Abstract
Background
The optimal duration and net clinical benefit of dual antiplatelet therapy (DAPT) after transcatheter aortic valve replacement (TAVR) have not been elucidated in real-world situations.
Methods
Using nationwide claims data from 2013 to 2021, we selected patients who underwent TAVR and categorized them into two groups: short- and long-term (≤ 3 and > 3 months, respectively) DAPT group. Propensity score matching was used to balance baseline characteristics. The primary endpoint was the occurrence of net adverse clinical events (NACEs), including all-cause death, myocardial infarction, stroke, any coronary and peripheral revascularization, systemic thromboembolism, and bleeding events, at 1 year. Survival analyses were conducted using Kaplan-Meier estimation and Cox proportional hazards regression.
Results
Patients who met the inclusion criteria (1,695) were selected. Propensity score matching yielded 1,215 pairs of patients: 416 and 799 in the short- and long-term DAPT groups, respectively. In the unmatched cohort, the mean ages were 79.8 ± 6.1 and 79.7 ± 5.8 years for the short- and long-term DAPT groups, respectively. In the matched cohort, the mean ages were 80.6 ± 5.9 and 79.9 ± 5.9 years for the short- and long-term DAPT groups, respectively. Over one year in the unmatched cohort, the NACE incidence was 11.9% and 11.5% in the short- and long-term DAPT groups, respectively (P = 0.893). The all-cause mortality rates were 7.4% and 4.7% (P = 0.042), composite ischemic event rates were 2.5% and 4.7% (P = 0.056), and bleeding event rates were 2.7% and 4.7% (P = 0.056) in the short- and long-term groups, respectively. In the matched cohort, the incidence of NACE was 9.6% in the short-term DAPT group and 11.6% in the long-term DAPT group, respectively (P = 0.329). The all-cause mortality rates were 6.5% and 4.9% (P = 0.298), composite ischemic event rates were 1.4% and 4.5% (P = 0.009), and bleeding event rates were 2.2% and 4.4% (P = 0.072) in the short- and long-term groups, respectively.
Conclusion
In patients who successfully underwent transfemoral TAVR, the short- and long-term DAPT groups exhibited similar one-year NACE rates. However, patients in the long-term DAPT group experienced more bleeding and ischemic events.
Keywords: Transcatheter Aortic Valve Replacement, Dual Anti-Platelet Therapy, Hemorrhage, Ischemia
Graphical Abstract
INTRODUCTION
Transcatheter aortic valve replacement (TAVR) has become a standard treatment method for older patients with symptomatic severe aortic valve stenosis across all surgical risks.1,2 Since the first introduction of TAVR procedure in 2002, it has been common practice to prescribe dual antiplatelet therapy (DAPT) for 6 months after the procedure, followed by lifelong single antiplatelet therapy (SAPT).3,4 This practice pattern of antiplatelet therapy after TAVR were derived from the protocols utilized in pivotal randomized studies, which, in turn, were based on the studies of patients undergoing percutaneous coronary intervention (PCI).5 Recently, the DAPT strategy has been challenged by two randomized trials, which suggested that aspirin monotherapy may yield better outcomes compared to a 3-month course of DAPT, primarily due to a reduction in bleeding events. However, it’s important to note that these trials were not sufficiently powered to draw definitive conclusions.6,7 Nevertheless, bleeding events observed in these studies appear to be clustered within the first few days following TAVR procedure, indicating that procedural factors exert more influence than the antiplatelet agents themselves. In this regard, limited data are available to evaluate both the efficacy and safety of antiplatelet therapy following successful TAVR in real-world practice.
This study aimed to assess the clinical outcomes of patients discharged after successful transfemoral TAVR compared with short-term DAPT with long-term DAPT.
METHODS
Study population
This retrospective cohort study included patients who underwent transfemoral TAVR using claims data from the Korean Health Insurance Review and Assessment Service (HIRA, research data M2022062802) spanning the period from 2013 to 2021.
