Author + information
- Received August 7, 2015
- Revision received September 10, 2015
- Accepted September 14, 2015
- Published online December 1, 2015.
- Alexander C. Egbe, MD, MPH∗,
- Sorin V. Pislaru, MD, PhD∗∗ (, )
- Patricia A. Pellikka, MD∗,
- Joseph T. Poterucha, DO∗,
- Hartzell V. Schaff, MD†,
- Joseph J. Maleszewski, MD‡ and
- Heidi M. Connolly, MD∗
- ∗Division of Cardiovascular Diseases, Mayo Clinic, Rochester, Minnesota
- †Division of Cardiovascular Surgery, Mayo Clinic, Rochester, Minnesota
- ‡Anatomic Pathology, Mayo Clinic, Rochester, Minnesota
- ↵∗Reprint requests and correspondence:
Dr. Sorin V. Pislaru, Division of Cardiovascular Diseases, Mayo Clinic, 200 First Street SW, Rochester, Minnesota 55905.
Background Bioprosthetic valve thrombosis (BPVT) is considered uncommon; this may be related to the fact that it is often unrecognized. Recent data suggest that BPVT responds to vitamin K antagonists, emphasizing the need for reliable diagnosis.
Objectives This study sought to determine the diagnostic features of BPVT and to formulate a diagnostic model for BPVT.
Methods Cases of BPVT occurring between 1997 and 2013 were identified from the Mayo Clinic pathology database. Patients with BPVT were matched 1:2 for age, sex, and prosthesis position with patients whose valves were explanted for structural failure. We formulated a diagnostic model for BPVT using multivariate linear logistic regression and receiver operating characteristic.
Results Among 397 consecutive cases of explanted bioprostheses, there were 46 cases of BPVT (11.6%; aortic 29, mitral 9, tricuspid 7, pulmonary 1), mean age was 63 years, and 68% were male. Thirty (65%) cases occurred >12 months post-implantation; median bioprosthetic valve longevity was 24 months (cases) versus 108 months (controls) (p < 0.001). Independent predictors of BPVT were >50% increase in mean echo-Doppler gradient from baseline within 5 years (odds ratio [OR]: 12.7), paroxysmal atrial fibrillation (OR: 5.19), subtherapeutic international normalized ratio (OR: 7.37), increased cusp thickness (OR: 12.2), and abnormal cusp mobility (OR: 6.94). Presence of all 5 diagnostic features was predictive of BPVT with 76% sensitivity, 93% specificity, 85% positive predictive value, and 89% negative predictive value (p < 0.001).
Conclusions BPVT is not uncommon and can occur several years after surgery. A combination of clinical and echocardiographic features can reliably diagnose BPVT.
The predominant mechanism of bioprosthetic valve (BPV) dysfunction is structural deterioration (1,2), and the risk of bioprosthetic valve thrombosis (BPVT) is considered very low. As a result, the American College of Cardiology/American Heart Association (ACC/AHA) and European Society of Cardiology (ESC) guidelines (3,4) do not recommend oral anticoagulation with vitamin K antagonists (VKAs) beyond 3 months for mitral, tricuspid, and pulmonary valve implantation. Furthermore, the guidelines are discordant for aortic BPVs, with aspirin preferred over VKA in the European guidelines and VKA recommended for 3 to 6 months in the ACC/AHA guidelines. The diagnosis of BPVT remains very challenging due to a general lack of awareness of its existence. Several case series have shown that BPVT can be effectively treated with VKA, avoiding the need for thrombolytic therapy and surgery (5–8).
We previously suggested that presence of an increased gradient >50% over baseline should raise suspicion of BPVT (9), but direct comparison of echocardiographic characteristics of BPVT and degenerated BPV has not been performed. Thus, we set forth to delineate the clinical and echocardiographic characteristics of pathologically proven BPVT to help clinicians recognize BPVT and, with effective VKA therapy, potentially help patients avoid surgical intervention.
Patient selection and characteristics
The Mayo Clinic Institutional Review Board approved the study protocol. The pathology and surgical databases were used to identify all BPVs explanted from adults (age ≥18 years). We reviewed the pathology reports of 397 patients whose prostheses were explanted within the study period, and BPVT was considered to be present whenever valve thrombosis was the main mechanism of BPV dysfunction (n = 46). We then matched BPVs that were explanted for structural valve failure to cases of BPVT (1 BPVT: 2 structural valve failures). The structural valve failure group was matched by age (±5 years), sex, and prosthesis position. To estimate the overall incidence of BPVT in our surgical practice, we also recorded the total numbers of BPV implantations performed at the Mayo Clinic during the same time interval. Our study objectives were to estimate the prevalence of BPVT as a reason for BPV explantation, identify clinical and echocardiographic characteristics of BPVT, and formulate a diagnostic model for BPVT.
