Introduction

The use of bioprostheses for patients requiring valve replacement has substantially increased over the last 20 years.¹ These temporal trends can be attributed to the aging population, improved durability of newer-generation surgical bioprosthetic valves, and the rapidly expanding field of transcatheter valve implantation. Recent evidence suggests that bioprosthetic valve thrombosis (BPVT) is more common than previously thought, particularly within a few years of implantation, which can lead to valve dysfunction and deterioration. Given that BPVT can be subclinical, adjustment in the optimum surveillance strategy may facilitate treatment to optimize outcomes for patients with bioprosthetic heart valves.

Is BPVT Uncommon or Unrecognized?

BPVT has traditionally been considered a rare event after bioprosthetic valve implantation. This perception was recently challenged by the results of a retrospective analysis of BPVT cases occurring between 1997 and 2013 at Mayo Clinic.² Among 397 consecutive patients requiring surgical explantation of a dysfunctional bioprosthetic valve, 46 cases (11.6%) were attributed to valve thrombosis based on pathological report. The overall incidence of BPVT was estimated ~1% when comparing diagnosed cases of BPVT to the total number of bioprosthetic valves implanted during the study period. However, this frequency may be an underestimate because it does not account for patients who were successfully treated with anticoagulation, those with BPVT who died prior to reoperation, or those who did not return to that medical center with their postoperative problems. Cases of BPVT were matched with patients requiring valve explantation for structural valve failure. Utilizing multivariate regression, a diagnostic model was formulated to identify predictors of BPVT. Echocardiographic findings independently associated with BPVT included >50% increase in mean echo-Doppler gradient within 5 years of baseline, increased cusp thickness, and abnormal cusp mobility. Not unexpectedly, paroxysmal atrial fibrillation and subtherapeutic international normalized ratio were also associated with BPVT. Median time to explantation was significantly shorter for those with BPVT compared with those with structural valve failure (24 vs. 108 months, p < 0.001). Overall, these data suggest that BPVT is not a rare cause of bioprosthetic valve failure, occurs earlier than structural degeneration, and is associated with specific echocardiographic and clinical parameters that may help diagnose patients at risk for BPVT. In addition, many patients categorized as structural failure may have evolved over time into a fibrotic histology from an earlier phase of leaflet thrombosis.

Two single-center case series evaluated patients with suspected valve dysfunction following surgical bioprosthetic valve placement in the mitral position.^3,4 BPVT was diagnosed in 6% and 6.2% of cases based primarily on echocardiographic findings. Even this percentage may underestimate the true incidence of BPVT for reasons similar to those already discussed. Additionally, recent reports from the transcatheter aortic valve replacement (TAVR) literature indicate that BPVT may be especially relevant to this patient population. Makkar et al. reported a concern for subclinical leaflet thrombosis of bioprosthetic aortic valves among clinical trial and registry participants who underwent TAVR or surgical aortic valve bioprosthesis implantation.⁵ Four-dimensional volume-rendered computed tomography (CT) scans showed reduced leaflet motion in 40% of the clinical trial TAVR group and 13% of the surgical aortic valve replacement group. Restoration of leaflet motion was noted in all patients who received anticoagulation. It is not clear if these findings are reproducible or if the same would be found in a prospective, well-controlled study. In a larger study of 460 consecutive patients undergoing TAVR, 7% were found to have BPVT as detected by CT scan. The use of anticoagulation was protective against BPVT in this cohort (relative risk 5.46; 95% confidence interval, 1.68-17.7 for those not receiving warfarin treatment). Treatment with warfarin effectively reverted 85% of patients with BPVT to normal, based on follow-up imaging.⁶ Taken together, these data suggest that the incidence of BPVT is more common than previously thought.

How Often is Routine Echocardiography Indicated After Bioprosthetic Valve Implantation?

General consensus in the past has favored use of bioprostheses in many patients, largely because of the perception that they do not need anticoagulation, in contrast to mechanical valves. Though not as durable, bioprostheses have very favorable long-term outcomes, with structural valve degeneration requring reoperation occuring in only 1.5% of patients at 10 years and 15% at 20 years.⁷ Presuming a previously unrecognized incidence of 6% of early BPVT, some fatal or requiring reoperation, the consideration for anticoagulation for bioprostheses has been omitted. Without knowledge of early BPVT, previously published guidelines recommendations have omitted any consideration of echocardiographic surveillance for 10 years, once the baseline transthoracic echocardiogram (TTE) is done 2-12 weeks postoperation. An interval echocardiogram is therefore omitted in most patients, presuming they are asymptomatic and in a stable hemodynamic state, unless there is a change in clinical symptoms or signs suggesting valve dysfunction.⁸ After the first 10 years following bioprosthetic valve implantation, asymptomatic patients may be considered for annual TTE surveillance. This Class IIa recommendation is based on the expectation that structural dysfunction of bioprosthetic valves increases after the first decade after valve implantation.

It is probable that we have been missing BPVT by omitting routine echocardiographic surveillance early after valve placement because BPVT is likely a progressive phenomenon beginning with a small degree of valvular thrombosis that is not initially associated with hemodynamic consequences significant enough to result in symptoms. Egbe et al. identify a change in transvalvular Doppler gradients >50% as an independent predictor of BPVT. The peak incidence of BPVT occurs in the first 13-24 months following bioprosthetic valve implantation. These data suggest that clinical examination alone, without serial echocardiographic assessment, is probably inadequate to detect BPVT in the early years following bioprosthetic valve implantation. Early routine surveillance with annual echocardiography seems warranted, especially because advanced BPVT is more likely to be resistant to medical therapy with anticoagulation or thrombolytics. CT is more sensitive to detect leaflet thrombus; however, expense, radiation exposure, and inability to measure valve gradients make CT a less desirable imaging modality for serial observations. A surveillance algorithm for BPVT is outlined in Figure 1.^9,10

Figure 1: Bioprosthetic Valve Thrombosis⁹

Should Surveillance Strategy Differ by Type of Valve?

