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Thromboembolic events remain clinically resolved after TAVR.
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DOAC use to reduce thrombosis associated with TAVR remains controversial.
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Coagulation parameters were significantly increased after TAVR.
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Hypercoagulation status were significantly lower in patients with DOAC.
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DOAC could reduce transient hypercoagulation following TAVR.
Thromboembolic events remain clinically unresolved after transcatheter aortic valve implantation (TAVI). The use of direct oral anticoagulant (DOAC) to reduce thrombosis associated with TAVI remains controversial. This study aimed at investigating the periprocedural change in blood coagulation and thrombolysis parameters in 199 patients undergoing transfemoral TAVI. Prothrombin activation fragment 1 + 2 (F1 + 2), thrombin–antithrombin complex (TAT), soluble fibrin monomer complex (SFMC), and fibrin/fibrinogen degradation product (FDP) levels were measured before and 1 hour after TAVI and 1, 2, and 7 days postoperatively. Of the 199 patients, 49 were treated with DOAC (apixaban in 32, edoxaban in 10, and rivaroxaban in 7). The F1 + 2 and TAT levels immediately increased 1 hour after TAVI and then gradually decreased in both groups. The SFMC level also significantly increased with a peak on day 1. The FDP level gradually increased, peaking on day 2. The values of F1 + 2, TAT, SFMC, and FDP in patients who used DOAC were significantly lower than those who did not use DOAC at 1 hour after TAVI in F1 + 2 (600 [452 to 765] vs 1055 [812 to 1340] pmol/L; p < 0.001), TAT (21.4 [16.2 to 37.0] vs 38.7 [26.4 to 58.7] μg/mL; p < 0.001) and on day 1 in SFMC (18.2 [9.4 to 57.9] vs 113.4 [70.9 to 157.3] μg/mL; p < 0.001) and day 2 in FDP (6.0 [4.7 to 10.0] vs 12.6 [8.2 to 17.4] μg/mL; p < 0.001). Ischemic stroke within 30 days after TAVI occurred in 3 patients (1.5%), who were not treated with DOAC.
Coagulation cascade activation was observed after TAVI. DOAC could reduce transient hypercoagulation following TAVI.
Thromboembolic events remain clinically unresolved after transcatheter aortic valve implantation (TAVI). , The mechanism of thromboembolic events after TAVI is multifactorial. The activation of the coagulation pathway induced by valve implantation may stimulate thrombus formation. , However, blood coagulation change following TAVI was not fully investigated. The incidence of preexisting atrial fibrillation in patients with severe aortic valve stenosis is as high as 20% to 30%. Although the use of direct oral anticoagulant (DOAC) for stroke prevention has increased, DOAC use to reduce thrombosis associated with TAVI remains controversial. This study aimed to investigate periprocedural change in blood coagulation and thrombolysis parameters in patients undergoing TAVR who used or did not use DOAC.
Methods
The study population consisted of 245 consecutive patients who underwent complete transfemoral TAVI for symptomatic severe aortic valve stenosis at Teikyo University Hospital from January 2017 to March 2019. Baseline demographics, procedural data, and clinical outcomes were prospectively collected. The exclusion criteria based on the TAVI procedure were as follows: (1) TAVI with a clinical trial valve (n = 6), (2) planned percutaneous coronary intervention, coronary artery bypass grafting, or thoracic endovascular aortic repair during TAVI (n = 2), (3) second valve implantation because of valve dislodgement (n = 2), and (4) transcatheter valve-in-valve implantation for degenerated aortic bioprosthetic valves (n = 2). Patients using vitamin K antagonist (n = 21) were also excluded from this study. Thus, 212 patients met the inclusion criteria. This study was approved by the institutional review board of the Teikyo University School of Medicine (Teikyo-14-045, 14-045-2). All patients provided informed consent before TAVI.
Severe aortic valve stenosis was diagnosed based on the results of physical examination and transthoracic echocardiography using Philips IE33 or EPIC E7. For aortic valve stenosis quantification, we measured the transaortic peak velocity, maximum and mean transaortic pressure gradient, and aortic valve area using the continuity equation based on the guidelines of the American Society of Echocardiography. Severe aortic valve stenosis was defined as transaortic peak velocity of ≥4 m/s and/or mean aortic valve gradient of ≥40 mm Hg. Additionally, the left ventricular stroke volume index was evaluated using the following formula: left ventricular outflow tract velocity time integral × left ventricular outflow tract area/body surface area. Low flow was defined as stroke volume index of <35 mL/m 2 . Patients with low-flow severe aortic valve stenosis (aortic valve area of ≤1.0 cm 2 ) were included in this study.
All study patients were treated with transfemoral TAVI using balloon-expandable valves as the SAPIEN 3 valve (Edwards Lifesciences, Irvine, CA) or self-expanding valves as the Evolut R or Evolut Pro (Medtronic, Minneapolis, MN). Transfemoral TAVI was performed with complete percutaneous access with vascular closure devices. The use of each valve device (balloon-expandable or self-expanding valve) was based on the decision of the operator depending on anatomical and clinical suitability of the study patient. Post-TAVI balloon dilatation was performed in patients with residual moderate or severe paravalvular regurgitation. The severity of paravalvular regurgitation was determined using either transthoracic echocardiography or transesophageal echocardiography immediately after TAVI.
Dual antiplatelet therapy with aspirin 100 mg/day and clopidogrel 75 mg/day was administered in the entire periprocedural phase until February 2018. From March 2018, patients received single antiplatelet therapy (aspirin or clopidogrel) before TAVI and dual antiplatelet therapy in the morning of the next day after TAVI. All patients received unfractioned heparin to maintain a minimum active clotting time of >250 seconds after the insertion of the femoral sheath. Protamine (1 mg for each 1000 U of heparin) was routinely administered at the time of puncture site closure.
