Over 200,000 people have undergone transcatheter aortic valve replacement (TAVR), and every year approximately 140,000 patients receive a surgical bioprosthetic valve.^1,2 Despite this increasing volume, the optimal postoperative anticoagulation strategy is often unclear. Specifically, two questions underscore the difficulty in decision-making for these common clinical scenarios:

1. In the initial months after bioprosthetic valve replacement, what complications are we trying to reduce with anticoagulation?
2. Should anticoagulation be provided to all patients to reduce these complications? Or should we have a more selective approach based upon risk factors?

Thrombotic Risks After Bioprosthetic Valve Replacement

Traditionally, the rationale for anticoagulation in the first few months after surgical valve replacement has been to mitigate against thrombotic complications, presumably related to suture material and a sewing ring that is not yet covered with biofilm and endothelialized.^3,4 The possible subsequent thrombotic complications are three-fold: thromboembolic events, overt thrombosis of the valve, and subclinical organized thrombus that may impair long-term valve function. Despite the frequency of bioprosthetic valve replacement, data related to these complications are limited, in part because these events are seemingly infrequent.

A recent meta-analysis highlighted the low event rate after bioprosthetic valve replacement. In this analysis of 31,740 patients, predominantly with surgical aortic valve replacement, early thromboembolic events occurred in 145 patients (1%) taking vitamin K antagonists and 262 patients (1.5%) not taking vitamin K antagonists (odds ratio 0.96; 95% confidence interval, 0.60-1.52).⁵ If we hypothesize that there is in fact a 0.5% increase in thromboembolic complications in the first months after surgical aortic valve replacement in patients not taking vitamin K antagonists, then an appropriately powered randomized controlled trial would require approximately 15,500 patients.⁶ To date, 2 randomized trials have been performed, totaling 268 patients.^7,8 Given the small number of patients, the lack of a statistically detectable difference in the 2 groups is not surprising.

In the absence of large randomized controlled trials, clinicians must turn to observational studies for insight, such as the analysis from the Danish National Patient Registry.⁹ In this study of 4,075 patients with bioprosthetic aortic valve replacements, discontinuation of warfarin was associated with increased thromboembolic events and cardiovascular deaths 1-6 months after surgery. Interestingly, although the stroke rate was increased in the first 3 months in the treatment group, the number of strokes between 3 and 6 months was no different between patients who continued or discontinued warfarin, though there were only 21 events during this period. In addition, there was no difference in bleeding events between 3 months and 1 year. This observation is counter to previous reports and clinical experience that patients on warfarin are more likely to be hospitalized for bleeding.⁵ Therefore, the authors' conclusions regarding cardiovascular mortality and thromboembolic events may have been related to residual confounding. Specifically, there may have been no difference in bleeding events because clinicians were less likely to start or continue anticoagulation in the highest-risk patients.

Unfortunately, compared with thromboembolic events, published data provide even less insight into inferential associations for bioprosthetic valve thrombosis. Few events have been reported, and most of the literature is confined to case series and single-center experiences.¹⁰ Consequently, the incidence of bioprosthetic valve thrombosis is not well-defined, though in one study, only 8 of 4,568 patients with bioprosthetic aortic valves required reoperation for aortic stenosis related to thrombus.¹¹ Likewise, the role of clinically silent thrombosis and possible accelerated bioprosthetic valve degeneration is largely unknown.

Selective Anticoagulation After Bioprosthetic Valve Replacement

Based on an unclear magnitude of benefit and a well-accepted bleeding risk, universal anticoagulation after bioprosthetic aortic valve replacement is difficult to justify; this uncertainty is reflected by the Class IIb recommendation in the 2014 American College of Cardiology and American Heart Association (ACC/AHA) valvular heart disease guidelines.¹² However, specific clinical situations may arise when anticoagulation should be more strongly considered. For example, in a recent case-control study including 46 patients with reoperation for bioprosthetic aortic valve thrombosis, an increase >50% in mean Doppler gradients on echocardiography from baseline, increased cusp thickness, and abnormal cusp mobility were all associated with valve thrombosis.¹³ Therefore, a trial of anticoagulation and follow-up echocardiography to assess Doppler gradients could be considered in these patients,¹⁴ although the extent to which short- and long-term valve function is modified by anticoagulation is unclear.

