We congratulate Fernandez et al. [1] for their recent article titled ‘Early Anticoagulation After Aortic Valve Replacement with Porcine Bioprosthesis Randomized Control Trial (ANTIPRO)’ published in the European Journal of Cardiothoracic Surgery. The study was a randomized open-label clinical trial comparing the effect of 3-month therapy with vitamin K antagonist (VKA) plus aspirin versus aspirin alone for the prevention of bioprosthetic valve thrombosis (BPVT) after surgical aortic valve replacement (AVR) using porcine bioprostheses. The study design, statistical methods and data interpretation were rigorous and appropriate. Furthermore, the target international normalized ratio of 2.5, the time spent in therapeutic range and the dose of aspirin (100 mg daily) used in the study were reflective of the treatment regimen currently used in clinical practice, thereby improving generalizability of the results. The study showed no difference in bioprosthetic valve haemodynamics, functional status and the incidence of thromboembolic and bleeding complication between the 2 groups. In this editorial, we will address the following issues: (i) BPVT diagnosis and treatment; (ii) BPVT prophylaxis; and (iii) clinical implications and knowledge gaps in the management of BPVT.
BPVT DIAGNOSIS AND TREATMENT
Clinically manifest BPVT occurs in 1–5% of patients following a surgical or transcatheter valve replacement using a bioprosthesis, and it is associated with higher risk of reinterventions and adverse outcomes [2, 3]. The differences in the incidence of BPVT observed in different studies can be explained by differences in the demographics of the study population, type and method of valve implantation, and type of imaging modality used for BPVT diagnosis [2–4]. Although BPVT can occur after bioprosthetic valve implantation in any position, most of the existing literature are derived from patients that had AVR, and early data suggested a higher incidence of BPVT after transcatheter AVR as compared to surgical AVR [4, 5]. However, the incidence of subclinical leaflet thrombosis as identified by 4D computed tomography angiography occurred to similar extent in transcatheter and surgical valves in the PARTNER 3 and CoreValve Evolut low risk clinical trials [6]. Furthermore, BPVT is not a perioperative phenomenon but can occur several years after AVR (mostly within the first 5 years) [2, 3]. In patients with known or suspected diagnosis of BPVT, anticoagulation with VKA is safe and effective for restoring valve function, thereby avoiding reintervention and associated periprocedural risks [7, 8].
BPVT PROPHYLAXIS
Both the American College of Cardiology/American heart Association and the European Society of Cardiology guidelines for the management of patients with valvular heart disease recommend the prophylactic anticoagulation with VKA for 3–6 months after surgical AVR with a bioprosthetic valve to reduce the risk of BPVT (Class of Recommendation IIa, Level of Evidence B) [9, 10]. These recommendations were based on observational studies demonstrating a lower risk of BPVT in patients who received prophylactic anticoagulation as compared to aspirin alone [4, 5]. Data from randomized controlled trials testing the efficacy (or lack thereof) of prophylactic anticoagulation for the prevention of BPVT are sparce, hence the clinical relevance of the recent clinical trial by Fernandez et al. The lack of clinical benefit of prophylactic anticoagulation for the prevention of BPVT observed in the current study is consistent with previous studies by Aramendi et al. and Rafiq et al. demonstrating similar risk of thromboembolic events and valve related death in patients that prophylactic anticoagulation with VKA as compared to aspirin alone [11, 12]. The strengths of the Fernandez et al. study, as compared to the previous clinical trials, relate to restricting the study population to patients who underwent surgical AVR with porcine bioprosthesis (thereby minimizing confounders), and the fact that it was powered to test the effect of prophylactic VKA on valve dysfunction as a primary end point (rather than as part of a composite end point as used in prior clinical trials).
CLINICAL IMPLICATIONS AND FUTURE DIRECTIONS
Unfortunately, there is still a lack of clarity regarding the optimal strategy to prevent BPVT in clinical practice, with data from observational studies suggesting clinical benefit of prophylactic anticoagulation, and data from the clinical trial showing lack of benefit of prophylactic coagulation over antiplatelet therapy. Although randomized controlled trial provides a stronger level of evidence as compared to observational studies, it is important to reconcile the discordant results. We postulate that the differences in outcome may be explained by the duration of prophylactic anticoagulation and the duration as well as type of imaging follow-up. In the observational studies, most of the patients were already on anticoagulation prior to AVR and remained on anticoagulation for >1 year afterwards, in contrast to 3-month course of prophylactic anticoagulation used in the clinical trial [4, 5, 11, 12]. In addition, the incidence of BPVT in the current clinical trial was based on echocardiographic assessment of prosthesis function at 1 year after AVR. Transthoracic echocardiography might be insensitive for the diagnosis of BPVT. In addition, the follow-up period may not have been long enough to detect a difference in incidence of BPVT since BPVT can occur beyond the first year after AVR, and even up to 5 years after AVR [2, 3].
Once again, we congratulate Fernandez et al. for a well-designed and well-executed clinical trial. However, there is need for more studies before making changes to the current guideline recommendations for prophylactic anticoagulation after bioprosthetic AVR. Such studies should focus on determining whether longer duration of prophylactic anticoagulation would be beneficial, and whether prophylactic anticoagulation will be better suited for patients at higher risk for BPVT since previous studies have shown that the risk of BPVT is not same for all patients [2]. Furthermore, the role of direct oral anticoagulant for BPVT prophylaxis needs to be further elucidated [4]. In the meantime, it is important to emphasize that BPVT can, and does, occur after implantation of a bioprosthesis and that anticoagulation is effective for the treatment of confirmed or suspected BPVT, which will, in turn, reduce the risk associated with of valve reintervention.
Contributor Information
Alexander C Egbe, Department of Cardiovascular Medicine, Mayo Clinic, Rochester, MN, USA.
William R Miranda, Department of Cardiovascular Medicine, Mayo Clinic, Rochester, MN, USA.
Heidi M Connolly, Department of Cardiovascular Medicine, Mayo Clinic, Rochester, MN, USA.
Sorin V Pislaru, Department of Cardiovascular Medicine, Mayo Clinic, Rochester, MN, USA.
Funding
Alexander C. Egbe is supported by National Heart, Lung, and Blood Institute (NHLBI) grants (R01 HL158517 and R01 HL160761). The MACHD Registry is supported by the Al-Bahar Research grant.
Conflict of interest: none declared.
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