Abstract
Background
Antithrombotic therapy (AT) after cardiac valve surgery is complex, with guidelines often relying on limited evidence.
Objectives
This study examines real-world adherence to the European Society of Cardiology Class II, level C recommendations for AT in valve surgery, as well as the 6-month impact of AT on patient outcomes.
Methods
This prospective, observational subanalysis of the European Society of Cardiology EURObservational Research Programme Valvular Heart Disease II survey included 6 substudies examining different valve interventions and AT regimens. Patient demographics, clinical characteristics, and 6-month outcomes were compared between groups receiving the recommended AT and those who did not.
Results
Guideline adherence varied widely (39.5%-81.1%) across substudies. Factors influencing AT decisions included cardiovascular risk factors, atrial fibrillation, and prior percutaneous coronary intervention. In unadjusted analyses of 3 substudies, 6-month all-cause mortality was significantly higher in patients not receiving the recommended AT. However, no significant differences were observed in thromboembolic events, bleeding, or other complications between AT and non-AT groups across all substudies at 6 months.
Conclusion
This analysis reveals potential mortality benefits associated with guideline-recommended AT in some patient groups. However, the observational nature of the study limits causal inferences, emphasizing the importance of further prospective research to optimize AT strategies and improve patient outcomes in this complex clinical setting, particularly as new AT and valve types emerge.
Keywords: anticoagulation, antiplatelet therapy, cardiac valve surgery, registry, valve disease
Essentials
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Antithrombotic therapy guidance after valve surgery is complex and often based on limited evidence.
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This study used real-world data from a 2017 European survey of patients with heart valve surgery.
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Adherence to the guidelines varied widely (39%-81%), influenced by other patient risk factors.
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Guideline use showed potential mortality benefits, but more robust, randomized trials are urgently needed.
1. Introduction
Valvular heart disease (VHD) poses a significant and increasing global challenge, with valve intervention being the only effective treatment for severe cases. Patients undergoing cardiac valve surgery are at an increased risk of prothrombotic complications and generally require antithrombotic therapy (AT), encompassing both anticoagulation and antiplatelet treatment [[1], [2], [3]]. AT needs to be individualized and depends on factors such as the affected heart valve, the type of valvular intervention (mechanical or biological), the patient’s clinical condition and bleeding risk, and additional indications for AT, as VHD frequently coexists with conditions such as atrial fibrillation (AF) or coronary artery disease (CAD) [4,5]. In recent years, the arsenal of AT has expanded, and clinicians are increasingly confronted with complex clinical challenges. In such situations, the guidelines provided by the European Society of Cardiology (ESC) on AT in VHD can be a valuable reference. Nevertheless, while some current recommendations have received validation through randomized clinical trials or large nonrandomized studies (Class I), a significant portion of the guidelines, despite recent updates, continue to rely on expert opinion or retrospective, observational data from nonrandomized trials (Class IIa or Class IIb, level of evidence C) [1,6,7]. Unfortunately, comprehensive, prospective real-world data on the use of AT after cardiac valve surgery that might support these recommendations are generally lacking [1,4].
The ESC EURObservational Research Programme (EORP) VHD II survey is an international, multicenter, prospective, observational cohort study, investigating care and outcomes of patients with VHD at hospitals in Europe and ESC-affiliated/nonaffiliated countries [8]. Study objectives included evaluation of the medical management of patients following a cardiac valve intervention. The aim of this VHD II subanalysis was to examine the contemporary, real-life adherence to the Class II, level of evidence C recommendations of AT application in patients with heart valve surgery, as outlined in the ESC guidelines [1,6]. Furthermore, this analysis aimed to determine the patient factors that may have influenced the decision to administer AT in these individuals. Additionally, we sought to explore the 6-month impact of AT on patient outcomes, including mortality, thromboembolic events, bleeding, and the incidence of prosthetic dysfunction.
2. Materials and Methods
2.1. Study design and data collection
The detailed methodology of the ESC EORP VHD II survey has been previously reported [8]. This international, prospective, multicenter, observational survey was conducted from January to August 2017. Its aim was to compare the management of patients with VHD with the latest guidelines at that time, published in 2012 by the ESC/European Association of Cardiothoracic Surgery (EACTS), and immediately before publication of the revised ESC/EACTS guidelines of 2017 [6,7]. Participating university, public, and private centers in Europe and ESC-affiliated/nonaffiliated countries with or without onsite cardiac surgery or interventional cardiology were included on a voluntary basis. A total of 7247 patients aged at least 18 years with severe native VHD according to the 2012 ESC/EACTS guidelines or with any previous valvular intervention were included during hospitalization or in the outpatient clinic. Exclusion criteria were acute infective endocarditis, enrollment in a valve intervention study affecting management, and VHD related to complex congenital heart disease. Patients presenting with native VHD who had undergone a previous valvular intervention on another valve were classified in the previous valvular intervention group to avoid double-counting. Drug prescription and indications for diagnostic/therapeutic procedures were left to the discretion of the attending physician. The recruitment period was 3 months for each center, with follow-up at 6 months. Baseline data included demographics (age, male, and female), cardiac history, comorbidities (AF, CAD, peripheral arterial disease, risk factors, and congestive heart failure), complications during the last year (heart failure hospitalization, thromboembolic, or hemorrhagic events), and baseline and discharge medical treatments. Data collected at 6 months were vital status, hospitalizations for cardiac reasons (heart failure, prosthetic dysfunction, bleeding, or thromboembolic events), and new valvular interventions. The study was approved by each national or regional ethics committee or institutional review board, according to local regulations. Written informed consent was obtained from all participants. This study complies with the Declaration of Helsinki.
2.2. Data management
Data were collected by the collecting officers at the participating sites and entered into an online electronic case report form (CRF). The survey was overseen by an Executive Committee and managed by the EORP department of the ESC, which was also responsible for study management, data quality control, and statistical analyses.
2.3. AT substudies
The objective of this VHD II ancillary analysis was to examine the application and outcomes of AT in patients with heart valve surgery, considering the 6 available Class II, level of evidence C recommendations for antithrombotic management in VHD, as outlined in the ESC/EACTS 2012 guidelines, which were applicable during the study period [6]. The levels of evidence and the strengths of these recommendations were weighed and graded according to predefined scales, as defined in Supplementary Tables S1 and S2. Table 1 gives an overview of the 6 substudies: 3 investigated the use of low-dose acetyl salicylic acid (ASA), while 3 others examined the utilization of oral anticoagulation (OAC). OAC was defined as a vitamin K antagonist (VKA) or direct oral anticoagulant (DOAC), such as dabigatran, rivaroxaban, apixaban, or edoxaban.
Table 1.
Substudies on application of antithrombotic treatment in patients with heart valve surgery, based on the European Society of Cardiology/European Association of Cardiothoracic Surgery 2012 Class II, level of evidence C guideline recommendations for antithrombotic management in valvular heart disease.
| Substudy | ESC/EACTS 2012 guideline recommendation | Level of evidence |
|---|---|---|
| 1 | The addition of low-dose aspirin should be considered in patients with a mechanical prosthesis and concomitant atherosclerotic disease. | IIa C |
| 2 | The addition of low-dose aspirin should be considered in patients with a mechanical prosthesis after thromboembolism, despite adequate INR. | IIa C |
| 3 | Low-dose aspirin should be considered for the first 3 months after implantation of an aortic bioprosthesis. | IIa C |
| 4 | OAC may be considered for the first 3 months after implantation of an aortic bioprosthesis. | IIb C |
| 5 | OAC should be considered for the first 3 months after implantation of a mitral or tricuspid bioprosthesis. | IIa C |
| 6 | OAC should be considered for the first 3 months after mitral valve repair. | IIa C |
EACTS, European Association of Cardiothoracic Surgery; ESC, European Society of Cardiology; INR, international normalized ratio; OAC, oral anticoagulation.
2.3.1. Substudy 1
Patients from the VHD II survey were selected who had a mechanical valve prosthesis and concurrent atherosclerotic disease, defined as previous myocardial infarction, carotid atherosclerosis, or lower-limb atherosclerosis, as recorded in the CRF. Baseline and outcome parameters at 6 months were compared between patients who received uninterrupted ASA (group 1) and patients without ASA (group 2).
2.3.2. Substudy 2
VHD II survey patients with a mechanical valve prosthesis were selected that experienced a severe thromboembolic event within the last year, despite maintaining adequate international normalized ratio, as documented in the CRF. Baseline and outcome measures at 6 months were compared between patients receiving ASA (group 1) at inclusion and patients without ASA (group 2).
2.3.3. Substudy 3
VHD II survey patients with a newly successfully implanted aortic valve bioprosthesis were selected from the CRF. Patients with AF or who underwent a prosthetic replacement in the mitral or tricuspid position during the same surgical procedure were excluded. Baseline and outcome measures at 6 months were compared between patients who received ASA at discharge (group 1) and patients without ASA (group 2).
