Patients who undergo transcatheter aortic valve implantation are generally discharged on dual-antiplatelet therapy. However, many of these patients also have indications for anticoagulant therapy, and it is unclear what the best antithrombotic strategy is in these cases. Data from 360 patients who underwent transcatheter aortic valve implantation were retrospectively analyzed, of whom 60 (16.7%) had indications for anticoagulant treatment, mainly because of atrial fibrillation. The antithrombotic regimen was decided according to clinical evaluation of thrombotic and hemorrhagic risk; most of these patients (n = 43) were discharged with warfarin plus a single antiplatelet drug. Their outcomes were compared to those in a group with no indications for anticoagulation (n = 300) treated with dual-antiplatelet therapy. During the follow-up period (median 11 months), 53 patients (15%) died; mortality was not associated with antithrombotic regimen. The incidence of cerebral events or intracranial hemorrhage (4.6% and 1.1%, respectively) was low in the study population, and no significant differences were detected between groups; the bleeding rate was also unaffected by antithrombotic therapy. In conclusion, when anticoagulation is indicated after transcatheter aortic valve implantation, many variables must be taken into account. The most frequent scenario in this study was patients in atrial fibrillation, most of whom were discharged with warfarin plus a single antiplatelet medication. When bleeding was a concern, especially in the absence of coronary disease, warfarin alone was prescribed. These results suggest that this approach is safe, but data from larger, randomized studies are needed.
Common practice in cardiac surgery is to administer anticoagulants for ≥3 months after prosthetic valve implantation, waiting for healing of the prosthesis and endothelialization. Similarly, it has been demonstrated that percutaneously implanted aortic prosthetic valves soon become covered by fibrin, which is then replaced by smooth muscle cells and finally by endothelium, thereby incorporating the foreign body into the surrounding tissues and restoring a normal interface for blood. This process is estimated to be completed within a few months, but until the prosthetic material is completely endothelialized, there is concern that small thrombi may detach from the valve and cause cerebral ischemia. To protect patients from this possible complication during the first months after intervention, dual-antiplatelet therapy (DAT) is generally started before the intervention and continued for 3 to 6 months after the procedure, an approach that is empirically derived from coronary artery stenting. After publication of the results of the Placement of Aortic Transcatheter Valves (PARTNER) trial, which showed a non-negligible incidence of periprocedural strokes and cerebral ischemic events, even more emphasis is being placed on identifying and preventing cerebral embolization. However, many of these patients also have indications for long-term anticoagulant therapy, mainly because of the high incidence of atrial fibrillation in this elderly population. It is unclear what the best therapeutic approach is in these patients.
Methods
To assess this issue, we retrospectively evaluated patients who underwent transcatheter aortic valve implantation (TAVI) at our institution from November 2007 to October 2011, focusing on outcomes according to antithrombotic therapy at discharge. Patients with indications for anticoagulant treatment were considered the study group, while the others served as a control group.
Patients were considered eligible for TAVI if they had severe, symptomatic aortic stenosis and were considered at high surgical risk according to current recommendations. Both self-expanding devices and balloon-expandable prostheses were implanted. In the absence of contraindications, patients were pretreated with aspirin and clopidogrel (with a 300-mg loading dose on the day before the procedure) and were discharged on DAT for a period of 3 to 6 months, after which only aspirin was recommended. Transfemoral access was preferred whenever feasible; in the case of transapical, transaortic, or transaxillary access, only aspirin was administered before the procedure. Heparin was administered periprocedurally to all patients, according to standard practice, to prevent catheter thrombosis.
In patients with concomitant indications for anticoagulant therapy, treatment was decided on an individual basis according to the clinical evaluation of the risk for thrombotic and hemorrhagic events. When anticoagulation was thought to be necessary, patients were treated with low–molecular weight heparin for the periprocedural period and then discharged on warfarin therapy.
Clinical and echocardiographic evaluation was performed at admission, before discharge, and later at scheduled outpatient visits at 30 days, 6 months, 1 year, and subsequently once a year. Data were prospectively entered in a dedicated database; personnel who adjudicated adverse events were unblinded to antithrombotic therapy. All end points were defined according to the Valve Academic Research Consortium definitions.