Clinical, echocardiographic, and surgical data at the time of initial BPV implantation, during follow-up, and at the time of BPV dysfunction and explantation were retrieved from the medical record. We classified atrial fibrillation (AF) into: paroxysmal AF (defined as history of AF lasting <7 days documented in clinical notes, electrocardiogram, or Holter monitoring), perioperative AF (defined as AF occurring within 1 month of valve surgery), and persistent AF (defined as AF >7 days duration that is being treated with VKA ± rate control therapy). We reviewed all international normalized ratio (INR) results obtained within the last 3 months prior to diagnosis of BPVT or explantation; patients were classified as having subtherapeutic INR if they had any INR <2.0.
Reports and digitally stored images of transthoracic echocardiogram (TTE) and transesophageal echocardiograms (TEE) were systematically reviewed. Baseline prosthetic gradients were obtained from the “fingerprint” echocardiogram performed early after surgical BPV implantation; when baseline data were unavailable because these prostheses were implanted elsewhere (n = 17), mean normal values from the published literature were used as surrogates for baseline post-implantation gradients (10,11). The images from the index echocardiogram (TTE = 94 and TEE = 108) at the time of diagnosis of BPV dysfunction were systematically reviewed (A.C.E). Two-dimensional (2D) morphology of the BPV was assessed using the following pre-defined parameters: cusp thickness, presence of abnormal cusp motion, possible intracardiac thrombus or spontaneous echocardiographic contrast, and presence of calcification. These 2D parameters were collected both for BPVT and structural valve failure. Increased cusp thickness was defined as thickness >2 mm or significantly thicker compared to “fingerprint” echocardiogram. An echocardiographer with experience in valvular disease and BPVT (S.V.P.) reviewed randomly selected studies in one-half of the entire cohort. Discordant interpretations were adjudicated after a third review by a senior echocardiographer (H.M.C). All reviewers were blinded to the interpretation of others and the etiology of BPV dysfunction.
All statistical calculations were performed with the JMP version 10.0 software (SAS Institute Inc., Cary, North Carolina). Categorical variables were expressed as percentages whereas continuous variables were expressed as mean ± SD or median and interquartile range (IQR) for skewed data. Comparison of categorical variables was performed using the chi-square test or Fisher exact test, whereas comparison of continuous variables was performed with Student t test or Wilcoxon rank sum test, as appropriate. To identify clinical and echocardiographic predictors of BPVT, data from BPVT and matched structural valve failure were analyzed with multivariable logistic regression model. Receiver operating characteristic (ROC) curves were plotted and the corresponding areas under the curve (AUC) were compared by the method of DeLong et al. (12) to determine the best combination of these clinical and echocardiographic predictors that identified BPVT, providing optimal balance between sensitivity and specificity.
Baseline clinical characteristics of BPVT and structural valve failure groups are shown in Table 1. Between January 1997 and December 2013, a total of 397 adult patients underwent surgical explantation of a BPV at the Mayo Clinic. Excluded from analysis were patients with mixed disease (thrombosis and degeneration) in whom the main mechanism could not be established (n = 4), those with active endocarditis (n = 2), and those with history of thrombophilia (n = 1). A diagnosis of BPVT was identified in the pathology report of 46 patients, of which 29 (63%) were aortic, 9 (20%) mitral, 7 (15%) tricuspid, and 1 (2%) pulmonary. Porcine valves were the most common type in the BPVT group (n = 36; 78%), followed by pericardial valves (n = 8; 18%) and homografts (n = 2; 4%). Isolated stenosis without evidence of BPV regurgitation was seen in 25 (54%) patients; isolated prosthetic regurgitation was noted in only 5 (11%); and a mixed mechanism of prosthetic dysfunction was present in 15 (33%) patients.
A total of 92 patients with pathology-demonstrated structural failure and no thrombus were selected as matched controls. Porcine valves were explanted from 50 (54%), pericardial valves from 41 (45%), and homografts from 1 (1%). Isolated stenosis or regurgitation was seen each in 30 (33%) patients, while a mixed mechanism was noted in 32 (35%) patients. BPVT patients and structural valve failure patients were well matched for main demographic characteristics (Table 1).