2.3.4. Substudy 4
VHD II survey patients with a newly successfully implanted aortic valve bioprosthesis were selected from the CRF. Those who underwent prosthetic replacement in the mitral or tricuspid position during the same procedure were excluded. Baseline and outcome parameters at 6 months were compared between patients who received OAC at discharge, either for a scheduled duration of 3 months or lifelong (group 1), and patients without OAC (group 2).
2.3.5. Substudy 5
Patients participating in the VHD II survey with a newly successfully implanted mitral or tricuspid bioprosthesis were selected from the CRF. Baseline and outcome measures at 6 months were compared between patients who received OAC at discharge, either for a scheduled duration of 3 months or lifelong (group 1), and patients without OAC (group 2).
2.3.6. Substudy 6
VHD II survey patients with a new successful mitral valve repair were selected from the CRF. Baseline and outcome parameters at 6 months were compared between patients who received OAC at discharge, with a scheduled duration of 3 months or lifelong (group 1), and patients without OAC (group 2).
2.4. Statistical analysis
Continuous variables are expressed as mean ± SD or as median and IQR. Missing data were not replaced. Comparisons among groups were performed using Kruskal–Wallis test for nonparametric, continuous data. Categorical variables are expressed as frequencies and percentages. Among-group 2 × 2 comparisons were made using Pearson’s chi-squared test or Fisher’s exact test if any expected cell count was <5. In other cases, the Monte–Carlo estimate of the exact P value was used. Furthermore, in substudies where significant unadjusted differences in 6-month all-cause mortality were observed between AT groups, multivariable logistic regression analyses were performed to assess the association between AT and mortality while adjusting for potential confounders. Covariates included in these models were OAC use, antiplatelet use, age, previous coronary intervention, previous myocardial infarction, previous stroke, congestive heart failure, active smoking, arterial hypertension, diabetes mellitus, cancer, preoperative AF, prior severe thromboembolic event, prior severe hemorrhagic event, left ventricular ejection fraction, and The European System for Cardiac Operative Risk Evaluation (EuroSCORE) II.. Several measures of model fit, including concordance and the goodness-of-fit test proposed by May and Hosmer [9], were considered. A 2-sided P value < .05 was considered statistically significant. All analyses were performed with SAS statistical software version 9.4 (SAS Institute Inc).
3. Results
3.1. Real-world implementation of guideline recommendations
In this real-world prospective ancillary analysis, application of Class II guideline recommendations for AT in VHD was highest in subanalysis 6 involving mitral valve repair, with 81.1% of patients receiving the recommended OAC after intervention. In contrast, implementation was lowest for substudy 1 (low-dose ASA should be considered in patients with a mechanical prosthesis and concomitant atherosclerotic disease), with only 39.5% of patients receiving the proposed AT. For the other 4 substudies, the application of Class II guideline recommendations ranged from 42.1% to 76.2%, as shown in Table 2 for substudies 1 to 3 focusing on ASA utilization, and in Table 3 for substudies 4 to 6 concerning OAC usage.
Table 2.
Baseline patient demographics and characteristics in substudies investigating low-dose acetyl salicylic acid utilization.
| Characteristics | Substudy 1 Mechanical prosthesis and atherosclerotic disease |
Substudy 2 Mechanical prosthesis after thromboembolism |
Substudy 3 Aortic bioprosthesis after intervention |
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|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Total | Group 1 (ASA) | Group 2 (no ASA) | P value | Total | Group 1 (ASA) | Group 2 (no ASA) | P value | Total | Group 1 (ASA) | Group 2 (no ASA) | P value | |
| n | 195 | 77/195 (39.5) | 118/195 (60.5) | NA | 19 | 8/19 (42.1) | 11/19 (57.9) | NA | 372 | 219/372 (58.9) | 153/372 (41.1) | NA |
| Demographics | ||||||||||||
| Age (y), mean (SD) | 67.0 (10.0) | 66.5 (9.4) | 67.3 (10.4) | .37 | 61.0 (15.0) | 64.8 (10.0) | 58.3 (17.9) | .48 | 70.8 (8.1) | 70.6 (8.5) | 71.2 (7.6) | .918 |
| Gender: male | 117/195 (60.0) | 42/77 (54.5) | 75/118 (63.6) | .209 | 10/19 (52.6) | 6/8 (75.0) | 4/11 (36.4) | .17 | 207/372 (55.6) | 126/219 (57.5) | 81/153 (52.9) | .38 |
| CV history | ||||||||||||
| Previous MI | 61/189 (32.3) | 28/73 (38.4) | 33/116 (28.4) | .156 | 4/19 (21.1) | 3/8 (37.5) | 1/11 (9.1) | .26 | 28/369 (7.6) | 18/217 (8.3) | 10/152 (6.6) | .54 |
| Previous coronary intervention | 146/193 (75.6) | 63/77 (81.8) | 83/116 (71.6) | .10 | 4/16 (25.0) | 3/8 (37.5) | 1/8 (12.5) | .569 | 48/371 (12.9) | 34/218 (15.6) | 14/153 (9.2) | .069 |
| PCI | 72/193 (37.3) | 31/77 (40.3) | 41/116 (35.3) | .489 | 3/16 (18.8) | 2/8 (25.0) | 1/8 (12.5) | 1.00 | 42/370 (11.4) | 29/217 (13.4) | 13/153 (8.5) | .146 |
| CABG | 88/192 (45.8) | 40/77 (51.9) | 48/115 (41.7) | .16 | 1/16 (6.3) | 1/8 (12.5) | 0/8 (0.0) | 1.00 | 5/371 (1.3) | 4/218 (1.8) | 1/153 (0.7) | .65 |
| Previous AV intervention | 112/195 (57.4) | 39/77 (50.6) | 73/118 (61.9) | .12 | 10/19 (52.6) | 5/8 (62.5) | 5/11 (45.5) | .65 | 8/372 (2.2) | 4/219 (1.8) | 4/153 (2.6) | .72 |
| Previous MV intervention | 81/195 (41.5) | 29/77 (37.7) | 52/118 (44.1) | .375 | 15/19 (78.9) | 7/8 (87.5) | 8/11 (72.7) | .60 | 1/372 (0.3) | 1/219 (0.5) | 0/153 (0.0) | 1.00 |
| Previous TV intervention | 12/195 (6.2) | 4/77 (5.2) | 8/118 (6.8) | .767 | 1/19 (5.3) | 0/8 (0.0) | 1/11 (9.1) | 1.00 | 0/372 (0.0) | 0/219 (0.0) | 0/153 (0.0) | NA |
| Previous PV intervention | 0/195 (0.0) | 0/77 (0.0) | 0/118 (0.0) | NA | 0/19 (0.0) | 0/8 (0.0) | 0/11 (0.0) | NA | 0/372 (0.0) | 0/219 (0.0) | 0/153 (0.0) | NA |
| Lower-limb atherosclerosis | 21/176 (11.9) | 6/68 (8.8) | 15/108 (13.9) | .31 | 2/17 (11.8) | 1/7 (14.3) | 1/10 (10.0) | 1.00 | 12/354 (3.4) | 7/209 (3.3) | 5/145 (3.4) | 1.00 |
| Carotid atherosclerosis: stenosis > 50% | 33/156 (21.2) | 14/60 (23.3) | 19/96 (19.8) | .598 | 4/15 (26.7) | 3/6 (50.0) | 1/9 (11.1) | .235 | 24/357 (6.7) | 16/211 (7.6) | 8/146 (5.5) | .435 |