Data collection
All healthcare providers in South Korea are mandated to participate in the fee-for-service National Health Insurance Service (NHIS) system. The database includes demographic information, diagnoses using the Korean Standard Classification of Diseases (KCD) code (equivalent to the International Classification of Diseases Tenth Revision), prescriptions, medical devices, and procedure records. The NHIS functions as an insurer, whereas the HIRA is responsible for conducting claims reviews and quality assessments of healthcare services. Individuals with regular follow-up claims data spanning at least 1-year (unless deceased) and medical records documenting the use of study medications were eligible for this study. Comorbidities and adverse clinical events were determined based on KCD codes, relevant imaging tests, and procedures, according to the operational definitions in Supplementary Tables 1 and 2.8 For past medical history, a condition was diagnosed based on relevant KCD codes or procedure codes, regardless of admission status. However, for events occurring after the index procedure, the admission status was required for diagnosis in combination with KCD, imaging, and procedural codes. Patients were considered to be on the study medication from the dispensing date until the last day of supply. Patients receiving DAPT continuously for more than three months after the index TAVR were classified into the long-term DAPT group, while those who received DAPT continuously less than three months were categorized into the short-term DAPT group. For those who experienced an event within three months of the index TAVR, group assignment was based on the dominant mediation status during the 15 days prior to the event. A gap of less than 10 days between each prescription period was not considered a discontinuation of the study drug.
Study endpoints
The ischemic endpoint was defined as a composite of acute myocardial infarction, ischemic stroke, thromboembolism in the systemic artery, and revascularization in the coronary or peripheral arteries. The bleeding endpoints included major bleeding events requiring intervention or transfusion. The primary endpoint was net adverse clinical events (NACEs), a composite measure encompassing all-cause death and ischemic and bleeding endpoints. Major adverse cardiovascular and cerebrovascular events include composite ischemic events and all-cause mortality.
Statistical analysis
Continuous variables were expressed as mean ± standard deviation, compared using an unpaired Student’s t-test or as median [quartile 1, quartile 3], and compared using the Kruskal-Wallis rank sum test. Categorical variables are presented as frequencies (percentages) and analyzed using the chi-square test. One-to-two propensity score matching was performed to adjust the baseline characteristics between the two groups using the nearest neighbor method within a caliper width of 0.1 and the standard deviation of the logit of the estimated propensity score.9 The propensity score was generated using a logistic regression model that included age, sex, baseline comorbidities, and discharge medications presented (except antiplatelets), as presented in Table 1. The balance of covariates after matching was measured using standardized mean difference (SMD). To assess clinical outcomes, estimated event-free survival curves were constructed and compared using the Kaplan-Meier method along with the log-rank test. The association between antiplatelet therapy and the 1-year clinical outcomes was tested using the Cox proportional hazards model. Variables with a P value of less than 0.10 from the univariate analysis were included in the multivariable model, along with age, sex, and the DAPT grouping variable. An exploratory subgroup analysis was conducted to assess group differences by introducing an interaction term into the Cox proportional hazards model. Statistical analyses were performed using R (version 3.5.1; R Foundation for Statistical Computing, Vienna, Austria).
Table 1. Baseline characteristics.
