The Beneficial Effect of Anticoagulation in Aortic Bioprosthesis is Associated with its Size

Objective To evaluate the clinical and echocardiographic outcomes in aortic valve replacement (AVR) patients with aortic bioprosthesis under oral anticoagulation (OA). Methods Patients who underwent AVR with bioprosthesiswere prospectively enrolled. They were classified based on postoperative use of OA. Clinical and operative variables were collected. Echocardiographic and clinical follow-ups were performed two years after surgery. The primary outcome evaluated was change in transprosthetic gradient. Secondary outcomes analyzed were change in New York Heart Association (NYHA) class, major bleeding episodes, hospitalization, stroke, and transient ischemic attack. Results We included 103 patients (61 without OA and 42 with OA). Clinical characteristics were similar among groups, except for younger age (76±6.3 vs. 72.4±8.1 years, P=0.016) and higher prevalence of atrial fibrillation (0% vs. 23.8%, P<0.001) in the OA group. Mean (21.4±10 mmHg vs. 16.8±7.7 mmHg, P=0.037) and maximum (33.4±13.7 mmHg vs. 28.4±10.2 mmHg, P=0.05) transprosthetic gradients were higher in patients without OA. Improvement in NYHA class was more frequent in patients with OA (73% vs. 45.3%, P=0.032). Major bleeding, stroke, and hospitalization were similar among groups. OA was the only independent predictor for improvement of NYHA class after multivariate logistic regression analysis (odds ratio [OR]: 5.9, 95% confidence interval [CI]: 1.2-29.4; P=0.028). Stratification by prosthesis size showed that patients with ≤ 21 mm prosthesis benefited from OA. Conclusion Early anticoagulation after AVR with bioprosthesis was associated with significant decrease of transprosthesis gradient and improvement in NYHA class. These associations were seen mainly in patients with ≤ 21 mm prosthesis.

Comprehensive transthoracic echocardiograms (TTEs) were performed in all patients before hospital discharge (baseline TTE) and at follow-up (follow-up TTE). Mean time of echocardiographic follow-up was similar between groups (2.05±1.02 and 2.02±1.00 years in non-OA and OA groups, respectively). All TTE examinations were conducted according to the American Society of Echocardiography guidelines [8] . The mean transprosthetic gradient was calculated by using the modified Bernoulli formula. The effective orifice area (EOA) of the prosthesis was calculated by using the continuity equation.

Statistics
Continuous variables were expressed as mean±standard deviation. Categorical variables were expressed as absolute value (%). Comparison between groups was performed using t-test and chi-square test.
The predictive role of OA on the primary and secondary outcomes was evaluated using logistic regression. The following variables were independently tested and those with a P<0.2 were entered in the multivariate model (age, gender, hypertension, diabetes, smoking, previous AF, associated coronary artery bypass grafting, associated MVR, left ventricular ejection fraction, creatininemia, and OA).

RESULTS
Clinical and echocardiographic prospective follow-ups were performed on 103 patients (61 without OA and 42 with OA) who agreed to participate in this study. Clinical characteristics were similar among groups, except for increased age (76±6.3 vs. 72.4±8.1 years, P=0.016) and increased incidence of AF (0% vs. 23.8%, P<0.001) in the OA group (Table 1).
Operative and postoperative outcomes did not differ among groups (Table 2), except for higher incidence of MVR in the OA group (11.9% vs. 0%, P=0.006). Type and size of bioprosthesis were similar between groups. No patient at either group suffered major bleeding episodes, hospitalization, stroke, or TIA.
Patients in the OA group received anticoagulation for a mean of 11.7±13.2 months. Warfarin was used in 25 patients (60%) and non-warfarin OA in 17 patients (40%).
Adequate evaluation of leaflet mobility was not possible since all echocardiograms were transthoracic.
Clinical evaluation revealed higher percentage in NYHA class improvement in patients with OA (73% vs. 45.3%, P=0.032) (Figure 1). Hemodynamic and clinical findings did not change after excluding patients who had concomitant MVR.

INTRODUCTION
The use of bioprosthesis for aortic valve replacement (AVR) has increased over the last couple of years. This is mainly due to the improvement in bioprosthesis durability as well as the increased tendency to operate on elderly patients. The main advantage of bioprosthesis is the lack of long term oral anticoagulation (OA) [1] . Nonetheless, bioprosthetic valve thrombosis (BPVT) is increasingly being recognized as a potentially reversible cause for structural valve degeneration (SVD) [1][2][3] .
BPVT is present in 11% of bioprosthetic valves explanted because of prosthesis dysfunction [1,2] . This entity may be suspected in patients with increased mean aortic valve gradient and is confirmed with the use of different imaging modalities [2,4,5] . Data from several small case series as well as non-randomized observational studies suggest that warfarin may be beneficial as a first-line therapy for suspected BPVT [1][2][3][4][5]6,7] . Although OA has been shown to be useful in this setting, there is not data regarding its association with prosthesis size.
Based on the previous data, our hypothesis was that patients under OA after AVR would have lower gradients and therefore better functional New York Heart Association (NYHA) class than patients without OA and that this effect would be seen mainly in patients with smaller prosthesis. The aim of our study was to evaluate the clinical and echocardiographic outcomes of patients with aortic bioprosthesis with and without OA.