Some patients were on DOACs prior to TAVI for clinical indications, and the DOAC was discontinued on the day of the procedure, but resumed the day after the procedure. DOAC and single antiplatelet therapy combination was generally used after TAVI in patients needing anticoagulant therapy.
Prothrombin activation fragment 1 + 2 (F1 + 2) as a molecular marker of thrombin generation, thrombin–antithrombin complex (TAT) as a marker of thrombin neutralization, soluble fibrin monomer complex (SFMC) as a marker of thrombophilia, and fibrin/fibrinogen degradation product (FDP) as a marker of fibrinolysis were assessed before and 1 hour (POD 0) after TAVI and 1 (POD 1) and 2 (POD 2) days postoperatively. If possible, coagulation parameters were also measured 7 days (POD 7) after TAVI. F1 + 2 was assessed using enzyme-linked immunosorbent assay. TAT level was measured using chemiluminescent enzyme immunoassay, SFMC using latex immunoturbidimetric assay, and FDP using latex agglutination method. The reference value for each molecular marker was determined by the manufacturer: F1 + 2, 69 to 229 pmol/L; TAT, ≤2.9 ng/mL; SFMC, ≤6.1 μg/mL; and FDP, ≤4.9 μg/mL.
We investigated the clinical endpoints as 30-day mortality, ischemic stroke, myocardial infarction, and vascular and bleeding complications according to VARC-2 criteria.
Categorical data were expressed as frequency counts and percentages. Continuous data were expressed as median and interquartile range. Categorical data were compared using the chi-squared or Fisher’s exact test. Continuous data were compared between groups using the Mann–Whitney U test or Wilcoxon signed-rank test, as appropriate. A p value of <0.05 was considered statistically significant. All analyses were performed using SPSS Statistics software (version 25.0, SPSS, Inc., Chicago, Illinois).
Results
Because of the clinical course after TAVI, 13 patients were excluded as follows: (1) patients who did not receive antiplatelet drug (n = 5), (2) patients who newly started oral anticoagulant (OAC) until 24 hours postoperatively (n = 4), and (3) lack of blood coagulation parameters until POD 2 (n = 4). Therefore, 199 patients were included in this study. Baseline characteristics of study patients are shown in Table 1 . Of all study patients, 49 were treated with DOAC because of a preexisting atrial fibrillation. Regarding DOAC therapy, 32 patients (65.3%) received apixaban (2.5 mg twice daily), 10 (20.4%) received edoxaban (30 mg daily), and 7 (14.3%) received rivaroxaban (10 mg daily). Echo parameters (ejection fraction, transaortic peak velocity, and aortic valve mean gradient) were significantly different in patients who used and did not use DOAC.
| Variable | DOAC | p value | |
|---|---|---|---|
| NO (n = 150) | YES (n = 49) | ||
| Age (years) | 84 (82-88) | 84 (81-89) | 0.893 |
| Men | 38 (25%) | 15 (31%) | 0.468 |
| Hypertension | 129 (86%) | 44 (90%) | 0.494 |
| Dyslipidemia * | 103 (69%) | 33 (67%) | 0.863 |
| Diabetes Mellites | 57 (38%) | 17 (35%) | 0.678 |
| Chronic kidney disease | 73 (49%) | 26 (53%) | 0.593 |
| Smoker | 25 (17%) | 8 (16%) | 0.956 |
| Active cancer | 8 (5%) | 3 (6%) | 0.537 |
| Echo parameters | |||
| Ejection Fraction, % | 61.0 (55.0-64.0) | 57.0 (46.0-62.0) | 0.002 |
| Baseline trans-aortic peak velocity, m/sec | 451.5 (408.0-513.0) | 405.0 (349.5-448.0) | < 0.001 |
| Baseline aortic valve mean gradient, mmHg | 46.0 (36.0-58.3) | 39.0 (24.3-48.3) | < 0.001 |
| Baseline aortic valve area, cm 2 | 0.69 (0.51-0.81) | 0.65 (0.55-0.82) | 0.834 |
| Procedural characteristics | |||
| Post-dilatation | 4 (3%) | 1 (2%) | 0.641 |
| Balloon expandable valve | 91 (61%) | 33 (67%) | 0.402 |
| Prosthesis regurgitation (grade ≥2) | 7 (5%) | 2 (4%) | 0.611 |
⁎ Dyslipidemia was defined as abnormal level of lipids in the blood.
Coagulation and fibrinolysis parameters could be measured until POD 2 after TAVI in 199 patients, but until POD 7 in 180 (90.5%) patients. Changes over time of coagulation and fibrinolysis status in patients who used and did not use DOAC following TAVI are shown in Figure 1 and Table 2 . The F1 + 2 and TAT levels immediately increased, and the median F1 + 2 and TAT levels after TAVI were extremely high and then gradually decreased in both groups. The SFMC level also significantly increased with a peak on POD 1 and gradually decreased. The FDP level gradually increased after TAVI, peaking on POD 2 and decreasing on POD 7. The F1 + 2, TAT, SFMC, and FDP levels on POD 7 were statistically significantly higher compared with those at baseline ( Table 2 ). Moreover, in patients who did not use DOAC, the values of these parameters were significantly greater than those with DOAC at all measurement points (POD 0 to 7; Figure 1 ). The difference in the coagulation status between 3 DOACs (F1 + 2, TAT, and SFMC) is shown in Table 3 . The maximum values of the 3 coagulation parameters after TAVI were the most suppressed with apixaban compared with the 2 other DOACs.