| Variables | Before matching | After matching | SMD | |||||
|---|---|---|---|---|---|---|---|---|
| Short-term DAPT (n = 445) | Long-term DAPT (n = 1,250) | P value | Short-term DAPT (n = 416) | Long-term DAPT (n = 799) | P value | |||
| Age, yr | 79.8 ± 6.1 | 79.7 ± 5.8 | 0.518 | 80.0 ± 6.0 | 79.9 ± 5.8 | 0.900 | 0.008 | |
| Sex, female | 268 (60.2) | 657 (52.6) | 0.006 | 247 (59.4) | 468 (58.6) | 0.835 | 0.016 | |
| Hypertension | 421 (94.6) | 1,162 (93.0) | 0.276 | 393 (94.5) | 749 (93.7) | 0.704 | 0.031 | |
| Diabetes | 294 (66.1) | 794 (63.5) | 0.365 | 271 (65.1) | 506 (63.3) | 0.574 | 0.038 | |
| MI | 32 (7.2) | 134 (10.7) | 0.040 | 29 (7.0) | 60 (7.5) | 0.821 | 0.021 | |
| PCI > 3 mon prior to TAVR | 29 (6.5) | 67 (5.4) | 0.431 | 24 (5.8) | 43 (5.4) | 0.882 | 0.017 | |
| CABG | 13 (2.9) | 19 (1.5) | 0.096 | 8 (1.9) | 14 (1.8) | 1.000 | 0.013 | |
| PAD | 163 (36.6) | 484 (38.7) | 0.470 | 150 (36.1) | 293 (36.7) | 0.882 | 0.013 | |
| Stroke | 81 (18.2) | 180 (14.4) | 0.067 | 74 (17.8) | 127 (15.9) | 0.446 | 0.051 | |
| Atrial fibrillation | 34 (7.6) | 89 (7.1) | 0.797 | 32 (7.7) | 59 (7.4) | 0.937 | 0.012 | |
| Thromboembolism | 19 (4.3) | 31 (2.5) | 0.080 | 16 (3.8) | 26 (3.3) | 0.711 | 0.032 | |
| PTE/DVT | 13 (2.9) | 20 (1.6) | 0.125 | 12 (2.9) | 18 (2.3) | 0.632 | 0.040 | |
| COPD | 73 (16.4) | 240 (19.2) | 0.217 | 68 (16.3) | 130 (16.3) | 1.000 | 0.002 | |
| CKD | 102 (22.9) | 191 (15.3) | < 0.001 | 84 (20.9) | 149 (18.6) | 0.567 | 0.039 | |
| Dialysis | 28 (6.3) | 45 (3.6) | 0.023 | 17 (4.1) | 35 (4.4) | 0.928 | 0.015 | |
| ICH | 4 (0.9) | 24 (1.9) | 0.217 | 4 (1.0) | 5 (0.6) | 0.768 | 0.038 | |
| GIB | 60 (13.5) | 168 (13.4) | 1.000 | 54 (13.0) | 113 (14.1) | 0.638 | 0.034 | |
| Bleeding others | 8 (1.8) | 14 (1.1) | 0.400 | 5 (1.2) | 11 (1.4) | 1.000 | 0.015 | |
| Days of hospitalization | 8 [6, 15] | 8 [6, 13] | 0.592 | 8 [6, 13] | 9 [7, 14] | 0.007 | 0.025 | |
| Discharge medications | ||||||||
| Aspirin | 331 (74.4) | 1,246 (99.7) | < 0.001 | 309 (74.3) | 795 (99.5) | < 0.001 | 0.806 | |
| P2Y12i | 386 (86.7) | 1,248 (99.8) | < 0.001 | 367 (88.2) | 797 (99.7) | < 0.001 | 0.500 | |
| PPI | 168 (37.8) | 458 (36.6) | 0.718 | 160 (38.5) | 302 (37.8) | 0.870 | 0.014 | |
| CCB | 138 (31.0) | 415 (33.2) | 0.431 | 133 (32.0) | 246 (30.8) | 0.721 | 0.025 | |
| Β-Blocker | 76 (17.1) | 267 (21.4) | 0.063 | 72 (17.3) | 134 (16.8) | 0.876 | 0.014 | |
| Statin | 244 (54.8) | 801 (64.1) | 0.001 | 237 (57.0) | 476 (59.6) | 0.416 | 0.053 | |
| ACEi/ARB | 139 (31.2) | 451 (36.1) | 0.074 | 135 (32.5) | 278 (34.8) | 0.451 | 0.050 | |
| ARNI | 0 (0.0) | 4 (0.3) | 0.531 | 0 (0.0) | 0 (0.0) | NA | < 0.001 | |
| Loop diuretics | 93 (20.9) | 338 (27.0) | 0.013 | 91 (21.9) | 185 (23.2) | 0.665 | 0.031 | |
| Thiazide | 24 (5.4) | 76 (6.1) | 0.681 | 24 (5.8) | 43 (5.4) | 0.882 | 0.017 | |
| MRA | 39 (8.8) | 133 (10.6) | 0.301 | 37 (8.9) | 78 (9.8) | 0.699 | 0.030 | |
| DAPT duration (days) post-TAVR | 17 [6, 31] | 351 [197, 365] | < 0.001 | 16.5 [6, 31] | 317 [195, 365] | < 0.001 | 3.062 | |
Variables are expressed as mean ± standard deviation, median [Q1, Q3] or number (%).
