Asian Cardiovasc Thorac Ann 2005;13:341-344
© 2005 Asia Publishing EXchange Ltd
Low-Dose Anticoagulation in Chinese Patients with Mechanical Heart Valves
Xin-Min Zhou, MD,
Wei Zhuang, MD,
Jian-Guo Hu, MD,
Jian-Min Li, MD,
Jie-Feng Yu, BA,
Ling Jiang, BA
Department of Cardiovascular Surgery, The Second Xiang-Ya Hospital of Central South University, Changsha, Hunan, China
For reprint information contact: Xin-Min Zhou, MD Tel: 86 731 222 8128 Fax: 86 731 553 3525 Email: Mark037100{at}163.com, Department of Cardiovascular Surgery, Second Xiang-Ya Hospital, Central South University, Changsha, Hunan 410011, China.
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ABSTRACT
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The aim of this study was to provide guidelines for optimal anticoagulation in Chinese patients after mechanical heart valve replacement. A Carbomedics valve was implanted in 178 patients between July 2000 and July 2003. During follow-up, 22 bleeding events and 1 thromboembolic complication occurred. The linearized rates of bleeding and thromboembolism were 5.83% and 0.26% per patient-year, respectively. The linearized mortality rate was 0.79% per patient-year. The final mean international normalized ratio (INR) was 1.68 ± 0.38, however there was a significant variation between the early and late periods of follow-up. For Chinese patients with mechanical heart valves, bleeding was the major complication rather than thromboembolism. Low-dose anticoagulation (international normalized ratio 1.4–2.0) could markedly decrease bleeding and effectively prevent thromboembolism. As the INR was most unstable in the first postoperative month, re-examination of patients in this period is critical.
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INTRODUCTION
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Due to differences in blood coagulation characteristics, Oriental patients have a greater tendency to bleed during anticoagulation therapy than Western patients. Therefore, the guidelines advised by the American College of Chest Physicians may not be relevant, and it may not be appropriate to extrapolate data from Western patients to the Chinese population. The aim of this study was to provide guidelines for optimal anticoagulation in Chinese patients after mechanical heart valve replacement.
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PATIENTS AND METHODS
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From July 2000 to July 2003, 215 patients underwent valve replacement surgery with a Carbomedics mechanical heart valve (Carbomedics, Inc., Austin, TX, USA) in our unit. Follow-up in the outpatient clinic was completed in 178 patients who were enrolled in this study. There were 86 males and 92 females, aged 16–64 years. Preoperative hepatic function, platelet count, and prothrombin time (PT) were normal (Table 1
). Operations were performed using cardiopulmonary bypass with moderate hypothermia and cold crystalloid cardioplegia. The mean cardiopulmonary bypass and aortic crossclamp times were 96.51 ± 25.36 min and 63.39 ± 21.37 min, respectively. Oral anticoagulation therapy was commenced with an initial dose of 2.5 mg of warfarin on the second postoperative evening, and intravenous administration of heparin was started at 0.5 mg·kg–1 every 4 to 6 hours for patients maintained on mechanical ventilation. A Hemochron Jr. Whole Blood Microcoagulation System (International Technidyne Corp., Edison, NJ, USA) was used to perform the prothrombin time and INR tests. The test reagent was a comparative plasma-based thromboplastin with an international sensitivity index of 1.0. The target INR range was 1.4 to 1.9 for patients with aortic prostheses and 1.5 to 2.0 for those with mitral or double prostheses. All patients were required to present for outpatient assessment after hospital discharge at the following intervals: twice in the first month; monthly in the first 6 months; every two months in the succeeding 6 months, and at least three times in the following year.
All data were collected prospectively. Valve-related complications and deaths were defined in compliance with the guidelines established by the American College of Chest Physicians in 1996.1 All continuous variables were expressed as mean ± standard deviation. Variables were compared using the Student t test, chi-squared test, and repeated measures analysis of variance, using SPSS version 10.0 software (SPSS, Inc., Chicago, IL, USA).
