Interact CardioVasc Thorac Surg 2009;8:417-420. doi:10.1510/icvts.2008.196675
© 2009 European Association of Cardio-Thoracic Surgery
Institutional report - Valves |
Coagulant activity during one year after bioprosthetic aortic valve replacement
Hiroshi Imagawa*,
Masahiro Ryugo,
Fumiaki Shikata,
Tatsuhiro Nakata,
Mitsugi Nagashima and
Kannji Kawachi
Department of Organ Regenerative Surgery, Ehime University, School of Medicine, To-on, Ehime, 791-0295, Japan
Received 16 October 2008;
received in revised form 14 December 2008;
accepted 16 December 2008
*Corresponding author. Tel.: +81-89-960-5331, fax: +81-89-960-5335.
E-mail address: imagawa{at}m.ehime-u.ac.jp (H. Imagawa).
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Abstract
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Anticoagulant therapy with warfarin is recommended in the early postoperative period after bioprosthetic aortic valve replacement (bAVR). However, some studies have addressed questions about its necessity. We evaluated postoperative coagulant activity data including prothrombin time-international normalized ratio (PT-INR) and thrombin–antithrombin III complex (TAT), measured every month in 21 bAVR patients during the 1st postoperative year. The results were divided into four time intervals after the operation: 1–3 months (P-1), 4–6 (P-2), 7–9 (P-3), and 10–12 (P-4). Warfarin, which was administrated in the first six months, in combination with aspirin, 100 mg, was started targeting PT-INR of 1.75–2.25. The values of TAT in P-1, P-2, P-3 and P-4 were 1.35±1.07 (ng/ml), 0.82±0.55, 0.81±0.78, and 0.72±0.62, respectively, showing significantly high values in P-1. Furthermore, the TAT values of P-1 and P-2 within the range of PT-INR from 1.75 to 2.25 were 1.15±0.71 (ng/ml) and 0.79±0.52; demonstrating statistical difference between them. The coagulant activity assessments suggest that warfarin administration during the first three months is necessary for bAVR patients to keep the TAT within the normal range.
Key Words: Aortic valve replacement; Heart valve; Bioprosthesis; Blood; Anticoagulation
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1. Introduction
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Anticoagulant therapy is recommended in patients with bioprosthetic heart valves during the early postoperative period [1, 2]. However, some studies have addressed that aspirin (acetylsalicylic acid) is as effective as warfarin in protecting patients with biologic aortic valves from thromboembolic episodes in the early postoperative period [3, 4]. To evaluate the efficacy of anticoagulant therapy with warfarin after bioprosthetic aortic valve replacement [5], coagulant activity was assessed through serial measurements of blood coagulation-related factors including thrombin–antithrombin III complex (TAT).
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2. Patients and methods
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2.1. Patients
Twenty-one patients who underwent bioprosthetic aortic valve replacement between April 2004 and June 2007 were enrolled in this study. The subjects comprised 12 men and 9 women whose mean age at the time of the surgery was 73.5±9.1 (65–84) years. Preoperative demographic characteristics as well as laboratory data including coagulant parameters of the patients are summarized in Tables 1 and 2; those were within the normal range. Preoperative diagnoses consisted of aortic stenosis in 17 patients, aortic regurgitation in two, and aortic steno-regurgitation in two. Patients with atrial fibrillation, infective endocarditis, aneurysmal disease, impaired left ventricular (LV) function with LV ejection fraction <40% by echocardiography, deep vein thrombosis, or other diseases affecting the blood coagulation system were excluded from the study in accordance with exclusion criteria.
2.2. Surgery
The patients underwent operation under cardiopulmonary bypass with crossclamp in moderate hypothermia. Cardiac arrest was achieved with cold blood cardioplegic solution, either antegrade or retrograde, administered at 20-min intervals. The aortic bioprosthesis was implanted through a transaortic approach, using multiple interrupted 2-0 Ethibond (Ethicon, Somerville, NJ) sutures, reinforced with Teflon pledgets. Thirteen patients received Carpentier– Edwards Pericardial valves and eight patients Medtronic Mosaic valves.
2.3. Antithrombotic therapy
Heparin-sodium was administered routinely starting from the second postoperative day in the absence of significant blood loss from drainage tubes. Oral antithrombotic prophylaxis with warfarin was started on the second postoperative day targeting INR of 1.75–2.25, which was resumed between the postoperative 7th and 9th month. Aspirin was also administered from the second postoperative day.