DAPT = dual antiplatelet therapy, SMD = standardized mean difference, MI = myocardial infarction, PCI = percutaneous coronary intervention, TAVR = transcatheter aortic valve replacement, CABG = coronary artery bypass graft, PAD = peripheral artery disease, Thromboembolism = arterial systemic thromboembolism, PTE = pulmonary thromboembolism, DVT = deep vein thrombosis, COPD = chronic obstructive pulmonary disease, CKD = chronic kidney disease, ICH = intracranial hemorrhage, GIB = gastrointestinal bleeding, P2Y12i = P2Y12 inhibitors, PPI = proton pump inhibitor, CCB = calcium channel blocker, ACEi = angiotensin-converting enzyme inhibitor, ARB = angiotensin receptor blocker, ARNI = angiotensin receptor neprilysin inhibitor, NA = not available, MRA = mineralocorticoid receptor antagonist.
Ethics statement
This study was approved by the Institutional Review Board (IRB) of the Pusan National University Hospital (IRB No. 2203-027-113). The requirement for informed consent was waived due to the nationwide, retrospective nature of the data.
RESULTS
A total of 4,196 patients who underwent transfemoral TAVR for severe aortic valve stenosis between January 2013 and December 2021 were identified. We identified 2,931 patients who had a minimum of one year of follow-up starting in January 2016, which also ensured at least three years of medical records prior to the index TAVR procedure. From this group, 1,236 patients were excluded for the following reasons: 201 underwent PCI within 3 months before TAVR, 674 used anticoagulants within the first three months post-TAVR without a clinical event, 343 discontinued antiplatelets prematurely (within three months) without an event, and 18 did not initiate antiplatelet therapy within three months post-TAVR. Consequently, the final study cohort consisted of 1,695 patients. Propensity score matching resulted in 1,215 patients, with 416 in the short-term DAPT group and 799 in the long-term DAPT group (Fig. 1).
Fig. 1. Flowchart for patient selection and exclusion.
TAVR = transcatheter aortic valve replacement, PCI = percutaneous coronary intervention, DAPT = dual antiplatelet therapy.
Baseline characteristics
The baseline demographics and clinical characteristics are summarized in Table 1. In the unmatched cohort, the short-term DAPT group had higher incidences of female sex, chronic kidney disease, and dialysis, whereas the long-term DAPT group exhibited higher proportions of myocardial infarction and use of beta-blockers and statins. In the long-term DAPT group, three patients discontinued aspirin before discharge because of stroke, intracranial hemorrhage, and gastrointestinal bleeding. Additionally, one patient was discharged without aspirin but resumed its use during follow-up visits.
After propensity score matching, all baseline characteristic variables, except for the use of aspirin and P2Y12 inhibitors at discharge according to the predefined group criteria, were well balanced between the two groups, with SMDs less than 0.10 for each variable (Supplementary Fig. 1).
Clinical outcomes
The one-year clinical outcomes of the unmatched and matched cohorts are shown in Table 2. In the unmatched cohort, the overall 1-year NACE rate was 11.6%, with similar rates observed between the two groups: 11.9% in the short-term DAPT group and 11.5% in the long-term DAPT group (P = 0.893). The incidence of all-cause mortality was significantly higher in the short-term DAPT group (7.2% vs. 4.7%, P = 0.042), whereas ischemic events were more frequent in the long-term DAPT group (2.5% vs. 4.7%, P = 0.056). Non-cardiac causes accounted for 78.2% of all deaths, with no significant differences between the groups (5.4% vs. 3.8%, P = 0.208) (Supplementary Table 3). The Kaplan-Meier event-free survival curves for each component of the 1-year clinical outcomes are shown in Fig. 2. In the matched cohort, the overall 1-year NACE rate was 10.9%, with similar rates observed between the two groups as those in the unmatched cohort: 9.6% in the short-term DAPT group and 11.6% in the long-term DAPT group (P = 0.329). The incidence of all-cause death was numerically higher in the short-term DAPT group (6.5% vs. 4.9%, P = 0.298). By contrast, the long-term DAPT group had higher rates of ischemia (1.4% vs. 4.5%, P = 0.009) and bleeding events (2.2% vs. 4.4%, P = 0.072). The Kaplan-Meier event-free survival curves for the matched cohort are shown in Supplementary Fig. 2.