| Previous stroke/TIA | 28/195 (14.4) | 14/77 (18.2) | 14/118 (11.9) | .219 | 15/19 (78.9) | 6/8 (75.0) | 9/11 (81.8) | 1.00 | 23/372 (6.2) | 14/219 (6.4) | 9/153 (5.9) | .84 |
| Congestive heart failure | 36/195 (18.5) | 10/77 (13.0) | 26/118 (22.0) | .11 | 6/19 (31.6) | 4/8 (50.0) | 2/11 (18.2) | .319 | 43/372 (11.6) | 29/219 (13.2) | 14/153 (9.2) | .225 |
| Risk factors and comorbidities | ||||||||||||
| Active smoking | 15/195 (7.7) | 11/77 (14.3) | 4/118 (3.4) | .005a | 2/19 (10.5) | 1/8 (12.5) | 1/11 (9.1) | 1.00 | 47/372 (12.6) | 28/219 (12.8) | 19/153 (12.4) | .916 |
| Arterial hypertension | 155/195 (79.5) | 68/77 (88.3) | 87/118 (73.7) | .01a | 11/19 (57.9) | 6/8 (75.0) | 5/11 (45.5) | .35 | 299/372 (80.4) | 175/219 (79.9) | 124/153 (81.0) | .786 |
| Hyperlipidemia | 127/195 (65.1) | 61/77 (79.2) | 66/118 (55.9) | <.001a | 8/19 (42.1) | 5/8 (62.5) | 3/11 (27.3) | .18 | 193/372 (51.9) | 121/219 (55.3) | 72/153 (47.1) | .12 |
| Diabetes | 47/195 (24.1) | 22/77 (28.6) | 25/118 (21.2) | .239 | 4/19 (21.1) | 2/8 (25.0) | 2/11 (18.2) | 1.00 | 105/372 (28.2) | 62/219 (28.3) | 43/153 (28.1) | .965 |
| Family history of CV disease | 34/149 (22.8) | 15/58 (25.9) | 19/91 (20.9) | .48 | 1/11 (9.1) | 1/4 (25.0) | 0/7 (0.0) | .36 | 53/297 (17.8) | 29/180 (16.1) | 24/117 (20.5) | .33 |
| Creatinine clearance (mL/min), mean (SD) | 72.8 (29.8) | 76.9 (29.9) | 70.2 (29.5) | .165 | 82.0 (40.2) | 73.9 (22.2) | 89.2 (51.7) | .70 | 76.4 (27.5) | 77.2 (27.6) | 75.4 (27.5) | .497 |
| Chronic dialysis | 3/195 (1.5) | 1/77 (1.3) | 2/118 (1.7) | 1.00 | 0/19 (0.0) | 0/8 (0.0) | 0/11 (0.0) | NA | 3/372 (0.8) | 2/219 (0.9) | 1/153 (0.7) | 1.00 |
| Chronic pulmonary disease | 27/194 (13.9) | 13/77 (16.9) | 14/117 (12.0) | .33 | 2/19 (10.5) | 1/8 (12.5) | 1/11 (9.1) | 1.00 | 41/371 (11.1) | 26/218 (11.9) | 15/153 (9.8) | .52 |
| Liver dysfunction | 2/195 (1.0) | 0/77 (0.0) | 2/118 (1.7) | .52 | 0/19 (0.0) | 0/8 (0.0) | 0/11 (0.0) | NA | 9/367 (2.5) | 5/216 (2.3) | 4/151 (2.6) | 1.00 |
| Cancer | 16/195 (8.2) | 6/77 (7.8) | 10/118 (8.5) | .865 | 2/19 (10.5) | 1/8 (12.5) | 1/11 (9.1) | 1.00 | 28/372 (7.5) | 14/219 (6.4) | 14/153 (9.2) | .32 |
| Charlson’s index, mean (SD) | 4.0 (2.2) | 3.9 (2.0) | 4.0 (2.3) | .94 | 3.8 (2.4) | 4.7 (2.8) | 3.2 (1.9) | .348 | 3.8 (1.6) | 3.8 (1.6) | 3.8 (1.5) | .77 |
| CV complications during the last year | 52/195 (26.7) | 15/77 (19.5) | 37/118 (31.4) | .067 | 19/19 (100.0) | 8/8 (100.0) | 11/11 (100.0) | NA | 50/372 (13.4) | 32/219 (14.6) | 18/153 (11.8) | .428 |
| Hospitalization for heart failure during the last year | 33/195 (16.9) | 7/77 (9.1) | 26/118 (22.0) | .018a | 6/19 (31.6) | 2/8 (25.0) | 4/11 (36.4) | 1.00 | 43/372 (11.6) | 27/219 (12.3) | 16/153 (10.5) | .579 |
| Severe thromboembolic event during the last year | 9/195 (4.6) | 5/77 (6.5) | 4/118 (3.4) | .32 | 19/19 (100.0) | 8/8 (100.0) | 11/11 (100.0) | NA | 3/372 (0.8) | 2/219 (0.9) | 1/153 (0.7) | 1.00 |
| Severe hemorrhagic event during the last year | 6/195 (3.1) | 1/77 (1.3) | 5/118 (4.2) | .406 | 2/19 (10.5) | 1/8 (12.5) | 1/11 (9.1) | 1.00 | 1/372 (0.3) | 0/219 (0.0) | 1/153 (0.7) | .41 |
| Endocarditis episodes during the last year | 2/195 (1.0) | 1/77 (1.3) | 1/118 (0.8) | 1.00 | 0/19 (0.0) | 0/8 (0.0) | 0/11 (0.0) | NA | 0/372 (0.0) | 0/219 (0.0) | 0/153 (0.0) | NA |
| New onset of AF during the last year | 10/194 (5.2) | 3/77 (3.9) | 7/117 (6.0) | .74 | 3/19 (15.8) | 1/8 (12.5) | 2/11 (18.2) | 1.00 | 6/370 (1.6) | 4/218 (1.8) | 2/152 (1.3) | 1.00 |
| Baseline AT | ||||||||||||
| Oral anticoagulant | 161/195 (82.6) | 55/77 (71.4) | 106/118 (89.8) | <.001a | 18/19 (94.7) | 7/8 (87.5) | 11/11 (100.0) | .42 | 28/372 (7.5) | 12/219 (5.5) | 16/153 (10.5) | .07 |
| VKA | 161/161 (100.0) | 55/55 (100.0) | 106/106 (100.0) | NA | 18/18 (100.0) | 7/7 (100.0) | 11/11 (100.0) | NA | 18/28 (64.3) | 8/12 (66.7) | 10/16 (62.5) | 1.00 |
| DOAC | - | - | - | - | - | - | 10/28 (35.7) | 4/12 (33.3) | 6/16 (37.5) | |||
| Dabigatran | - | - | - | NA | - | - | - | NA | 1/10 (10.0) | 0/4 (0.0) | 1/6 (16.7) | 1.00 |
| Rivaroxaban | - | - | - | - | - | - | 3/10 (30.0) | 1/4 (25.0) | 2/6 (33.3) | |||
| Apixaban | - | - | - | - | - | - | 6/10 (60.0) | 3/4 (75.0) | 3/6 (50.0) | |||
| Edoxaban | - | - | - | NA | - | - | - | NA | - | - | - | NA |
| ASA | 77/195 (39.5) | 77/77 (100.0) | 0/118 (0.0) | <.001a | 8/19 (42.1) | 8/8 (100.0) | 0/11 (0.0) | <.001a | 189/360 (52.5) | 117/212 (55.2) | 72/148 (48.6) | .22 |
| Clopidogrel | 26/195 (13.3) | 15/77 (19.5) | 11/118 (9.3) | .04a | 3/19 (15.8) | 2/8 (25.0) | 1/11 (9.1) | .546 | 25/360 (6.9) | 19/212 (9.0) | 6/148 (4.1) | .07 |
| Other antiplatelet | 6/195 (3.1) | 3/77 (3.9) | 3/118 (2.5) | .68 | 1/19 (5.3) | 0/8 (0.0) | 1/11 (9.1) | 1.000 | 4/360 (1.1) | 1/212 (0.5) | 3/148 (2.0) | .31 |
| Discharge AT | ||||||||||||
| VKA | 94/105 (89.5) | 38/42 (90.5) | 56/63 (88.9) | .746 | 13/13 (100.0) | 6/6 (100.0) | 7/7 (100.0) | NA | 156/372 (41.9) | 62/219 (28.3) | 94/153 (61.4) | <.001a |
| DOAC | - | - | - | - | - | - | 6/372 (1.6) | 2/219 (0.9) | 4/153 (2.6) | |||
| Dabigatran | - | - | - | NA | - | - | - | NA | 1/6 (16.7) | 0/2 (0.0) | 1/4 (25.0) | 1.000 |
| Rivaroxaban | - | - | - | NA | - | - | - | NA | 3/6 (50.0) | 1/2 (50.0) | 2/4 (50.0) | |
| Apixaban | - | - | - | NA | - | - | - | NA | 2/6 (33.3) | 1/2 (50.0) | 1/4 (25.0) | |
| Edoxaban | - | - | - | NA | - | - | - | NA | - | - | - | NA |
| ASA | 42/105 (40.0) | 42/42 (100.0) | 0/63 (0.0) | <.001a | 6/13 (46.2) | 5/6 (83.3) | 1/7 (14.3) | .029a | 219/372 (58.9) | 219/219 (100.0) | 0/153 (0.0) | <.001a |
| Clopidogrel | 14/105 (13.3) | 11/42 (26.2) | 3/63 (4.8) | .002a | 2/13 (15.4) | 2/6 (33.3) | 0/7 (0.0) | .19 | 14/371 (3.8) | 9/218 (4.1) | 5/153 (3.3) | .669 |
| Other antiplatelet | 2/105 (1.9) | 0/42 (0.0) | 2/63 (3.2) | .515 | 0/13 (0.0) | 0/6 (0.0) | 0/7 (0.0) | NA | 5/371 (1.3) | 1/218 (0.5) | 4/153 (2.6) | .16 |
Data are presented as n/N (%) unless otherwise specified.
Group 1: patients receiving ASA. Group 2: patients not receiving ASA.
AF, atrial fibrillation; ASA, acetyl salicylic acid; AT, antithrombotic treatment; AV, aortic valve; CABG, coronary artery bypass graft; CV, cardiovascular; DOAC, direct oral anticoagulant; MI, myocardial infarction; MV, mitral valve; NA, not applicable; PCI, percutaneous coronary intervention; PV, pulmonary valve; TIA, transient ischemic attack; TV, tricuspid valve; VKA, vitamin K antagonist.
