Dual antiplatelet therapy (DAPT) with clopidogrel and aspirin is a widely accepted strategy in patients undergoing transcatheter aortic valve implantation (TAVI), but this approach is not evidence based. The goal of the present study was to determine whether DAPT in patients undergoing TAVI is associated with improved outcomes compared to aspirin alone. From May 2009 to August 2010, consecutive patients were randomized to receive a 300-mg loading dose of clopidogrel on the day before TAVI followed by a 3-month maintenance daily dose of 75 mg plus aspirin 100 mg lifelong (DAPT group) or aspirin 100 mg alone (ASA group). The primary end point was the composite of major adverse cardiac and cerebrovascular events, defined as death from any cause, myocardial infarction, major stroke, urgent or emergency conversion to surgery, or life-threatening bleeding. The cumulative incidence of major adverse cardiac and cerebrovascular events at 30 days and 6 months was 14% and 16%, respectively. No significant differences between the DAPT and ASA groups were noted at both 30 days (13% vs 15%, p = 0.71) and 6 months (18% vs 15%; p = 0.85). In conclusion, the strategy of adding clopidogrel to aspirin for 3 months after TAVI was not found to be superior to aspirin alone. These results must be confirmed in a larger randomized trial.
After transcatheter aortic valve implantation (TAVI), it is a widely accepted practice to prescribe clopidogrel in addition to aspirin for a 3- to 6-month period. Whether the risk/benefit ratio of dual antiplatelet therapy (DAPT) is acceptable in this scenario, however, it has never been prospectively investigated with a randomized design. The aim of the present trial was to assess whether adding clopidogrel to aspirin achieves superior 6-month outcomes than using aspirin alone in patients with severe aortic stenosis who are undergoing TAVI.
Methods
We designed a randomized, open-label, single-center study with blinded assessment of the study end points. The local institutional ethical committee approved the study protocol, and all participating patients provided informed consent. The baseline demographic and clinical characteristics and the procedural, postprocedural, and follow-up data were entered into a dedicated database.
From May 2009 to August 2010, consecutive patients who met the clinical and anatomic criteria for TAVI were randomized to receive a 300-mg loading dose of clopidogrel on the day before TAVI followed by a 3-month maintenance daily dose of 75 mg clopidogrel plus aspirin 100 mg lifelong (DAPT group) or aspirin 100 mg alone (ASA group).
The inclusion and exclusion criteria for TAVI have been previously reported. The TAVI device was the third-generation 18F CoreValve Revalving System (Medtronic, Minneapolis, Minnesota). Full details of the procedure have been previously described. All patients screened for TAVI underwent a comprehensive assessment by a multispecialty team. The surgical risk was estimated using the logistic EuroSCORE and Society of Thoracic Surgeons Predicted Risk of Mortality risk scoring algorithms. The risk contraindications to surgical aortic valve replacement not included in the logistic EuroSCORE and Society of Thoracic Surgeons Predicted Risk of Mortality models were liver cirrhosis, recurrent pulmonary embolism, porcelain aorta, respiratory failure, history of radiotherapy to the mediastinum, and severe connective tissue disease. Additional exclusion criteria relevant to the trial design included previous percutaneous coronary intervention or acute coronary syndrome requiring DAPT, the need for oral anticoagulation therapy, and allergy or intolerance to any of the study drugs.
Follow-up data were obtained by outpatient visits and telephone interviews at 30 days and 6 months. The primary end point was the composite of major adverse cardiac and cerebrovascular events (MACCE). MACCE were defined as the composite of death from any cause, myocardial infarction, major stroke, urgent or emergency conversion to surgery, and life-threatening bleeding.
To ensure consistency and facilitate meaningful interpretation, the clinical end points were defined according to the Valve Academic Research Consortium criteria. Procedural success was defined as device deployment with a reduction in the transaortic peak-to-peak gradient, without any MACCE within 24 hours of prosthesis implantation.
All analyses were performed according to the intention-to-treat principle. A formal sample size estimation was not provided because of the exploratory nature of the study. Continuous variables are presented as the mean ± SD and compared to the use of the paired or unpaired t test, as appropriate, in the case of normal distribution, or the Wilcoxon or Mann-Whitney U test, as appropriate, in the case of non-normal distribution. Categorical variables are presented as counts and percentages and compared using Fisher’s exact or chi-square test, as appropriate. A 2-sided p value of <0.05 was considered of statistical significance. All data were processed using the Statistical Package for Social Sciences, version 17 (SPSS, Chicago, Illinois).