Table 2. Clinical events and safety outcomes at 1 year.
| Variables | Unmatched cohort | Matched cohort | |||||||
|---|---|---|---|---|---|---|---|---|---|
| Overall (N = 1,695) | Short-term DAPT (n = 445) | Long-term DAPT (n = 1,250) | P value | Overall (N = 1,215) | Short-term DAPT (n = 416) | Long-term DAPT (n = 799) | P value | ||
| NACE | 197 (11.6) | 53 (11.9) | 144 (11.5) | 0.893 | 133 (10.9) | 40 (9.6) | 93 (11.6) | 0.329 | |
| MACCE | 152 (9.0) | 44 (9.9) | 108 (8.6) | 0.487 | 102 (8.4) | 33 (7.9) | 69 (8.6) | 0.759 | |
| All-cause death | 92 (5.4) | 33 (7.4) | 59 (4.7) | 0.042 | 66 (5.4) | 27 (6.5) | 39 (4.9) | 0.298 | |
| Ischemic events | 70 (4.1) | 11 (2.5) | 59 (4.7) | 0.056 | 42 (3.5) | 6 (1.4) | 36 (4.5) | 0.009 | |
| AMI | 4 (0.2) | 1 (0.2) | 3 (0.2) | 1.000 | 4 (0.3) | 1 (0.2) | 3 (0.4) | 1.000 | |
| Stroke | 25 (1.4) | 3 (0.7) | 20 (1.6) | 0.226 | 12 (1.0) | 2 (0.5) | 10 (1.3) | 0.325 | |
| Revascularization (coronary artery) | 8 (0.5) | 1 (0.2) | 7 (0.6) | 0.629 | 6 (0.5) | 1 (0.2) | 5 (0.6) | 0.633 | |
| Revascularization (peripheral artery) | 33 (1.9) | 6 (1.3) | 27 (2.2) | 0.387 | 19 (1.6) | 2 (0.5) | 17 (2.1) | 0.051 | |
| Thromboembolism | 2 (0.1) | 0 (0.0) | 2 (0.2) | 0.968 | 1 (0.2) | 0 (0.0) | 1 (0.1) | 1.000 | |
| Bleeding | 61 (3.6) | 12 (2.7) | 49 (3.9) | 0.298 | 44 (3.6) | 9 (2.2) | 35 (4.4) | 0.072 | |
| GIB | 52 (3.1) | 11 (2.5) | 41 (3.3) | 0.491 | 36 (3.0) | 8 (1.9) | 28 (3.5) | 0.173 | |
| ICH | 3 (0.2) | 0 (0.0) | 3 (0.2) | 0.706 | 2 (0.2) | 0 (0.0) | 2 (0.2) | 0.783 | |
| Bleeding others | 6 (0.4) | 1 (0.2) | 5 (0.4) | 0.944 | 6 (0.5) | 1 (0.2) | 5 (0.6) | 0.633 | |
Variables are expressed as counts (%). There were 10 patients in the unmatched cohort, each involving both death and ischemic events.
DAPT = dual antiplatelet therapy, NACE = net adverse clinical event, MACCE = major adverse cardiac and cerebrovascular events, AMI = acute myocardial infarction, Thromboembolism = arterial systemic thromboembolism, GIB = gastrointestinal bleeding, ICH = intracranial hemorrhage.
Fig. 2. Kaplan-Meier curves for clinical events in the unmatched cohort. One-year Kaplan-Meier event-free survival curves for short-term DAPT (blue line) and long-term DAPT (green line) groups: (A) net adverse clinical event, (B) all-cause death, (C) ischemic events including acute myocardial infarction, stroke, revascularization (coronary or peripheral artery), and systemic embolism, and (D) bleeding events.
DAPT = dual antiplatelet therapy, TAVR = transcatheter aortic valve replacement.