Significant P values.
Table 3.
Baseline patient demographics and characteristics in substudies investigating oral anticoagulation utilization.
| Characteristics | Substudy 4 Aortic bioprosthesis after intervention |
Substudy 5 Mitral or tricuspid bioprosthesis after intervention |
Substudy 6 Mitral valve repair after intervention |
|||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Total | Group 1 (OAC) | Group 2 (no OAC) | P value | Total | Group 1 (OAC) | Group 2 (no OAC) | P value | Total | Group 1 (OAC) | Group 2 (no OAC) | P value | |
| n | 392 | 168/392 (42.9) | 224/392 (57.1) | NA | 105 | 80/105 (76.2) | 25/105 (23.8) | NA | 206 | 167/206 (81.1) | 39/206 (18.9) | NA |
| Demographics | ||||||||||||
| Age, mean (SD) | 71.1 (8.1) | 71.7 (8.5) | 70.6 (7.8) | .08 | 66.4 (12.7) | 66.1 (13.7) | 67.3 (9.3) | .657 | 62.9 (12.6) | 62.7 (12.4) | 63.8 (13.6) | .49 |
| Gender: male | 229/392 (58.4) | 107/168 (63.7) | 122/224 (54.5) | .067 | 39/105 (37.1) | 29/80 (36.3) | 10/25 (40.0) | .735 | 135/206 (65.5) | 113/167 (67.7) | 22/39 (56.4) | .18 |
| CV history | ||||||||||||
| Previous MI | 27/390 (6.9) | 13/167 (7.8) | 14/223 (6.3) | .56 | 7/105 (6.7) | 4/80 (5.0) | 3/25 (12.0) | .35 | 26/205 (12.7) | 23/166 (13.9) | 3/39 (7.7) | .425 |
| Previous coronary intervention | 43/390 (11.0) | 17/168 (10.1) | 26/222 (11.7) | .619 | 11/105 (10.5) | 4/80 (5.0) | 7/25 (28.0) | .003a | 18/206 (8.7) | 16/167 (9.6) | 2/39 (5.1) | .535 |
| PCI | 39/389 (10.0) | 17/168 (10.1) | 22/221 (10.0) | .957 | 9/105 (8.6) | 2/80 (2.5) | 7/25 (28.0) | <.001a | 14/206 (6.8) | 12/167 (7.2) | 2/39 (5.1) | 1.00 |
| CABG | 3/390 (0.8) | 0/168 (0.0) | 3/222 (1.4) | .26 | 2/104 (1.9) | 2/80 (2.5) | 0/24 (0.0) | 1.00 | 5/206 (2.4) | 4/167 (2.4) | 1/39 (2.6) | 1.00 |
| Previous AV intervention | 10/392 (2.6) | 3/168 (1.8) | 7/224 (3.1) | .526 | 5/105 (4.8) | 4/80 (5.0) | 1/25 (4.0) | 1.00 | 4/206 (1.9) | 4/167 (2.4) | 0/39 (0.0) | 1.00 |
| Previous MV intervention | 1/392 (0.3) | 1/168 (0.6) | 0/224 (0.0) | .429 | 16/105 (15.2) | 12/80 (15.0) | 4/25 (16.0) | 1.00 | 3/206 (1.5) | 3/167 (1.8) | 0/39 (0.0) | 1.00 |
| Previous TV intervention | 0/392 (0.0) | 0/168 (0.0) | 0/224 (0.0) | NA | 6/105 (5.7) | 4/80 (5.0) | 2/25 (8.0) | .627 | 0/206 (0.0) | 0/167 (0.0) | 0/39 (0.0) | NA |
| Previous PV intervention | 0/392 (0.0) | 0/168 (0.0) | 0/224 (0.0) | NA | 1/105 (1.0) | 1/80 (1.3) | 0/25 (0.0) | 1.00 | 0/206 (0.0) | 0/167 (0.0) | 0/39 (0.0) | NA |
| Lower-limb atherosclerosis | 17/369 (4.6) | 7/155 (4.5) | 10/214 (4.7) | .94 | 1/100 (1.0) | 1/78 (1.3) | 0/22 (0.0) | 1.00 | 2/190 (1.1) | 2/152 (1.3) | 0/38 (0.0) | 1.00 |
| Carotid atherosclerosis: stenosis > 50% | 29/371 (7.8) | 16/158 (10.1) | 13/213 (6.1) | .15 | 5/102 (4.9) | 5/79 (6.3) | 0/23 (0.0) | .585 | 11/187 (5.9) | 9/150 (6.0) | 2/37 (5.4) | 1.00 |
| Previous stroke/TIA | 22/392 (5.6) | 12/168 (7.1) | 10/224 (4.5) | .25 | 13/105 (12.4) | 11/80 (13.8) | 2/25 (8.0) | .729 | 11/206 (5.3) | 10/167 (6.0) | 1/39 (2.6) | .69 |
| Congestive heart failure | 48/392 (12.2) | 23/168 (13.7) | 25/224 (11.2) | .45 | 29/105 (27.6) | 23/80 (28.8) | 6/25 (24.0) | .64 | 48/206 (23.3) | 41/167 (24.6) | 7/39 (17.9) | .38 |
| Risk factors and comorbidities | ||||||||||||
| Active smoking | 48/392 (12.2) | 15/168 (8.9) | 33/224 (14.7) | .08 | 8/105 (7.6) | 7/80 (8.8) | 1/25 (4.0) | .677 | 30/206 (14.6) | 24/167 (14.4) | 6/39 (15.4) | .87 |
| Arterial hypertension | 314/392 (80.1) | 132/168 (78.6) | 182/224 (81.3) | .51 | 70/105 (66.7) | 56/80 (70.0) | 14/25 (56.0) | .195 | 117/206 (56.8) | 97/167 (58.1) | 20/39 (51.3) | .44 |
| Hyperlipidemia | 208/392 (53.1) | 101/168 (60.1) | 107/224 (47.8) | .015a | 38/105 (36.2) | 29/80 (36.3) | 9/25 (36.0) | .98 | 74/206 (35.9) | 63/167 (37.7) | 11/39 (28.2) | .265 |
| Diabetes | 113/392 (28.8) | 50/168 (29.8) | 63/224 (28.1) | .72 | 17/105 (16.2) | 11/80 (13.8) | 6/25 (24.0) | .228 | 21/206 (10.2) | 17/167 (10.2) | 4/39 (10.3) | 1.00 |
| Family history of CV disease | 47/312 (15.1) | 19/128 (14.8) | 28/184 (15.2) | .928 | 10/87 (11.5) | 6/66 (9.1) | 4/21 (19.0) | .245 | 38/171 (22.2) | 34/136 (25.0) | 4/35 (11.4) | .085 |
| Creatinine clearance (mL/min), mean (SD) | 76.3 (27.5) | 75.2 (24.2) | 77.2 (29.7) | .47 | 68.4 (30.5) | 67.2 (32.2) | 72.5 (24.1) | .22 | 81.0 (29.0) | 80.2 (28.2) | 84.3 (32.1) | .468 |
| Chronic dialysis | 3/392 (0.8) | 0/168 (0.0) | 3/224 (1.3) | .26 | 2/105 (1.9) | 2/80 (2.5) | 0/25 (0.0) | 1.00 | 0/206 (0.0) | 0/167 (0.0) | 0/39 (0.0) | NA |
| Chronic pulmonary disease | 41/390 (10.5) | 17/167 (10.2) | 24/223 (10.8) | .85 | 13/103 (12.6) | 7/78 (9.0) | 6/25 (24.0) | .078 | 29/204 (14.2) | 24/165 (14.5) | 5/39 (12.8) | .78 |
| Liver dysfunction | 9/387 (2.3) | 5/164 (3.0) | 4/223 (1.8) | .50 | 5/104 (4.8) | 3/80 (3.8) | 2/24 (8.3) | .326 | 8/198 (4.0) | 6/159 (3.8) | 2/39 (5.1) | .657 |
| Cancer | 28/392 (7.1) | 12/168 (7.1) | 16/224 (7.1) | 1.00 | 10/105 (9.5) | 10/80 (12.5) | 0/25 (0.0) | .11 | 14/206 (6.8) | 13/167 (7.8) | 1/39 (2.6) | .477 |
| Charlson’s index, mean (SD) | 3.9 (1.6) | 3.9 (1.5) | 3.8 (1.7) | .72 | 3.9 (2.1) | 3.9 (2.1) | 4.1 (2.1) | .84 | 2.9 (2.0) | 3.0 (2.1) | 2.8 (1.8) | .766 |
| CV complications during the last year | 58/392 (14.8) | 32/168 (19.0) | 26/224 (11.6) | .04a | 42/105 (40.0) | 36/80 (45.0) | 6/25 (24.0) | .06 | 65/206 (31.6) | 58/167 (34.7) | 7/39 (17.9) | .04a |
| Hospitalization for heart failure during the last year | 48/392 (12.2) | 26/168 (15.5) | 22/224 (9.8) | .09 | 37/105 (35.2) | 31/80 (38.8) | 6/25 (24.0) | .178 | 49/206 (23.8) | 44/167 (26.3) | 5/39 (12.8) | .07 |
| Severe thromboembolic event during the last year | 3/392 (0.8) | 1/168 (0.6) | 2/224 (0.9) | 1.00 | 4/105 (3.8) | 4/80 (5.0) | 0/25 (0.0) | .57 | 5/206 (2.4) | 4/167 (2.4) | 1/39 (2.6) | 1.00 |