METHODS
This is a prospective cohort-based study in which we included patients who underwent AVR and received a bioprosthesis from January 2013 until December 2016. Patients were divided according to the postoperative use of OA. Baseline and operative variables were extracted from the institution's database.
The primary outcome was change in aortic gradient. Secondary outcomes analyzed were change in NYHA class, major bleeding episodes, hospitalization, stroke, and transient ischemic attack (TIA).
Operative mortality was defined as death within the first 30 days after surgery or during the index hospitalization.
Extended inotrope use was defined as inotrope use beyond 12 hours from surgery.
Clinical follow-up was performed at the time of echocardiographic evaluation and the following variables were recorded: NYHA class, previous bleeding, hospitalization, stroke, and TIA.
The institution's review board approved the study and informed consent was given before the surgical procedure.

Surgery
AVR was performed through a median sternotomy with cardiopulmonary bypass and aortic cross-clamp (crystalloid cardioplegia was used in every case). Aortic valve was removed, and the annulus was decalcified. Interrupted "U" polyester 2-0 sutures with pledgets were used to anchor the prosthesis.

DISCUSSION
OA in patients who received aortic bioprosthesis was associated with lower aortic gradient and was found to be the only independent predictor for improvement in NYHA class after AVR. Although evaluation of leaflet mobility was not possible, we were able to find an association between OA and clinical improvement, probably due to the lower aortic gradient. Similar iEOA between both groups of patients suggests that the higher gradient may be due to alterations in leaflet mobility, which have been described in patients with subclinical bioprosthetic thrombosis [2,6] . Our preliminary data suggest that the benefit of OA after AVR may be restricted mainly to patients with ≤ 21 mm biosprosthesis. The latter has not been previously reported.
Although symptomatic thrombosis represents the extreme end of the spectrum of BPVT and is probably underreported (prevalence of 1-2%), subclinical leaflet thrombosis with no associated symptoms is more frequent [2,5,6] . Reduced leaflet     motion detected with high-resolution computed tomography (CT) in bioprosthetic aortic valves has been attributed to subclinical leaflet thrombosis [2,9,10] , which is associated with higher gradients, irrespective of iEOA. Chakravarty et al. [2] showed that in among the 55% of patients with reduced leaflet motion who had follow-up imaging, anticoagulation for three months was associated with restoration of normal leaflet motion in 36 (100%) of 36 patients, whereas reduced leaflet motion persisted or progressed in 20 (91%) of 22 patients who did not receive anticoagulation. These authors also found out that the mean aortic valve gradient at the time of the first CT scan was significantly higher in patients with reduced leaflet motion than in those without it. Patients with reduced leaflet motion were more likely to have aortic valve gradients < 20 mmHg than those with normal leaflet motion [2] . After detection of reduced leaflet motion, anticoagulation for three months was associated with a greater change in aortic valve mean gradients (decreased by 7.9 mmHg) than no anticoagulation.
Makkar et al. [6] found out that reduced leaflet motion was detected among patients with multiple bioprosthesis types, including transcatheter aortic valve replacement (TAVR) and surgical bioprostheses. Therapeutic anticoagulation with warfarin, as compared with dual antiplatelet therapy, was associated with a decreased incidence of reduced leaflet motion [6] . In patients who were reevaluated with follow-up CT, restoration of leaflet motion was noted in all patients who were receiving anticoagulation.
Protocols for the diagnosis of subclinical BPVT have been published [7] . CT scan is by far the most accurate imaging tool for the diagnosis of subclinical thrombosis. Hypoattenuation associated with bioprosthetic leaflets, also described as hypoattenuated leaflet thickening, is the hallmark of subclinical leaflet thrombosis [7,11] . The hypoattenuating lesions involve the periphery and base of the leaflet and extend to varying degrees to the edges of the leaflet in the center of the bioprosthetic frame. Three-dimensional volume-rendered views may demonstrate abnormal leaflets visible as semilunar opacities in both systole and diastole [11][12][13][14][15] .
It has been established in recent studies that anticoagulation can reverse the hypoattenuation and restore normal leaflet motion with a significant impact on the mean aortic gradients measured by echocardiography [2,6] . Similar findings were observed on the follow-up of patients in the Portico trial [2] .
In an analysis of pooled data from the Portico IDE study, the RESOLVE and SAVORY registries, hypoattenuation and hypomotility were observed among various TAVR and surgical AVR devices in patients with aortic valve gradients within the normal range [2] . Therapeutic anticoagulation was associated with a reduced prevalence of hypoattenuation compared no therapy, suggesting a thrombotic mechanism. Moreover, leaflet mobility was fully restored after resolution of the phenomenon by warfarin, suggesting that reduced motion is a result rather than a cause of valve leaflet thrombosis.
The main finding of our study is that early anticoagulation after AVR is beneficial and associated with low risk of adverse events. We observed significantly lower mean and maximum