Multivariable analysis
Multivariable Cox regression analysis of 1-year NACE for the unmatched cohort identified female sex, hypertension, dialysis, and statin use as independent predictors. However, long-term DAPT was not significantly associated with the 1-year NACE outcome (hazard ratio, 1.26; 95% confidence interval, 0.87–1.82; P = 0.228) (Table 3; matched cohort in Supplementary Table 4).
Table 3. Univariable and multivariable analyses for NACE at 1 year in unmatched cohort.
| Variables | Univariable | Multivariable | ||
|---|---|---|---|---|
| HR (95% CI) | P value | HR (95% CI) | P value | |
| Age, yr | 1.01 (0.98–1.03) | 0.651 | 1.03 (1.00–1.05) | 0.035 |
| Sex, female | 0.62 (0.46–0.82) | 0.001 | 0.64 (0.48–0.85) | 0.002 |
| Long-term DAPT | 0.97 (0.74–1.32) | 0.829 | 1.06 (0.77–1.46) | 0.719 |
| Index year | 0.95 (0.86–1.06) | 0.388 | ||
| HTN | 2.87 (1.18–6.97) | 0.020 | 2.44 (1.00–5.97) | 0.051 |
| DM | 1.56 (1.14–2.13) | 0.006 | 1.39 (1.01–1.92) | 0.041 |
| MI | 0.90 (0.56–1.46) | 0.677 | ||
| PCI > 3 mon prior to TAVR | 0.89 (0.47–1.68) | 0.724 | ||
| PAD | 1.40 (1.05–1.85) | 0.020 | ||
| Stroke | 1.24 (0.87–1.78) | 0.239 | ||
| COPD | 1.50 (1.08–2.07) | 0.014 | ||
| Atrial fibrillation | 1.80 (1.17–2.78) | 0.008 | ||
| Dialysis | 4.21 (2.82–6.29) | < 0.001 | 3.63 (2.35–5.59) | < 0.001 |
| Thromboembolism | 1.04 (0.46–2.34) | 0.926 | ||
| Prior bleeding | 1.75 (1.26–2.43) | 0.001 | 1.42 (1.02–1.99) | 0.040 |
| PPI | 1.08 (0.81–1.43) | 0.619 | ||
| CCB | 0.99 (0.74–1.34) | 0.955 | ||
| Statin | 0.71 (0.54–0.94) | 0.018 | 0.75 (0.56–1.00) | 0.048 |
| Beta-blocker | 1.07 (0.76–1.50) | 0.703 | ||
| ACEi/ARB | 0.85 (0.63–1.15) | 0.299 | ||
| ARNI | 2.75 (0.39–19.64) | 0.313 | ||
| Loop diuretics | 1.02 (0.74–1.40) | 0.906 | ||
| Thiazide | 0.76 (0.39–1.48) | 0.418 | ||
| MRA | 0.77 (0.46–1.29) | 0.322 | ||
NACE = net adverse clinical events, HR = hazard ratio, CI = confidence interval, DAPT = dual antiplatelet therapy, HTN = hypertension, DM = diabetes mellitus, MI = myocardial infarction, PCI = percutaneous coronary intervention, TAVR = transcatheter aortic valve replacement, PAD = peripheral artery disease, COPD = chronic obstructive pulmonary disease, Thromboembolism = arterial systemic thromboembolism, PPI = proton pump inhibitor, CCB = calcium channel blocker, ACEi = angiotensin-converting enzyme inhibitor, ARB = angiotensin receptor blocker, ARNI = angiotensin receptor neprilysin inhibitor, MRA = mineralocorticoid receptor antagonist.
Subgroup analysis
The forest plot for the subgroup analyses of 1-year NACE in the unmatched cohort indicated no significant interaction across most subgroups. However, among patients dependent on dialysis, short-term DAPT was preferred over long-term DAPT (Fig. 3). In the matched cohort, subgroup analysis revealed findings similar to those in the unmatched cohort. There was no significant interaction, except in the dialysis subgroup, which showed a preference for short-term DAPT, as shown in Supplementary Fig. 3.
Fig. 3. Forest plot of subgroup analyses for 1-year net adverse clinical event outcomes in the unmatched cohort. Only patients who underwent PCI three months prior to the index transcatheter aortic valve replacement procedure were included.