Normally distributed continuous variables are expressed as mean ± SD, and medians and interquartile ranges (IQRs) are used to report variables with skewed distributions; the normality of the distributions of continuous variables was tested using Kolmogorov-Smirnov goodness-of-fit tests. Categorical variables are expressed as absolute numbers and percentages. Continuous variables were compared using Student’s t tests or Wilcoxon-Mann-Whitney tests for normally or non-normally distributed variables, respectively. When multiple comparisons were made, analysis of variance with Fisher’s least-significant-difference post hoc tests was used. Categorical variables were compared using chi-square or Fisher’s exact tests as appropriate. Two-sided p values <0.05 were used as a threshold for statistical significance.
Results
In the study period, 360 patients underwent TAVI at our institution using the Medtronic CoreValve (n = 144 [40%]; Medtronic, Inc., Minneapolis, Minnesota) or Edwards Sapien (n = 216 [60%]; Edwards Lifesciences, Irvine, California). Of these, 60 patients (16.7%) had ≥1 indication for anticoagulant therapy, mainly because of atrial fibrillation, which was present in 15.6% of the overall population ( Table 1 ).
| Indication | Frequency ∗ |
|---|---|
| Atrial fibrillation | 56 (15.6%) |
| Previous deep vein thrombosis | 7 (1.9%) |
| Mechanical mitral valve prosthesis | 3 (0.8%) |
| Previous arterial thrombosis | 1 (0.3%) |
∗ Percentages are calculated on the basis of the overall population (n = 360).
All patients in atrial fibrillation had high CHADS-VASc scores (mean 5 ± 1.2), reflecting the high prevalence of heart failure, advanced age, and other co-morbidities in this population. In contrast, advanced age and frailty, which are almost universal in patients with TAVI, represent important risk factors for bleeding.
According to the clinical evaluation of thrombotic and hemorrhagic risk, these 60 patients were discharged with different therapeutic regimens: 43 (71.7%) with an anticoagulant plus 1 antiplatelet agent, of whom 11 (18.3%) had an anticoagulant plus aspirin and 32 (53.4%) had an anticoagulant plus clopidogrel; 14 (23.3%) with an anticoagulant without any antiplatelet therapy; 2 (3.3%) on DAT; and 1 (1.7%) with an anticoagulant plus DAT because of concomitant coronary artery revascularization with a bare-metal stent.
We limited most of our analyses to a comparison between a control group, discharged on DAT for 3 to 6 months (n = 300), and the group of patients receiving therapy with an anticoagulant and a single antiplatelet drug (n = 43).
Baseline clinical characteristics of the 2 groups are listed in Table 2 . Compared to patients on DAT, insulin-dependent diabetes mellitus and a history of cerebrovascular or coronary artery disease were slightly less prevalent in subjects with an anticoagulant and a single antiplatelet drug. No statistically significant differences were found between groups regarding the type and size of prosthesis implanted or the type of vascular access adopted; procedural variables are summarized in Table 3 .
| Variable | Overall (n = 360) | DAT (n = 300) | Anticoagulant Plus Single Antiplatelet (n = 43) | p Value |
|---|---|---|---|---|
| Age (yrs) | 79 ± 7 | 79 ± 8 | 80 ± 6 | 0.232 |
| Men | 180 (50%) | 156 (52%) | 21 (49%) | 0.077 |
| Body surface area (m 2 ) | 1.77 ± 0.18 | 1.76 ± 0.18 | 1.82 ± 0.2 | 0.300 |
| Body mass index (kg/m 2 ) | 26 ± 5 | 26 ± 5 | 27 ± 5 | 0.627 |
| Diabetes mellitus | 108 (30%) | 94 (31%) | 8 (19%) | 0.085 |
| Insulin-dependent diabetes mellitus | 36 (10%) | 35 (12%) | 0 | 0.013 ∗ |
| Hypertension | 269 (76%) | 219 (73%) | 38 (88%) | 0.032 ∗ |
| Chronic renal failure | 117 (33%) | 103 (37%) | 12 (28%) | 0.388 |
| Chronic hemodialysis | 13 (4%) | 10 (3%) | 2 (5%) | 0.670 |
| Creatinine clearance | 52.2 ± 24.1 | 52 ± 24.6 | 54.8 ± 23.2 | 0.481 |