The overall prevalence of BPVT was 11.6% (46 of 397 explanted BPVs), with no significant differences among various valve positions (Table 2). There were 6,178 BPV implantations; 3,161 (51%) had a follow-up echocardiogram at the Mayo Clinic up to 24 months post-surgery. The incidence of BPVT based on the total number of BPV implantations performed in the similar interval is thus estimated at 0.74%, or 1.46% if only those with a follow-up echocardiogram are included.
Timing of BPV explantation
The time interval to surgical explantation is presented in Figure 1. Only 16 (35%) instances of BPVT occurred within the first 12 months of initial implantation, with a median time-to-explantation of 24 months (IQR: 12 to 60 months). Late BPVT (more than 5 years post-implantation) was seen in 7 (15%) patients. The timing of BPVT did not vary significantly by prosthesis position (p = 0.77). Analysis of matched cases of structural valve failure showed that the time to explantation for structural valve failure occurred significantly later (median: 108 months; IQR: 72 to 132 months; p < 0.001), regardless of BPV position (Figure 1B). Freedom from explantation was significantly lower for BPVT (39% and 15% at 3 and 6 years, respectively) compared to structural valve failure (81% and 66% at 3 and 6 years, respectively) (p < 0.001) (Figure 1A, Central Illustration).
The index TTE and TEE reports described abnormal BPV in each case; possible BPVT was mentioned in only 2 of 42 TTEs (5%) and in 6 of 45 TEEs (13%). Description of the 2D morphology of the BPV by review of all available digital images for BPVT and structural valve failures is shown in Table 3.
BPVT usually presented with increased cusp thickness (commonly on the downstream aspect of the valve), and associated reduced cusp mobility with increased gradients; moderate or more regurgitation was less common in BPVT compared to structural valve failure patients for aortic (p < 0.001) and mitral (p = 0.056) positions (Table 3). On the other hand, structural valve failure was more commonly associated with calcified cusps, reduced leaflet mobility, and significant regurgitation. The typical echocardiographic features of BPVT and structural valve failure are illustrated in Figure 2 and in Online Videos 1 and 2.
Risk factors and independent predictors for BPVT
Forty patients (10%) in the entire cohort were on VKA at the time of diagnosis of BPV dysfunction; 19 (48%) of these patients had subtherapeutic INRs within the last 3 months before diagnosis of BPV dysfunction. One additional patient was started on unfractionated heparin at the time of BPVT diagnosis and underwent surgery 2 days later. No patient received novel anticoagulant or thrombolytic therapy and none of the patients had high cardiac output state.
In considering univariate and multivariate analysis of BPVT predictors (Table 4), multivariate logistic regression analysis showed that paroxysmal AF, subtherapeutic INR for patients on VKA therapy, an increase in mean transvalvular gradient of >50% above baseline within 5 years in the absence of a high cardiac output state, increased cusp thickness, and abnormal cusp mobility all were strongly associated with BPVT. Multiple ROC curves were generated to determine the diagnostic accuracy of each of the 5 independent predictors of BPVT. The comparison of the discriminatory ability of the different ROC models showed that the combination of all 3 echocardiographic predictors (50% increase in gradient within 5 years, increased cusp thickness, and abnormal cusp mobility) had the highest AUC (AUC = 0.852; 95% confidence interval [CI]: 0.763 to 0.940) compared to the other models. The presence of all 3 echocardiographic predictors reliably diagnosed BPVT with sensitivity of 72% and specificity of 90% when we applied it to the 138 patients included in our cohort (Table 5).
To the best of our knowledge, this is the first study to directly compare the clinical and echocardiographic characteristics of thrombosed and degenerated bioprostheses. Our major findings are: 1) BPVT referred for surgical intervention occurs significantly earlier than BPV degeneration, after a median of 24 months post-implantation; 2) BPVT is more common than previously reported; and 3) concomitant presence of 3 echocardiographic characteristics (an increased gradient >50% over baseline within first 5 years after implantation, increased cusp thickness, and abnormal cusp mobility) appears to characterize BPVT with acceptable sensitivity and high specificity in the setting of concordant clinical features.