2.4. Coagulant-related factors
Coagulant-related factors were measured every month after operation. For the purpose of analysis the measurement results were divided into four time intervals after operation: 1–3 months (period #1: P-1), 4–6 months (period #2: P-2), 7–9 months (period #3: P-3), and 10–12 months (period #4: P-4). Blood samples were taken from the antecubital vein with the patient at rest in the morning at our outpatient clinic. Activated partial thromboplastin time (APTT), prothrombin time-international normalized ratio (PT-INR), fibrinogen, and C-reactive protein (CRP) were measured using conventional methods. Plasma concentration of thrombin–antithrombin III complex (TAT) was assessed by the time-resolved fluorometry technique using Europium particle (LPIA-A700, Mitsubishi Kagaku Iantron, Inc, Yachiyo, Japan) [6].
2.5. Statistical analysis
Results are expressed as mean±S.D. The Shapiro–Wilk test was performed for normal distribution, Levene test for homogeneity of variances, one-way ANOVA and Welch test in normally distributed data, Kruskal–Wallis test as non-parametric test, Tukey test or Games–Howell test for multiple comparison among four groups, and an unpaired t-test between P-1 and P-2. All analyses were computed using SPSS statistical software, version 11.0.1J (SPSS, Inc, Chicago, IL). A P<0.05 was considered statistically significant.
The clinical results and complications were analyzed according to Edmunds' guidelines for valve thrombosis, embolism, and bleeding events [7].
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3. Results
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All data concerning postoperative PT, PT-INR, APTT, fibrinogen, TAT, and CRP are presented in Table 3. The results of PT-INR were highly increased in P-1 (2.01±0.36) and P-2 (2.00±0.35) due to warfarin therapy, which showed slight decrease in P-3 (1.36±0.31) and turned to normal range in P-4 (1.02±0.17). The mean values of TAT in P-1, P-2, P-3, and P-4 were 1.35±1.07 ng/ml, 0.84±0.55 ng/ml, 0.81±0.78 ng/ml, and 0.72±0.62 ng/ml. The TAT was significantly high in P-1 as compared with the other three groups. The fibrinogen and CRP in P-1 also demonstrated statistically high values as compared with P-2, P-3, or P-4.
The relations between PT-INR and TAT of P-1 and P-2 are presented in Fig. 1. In PT-INR measurements nine results (14%) were under the target range, 44 within, and 10 above in P-1, and 10 under, 43 within, and 10 above in P-2, respectively. The TAT values within the range of PT-INR from 1.75 to 2.25 (the shaded portion in Fig. 1) were 1.15±0.71 ng/ml in P-1 and 0.79±0.53 ng/ml in P-2; there was a statistical difference between them. In P-1 five results (7.9%) demonstrated increase of TAT with PT-INR of 1.47, 1.50, 1.71, 1.73 and 2.03. There were no patients in P-2 who had increased TAT values beyond 2.7 ng/ml, though 10 data showed PT-INR <1.75.
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Fig. 1. Five results demonstrated increase of TAT with PT-INR of 1.47, 1.50, 1.71, 1.73 and 2.03 in P-1. There were no patients in P-2 who had increased TAT values beyond 2.7 ngml, though 10 data showed PT-INR <1.75.
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During the follow-up period, no patient developed valve-related morbidities including such as thrombosis, bleeding events, paravalvular leak, endocarditis, non-structural dysfunction, sudden death, or thromboembolism.
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4. Discussion
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Antithrombotic therapy has been recommended even for low-risk bAVR patients for the period until the exposed components of the bioprosthesis (sewing ring, suture knots, and valve leaflets) are fully endothelialized. Many guidelines referred to warfarin therapy as a preferred option not only for patients receiving mechanical prosthesis but also for low-risk bAVR patients especially for the first three postoperative months. Specifically, the American College of Cardiology/American Heart Association guidelines recommended warfarin with PT-INR of 2.0–3.0 during the first three months after biologic AVR (class I) in the 1998 edition [8]. In the 2006 edition, aspirin of 75–100 mg per day is indicated in biologic valve replacement patients with no risk factors as class I (evidence C), and warfarin therapy of PT-INR 2.5–3.5 is suggested as class IIa (evidence C) [1]. The European Society of Cardiology guidelines recommended warfarin with PT-INR of 2.5 in low-risk patients with bioprosthesis for the first three months [2]. In the meantime, Babin-Ebel et al. [9] and Gherli et al. [10] argued that there were no differences in morbidity events in patients who received either warfarin or aspirin in the first three months after bioprosthetic AVR. The disputes have been debated on the basis of clinical data including those on valve thrombosis, embolism, and bleeding events. Details of the coagulation activity in early post-bAVR period have not been elucidated.