| Severe hemorrhagic event during the last year | 3/392 (0.8) | 1/168 (0.6) | 2/224 (0.9) | 1.00 | 0/105 (0.0) | 0/80 (0.0) | 0/25 (0.0) | NA | 2/206 (1.0) | 2/167 (1.2) | 0/39 (0.0) | 1.00 |
| Endocarditis episodes during the last year | 0/392 (0.0) | 0/168 (0.0) | 0/224 (0.0) | NA | 3/105 (2.9) | 3/80 (3.8) | 0/25 (0.0) | 1.00 | 3/206 (1.5) | 2/167 (1.2) | 1/39 (2.6) | .469 |
| New onset AF during the last year | 12/390 (3.1) | 9/166 (5.4) | 3/224 (1.3) | .02a | 14/105 (13.3) | 14/80 (17.5) | 0/25 (0.0) | .02a | 20/205 (9.8) | 19/166 (11.4) | 1/39 (2.6) | .13 |
| Baseline AT | ||||||||||||
| OAC | 54/392 (13.8) | 46/168 (27.4) | 8/224 (3.6) | <.001a | 56/105 (53.3) | 49/80 (61.3) | 7/25 (28.0) | .004 | 76/206 (36.9) | 67/167 (40.1) | 9/39 (23.1) | .047 |
| VKA | 28/54 (51.9) | 24/46 (52.2) | 4/8 (50.0) | 1.00 | 47/56 (83.9) | 40/49 (81.6) | 7/7 (100.0) | .58 | 53/76 (69.7) | 47/67 (70.1) | 6/9 (66.7) | 1.00 |
| DOAC | 26/54 (48.1) | 22/46 (47.8) | 4/8 (50.0) | 9/56 (16.1) | 9/49 (18.4) | 0/7 (0.0) | 23/76 (30.3) | 20/67 (29.9) | 3/9 (33.3) | |||
| Dabigatran | 2/26 (7.7) | 2/22 (9.1) | 0/4 (0.0) | .49 | 3/9 (33.3) | 3/9 (33.3) | 0/0 (0.0) | NA | 6/23 (26.1) | 5/20 (25.0) | 1/3 (33.3) | 1.00 |
| Rivaroxaban | 7/26 (26.9) | 7/22 (31.8) | 0/4 (0.0) | 4/9 (44.4) | 4/9 (44.4) | 0/0 (0.0) | 7/23 (30.4) | 6/20 (30.0) | 1/3 (33.3) | |||
| Apixaban | 17/26 (65.4) | 13/22 (59.1) | 4/4 (100.0) | 2/9 (22.2) | 2/9 (22.2) | 0/0 (0.0) | 10/23 (43.5) | 9/20 (45.0) | 1/3 (33.3) | |||
| Edoxaban | - | - | - | - | - | - | - | - | - | |||
| ASA | 191/382 (50.0) | 79/162 (48.8) | 112/220 (50.9) | .679 | 33/103 (32.0) | 21/80 (26.3) | 12/23 (52.2) | .019a | 55/199 (27.6) | 49/161 (30.4) | 6/38 (15.8) | .069 |
| Clopidogrel | 25/382 (6.5) | 10/162 (6.2) | 15/220 (6.8) | .80 | 7/103 (6.8) | 5/80 (6.3) | 2/23 (8.7) | .65 | 14/199 (7.0) | 14/161 (8.7) | 0/38 (0.0) | .076 |
| Other antiplatelet | 5/382 (1.3) | 2/162 (1.2) | 3/220 (1.4) | 1.00 | 3/103 (2.9) | 3/80 (3.8) | 0/23 (0.0) | 1.00 | 3/199 (1.5) | 3/161 (1.9) | 0/38 (0.0) | 1.00 |
| Discharge AT | ||||||||||||
| VKA | 160/392 (40.8) | 160/168 (95.2) | 0/224 (0.0) | <.001a | 78/105 (74.3) | 78/80 (97.5) | 0/25 (0.0) | <.001a | 163/206 (79.1) | 163/167 (97.6) | 0/39 (0.0) | <.001a |
| DOAC | 8/392 (2.0) | 8/168 (4.8) | 0/224 (0.0) | 2/105 (1.9) | 2/80 (2.5) | 0/25 (0.0) | 4/206 (1.9) | 4/167 (2.4) | 0/39 (0.0) | |||
| Dabigatran | 1/8 (12.5) | 1/8 (12.5) | 0/0 (0.0) | NA | - | - | - | NA | 2/4 (50.0) | 2/4 (50.0) | 0/0 (0.0) | NA |
| Rivaroxaban | 5/8 (62.5) | 5/8 (62.5) | 0/0 (0.0) | 1/2 (50.0) | 1/2 (50.0) | 0/0 (0.0) | 1/4 (25.0) | 1/4 (25.0) | 0/0 (0.0) | |||
| Apixaban | 2/8 (25.0) | 2/8 (25.0) | 0/0 (0.0) | 1/2 (50.0) | 1/2 (50.0) | 0/0 (0.0) | 1/4 (25.0) | 1/4 (25.0) | 0/0 (0.0) | |||
| Edoxaban | - | - | - | - | - | - | - | - | - | |||
| ASA | 219/390 (56.2) | 55/167 (32.9) | 164/223 (73.5) | <.001a | 24/105 (22.9) | 16/80 (20.0) | 8/25 (32.0) | .21 | 70/206 (34.0) | 52/167 (31.1) | 18/39 (46.2) | .075 |
| Clopidogrel | 16/389 (4.1) | 4/167 (2.4) | 12/222 (5.4) | .139 | 3/105 (2.9) | 0/80 (0.0) | 3/25 (12.0) | .01a | 5/206 (2.4) | 4/167 (2.4) | 1/39 (2.6) | 1.00 |
| Other antiplatelet | 5/389 (1.3) | 0/167 (0.0) | 5/222 (2.3) | .07 | 2/105 (1.9) | 0/80 (0.0) | 2/25 (8.0) | .055 | 1/205 (0.5) | 0/166 (0.0) | 1/39 (2.6) | .19 |
Data are presented as n/N (%) unless otherwise specified.
Group 1: patients receiving OAC. Group 2: patients not receiving OAC.
AF, atrial fibrillation; ASA, acetyl salicylic acid; AT, antithrombotic treatment; AV, aortic valve; CABG, coronary artery bypass graft; CV, cardiovascular; DOAC, direct oral anticoagulant; MI, myocardial infarction; MV, mitral valve; NA, not applicable; OAC, oral anticoagulation; PCI, percutaneous coronary intervention; PV, pulmonary valve; TIA, transient ischemic attack; TV, tricuspid valve; VKA, vitamin K antagonist.
Significant P values.
3.2. Patient demographics and baseline characteristics in the 6 substudies
Baseline patient demographics and characteristics can be found in Table 2 for substudies 1 to 3 focusing on ASA utilization, and in Table 3 for substudies 4 to 6 concerning OAC usage. In substudies 3 and 4, examining aortic bioprostheses, patients tended to be older (∼71 years) compared with the substudies on mechanical prostheses, mitral or tricuspid bioprosthesis, and mitral valve repair, where the average age ranged from 61 to 67 years. However, there were no significant age differences between groups with and without AT in any of the 6 subanalyzes.
3.2.1. Cardiovascular history
In substudy 5 (involving OAC utilization in mitral or tricuspid bioprosthesis after intervention), group 2, not receiving OAC, exhibited a notably higher incidence of prior percutaneous coronary intervention (PCI; P < .001), potentially explaining a preference for antiplatelet therapy in this group instead (clopidogrel use at discharge in group 1: 0.0% vs group 2: 12.0%; P = .01). There were no other significant differences in cardiovascular history between the AT and non-AT groups in any of the 6 substudies.
3.2.2. Risk factors and comorbidities
In the substudies of older patients (particularly substudies 3 and 4), there was a higher prevalence of cardiovascular risk factors such as arterial hypertension, hypercholesterolemia, and diabetes mellitus. In substudy 1, investigating the association of ASA in mechanical prostheses and atherosclerotic disease, group 1 exhibited a significantly higher prevalence of risk factors such as arterial hypertension, hyperlipidemia, and smoking, which may have influenced the decision to prescribe ASA to these patients.