HR = hazard ratio, CI = confidence interval, DM = diabetes mellitus, PCI = percutaneous coronary intervention, PAD = peripheral artery disease, Thromboembolism = arterial systemic thromboembolism, COPD = chronic obstructive pulmonary disease, DAPT = dual antiplatelet therapy.
DISCUSSION
This study assessed the efficacy and safety, defined as NACE, of different durations of DAPT in a large population undergoing TAVR in real-world practice.
The major findings of our study are as follows: 1) the majority of patients undergoing TAVR were prescribed DAPT at the time of discharge. 2) Approximately three-quarters of these patients continued DAPT for > three months. 3) The incidence of NACE, including adverse bleeding events, was comparable between the two groups. However, there were higher rates of ischemic and bleeding events in the long-term DAPT group. 4) After adjusting for comorbidities, the duration of DAPT was not an independent predictor of 1-year NACE outcomes.
When introducing the TAVR procedure, DAPT was adopted as the standard antithrombotic strategy, based on extrapolations from data in coronary artery stenting, with the aim of reducing ischemic and thromboembolic events.10 As experience with TAVR has grown, concerns regarding bleeding events associated with DAPT strategies have become more pronounced, particularly in the elderly population. Contemporary global experts recommend SAPT, particularly aspirin, for patients undergoing bioprosthetic TAVR without indications for oral anticoagulation, as a Class 2a recommendation in the ACC/AHA guidelines and a Class IA recommendation in the ESC guidelines.1,11 DAPT or vitamin K anticoagulation for the initial 3–6 months is recommended, particularly in patients with a low bleeding risk, as a Class 2b recommendation.
These revised recommendations were based on the findings of two clinical trials: Aspirin Versus Aspirin + Clopidogrel Following Transcatheter Aortic Valve Implantation (ARTE) and Antiplatelet therapy for patients undergoing transcatheter aortic valve implantation (POPular TAVI). These trials compared the effects of a 3-months course of DAPT and SAPT on clinical outcomes over 3-month and 1-year period, respectively6,7 Although underpowered for ischemic events, the use of DAPT was associated with an increase in major or life-threatening bleeding events (10.8% vs. 3.6% in ARTE and 10.8% vs. 5.1% in POPular TAVR), whereas there were no differences in ischemic events.
The population characteristics of this study were similar to those of the two trials, with a mean age of nearly 80 years; however, the prevalence of hypertension, diabetes, and peripheral artery disease was higher in this study. Although the all-cause mortality rate (5.4% at 1 year) in this study was between the rates observed in ARTE (3.6–6.3% at 3 months) and POPular TAVI (5.7–6.3% at 1 year), the incidence of bleeding events was significantly lower in this study (3.6%) than in those reported in these studies (up to 10.8%). This discrepancy may be due to methodological differences between the studies.
First, in our study, none of the TAVR procedures were conducted via the transapical or transaortic approach, in contrast to the ARTE and POPular TAVI studies, where 25.4% and 12% of the procedures were performed using these alternative approaches, respectively. The predominant use of the transfemoral approach was also evident in the K-TAVI registry, which compiled data from 17 TAVR centers between 2015 and 2017. This registry revealed that the majority of TAVR procedures (98.3%) were performed using transfemoral approach.12 When transfemoral route was utilized, a similar trend was reported in the analysis of TVT registry data, where the majority of patients (81.1%) were discharged on DAPT. This did not result in increased mortality at 1 year but was associated with a higher risk of major bleeding.13 Considering the transfemoral route as the predominant access site, and with more than half of major bleeding events being related to the access site, our study provides valuable insights into contemporary TAVR procedures and subsequent antithrombotic strategies, predominantly conducted through the transfemoral approach. Second, more than three-quarters of the patients in the short-term DAPT group were on DAPT at the time of discharge from the index TAVR procedure. By contrast, in these randomized studies, most patients received the allocated antiplatelet medication during the index procedure. This discrepancy may have diminished the group differences observed in our study.