| Hemoglobin (g/dl) | 12 ± 1.7 | 12 ± 1.8 | 12.2 ± 1.6 | 0.521 |
| Chronic obstructive pulmonary disease | 131 (37%) | 110 (37%) | 17 (40%) | 0.728 |
| Permanent pacemaker | 30 (9%) | 23 (8%) | 7 (16%) | 0.082 |
| Cerebrovascular disease | 42 (15%) | 49 (16%) | 2 (5%) | 0.043 ∗ |
| Peripheral arterial disease | 108 (31%) | 92 (31%) | 11 (26%) | 0.472 |
| Coronary artery disease | 145 (42%) | 134 (46%) | 11 (26%) | 0.017 ∗ |
| Previous acute myocardial infarction | 76 (21%) | 69 (26%) | 7 (16%) | 0.316 |
| Previous percutaneous coronary intervention | 72 (20%) | 67 (22%) | 5 (12%) | 0.105 |
| Previous coronary artery bypass graft | 74 (21%) | 66 (22%) | 8 (19%) | 0.605 |
| Previous aortic bioprosthesis | 5 (2%) | 4 (1%) | 1 (2%) | 0.100 |
| “Porcelain” aorta | 63 (19%) | 55 (19%) | 7 (16%) | 0.652 |
| Aortic annulus (mm) | 23.5 ± 1.9 | 23.5 ± 1.8 | 23.5 ± 1.9 | 0.945 |
| Aortic valve area (cm 2 ) | 0.7 ± 0.2 | 0.7 ± 0.2 | 0.7 ± 0.2 | 0.858 |
| Mean aortic gradient (mm Hg) | 53 ± 17 | 52 ± 17 | 56 ± 15 | 0.564 |
| Maximal aortic gradient (mm Hg) | 85 ± 25 | 84 ± 24 | 90 ± 23 | 0.452 |
| Peak aortic valve velocity (cm/s) | 461 ± 250 | 458 ± 245 | 474 ± 240 | 0.487 |
| Left ventricular ejection fraction (%) | 52 ± 13 | 52 ± 13 | 52 ± 12 | 0.697 |
| Left ventricular ejection fraction ≤35% | 51 (14%) | 42 (14%) | 6 (14%) | 0.974 |
| New York Heart Association class III or IV | 239 (68%) | 196 (66%) | 31 (72%) | 0.769 |
| Aortic regurgitation 3 to 4+ | 47 (14%) | 37 (13%) | 7 (17%) | 0.845 |
| Logistic European System for Cardiac Operative Risk Evaluation score | 19.5 (11.4–31.2) | 19.5 (11.4–31.4) | 20.3 (11–30.5) | 0.977 |
| Society of Thoracic Surgeons score | 6 (4–10) | 6 (4–10) | 6 (4.3–8.5) | 0.985 |
| Iliofemoral minimal luminal diameter (therapeutic access) | 7.5 ± 1.23 | 7.5 ± 1.22 | 7.4 ± 1.26 | 0.987 |
| CHADS-VASc score | 5 ± 1.2 | 4.9 ± 1.3 | 4.9 ± 1.2 | 0.182 |
| Variable | Overall (n = 360) | DAT (n = 300) | Anticoagulant Plus Single Antiplatelet (n = 43) | p Value |
|---|---|---|---|---|
| Valve type | ||||
| Edwards | 216 (60.5%) | 187 (62.3%) | 23 (53.5%) | 0.285 |
| Sapien | 101 (26.8%) | 89 (28.2%) | 10 (23.2%) | 0.612 |
| Sapien XT | 115 (33.7%) | 98 (34.1%) | 13 (30.2%) | 0.612 |
| Medtronic CoreValve | 141 (39.5%) | 113 (37.7%) | 20 (46.5%) | 0.209 |
| Valve size (mm) | ||||
| 23 | 90 (25.2%) | 77 (25.7%) | 9 (20.9%) | 0.300 |
| 26 | 176 (49.3%) | 150 (50%) | 22 (51.2%) | 0.763 |
| 29 | 90 (25.2%) | 73 (24.3%) | 12 (27.9%) | 0.649 |
| Access | ||||
| Transfemoral | 280 (82.1%) | 237 (82.7%) | 36 (83.7%) | 0.853 |
| Transapical | 24 (7%) | 20 (7%) | 2 (4.7%) | 0.570 |
| Transaxillary | 35 (10.3%) | 28 (9.8%) | 5 (11.6%) | 0.703 |
| Transaortic | 3 (0.8%) | 2 (0.7%) | 1 (2.3%) | 0.294 |
| Sheath size (Fr) | 19.6 ± 2.3 | 19.6 ± 2.3 | 19.4 ± 2.3 | 0.655 |
| Elective surgical closure | 69 (20.2%) | 55 (19.2%) | 10 (23.3%) | 0.529 |
| Failure of percutaneous closure | 22 (7.9%) | 17 (7.2%) | 4 (12.1%) | 0.607 |
| Heparin (U/kg) | 75 ± 21 | 76 ± 20 | 70 ± 22 | 0.767 |
| Prevalvuloplasty | 288 (80.7%) | 246 (82%) | 38 (88.4%) | 0.639 |
| Postdilatation | 64 (18.4%) | 47 (16%) | 12 (28.6%) | 0.296 |
Median follow-up was 11 months (IQR 6 to 15), and during this period, 53 patients (15% of the total population) died; cardiovascular mortality accounted for about half of these cases. Outcomes are listed in detail in Table 4 ; no outcomes were found to be statistically different between the groups. Figure 1 shows the mortality rate at 1 year for patients receiving DAT compared to warfarin and a single antiplatelet drug. The only patient receiving “triple therapy” died because of cardiogenic shock 5 days after the procedure. We found no difference in mortality between patients taking or not taking anticoagulant therapy (13.8% vs 15.4%, p = 0.757) or considering patients in atrial fibrillation versus sinus rhythm (14.3% vs 15.3%, p = 0.848).