In the present study we assessed the coagulant activity in low-risk bAVR patients by the serial measurement of blood coagulation-related factors including TAT and evaluated efficacy of anticoagulant therapy with warfarin in post-bAVR patients. Thrombin–antithrombin III complex (TAT) is an indicator of hypercoagulation, reflecting thrombin formation due to activation of the coagulant mechanism [11]. An increase of TAT indicates thrombin generation and thereby an activation of the coagulation cascade. In our measurements of PT-INR, some results were beyond the target limit of 1.75–2.25; those data would naturally cause the elevation of TAT. Accordingly we compared the TAT values within the range of PT-INR 1.75–2.25.
It was shown by our data that in P-1 about 8% of the TAT measurement results were over the normal range, suggesting activation of the coagulation system with PT-INR being 1.47–2.03. To completely suppress activation of TAT during the first three months, more strict control of PT-INR would be required in some patients. Thromboembolism after prosthetic valve replacement has been reported to occur in the early postoperative period. Heras et al. reported that incidence of thromboembolic episodes was 41% per year during the first 10 postoperative days in patients with bioprosthetic aortic valve replacement when anticoagulation was either not administered or subtherapeutic; the incidence was, however, decreased to 3.6% and 1.9% per year, 11–90 days and >90 days after operation, respectively [12]. Our data seem to support the results of their study. Fibrinogen and CRP showed statistically significant rise in P-1 as compared with the other three periods. Postoperative inflammatory response may cause some concerns about acceleration of TAT in the first three postoperative months. From a recent report reviewing coagulant factor measurements in patients undergoing major hip or knee surgery, TAT levels of >5.5 ng/ml showed statistically high incidence of calf and proximal deep vein thrombosis [13]. A detailed assessment of coagulant factors including TAT in a large patient group should be performed in order to identify valid indices for the control of anticoagulation. Our measurements showed that TAT in P-2 was not increased even in patients with PT-INR <1.75, suggesting that warfarin therapy with PT-INR of 1.5–1.75 may be therapeutic value for post-bAVR patients who do not have thromboembolic risk factors in this period.
PT-INR is a useful tool for evaluating activity of extrinsic pathway of the coagulation system. High levels of PT-INR do not always signify suppression of the coagulation cascade. Brummel et al. reported that patients having similar PT-INR showed differences in their tissue factor coagulation response and suggested that control of anticoagulation in patients to a set PT-INR therapeutic range may be less secure than anticipated [14]. The decision to anticoagulate a patient is made on the basis of several factors relating to patient's condition and affecting his thromboembolic risk. It is beyond doubt that anticoagulation in patients with thromboembolic risk factors is beneficial. The question is effectiveness of anticoagulant agents after bAVR in patients without these thromboembolic risk factors. The results of the present study suggest that it is recommended to administer warfarin during the first three months after biological AVR in patients without thromboembolic risk factors.
4.1. Study limitations
One of the reasons for the small number of patients in our study is difficulties/complexity in having informed consents from patients. There is also a natural bias in the clinical assessment of the patient group. Despite these limitations, the present study about the coagulant activity assessments suggests that warfarin administration during the first three months is necessary for bAVR patients to keep the TAT within the normal range.
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5. Conclusion
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Coagulant activities were assessed during the first year after bAVR with anticoagulant therapy of 1.75–2.25 PT-INR in combination with aspirin 100 mg. The coagulant activity may be accelerated in some patients on warfarin with PT-INR control of 1.75–2.25 during the first three months after bAVR. In postoperative 4–6 months TAT was not accelerated even in patients with PT-INR <1.75. Our study of the coagulant activity assessment concluded that warfarin administration during the first three months is necessary for bAVR patients to keep the TAT within the normal range. Thrombin–antithrombin III (TAT) monitoring is useful for identifying accelerations of coagulant activity in post-bAVR patients.
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Abstract
1. Introduction