An unexpected finding in this study was that patients in the long-term DAPT group experienced more ischemic and bleeding events than those in the short-term DAPT group. It is unclear whether this result was incidental or related to unmeasured factors in our data. However, several factors may explain this finding. The short-term DAPT group had a higher rate of all-cause mortality (statistically significant in the unmatched cohort and numerically higher in the matched cohort) than the long-term DAPT group. Death may act as a competing risk factor for ischemic events, indicating that patients might have experienced an ischemic event if they had not died early. In addition, some patients experienced both ischemic and bleeding events. Due to the limitations of the claims data, we could not determine the exact sequence of these events. A patient on DAPT might have had an ischemic event followed by a bleeding event or vice versa, in which the medication was switched to SAPT after a bleeding event followed by an ischemic event. Both situations may have resulted in higher rates of ischemic and bleeding events in the long-term DAPT group.
There were several limitations to consider when interpreting our results. First, as this study was non-randomized and observational, unmeasured biases may have influenced the analysis, even with propensity score matching. Second, the use of claims data may have led to misclassification or underreporting. Furthermore, we could only obtain the starting dates of claims that contained relevant information regarding the codes used to judge an event. Therefore, this date was considered the date on which the event occurred rather than the actual onset date. When a claim included codes for both bleeding and ischemic events, the temporal sequence could not be determined and patients were recorded as having experienced both events simultaneously. This may partly explain the higher rates of bleeding and ischemic events observed in the long-term DAPT group. Third, the study lacked detailed information on hemodynamic and laboratory tests such as valve area, pressure gradient, and ejection fraction. Fourth, drug adherence could not be verified using claims data. Finally, these results may not be generalizable to patients indicated for anticoagulation therapy.
In conclusion, no significant differences were observed between the long-term DAPT group (three months or more) and the short-term DAPT group (less than three months) regarding NACE at one year in patients who underwent transfemoral TAVR successfully. However, patients in the long-term DAPT group experienced more bleeding and ischemic events. This finding warrants further validation in future studies with larger sample sizes.
Footnotes
Funding: This work was supported by a grant from Samjin Pharmaceutical Co. in 2022. The funders had no role in study design, data collection, and analysis, decision to publish, or preparation of the manuscript.
Disclosure: The authors have no potential conflicts of interest to disclose.
- Conceptualization: Oh JH, Choi JH.
- Data curation: Lee SH, Choe JC.
- Formal analysis: Kim J.
- Investigation: Oh JH, Ahn J.
- Methodology: Kim MS.
- Software: Oh JH.
- Supervision: Kim JS.
- Validation: Lee HC, Cha KS.
- Visualization: Oh JH, Lee HW.
- Writing - original draft: Oh JH, Choi JH.
- Writing - review & editing: Oh JH, Choi JH, Kim JS.
SUPPLEMENTARY MATERIALS
Operational definitions for comorbidities
Operational definitions for study outcomes
Causes of death at 1 year in the unmatched cohort
Univariable and multivariable analyses for NACE at 1 year in matched cohort
Love plot comparing standardized mean differences before and after matching.
Kaplan-Meier curves for clinical events in the matched cohort. The 1-year Kaplan-Meier event-free survival curves for short-term DAPT (blue line) and long-term DAPT (green line) groups; (A) net adverse clinical event, (B) all-cause death, (C) ischemic events including acute myocardial infarction, stroke, revascularization (coronary or peripheral artery), and systemic embolism, (D) bleeding event.
Forest plot of subgroup analyses for 1-year net adverse clinical event outcomes in the matched cohort. Previous PCI included only those who had PCI three months prior to index transcatheter aortic valve replacement procedure.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Operational definitions for comorbidities
Operational definitions for study outcomes
Causes of death at 1 year in the unmatched cohort
Univariable and multivariable analyses for NACE at 1 year in matched cohort
Love plot comparing standardized mean differences before and after matching.
Kaplan-Meier curves for clinical events in the matched cohort. The 1-year Kaplan-Meier event-free survival curves for short-term DAPT (blue line) and long-term DAPT (green line) groups; (A) net adverse clinical event, (B) all-cause death, (C) ischemic events including acute myocardial infarction, stroke, revascularization (coronary or peripheral artery), and systemic embolism, (D) bleeding event.
Forest plot of subgroup analyses for 1-year net adverse clinical event outcomes in the matched cohort. Previous PCI included only those who had PCI three months prior to index transcatheter aortic valve replacement procedure.