3.2.3. Cardiovascular complications during the last year
In substudy 1 (which examined the association of ASA in mechanical prosthesis and atherosclerotic disease), the non–ASA-treated group (group 2) had significantly more hospitalizations for heart failure compared with the ASA-treated group (22.0% vs 9.1%; P = .018), potentially linked to a slightly higher prevalence of congestive heart failure at baseline (group 2: 22.0% vs group 1: 13.0%; P = .11). Despite the baseline ASA treatment in group 1 of substudy 1, there were no significant differences in thromboembolic or hemorrhagic events during the last year compared with group 2 without ASA.
In substudies 4 (involving OAC usage in aortic bioprosthesis postintervention) and 5 (OAC utilization in mitral or tricuspid bioprosthesis after intervention), AF was significantly more prevalent in the OAC-treated groups, possibly influencing the decision to prescribe OAC in these patients (substudy 4: 5.4% vs 1.3%, P = .02; substudy 5: 17.5% vs 0.0%, P = .02).
Across all substudies, there were no other significant differences in cardiovascular complications during the last year between groups receiving AT and those who did not.
3.3. Clinical outcomes at 6 months in the 6 substudies
Clinical outcomes can be found in Table 4 for substudies 1 to 3 focusing on ASA utilization, and in Table 5 for substudies 4 to 6 concerning OAC usage. In substudies 3 (ASA usage in aortic bioprosthesis postintervention), 4 (OAC usage in aortic bioprosthesis postintervention), and 5 (OAC utilization in mitral or tricuspid bioprosthesis after intervention), the 6-month all-cause mortality rate was significantly higher in group 2 patients who did not receive AT. In the other 3 subanalyzes, no significant difference was observed in 6-month all-cause mortality between patients who received AT and those who did not. To explore the potential influence of confounding factors on mortality differences, multivariable logistic regression analyses were performed. In substudy 4 (OAC usage in aortic bioprosthesis), after adjusting for baseline covariates, neither OAC use (odds ratio [OR], 1.69 [95% CI, 0.46-6.21]; P = .427) nor antiplatelet use (OR, 0.31 [95% CI, 0.09-1.10]; P = .07) was a statistically significant independent predictors of 6-month mortality, as found in Table 6. Significant predictors in this adjusted model included EUROSCORE-II (OR, 1.15 [95% CI, 1.01-1.31]; P = .03) and left ventricular ejection fraction (20%-29% vs 40%-49%; OR, 17.82 [95% CI, 1.15-275.51]; P = .039). For substudies 3 (ASA usage in aortic bioprosthesis patients) and 5 (OAC utilization in mitral or tricuspid bioprosthesis), a multivariable logistic regression model could not be reliably fitted due to model instability, related to an insufficient number of events in these subgroups. Furthermore, there were no significant differences between substudies or groups in any other events at 6 months follow-up, including thromboembolic events and bleeding.
Table 4.
Clinical outcomes at 6 months in substudies investigating low-dose acetyl salicylic acid utilization.
| Clinical outcome | Substudy 1 Mechanical prosthesis and atherosclerotic disease |
Substudy 2 Mechanical prosthesis after thromboembolism |
Substudy 3 Aortic bioprosthesis after intervention |
|||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Total | Group 1 (ASA) | Group 2 (no ASA) | P value | Total | Group 1 (ASA) | Group 2 (no ASA) | P value | Total | Group 1 (ASA) | Group 2 (no ASA) | P value | |
| n | 195 | 77/195 (39.5) | 118/195 (60.5) | NA | 19 | 8/19 (42.1) | 11/19 (57.9) | NA | 372 | 219/372 (58.9) | 153/372 (41.1) | NA |
| Mortality | 9/195 (4.6) | 1/77 (1.3) | 8/118 (6.8) | .09 | 0/19 (0.0) | 0/8 (0.0) | 0/11 (0.0) | NA | 16/372 (4.3) | 3/219 (1.4) | 13/153 (8.5) | <.001a |
| Thromboembolic event | 0/163 (0.0) | 0/65 (0.0) | 0/98 (0.0) | NA | 0/16 (0.0) | 0/8 (0.0) | 0/8 (0.0) | NA | 7/331 (2.1) | 3/196 (1.5) | 4/135 (3.0) | .449 |
| Bleeding | 2/195 (1.0) | 2/77 (2.6) | 0/118 (0.0) | .155 | 0/19 (0.0) | 0/8 (0.0) | 0/11 (0.0) | NA | 17/372 (4.6) | 9/219 (4.1) | 8/153 (5.2) | .61 |
| Hospitalization for cardiac reasons | 39/163 (23.9) | 16/65 (24.6) | 23/98 (23.5) | .867 | 3/16 (18.8) | 1/8 (12.5) | 2/8 (25.0) | 1.00 | 34/330 (10.3) | 19/196 (9.7) | 15/134 (11.2) | .66 |
| Heart failure | 14/163 (8.6) | 4/65 (6.2) | 10/98 (10.2) | .366 | 1/16 (6.3) | 1/8 (12.5) | 0/8 (0.0) | 1.00 | 11/330 (3.3) | 7/196 (3.6) | 4/134 (3.0) | 1.00 |
| Prosthetic dysfunction | 5/163 (3.1) | 2/65 (3.1) | 3/98 (3.1) | 1.00 | 1/16 (6.3) | 0/8 (0.0) | 1/8 (12.5) | 1.00 | 1/330 (0.3) | 0/196 (0.0) | 1/134 (0.7) | .406 |
| Endocarditis | 0/163 (0.0) | 0/65 (0.0) | 0/98 (0.0) | NA | 0/16 (0.0) | 0/8 (0.0) | 0/8 (0.0) | NA | 1/330 (0.3) | 0/196 (0.0) | 1/134 (0.7) | .406 |
| New valvular intervention | 4/163 (2.5) | 1/65 (1.5) | 3/98 (3.1) | 1.00 | 0/16 (0.0) | 0/8 (0.0) | 0/8 (0.0) | NA | 2/330 (0.6) | 1/196 (0.5) | 1/134 (0.7) | 1.00 |
Data are presented as n/N (%) unless otherwise specified.
Group 1: patients receiving ASA. Group 2: patients not receiving ASA.
ASA, acetyl salicylic acid; NA, not applicable.
Significant P values.
Table 5.
Clinical outcomes at 6 months in substudies investigating oral anticoagulation utilization.
| Clinical outcome | Substudy 4 Aortic bioprosthesis after intervention |
Substudy 5 Mitral or tricuspid bioprosthesis after intervention |
Substudy 6 Mitral valve repair after intervention |
|||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Total | Group 1 (OAC) | Group 2 (no OAC) | P value | Total | Group 1 (OAC) | Group 2 (no OAC) | P value | Total | Group 1 (OAC) | Group 2 (no OAC) | P value | |
| n | 392 | 168/392 (42.9) | 224/392 (57.1) | NA | 105 | 80/105 (76.2) | 25/105 (23.8) | NA | 206 | 167/206 (81.1) | 39/206 (18.9) | NA |
| Mortality | 20/392 (5.1) | 3/168 (1.8) | 17/224 (7.6) | .01a | 8/105 (7.6) | 0/80 (0.0) | 8/25 (32.0) | <.001a | 6/206 (2.9) | 3/167 (1.8) | 3/39 (7.7) | .08 |
| Thromboembolic event | 8/348 (2.3) | 5/153 (3.3) | 3/195 (1.5) | .307 | 1/94 (1.1) | 1/76 (1.3) | 0/18 (0.0) | 1.00 | 1/181 (0.6) | 1/146 (0.7) | 0/35 (0.0) | 1.00 |
| Bleeding | 20/392 (5.1) | 6/168 (3.6) | 14/224 (6.3) | .23 | 8/105 (7.6) | 6/80 (7.5) | 2/25 (8.0) | 1.00 | 4/206 (1.9) | 4/167 (2.4) | 0/39 (0.0) | 1.00 |
| Hospitalization for cardiac reasons | 39/347 (11.2) | 22/153 (14.4) | 17/194 (8.8) | .10 | 21/94 (22.3) | 16/76 (21.1) | 5/18 (27.8) | .54 | 33/181 (18.2) | 27/146 (18.5) | 6/35 (17.1) | .85 |
| Heart failure | 12/347 (3.5) | 8/153 (5.2) | 4/194 (2.1) | .109 | 8/94 (8.5) | 5/76 (6.6) | 3/18 (16.7) | .177 | 7/181 (3.9) | 6/146 (4.1) | 1/35 (2.9) | 1.00 |
| Prosthetic dysfunction | 1/347 (0.3) | 1/153 (0.7) | 0/194 (0.0) | .44 | 0/94 (0.0) | 0/76 (0.0) | 0/18 (0.0) | NA | 1/181 (0.6) | 1/146 (0.7) | 0/35 (0.0) | 1.00 |
| Endocarditis | 1/347 (0.3) | 1/153 (0.7) | 0/194 (0.0) | .44 | 1/94 (1.1) | 1/76 (1.3) | 0/18 (0.0) | 1.00 | 0/181 (0.0) | 0/146 (0.0) | 0/35 (0.0) | NA |
| New valvular intervention | 3/347 (0.9) | 1/153 (0.7) | 2/194 (1.0) | 1.00 | 1/94 (1.1) | 1/76 (1.3) | 0/18 (0.0) | 1.00 | 4/181 (2.2) | 2/146 (1.4) | 2/35 (5.7) | .169 |
Data are presented as n/N (%) unless otherwise specified.