In addition, patients with a bioprosthetic mitral valve seem to be at higher risk for thromboembolic events and valve thrombosis (see the Illustrative Case, with Figures 1-2 and Videos 1-2, below). Because bioprosthetic mitral valve replacement is much less common than aortic valve replacement, data are even more limited. However, in a single-center study of 216 patients with bioprosthetic mitral valve replacement, 10 (5%) had an ischemic stroke within 6 months.¹⁵ Moreover, in another study of 149 consecutive patients, 9 (6%) developed bioprosthetic mitral valve thrombosis.¹⁶ Therefore, patients with bioprosthetic mitral valve replacement appear to be at higher risk, and routine anticoagulation should be considered for 3-6 months, again reflected by the Class IIa recommendation in the 2014 ACC/AHA valvular heart disease guidelines.¹²

Illustrative Case: Bioprosthetic Mitral Valve Thrombosis

A 71-year-old woman presented with heart failure 8 months after bioprosthetic mitral valve replacement for rheumatic mitral stenosis. Postoperatively, she had been treated with coumadin for 3 months and continued on aspirin. She had no history of atrial fibrillation and had been afebrile, and blood cultures were negative.

Video 1

Figure 1

Video 2

Figure 2

Finally, and perhaps most contentious, is whether our approach to anticoagulation should differ for patients who have had TAVR. The initial default has been to treat these patients with aspirin and clopidogrel because this was the approach undertaken in the randomized trials. More recently, with electrocardiography-gated four-dimensional computed tomography angiography (CTA), reduced bioprosthetic aortic valve leaflet mobility and hypoattenuated leaflet thickening have been described, implicating valve thrombosis.^17,18 Often, these patients are asymptomatic and have normal Doppler gradients on echocardiography, suggesting that these findings may be subclinical. Importantly, these CTA abnormalities may resolve with warfarin, and lack of initial anticoagulation is emerging as a possible risk factor.¹⁹ At present, however, these imaging findings are of unclear clinical significance.²⁰ Fortunately, a randomized trial, GALILEO (Global Study Comparing a Rivaroxaban-Based Antithrombotic Strategy to an Antiplatelet-Based Strategy After Transcatheter Aortic Valve Replacement to Optimize Clinical Outcomes) comparing rivaroxaban to antiplatelet therapy after TAVR is underway and should provide valuable insight.²¹ Still, despite an estimated enrollment of 1,520 patients, the trial may not be adequately powered for clinical events.

Conclusions

Overall, in patients with bioprosthetic valves, early nonprocedural thromboembolic events are uncommon. Moreover, the incidence of overt valve thrombosis is likely low, and the effect of subacute valve thrombosis on valve durability is still being defined. Given these observations, coupled with the increased bleeding risk with warfarin, we advocate a selective approach to postoperative anticoagulation (Figure 3). For patients with bioprosthetic aortic valves, anticoagulation for 3-6 months is indicated in patients with established risk factors, such as atrial fibrillation. Based on recent emerging evidence, anticoagulation and close follow-up should be considered in patients with abnormal echocardiographic or CTA findings, such as an unexplained increase in Doppler valve gradients or hypoattenuated leaflet thickening. Finally, even though fewer data are available, patients with bioprosthetic mitral valves appear to be at higher risk for thrombotic complications, and routine anticoagulation for 3-6 months is recommended.

Figure 3: Proposed Approach to Anticoagulation After Bioprosthetic Valve Replacement

This article contains educational materials intended for licensed health care professionals and is intended to be used solely for educational and informational purposes. While the content may be about specific medical and health care issues, it is not a substitute for or replacement of personalized medical advice and is not intended to be used as the sole basis for making individualized medical or health-related decisions. The views and opinions expressed are those of the contributing authors and editors and do not necessarily represent the views of the ACC. The material is not intended to present the only, or necessarily best, methods or procedures for the medical situations addressed, but rather is intended to represent an approach, view, statement or opinion.

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Keywords: Aortic Valve, Aortic Valve Stenosis, Atrial Fibrillation, Aspirin, Bioprosthesis, Case-Control Studies, Angiography, Constriction, Pathologic, Echocardiography, Transesophageal, Electrocardiography, Heart Failure, Heart Valve Diseases, Heart Valve Prosthesis, Mitral Valve, Mitral Valve Stenosis, Reoperation, Risk Factors, Stroke, Sutures, Thrombosis, Ticlopidine, Transcatheter Aortic Valve Replacement, Vitamin K, Warfarin

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