The study by Egbe et al. is the largest to date evaluating BPVT and demonstrates no significant difference in risk among aortic, mitral, pulmonic, and tricuspid valves. Therefore, a differential surveillance approach according to valve position does not appear necessary for surgically implanted bioprosthetic valves. TAVR typically has more frequent surveillance intervals given the multitude of parameters that are monitored with this newer technology, including patient-prosthesis mismatch, paravalvular leak, and valve degeneration. Following TAVR, guidelines recommend post-implantation TTE prior to hospital discharge, at 6 months and 1 year, and then annually subsequently.¹¹ Although the significance of the high rates of subclinical BPVT remain to be determined, these regular surveillance intervals will remain important.

What Research is Needed?

The effectiveness of annual echocardiographic screening following bioprosthetic valve implantation needs to be tested in prospective studies. Particularly, does routine echocardiographic screening identify clinically meaningful BPVT better than regular history and physical examination, or any other method? Does earlier detection of BPVT improve long-term outcomes including stroke, systemic embolization, and valve failure requiring re-operation? What specific echocardiographic criteria are optimal to trigger initiation of anticoagulation? What is the best duration of anticoagulation? Are the new direct oral anticoagulants effective to prevent or treat BPVT? How should the risks (e.g., bleeding) and benefits (e.g., decrease/elimination of thrombus) be weighed, and how do patient characteristics influence this balance? Case series suggest that anticoagulation improves imaging parameters including leaflet motion; however, routine use of anticoagulation in the first 3-6 months postoperation does result in some increased bleeding events.¹² Research is needed to identify appropriate thresholds for treatment and ensure that this treatment improves hard clinical outcomes. Routine echocardiographic examinations will be necessary to clarify these results.

References

1. Barreto-Filho JA, Wang Y, Dodson JA, et al. Trends in aortic valve replacement for elderly patients in the United States, 1999-2011. JAMA 2013;310:2078-85.
2. Egbe AC, Pislaru SV, Pellikka PA, et al. Bioprosthetic Valve Thrombosis Versus Structural Failure: Clinical and Echocardiographic Predictors. J Am Coll Cardiol 2015;66:2285-94.
3. Butnaru A, Shaheen J, Tzivoni D, Tauber R, Bitran D, Silberman S. Diagnosis and treatment of early bioprosthetic malfunction in the mitral valve position due to thrombus formation. Am J Cardiol 2013;112:1439-44.
4. Oliver JM, Gallego P, Gonzalez A, Dominguez FJ, Gamallo C, Mesa JM. Bioprosthetic mitral valve thrombosis: clinical profile, transesophageal echocardiographic features, and follow-up after anticoagulant therapy. J Am Soc Echocardiogr 1996;9:691-9.
5. Makkar RR, Fontana G, Jilaihawi H, et al. Possible Subclinical Leaflet Thrombosis in Bioprosthetic Aortic Valves. N Engl J Med 2015;373:2015-24.
6. Hansson NC, Grove EL, Andersen HR, et al. Transcatheter Aortic Valve Thrombosis: Incidence, Predisposing Factors, and Clinical Implications. J Am Coll Cardiol 2016;68:2059-69.
7. Johnston DR, Soltesz EG, Vakil N, et al. Long-term durability of bioprosthetic aortic valves: implications from 12,569 implants. Ann Thorac Surg 2015;99:1239-47.
8. Nishimura RA, Otto CM, Bonow RO, et al. 2014 AHA/ACC guideline for the management of patients with valvular heart disease: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2014;63:2438-88.
9. Pislaru SV, Pellikka PA, Schaff HV, Connolly HM. Bioprosthetic valve thrombosis: The eyes will not see what the mind does not know. J Thorac Cardiovasc Surg 2015;149:e86-7.
10. Stewart WJ. Thrombosis of Bioprosthetic Valves: Can We Afford to Ignore It? J Am Coll Cardiol 2015;66:2295-7.
11. Holmes DR Jr, Mack MJ, Kaul S, et al. 2012 ACCF/AATS/SCAI/STS expert consensus document on transcatheter aortic valve replacement: developed in collabration with the American Heart Association, American Society of Echocardiography, European Association for Cardio-Thoracic Surgery, Heart Failure Society of America, Mended Hearts, Society of Cardiovascular Anesthesiologists, Society of Cardiovascular Computed Tomography, and Society for Cardiovascular Magnetic Resonance. J Thorac Cardiovasc Surg 2012;144:e29-84.
12. Masri A, Gillinov AM, Johnston DM, et al. Anticoagulation versus antiplatelet or no therapy in patients undergoing bioprosthetic valve implantation: a systematic review and meta-analysis. Heart 2017;103:40-8.

Keywords: Anticoagulants, Aortic Valve, Atrial Fibrillation, Bioprosthesis, Echocardiography, Echocardiography, Transesophageal, Heart Valve Prosthesis, Hemodynamics, Risk, Stroke, Thrombosis, Tomography, Tomography, X-Ray Computed, Transcatheter Aortic Valve Replacement, Tricuspid Valve, Warfarin

< Back to Listings