUS, New Approach Rivaroxaban Inhibition of Factor Xa in a Global Trial vs. Aspirin to Prevent Embolism in Embolic Stroke of Undetermined Source.