Prosthetic dysfunction due to BPVT
The predominant mechanism of BPV dysfunction is structural deterioration (1,2), and in the past, the risk of thrombosis was considered to be very low. In contrast, our experience and that of others suggest that BPVT is not uncommon (6,7,13,14). Butnaru et al. (6) retrospectively reviewed TEEs of 149 patients who underwent mitral BPV implantation at a single center and identified BPVT in 9 patients (6%). The indication for TEE was prosthesis dysfunction suspected on TTE, and the mean time interval from implantation to TEE diagnosis was 12 months. The diagnosis of BPVT was confirmed by pathology in 3 patients who underwent reoperation and by resolution of prosthesis dysfunction in the other 6 patients treated with VKA. Similarly, Oliver et al. (7) reviewed TEEs of 161 patients with mitral BPV dysfunction and identified 10 cases of BPVT (6.2%). The time interval from implantation to TEE diagnosis was 83 months in their series. The diagnosis of BPVT was confirmed by pathology in 3 of their patients who underwent reoperation and by resolution of clinical and echocardiographic features of thrombosis after VKA anticoagulation in the other 7 patients (7). Our study showed that BPVT was present in 11.6% of all explanted BPV and in 12.7% of BPV in the mitral position. The median duration from the time of implantation to explantation was 24 months for our entire BPVT cohort and 31 months for mitral BPVT. We defined BPVT based on pathological diagnosis while Butnaru et al. (6) and Oliver et al. (7) defined BPVT based on echocardiographic diagnosis, which might have resulted in underestimation of the true incidence of BPVT in their cohorts because of missed diagnosis. Our result is consistent with BPVT prevalence of 10% to 11% reported in other pathology series of BPV explanted at surgery or autopsy (15,16).
A surgical study from our institution reported 8 cases of BPVT in the aortic position among 4,568 aortic BPV implantations (incidence of 0.18%), with significantly higher incidence in porcine valves compared to pericardial valves (13). In that study, Brown et al. (13) identified cases of BPVT by chart review of all patients who underwent reoperation for aortic BPV failure within 2 years of implantation. Our study did not show any significant difference in BPVT occurrence by prosthesis position or prosthesis type. The median time to explantation in our cohort was 24 months with 50% of prostheses explanted more than 2 years from the time of initial implantation. The lower incidence rate reported by Brown et al. (13) may be because their study design did not capture cases of BPVT that occurred more than 2 years after implantation.
Risk factors and predictive model for BPVT
In our series, clinical and echocardiographic characteristics associated with increased risk of BPVT were paroxysmal atrial fibrillation (AF), subtherapeutic INR for patients on VKA therapy, an increase in mean transvalvular gradient >50% above baseline values within 5 years, increased cusp thickness, and abnormal/restricted cusp mobility. The 3 echocardiographic features of BPVT were similar to those described in prior studies (5–7). Interestingly, persistent AF was not an independent risk factor for BPVT. Our data suggest that inadequate anticoagulation is significant in both persistent and paroxysmal AF. Most patients with paroxysmal AF in our cohort were not anticoagulated and that might be the reason for their increased risk of BPVT, as shown in our multivariate analysis.
Among our thrombosis cohort, the diagnosis of BPVT was correctly made on the initial echocardiogram in only a minority of patients (5% using TTE and 13% using TEE). This highlights not only the difficulty in identifying BPVT using echocardiography, but also suggests a low level of awareness that BPVT may occur late after implantation. Based on our proposed risk model, diagnosis of BPVT can be made with >70% sensitivity and >90% specificity in patients with 3 of 5 independent risk factors listed above. By applying this risk model retrospectively among the 138 patients included in our study, the diagnosis of BPVT would have been considered in the majority of patients in the case group, and the confirmatory criterion would be resolution of echocardiographic findings and associated clinical improvement after VKA therapy. Most likely some of these patients could have avoided reoperation.
Accurate diagnosis of BPVT is critical because these patients have been shown to respond very well to VKA (5–7,14). In a prior series from our institution, we compared efficacy and safety of VKA (target INR of 2.0 to 3.0) to surgery/thrombolysis in 31 patients with BPVT diagnosis (5). The endpoint for efficacy was improvement in prosthetic gradient and New York Heart Association functional class, while the safety endpoint was freedom from death and thromboembolic complications. VKA was similar to surgery/thrombolysis and there were no deaths or thromboembolic complications in either cohort. Similarly, other series have also demonstrated resolution in 88% to 100% of patients with BPVT in the mitral position after anticoagulation with VKA for 4 to 14 weeks (6,7). Data from a Danish registry showed that prophylactic anticoagulation with VKA beyond 6 months post-implantation of BPV in the aortic position is associated with decreased thromboembolic events and cardiovascular death without a significant increase in bleeding; this may be related to BPVT prevention (17). This observation led to a change in the 2014 ACC/AHA guidelines, which now recommend 3 to 6 months of VKA anticoagulation after aortic BPV implantation.