Group 1: patients receiving OAC. Group 2: patients not receiving OAC.
NA, not applicable; OAC, oral anticoagulation.
Significant P values.
Table 6.
Logistic modelization of all-cause mortality at 6 months in substudy 4 (patients with an aortic valve bioprosthesis).
| Confounder | OR | 95% CI | P value |
|---|---|---|---|
| AF | 0.76 | 0.15-3.94 | .74 |
| Age | 1.06 | 0.99-1.14 | .11 |
| Anticoagulant used | 1.69 | 0.46-6.21 | .427 |
| Antiplatelet agent used | 0.31 | 0.09-1.10 | .07 |
| Arterial hypertension | 0.63 | 0.18-2.22 | .475 |
| Cancer | 1.35 | 0.23-8.10 | .74 |
| Congestive heart failure | 2.42 | 0.65-9.10 | .189 |
| Diabetes | 0.16 | 0.02-1.26 | .08 |
| EUROSCORE-II | 1.15 | 1.01-1.31 | .03a |
| Hemorrhagic event (prior, severe) | 1.20 | 1.02-92.13 | .935 |
| LVEF (20%-29% vs 40%-49%) | 17.82 | 1.15-275.5 | .039a |
| PCI | 0.43 | 0.04-4.93 | .49 |
| Previous MI | 0.20 | 0.01-5.32 | .335 |
| Previous stroke/TIA | 4.55 | 0.59-35.12 | .146 |
| Smoking (active) | 1.34 | 0.23-7.68 | .74 |
| Thromboembolic event (prior, severe) | 2.61 | 0.04-172.33 | .653 |
Anticoagulant: nonvitamin K antagonist oral anticoagulant, vitamin K antagonist, or low-molecular-weight heparin. Antiplatelet agent: aspirin, clopidogrel, or other.
AF, atrial fibrillation; EuroSCORE, The European System for Cardiac Operative Risk Evaluation; LVEF, left ventricular ejection fraction (reference category for comparisons is 40%-49%); MI, myocardial infarction; OR, odds ratio; PCI, percutaneous coronary intervention; TIA, transient ischemic attack.
Significant P values. The Hosmer and Lemeshow test indicated a good model fit (P = .778), and the model had a concordance of 89.4%.
4. Discussion
This prospective observational subanalysis of the ESC EORP VHD II survey provides valuable insights into the real-world implementation of the ESC Class II, level of evidence C guideline recommendations for AT in patients undergoing cardiac valve surgery, as well as their outcomes after 6 months.
4.1. Real-world adherence to Class II guideline recommendations
The analysis of 6 substudies, based on the ESC EORP VHD II survey, reveals varying degrees of adherence to the Class II, level of evidence C recommendations concerning AT after heart valve surgery, as outlined in the ESC guidelines [1]. The highest adherence was observed in patients undergoing mitral valve repair (substudy 6), with 81.1% receiving the recommended OAC postintervention, despite limited evidence supporting the use of AT following surgical valve repair [5].
Conversely, the lowest adherence was seen in patients with mechanical prostheses and concomitant atherosclerotic disease (substudy 1), where only 39.5% received the recommended low-dose ASA. The low implementation rate may reflect clinicians’ hesitation to prescribe dual AT with both ASA and OAC. The recommendation to add low-dose ASA to therapeutic OAC in this population is largely based on older studies that included previous-generation prostheses [10]. More recently, there has been growing hesitation regarding the routine addition of ASA due to a lack of clear evidence of benefit and persistent concerns about increased bleeding risk [5]. Notably, the updated 2020 American College of Cardiology (ACC) / American Heart Association (AHA) guidelines no longer recommend the routine addition of low-dose ASA in patients with mechanical heart valves, while historically, its use alongside VKA had been a major point of contention between European and American guidelines [3,5]. Additionally, the recommendation for low-dose ASA in patients with mechanical prostheses and atherosclerosis was downgraded from Class IIa to Class IIb in the ESC/EACTS guidelines between 2012 and 2017 [6,7].
4.2. Patient factors possibly influencing AT administration decisions
Our study identifies several factors potentially influencing AT prescription in the 6 subanalyzes. Notably, in substudy 1, patients with a mechanical prosthesis and concomitant atherosclerotic disease treated with ASA had a significantly higher prevalence of cardiovascular risk factors (arterial hypertension, hyperlipidemia, and diabetes mellitus), which likely influenced the decision to initiate ASA. Additionally, the significantly higher prevalence of AF in patients receiving OAC in substudies 4 and 5 (following aortic, mitral, or tricuspid bioprosthesis implantation) indicates an important role of AF in guiding anticoagulation decisions in clinical practice. In contrast, the recent 2021 recommendations were updated to also consider OAC administration in aortic bioprosthesis patients without baseline indications for OAC [1]. Likewise, in substudy 6, there was a trend toward a higher AF prevalence in the OAC-treated group postmitral valve repair (11.4% vs 2.6%; P = .13), possibly influencing the OAC treatment decision.
In substudy 5, patients not receiving OAC after mitral or tricuspid bioprosthesis intervention had a significantly higher incidence of prior PCI, possibly explaining the preference for antiplatelet therapy instead of OAC in these patients (clopidogrel use of group 1, 0.0% vs group 2, 12.0%; P = .01). In substudy 3, those patients receiving ASA postaortic bioprosthesis implantation also exhibited a trend toward more frequent prior PCI (P = .069).
Interestingly, other patient demographics and cardiovascular histories were generally similar between groups receiving AT and those who did not across all substudies. This suggests that factors other than age, established atherosclerosis, previous thromboembolism, or bleeding may drive AT prescription decisions. For instance, in substudy 1, despite both groups having similar levels of atherosclerosis severity, >60% of patients in group 2 did not receive the recommended low-dose ASA on top of OAC. Remarkably, in the same substudy, although group 1 received uninterrupted ASA therapy, there were no significant differences in severe thromboembolic or hemorrhagic events over the past year compared with group 2, which did not receive ASA.
4.3. Clinical outcomes at 6 months
In unadjusted analyses of 3 of the 6 substudies (focused on ASA use in aortic bioprosthesis, OAC use in aortic bioprosthesis, and OAC utilization in mitral or tricuspid bioprosthesis), the 6-month all-cause mortality rate was significantly higher in patients who did not receive the recommended AT. Additionally, in substudies 1 (ASA use in mechanical prosthesis and concomitant atherosclerotic disease) and 6 (OAC after mitral valve repair), there was also a notable trend toward higher mortality in the non-AT groups at 6 months (P = .09 and P = .08, respectively). These higher mortality rates warrant further investigation to determine whether they might be related to the lack of AT. Importantly, multivariable logistic regression analysis for substudy 4 (OAC use in aortic bioprosthesis) demonstrated that, after adjusting for multiple baseline confounders, the association between OAC use and 6-month mortality was no longer statistically significant. This suggests that the unadjusted mortality differences were likely influenced by confounding patient characteristics rather than a direct effect of OAC use. For substudies 3 (ASA use in aortic bioprosthesis) and 5 (OAC use in mitral/tricuspid bioprosthesis), robust multivariable analyses could not be performed due to low event rates or model instability, meaning the unadjusted findings for these substudies should be interpreted with great caution regarding causality. Interestingly, no significant differences in thromboembolic events, bleeding complications, heart failure, or prosthetic dysfunction at 6 months were observed between the AT and non-AT groups across all substudies. This suggests that other confounding factors, like patient comorbidities, a worse general condition, or procedural outcomes, might be contributing to these mortality differences.
In substudy 1, which examined the use of ASA in patients with mechanical prostheses and atherosclerotic disease, no significant differences in clinical outcomes were observed at 6 months between those treated with or without ASA, except for an aforementioned trend toward higher mortality in the non-ASA group. Contrary to our findings, other studies have shown that adding an antiplatelet agent to OAC significantly reduces thromboembolic events and overall mortality. However, this advantage is often negated by an elevated risk of major bleeding [11,12].