Results
A total of 79 patients (mean age 81 ± 4 years, mean New York Heart Association functional class 2.8 ± 0.6; mean logistic EuroSCORE 21 ± 13%; mean Society of Thoracic Surgeons Score 7 ± 4%) undergoing TAVI were randomly 1:1 assigned to the DAPT (n = 40) or ASA (n = 39) group. The baseline clinical and echocardiographic characteristics were well balanced in the 2 arms of the study ( Table 1 ).
| Variable | Overall (n = 79) | DAPT (n = 40) | Aspirin (n = 39) | p Value |
|---|---|---|---|---|
| Age (years) | 81 ± 4 | 80 ± 6 | 81 ± 4 | 0.68 |
| Women | 43 (54%) | 20 (50%) | 23 (59%) | 0.44 |
| Hypertension | 66 (84%) | 35 (88%) | 31 (80%) | 0.96 |
| Diabetes mellitus | 21 (27%) | 13 (33%) | 8 (21%) | 0.35 |
| Peripheral vascular disease | 7 (9%) | 3 (8%) | 4 (10%) | 0.43 |
| Porcelain aorta | 2 (3%) | 1 (3%) | 1 (3%) | 0.72 |
| Congestive heart failure ⁎ | 32 (41%) | 18 (45%) | 14 (36%) | 0.65 |
| Previous myocardial infarction | 11 (14%) | 7 (18%) | 4 (10%) | 0.31 |
| Previous stroke | 6 (8%) | 2 (5%) | 4 (10%) | 0.28 |
| Previous transient ischemic attack | 4 (5%) | 2 (5%) | 2 (5%) | 0.68 |
| Previous coronary artery bypass grafting | 6 (8%) | 2 (5%) | 4 (10%) | 0.28 |
| Previous cardiac surgery † | 3 (4%) | 2 (5%) | 1 (3%) | 0.55 |
| Previous percutaneous coronary intervention | 21 (27%) | 12 (30%) | 9 (23%) | 0.35 |
| Chronic obstructive pulmonary disease | 17 (22%) | 10 (25%) | 7 (18%) | 0.60 |
| Liver cirrhosis | 1 (1%) | 0 | 1 (3%) | 0.47 |
| Chronic kidney failure | 11 (14%) | 6 (15%) | 5 (13%) | 0.92 |
| Permanent atrial fibrillation | 10 (13%) | 4 (10%) | 6 (15%) | 0.29 |
| Previous aortic valvuloplasty | 42 (53%) | 24 (60%) | 18 (46%) | 0.45 |
| Previous pacemaker | 5 (6%) | 4 (10%) | 1 (3%) | 0.22 |
| New York Heart Association class III and IV | 49 (62%) | 26 (65%) | 23 (59%) | 0.60 |
| Echocardiographic findings | ||||
| Mean gradient (mm Hg) | 53 ± 17 | 52 ± 6 | 57 ± 18 | 0.23 |
| Aortic valve area (cm 2 ) | 0.6 ± 0.2 | 0.6 ± 0.2 | 0.6 ± 0.3 | 0.70 |
| Left ventricular ejection fraction (%) | 52 ± 12 | 51 ± 12 | 54 ± 8 | 0.49 |
| Logistic EuroSCORE (%) | 21 ± 13 | 23 ± 15 | 21 ± 16 | 0.60 |
| Society of Thoracic Surgeons score (%) | 7.3 ± 4 | 8 ± 5 | 7 ± 3 | 0.37 |
⁎ At least 1 in-hospital admission for congestive heart failure in previous 6 months.
† All cardiac intervention, excluding coronary artery bypass grafting.