| Variable | Overall (n = 360) | DAT (n = 300) | Anticoagulant Plus Single Antiplatelet (n = 43) | p Value |
|---|---|---|---|---|
| Follow up (days) | 331 (121–452) | 330 (121–467) | 368 (245–417) | 0.247 |
| Overall mortality | 53 (15%) | 46 (15.5%) | 7 (16.3%) | 0.894 |
| Days to death | 146 (45–365) | 137 (44–355) | 364 (187–417) | 0.098 |
| Cardiovascular mortality | 27 (7.6%) | 24 (8.1%) | 3 (7%) | 0.802 |
| In-hospital mortality | 14 (4.1%) | 14 (4.9%) | 0 | 0.139 |
| Myocardial infarction | 7 (2%) | 6 (2%) | 1 (2.4%) | 0.890 |
| Cerebrovascular events | 16 (4.6%) | 14 (4.8%) | 2 (4.8%) | 1.000 |
| Stroke | 9 (2.5%) | 8 (2.7%) | 1 (2.4%) | 1.000 |
| Transient ischemic attack | 7 (1.9%) | 6 (2%) | 1 (2.4%) | 0.613 |
| Intracranial bleeding | 4 (1.1%) | 3 (1%) | 1 (2.4%) | 0.416 |
| Life-threatening bleeding | 83 (24.3%) | 70 (24.4%) | 10 (23.3%) | 0.889 |
| Major bleeding | 107 (31.4%) | 95 (33.1%) | 11 (25.6%) | 0.284 |
| Minor bleeding | 19 (5.6%) | 16 (5.6%) | 2 (4.7%) | 1.000 |
| Hemoglobin decrease (g/dL) | 2.7 ± 1.6 | 2.7 ± 1.7 | 2.6 ± 1.5 | 0.317 |
| Transfusion | 149 (43.8%) | 129 (45.1%) | 16 (37.2%) | 0.331 |
| Transfused red blood cells | 0 (0–2) | 0 (0–2) | 0 (0–2) | 0.223 |
| Acute kidney injury | 110 (32.1%) | 92 (31.9%) | 16 (37.2%) | 0.492 |
| Stage 1 | 64 (18.8%) | 53 (18.5%) | 10 (23.3%) | 0.456 |
| Stage 2 | 16 (4.7%) | 14 (4.9%) | 2 (4.7%) | 1.000 |
| Stage 3 | 26 (9.7%) | 23 (9.4%) | 3 (14%) | 1.000 |
| Renal replacement | 20 (5.6%) | 17 (5.7%) | 3 (7%) | 0.146 |
| Major vascular complications | 51 (15%) | 44 (15.3%) | 7 (16.3%) | 0.873 |
| Minor vascular complications | 34 (9.9%) | 25 (8.7%) | 8 (18.6%) | 0.055 |
| Aortic dissection | 3 (0.9%) | 3 (1%) | 0 | 0.501 |
| Device success | 323 (94.2%) | 268 (92.7%) | 41 (95.3%) | 0.542 |
| Freedom from combined safety end point (30 days) | 223 (67.8%) | 184 (66.9%) | 30 (71.4%) | 0.727 |
| In-hospital stay (days) | 6 (5–9) | 6 (5–9) | 7 (5–9) | 0.684 |
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