Estimating incidence of BPVT
Given the retrospective nature of our study, the true incidence of BPVT cannot accurately be determined. When comparing reoperation due to bioprosthetic thrombosis to the total number of bioprosthetic valve implantations during the study period, BPVT incidence appears relatively low: 0.74% to 1.46% (46 BPVT cases compared to a total 6,178 implantations, or to 3,161 patients who had at least 1 follow-up at the Mayo Clinic after initial implantation, respectively). However, this clearly underestimates the true incidence, as BPVT patients successfully treated with anticoagulation avoided surgery and, thus, are not captured in this study.
In a previous report we identified another 15 BPVT patients treated with anticoagulation alone in a similar time interval (5). Furthermore, both a lack of clinical awareness and of set echocardiographic diagnostic criteria for BPVT impacted our ability to detect this disease. Indeed, considering that the original TTE and TEE reports reviewed for this series mentioned BPVT diagnosis in <15% of confirmed cases, a significant number of BPVT cases were clinically missed. Of note, recent data on computed tomography evaluation post-transcatheter aortic valve replacement suggests BPVT may be present in 4% of patients (18). Whether the true incidence of BPVT in the community will be as high as the 11.6% prevalence among patients requiring reoperation (46 BPVT for 397 reoperations) remains to be determined in large, prospective trials.
The current ESC guidelines for the management of valvular heart disease do not recommend VKA for BPV in the aortic position beyond the first 3 months, and both ESC and current ACC/AHA guidelines do not recommend VKA for BPV beyond 3 months for mitral, tricuspid, and pulmonary valves (3,4). Additionally, routine TTE surveillance in the absence of change in clinical status is not recommended in patients with BPV until 10 years post-implantation (3,4).
Based on our results and experience we have changed our practice and recommend the following:
1. Patients with BPV in any position who require VKA for any indication such as AF or prior thromboembolic event should have their INR meticulously maintained between 2.0 and 3.0.
2. All patients with paroxysmal AF who receive BPV should be on VKA for anticoagulation unless contraindicated.
3. Patients who present with BPV dysfunction, especially when this is identified <5 years after implantation, should be meticulously evaluated for evidence of BPVT using the above-proposed risk model.
4. Patients who present with clinical and/or echocardiographic features of BPVT (and have no contraindications to anticoagulant therapy) should be considered for a trial of VKA as initial therapy rather than being referred directly for valve replacement.
5. Echocardiographic surveillance of BPV should be performed within 12 months of cessation of VKA in high-risk patients.
First, this is a retrospective study based on a cohort from a single tertiary center, which lends itself to potential bias. The cross-sectional study design makes it difficult to infer causality between associated risk factors and BPVT. There were 17 patients without baseline assessment of transvalvular gradient at the time of BPV implantation. We determined the performance of our diagnostic model in a highly selected population of 138 explanted BPV; thus, it may not be representative of the general population of patients with BPV dysfunction. Consequently, we anticipate that our model may be less predictive in other populations and a larger study is needed to prospectively validate this model in the general population of patients with BPV dysfunction. Finally, the exact onset of BPVT is unknown, as prosthetic thrombosis certainly preceded the time of explantation.
BPVT is not uncommon and can occur several years after surgery. A combination of clinical and echocardiographic features can reliably diagnose BPVT. It is crucial to consider the diagnosis of BPVT before referring for reoperation because VKA therapy may reverse the BPV dysfunction.
COMPETENCY IN MEDICAL KNOWLEDGE: Thrombosis of bioprosthetic heart valves can occur several years after implantation. Likely predictors of this complication include a >50% increase in mean echo-Doppler transvalvular gradient within 5 years, paroxysmal atrial fibrillation, subtherapeutic INR in patients anticoagulated with vitamin K antagonists, increased cusp thickness, and abnormal cusp mobility.
TRANSLATIONAL OUTLOOK: Additional studies are needed to validate these predictors of thrombosis in broad populations of patients with bioprosthetic valve dysfunction.
For the accompanying videos, please see the online version of this article.
The authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- Abbreviations and Acronyms
- atrial fibrillation
- bioprosthetic valve
- bioprosthetic valve thrombosis
- international normalized ratio
- transesophageal echocardiogram
- transthoracic echocardiogram
- vitamin K antagonist
- Received August 7, 2015.
- Revision received September 10, 2015.
- Accepted September 14, 2015.
- American College of Cardiology Foundation
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