In substudies 3 and 4, which both examined AT in aortic bioprosthesis patients, it is particularly notable that in unadjusted analyses, ASA (subanalysis 3) as well as OAC (subanalysis 4) use appeared to be associated with improved 6-month survival. Previous data from a large Danish observational registry also showed that discontinuing VKA after aortic bioprosthesis surgery was associated with a significant increase in cardiovascular death [13]. However, it is important to note that in both substudies, patients who did not receive the suggested AT were more likely to have been treated with the alternative therapy: OAC in substudy 3 (P < .001) and ASA in substudy 4 (P < .001). The rationale for selecting each treatment regimen is unclear, but bleeding risk may have influenced the choice, potentially introducing selection bias in the analysis. Given the overlapping nature of the guideline recommendations for substudies 3 and 4, a supplementary analysis was performed on the entire aortic bioprosthesis population (N = 411). Comparative analyses were conducted on baseline characteristics (found in Supplementary Table S3) and 6-month outcomes (found in Supplementary Table S4) between aortic bioprosthesis patients receiving any AT (ASA or OAC) vs those receiving neither ASA nor OAC. This analysis revealed that 6-month mortality remained significantly higher in the small group of patients (n = 59) who received no ASA or OAC compared with those who received either ASA or OAC (n = 352; 25.4% vs 1.4%; P < .001). However, the group without treatment may have been deemed too frail or high-risk for any AT, thus confounding the mortality outcome. These findings underscore the need for prospective randomized studies comparing ASA, OAC, and no therapy in aortic bioprosthesis patients, especially since the 2012 and 2017 ESC guidelines favored low-dose ASA over OAC for this population in case of sinus rhythm [4,6,7], although this was based on limited evidence [[14], [15], [16], [17], [18]]. In contrast, other studies of patients with bioprosthetic aortic valves who were in sinus rhythm and had no other indications for OAC found similar mortality rates between those treated with ASA and those receiving VKA [16]. While we found no significant difference in 6-month thromboembolism or bleeding rates in any of the substudies, earlier observational and prospective studies showed VKA to reduce thromboembolism risk and increase bleeding in aortic valve bioprosthesis patients [13,19,20].
For substudy 5, which examined OAC use in patients with mitral or tricuspid bioprostheses postintervention, the 6-month clinical outcomes were similar to those observed in substudies 3 and 4. This finding is expected, as recommendations for these patients are largely extrapolated from studies involving aortic bioprostheses [1,5].
In substudy 6 (OAC after mitral valve repair), no significant differences in clinical outcomes were observed at 6 months between patients treated with or without OAC. Surgically repaired valves are known to be less prone to thromboembolism compared with valve replacements [2]. Current guidelines, which advocate for the use of OAC following surgical valve repair, are largely based on expert opinion or drawn from retrospective, underpowered studies, and remain a topic of ongoing debate [4,21].
4.4. Study limitations
As an observational study, causality between AT use and 6-month outcomes, including all-cause mortality, cannot be established. Outcomes might be biased by confounding patient factors, procedural outcomes, or treatments, as strongly suggested by the multivariable analysis in substudy 4, where an unadjusted difference in mortality was no longer significant after accounting for confounding variables.
The heterogeneity of the VHD patient population in an observational setting, encompassing diverse concomitant conditions (such as AF, CAD, varying hemorrhagic risk, and prothrombotic states), likely contributes to the variability in therapeutic strategies. Additionally, variability in institutional protocols and expertise across participating centers likely also contributed to AT prescription. For instance, the ASA group in substudy 1 and the non-OAC group in substudy 5 both received significantly more concomitant clopidogrel than their respective comparison groups. While baseline and discharge medications are reported in Tables 2 and 3, a detailed analysis of all treatment combinations was beyond the scope of this study, and their unmeasured influence on outcomes remains a limitation.
Another limitation is the small sample size, in particular for substudy 2, which focused on ASA use in patients with mechanical prostheses following thromboembolism and included only 19 patients, which is insufficient for drawing statistically robust conclusions. Furthermore, the relatively short follow-up period of 6 months may not adequately reflect the long-term effects of AT. Conversely, the thromboembolic risk associated with bioprosthetic valves diminishes as endothelialization of the valve surface occurs, usually within 90 days. Beyond this point, the risk appears comparable whether or not AT is used. However, the optimal duration of AT remains uncertain, and further studies are required to determine the ideal treatment period [22]. This study also lacks information regarding why guidelines were not followed, making it difficult to assess the appropriateness of non-AT usage. Additionally, the study’s reliance on voluntary participation of centers may introduce selection bias. Finally, this analysis is based on a registry that dates to 2017 and was not specifically designed to study AT, which limits the applicability of the findings. Particularly, compliance with the AT regimen was not verified over time.
Despite these limitations, the study’s strengths include the prospective nature of the data collection from multiple centers across Europe, which provides a contemporary reflection of real-world clinical practices. Moreover, the quality of CRF completion adds credibility to the data.
4.5. Future perspectives
Our findings underscore the urgent need for more robust, randomized, prospective trials to resolve the clinical uncertainties surrounding AT in valvular heart surgery [4,23]. As newer antithrombotic agents and (transcatheter) valve types emerge, the decision-making process in clinical practice becomes increasingly complex [5]. In substudies 3 to 6 (aortic bioprosthesis, mitral/tricuspid bioprosthesis, and mitral valve repair), while the majority of OAC-treated patients received VKAs, 1.9% to 4.8% were treated with DOACs. Current guidelines recommend DOACs in patients with bioprostheses and AF, based on the randomized RIvaroxaban for Valvular heart diseasE and atRial fibrillation trial (RIVER) and Efficacy and Safety of Edoxaban in Patients after Heart Valve Repair or Bioprosthetic Valve Replacement (ENAVLE) trials. However, the safety and efficacy of DOACs in this population remain uncertain and warrant further investigation [1,24,25].
5. Conclusion
This prospective real-world subanalysis of the ESC EORP VHD II survey reveals variable adherence to ESC Class II, level of evidence C guideline recommendations for AT in cardiac valve surgery patients, with the highest adherence observed in patients undergoing mitral valve repair and the lowest in patients with mechanical prostheses and concomitant atherosclerotic disease. Cardiovascular risk factors and the presence of AF appear to influence AT prescription decisions. Although some patients without AT had higher unadjusted 6-month all-cause mortality, this difference was likely attributable to confounding baseline characteristics, as confirmed by multivariable analysis in one substudy. These findings underscore the need for more robust, randomized, prospective trials to resolve clinical uncertainties surrounding AT in valvular heart surgery, especially as newer AT and valve types emerge.
Appendix
EURObservational Research Programme (EORP) Oversight Committee, Registry Executive, and Steering Committees of EORP. The EORP Valvular Heart Disease II team: Souad Mekhaldi and Carole Toulouse as Clinical Project Managers, Katell Lemaitre and Gabrielle Bonneville as Project Officers, Sebastien Authier and Maryna Andaral as Data Managers, and Hervé Druais, Céline Arsac, and Emilie Soriano as EORP Department Head.
Acknowledgments
Statistical analyses were performed by Mrs Cécile Laroche and Soladis.
Funding
Since the start of the EURObservational Research Programme, the following companies have supported the program: Abbott Vascular International (2011-2018), Amgen Cardiovascular (2009-2018), AstraZeneca (2014-2020), Bayer AG (2009-2018), Boehringer Ingelheim (2009-2019), Boston Scientific (2009-2012), Bristol Myers Squibb and Pfizer Alliance (2011-2019), Daiichi Sankyo Europe GmbH (2011-2020), Alliance Daiichi Sankyo Europe GmbH and Eli Lilly and Company (2014-2017), Edwards Lifesciences (2016-2019), Ferrer Inernacional SA (2016-2019), Gedeon Richter Plc (2014-2016), Menarini International Operations (2009-2012), MSD-Merck and Co (2011-2014), Novartis Pharma AG (2014-2020), Novo Nordisk AS (2016-2019), Pfizer Ltd (2015-2018), ResMed (2014-2016), Sanofi (2009-2018), and Servier (2009-2018).
Author contributions
B.R., B.I., J.M., S.P., C.L., and B.C. contributed to the study conception and design. The methodology was conceptualized by B.R., B.I., J.M., S.P., C.L., and B.C. Data analysis was performed by B.R. and C.L. Data interpretation was done by B.R. and B.C. The first draft of the manuscript was written by B.R. B.I., J.M., S.P., C.L., J.-L.M., H.I., S.D., and B.C. commented on previous versions of the manuscript. B.I., J.M., S.P., C.L., J.-L.M., H.I., S.D., and B.C. read and approved the final manuscript.
Relationship Disclosure
S.P. declares unremunerated activities as Vice President and Board Member and Chair of the Advocacy Committee of the European Society of Cardiology. J.M. declares payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing, or educational events from Edwards Lifesciences, Boston Scientific, Medtronic, and Abbott; support for attending meetings and/or travel from Edwards Lifesciences, Abbott, and Medtronic; participation on a Data Safety Monitoring Board or Advisory Board for Amgen. C.L., B.I., H.I., J.-L.M., B.R., B.C., and S.D. have nothing to declare.
Data availability
The data presented in this study are available on request from the corresponding author.
Footnotes
Handling Editor: Dr Kristen Sanfilippo
The online version contains supplementary material available at https://doi.org/10.1016/j.rpth.2025.102988
Contributor Information
Bram Roosens, Email: bram.roosens@uzbrussel.be.
EURObservational Research Programme Valvular Heart Disease II Investigators Group:
Souad Mekhaldi, Carole Toulouse, Katell Lemaitre, Gabrielle Bonneville, Sebastien Authier, Maryna Andaral, Hervé Druais, Céline Arsac, and Emilie Soriano
Supplementary material
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data Availability Statement
The data presented in this study are available on request from the corresponding author.