Neither the European nor the American guidelines specifically recommend oral anticoagulation three months after surgery in patients in sinus rhythm (SR).

Both guidelines recommend DOAC three months after index valvular surgery in patients with bioprosthetic valves in aortic or mitral position and AF. These recommendations are regardless of CHA2DS2-VASc score.

The recommendations in the guidelines are supported by cumulative evidence from post-hoc analysis of the ARISTOTLE8 and ENGAGE AF-TIMI 489 trials, the small DAWA randomized controlled trial (RCT)5 and pooled analysis of these low-evidence studies in two metanalyses, by Malik et al.10 and Caldeira et al.11

Pooled analysis showed no statistically significant difference in stroke or systemic embolization (Malik et al.: hazard ratio [HR] 0.59; 95% confidence interval [CI] 0.13–2.69; p=0.49; I2=24%; Caldeira et al.: HR 0.65; 95% CI 0.20–2.08; p=0.46; I2=6%); major bleeding (Malik et al.: HR 0.67; 95% CI 0.27–1.63; p=0.38; I2=0%; Caldeira et al.: HR 0.94; 95% CI 0.28–3.18; p=0.93; I2=0%); or death (Malik et al.: HR 0.82; 95% CI 0.24–2.81; p=0.76; I2=0%).10,11 This evidence, however, is based on a small group of patients and events and presents wide CIs suggestive of low statistical power.

More recently, the RIVER trial,12 a multicenter, open-label, noninferiority trial, randomized 1005 patients with mitral bioprosthetic valves and AF (excluding post-operative transient AF) to receive either rivaroxaban (n=500) or warfarin (n=505). In this trial rivaroxaban achieved non-inferiority for the primary endpoint of mean time free from a composite of death, major cardiovascular events, or major bleeding at 12 months (rivaroxaban, 347.5 days; warfarin, 340.1 days; difference, 7.4 days; 95% CI −1.4 to 16.3; p<0.001 for noninferiority, p=0.10 for superiority). Additionally, stroke rates at 12 months were statistically different, favoring rivaroxaban (rivaroxaban, 0.6%; warfarin, 2.4%; HR 0.25; 95% CI 0.07–0.88). Other secondary endpoints were similar between the two groups including major bleeding, valve thrombosis and death.

Patients less than three to six months after the index valvular surgery present a particular challenge, as this is viewed as the most thrombogenic period.

The ACC/AHA guidelines recommend anticoagulation with a vitamin K antagonist (VKA) in the first three months after index valvular surgery, regardless of rhythm, valve type or position. This recommendation is based on observational studies, some of which have conflicting results.13–16

The ESC/EACTS guidelines also recommend VKAs in the first three months for valves in mitral position and for all patients in AF independently of valve position. In the ESC/EACTS guidelines the use of DOAC should be considered for patients with AF and bioprosthetic valves in mitral position (class of recommendation IIb). For patients with an aortic bioprosthetic valve in SR, the ESC/EACTS guidelines recommend either aspirin or a VKA with a IIa class recommendation. The latter recommendation is based on observational studies16,17 and a small RCT.18

Although still controversial, a growing body of evidence seems to indicate a potential role for DOAC use in the first three months after index surgery.

In the above-mentioned RIVER trial,12 18.8% of the randomized patients received either rivaroxaban or warfarin in the first three months after valve surgery. The authors found that the statistical difference between treatments (favoring rivaroxaban) regarding the primary endpoint was especially marked in this subgroup of patients (rivaroxaban, 6.4%; warfarin, 18.9%; HR 0.31; 95% CI 0.12–0.79). However, the authors did not report p-values for interaction in this subgroup (patients randomized in the first three months after surgery).

ENAVLE19 was a non-inferiority RCT which randomized patients to receive either edoxaban (n=109) or warfarin (n=109) for the first three months after bioprosthesis implantation regardless of rhythm and valve position. Edoxaban was non-inferior to warfarin regarding the primary efficacy endpoint of a composite of death, clinical thromboembolic events or asymptomatic intracardiac thrombosis (edoxaban 0%, warfarin 3.7%; risk difference [RD], −0.0367; 95% CI −0.0720 to −0.0014; p<0.001 for noninferiority), as well as for major bleeding events (edoxaban 2.8%, warfarin 0.9%; RD 0.0183; 95% CI −0.0172 to 0.0539; p=0.013). ENAVLE was also a small RCT with a small number of events, and the results should be interpreted accordingly.

One of the drawbacks of DOACs is the lack of rapidly available tests to measure their effect. Although general tests of coagulation such as activated partial thromboplastin time and prothrombin time can be useful to assess the effects of anticoagulation, the sensitivity of these tests is variable and a normal test does not exclude the presence of the drug. In cases of acute bleeding or need for emergent surgery, discontinuation of DOACs and general measures may be sufficient, due to their relatively short half-life, but DOAC-specific anti-Xa tests and ecarin chromogenic assays need to be readily available in order to identify patients who need reversal agents and to monitor reversal efficacy.

The authors of this editorial recently published a review of the best available evidence regarding DOAC use in the first three months following valve surgery.20 The above-mentioned results of the RIVER and ENAVLE trials are exciting and hypothesis-generating. However, the low number of events reported overall and wide confidence intervals warrant caution when interpreting these results. Lower evidence data derived from retrospective analyses are consistent with the results of these trials. DOACs appear to be as safe and as effective as VKAs regarding thromboembolic prophylaxis and bleeding event rates in patients with surgical bioprosthetic valves and AF within three months of implantation. However, stronger confirmatory evidence is needed to extend current recommendations.

Nevertheless, current recommendations are mainly based on observational and largely outdated data.13–18 Although not without its flaws, the most recent data from the above-mentioned RCTs appear to indicate a promising future for the expansion of DOAC use to the immediate postoperative period in patients with mitral valve prostheses and patients with AF.

The authors have no conflicts of interest to declare.