The procedural outcomes are listed in Table 2 . Of the 79 patients, 77 (98%) were treated using the transfemoral approach. A 26-mm prosthesis was implanted in 35 patients (44%) and a 29-mm prosthesis in 44 (56%). Procedural success was achieved in 94% of patients, with no significant differences between the patients in the DAPT and ASA groups (95% vs 92%, respectively, p = 0.49). In 3 patients (4%), a second prosthesis was deployed using the valve-on-valve technique. In 4 patients (5%), balloon postdilation was performed because of prosthesis underexpansion.
| Variable | Overall (n = 79) | DAPT (n = 40) | Aspirin (n = 39) | p Value |
|---|---|---|---|---|
| Procedural variables | ||||
| Procedure time (minutes) | 45 ± 26 | 44 ± 23 | 47 ± 23 | 0.70 |
| Fluoroscopy time (minutes) | 22 ± 13 | 22 ± 13 | 22 ± 13 | 0.48 |
| Approach | ||||
| Transfemoral | 77 (97%) | 38 (95%) | 39 (100%) | |
| Trans-subclavian | 2 (3%) | 2 (5%) | 0 | |
| Device | ||||
| CoreValve Revalving system 26-mm | 35 (44%) | 23 (56%) | 12 (31%) | |
| CoreValve Revalving system 29-mm | 44 (56%) | 17 (43%) | 27 (69%) | |
| Procedural success | 74 (94%) | 38 (95%) | 36 (92%) | 0.49 |
| Postdilation | 4 (5%) | 1 (3%) | 3 (8%) | 0.30 |
| Valve-on-valve | 3 (4%) | 2 (5%) | 1 (3%) | 0.51 |
| Valve-in-valve | 0 | 0 | 0 | — |
The in-hospital outcomes are listed in Table 3 . The mean time at the cardiac intensive care unit and mean hospital stay was 3 ± 2 and 5 ± 2 days, respectively. In-hospital MACCE occurred cumulatively in 7 patients (9%), with no significant difference between the DAPT and ASA groups (8% vs 10%, p = 0.49). Of the 79 patients, 3 patients (4%) died (3% vs 5% in the DAPT vs ASA group, respectively; p = 0.49). In the DAPT group, 1 patient died 72 hours after TAVI from an intraprocedural major stroke. In the ASA group, 2 patients died 18 and 72 hours after TAVI from disabling bleeding (retroperitoneal hemorrhage and traumatic retropharyngeal bleeding, respectively). A total of 3 patients (4%) experienced procedure-related major ischemic stroke (3% vs 5% in the DAPT and ASA group, respectively, p = 0.49), and 1 patient in each group experienced a transient ischemic attack (4 and 6 hours after TAVI, respectively). Overall, 4 patients (5%, 2 per group) experienced life-threatening bleeding during the hospital stay. In the DAPT group, cardiac tamponade due to cardiac wall perforation by a temporary pacemaker lead was reported, and another life-threatening bleeding event occurred from a peripheral vascular complication. In the ASA group, 2 fatal bleeding episodes developed, as mentioned. Major vascular complications were reported cumulatively in 6 patients (10%; 8% vs 8% in the DAPT and ASA groups, respectively; p = 0.65).
| Variable | Overall (n = 79) | DAPT (n = 40) | Aspirin (n = 39) | p Value |
|---|---|---|---|---|
| All-cause death | 3 (4%) | 1 (3%) | 2 (5%) | 0.49 |
| Cardiovascular death | 1 (1%) | 1 (3%) | 0 | 0.51 |
| Major stroke | 3 (4%) | 1 (3%) | 2 (5%) | 0.49 |
| Minor stroke | 0 | 0 | 0 | — |
| Transient ischemic attack | 2 (3%) | 1 (3%) | 1 (3%) | 0.75 |
| Myocardial infarction | 0 | 0 | 0 | — |
| Conversion to open heart surgery | 0 | 0 | 0 | — |
| Life-threatening bleeding | 4 (5%) | 2 (5%) | 2 (5%) | 0.92 |
| Major bleeding | 3 (4%) | 2 (5%) | 1 (3%) | 0.61 |
| Minor bleeding | 7 (9%) | 3 (8%) | 4 (10%) | 0.55 |
| Major adverse cardiac and cerebrovascular events | 7 (9%) | 3 (8%) | 4 (10%) | 0.49 |
| Cardiac tamponade | 1 (1%) | 1 (3%) | 0 | 0.51 |
| Major vascular complications | 6 (10%) | 3 (8%) | 3 (8%) | 0.65 |
| Minor vascular complications | 5 (6%) | 3 (8%) | 2 (5%) | 0.51 |
| Vascular intervention | ||||
| Percutaneous management | 8 (9%) | 4 (10%) | 4 (10%) | 0.97 |
| Surgical management | 1 (1%) | 1 (3%) | 0 | 0.53 |
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