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RESULTS
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Follow-up ranged from 2 to 36 months, with a mean of 2.12 years, and a total of 377.36 patient-years. The mean PT of the 1,218 PT measurements obtained was 22.11 ± 8.38 sec (INR: 1.68 ± 0.38). The mean warfarin dosage employed was 2.34 ± 0.80 mg. Eighteen patients experienced 20 minor bleeding episodes (subcutaneous, nasal, and conjunctival); linearized rate, 5.29% per patient-year (pty). Of these, 3 events occurred in 3 patients who underwent aortic valve replacement (AVR); linearized rate, 0.79% per pty, 13 occurred in 12 patients who had mitral valve replacement (MVR); linearized rate 3.44% per pty, and 4 events were recorded in 3 patients with double-valve replacement (DVR); linearized rate 1.06% per pty. Two patients experienced 2 major bleeding episodes (intracranial bleeding); linearized rate, 0.53% per pty. One occurred in a patient undergoing AVR; linearized rate, 0.26% per pty; the other was in a patient undergoing DVR; linearized rate, 0.26% per pty. The mean INR measured during the 22 bleeding events was 2.30 ± 0.62. The mean INR in 158 patients with no bleeding episodes was 1.68 ± 0.36. There was a statistically significant (p < 0.05) difference between these 2 groups. There were 237 INR measurements in AVR patients who suffered 1 bleeding event within an INR range of 1.4–1.9, and 3 events with an INR > 1.9 (p < 0.05). For MVR patients, 725 INR measurements were analyzed; there were 3 bleeding events within an INR range of 1.5–2.0 and 10 events with an INR > 2.0 (p < 0.05). For DVR patients, 256 INR measurements were assessed; there were 2 bleeding events within an INR range of 1.5–2.0 and 3 events with an INR > 2.0 (p < 0.05; Table 2).
One patient (0.26% per pty) who suffered from infective endocarditis and aortic regurgitation underwent AVR and subsequently experienced thromboembolism in the right femoral artery 70 days later. The INR measured when the event occurred was 1.5 (PT: 19.5 sec). This patient died from intracranial bleeding whilst receiving thrombolytic therapy. There were 2 other late deaths (0.79% per pty). The second patient died from acute pericardial tamponade, and the 3rd died from an unknown cause two months after discharge.
There were significant differences in the INR measured during the 5 postoperative periods, as analyzed by repeated measures analysis of variance (F = 5.072, p < 0.05). The difference in INR between the first postoperative month and the other 4 periods was significant (Table 3). However, the difference in INR among the other 4 postoperative periods was not significant. This indicates that the INR values within the first postoperative month fluctuated the most.
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DISCUSSION
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Patients who undergo mechanical heart valve replacements require life-long anticoagulation therapy.2 Anticoagulant-related bleeding is the major complication in these patients. The morbidity from bleeding is approximately 7% per pty, which is far greater than that of thromboembolism (1–2% per pty).3 Anticoagulation therapy requires a precise marker for monitoring. Prothrombin time and prothrombin time ratio (PTR) remain the primary markers for measuring the effect of anticoagulation in most Chinese hospitals; however, as different thromboplastin reagents reflect the effects of warfarin differently, PTR is not precise enough as a monitoring marker. Our unit began to use the standard thromboplastin reagent (International Sensitivity Index = 1.0) and adopted the INR as the monitoring marker in May 2000.
It is generally considered that the intensity of anticoagulation should be controlled within an ideal range to minimize hemorrhagic complications.4 In 2001, the American College of Chest Physicians advocated the implementation of low-intensity anticoagulation: INR 2.0–3.0 after AVR; 2.5–3.5 after MVR and DVR; and 2.5–3.5 for patients with a large left atrium or atrial fibrillation.5 Subsequently, Mori and colleagues6 found a significant increase in morbidity from bleeding in Japanese patients with an INR above 2.5. Uetsuka and colleagues7 reported their experiences in 1,157 Japanese patients with mechanical heart valve prostheses and discovered that the incidence of thromboembolism did not increase even when the INR was reduced to 1.5. Some domestic institutions have suggested a target INR of 2.0–2.5 for Chinese patients.8 Chenhsu and colleagues9 in Taipei noted a high incidence of bleeding and 3 fatal hemorrhages in 61 patients with a mean INR of 1.9. However, there are still no standard guidelines for anticoagulation in Chinese patients.
The target INR range set in this study was based on past clinical experience. The incidence of bleeding within the target INR range (1.4–1.9 for AVR, 1.5–2.0 for MVR and DVR) was much less than when the target range was exceeded. The final INR in patients without bleeding was 1.32–2.04, which suggests that an INR of 1.4–2.0 is optimal for Chinese patients, and this coincides with previous observations.7–9 Also in this study, the linearized rate of bleeding was 5.83% per pty, but only 0.26% per pty for thromboembolism. Therefore, it is more important to focus on preventing the occurrence of bleeding in Chinese patients rather than the incidence of thromboembolism.
In China, the monitoring of INR and subsequent warfarin dosage adjustment after hospital discharge is a significant challenge due to geographical restrictions, economic conditions, and lack of medical knowledge. Whilst almost all the patients in this group complied with the study protocol, most Chinese patients with a mechanical heart valve prosthesis cannot return to hospital for regular follow-up. Thus, it is necessary to set an optimal regime which could make the anticoagulation more precise, and also decrease the cost and frequency of follow-up. The fluctuation of INR in the first study month was greater than in other periods, demonstrating that the INR was most unstable in the immediate postoperative period. During this time, many factors such as hepatic function, platelet levels, and concomitant medication can influence the effect of anticoagulation. Therefore, follow-up in the first month after discharge from hospital is the most critical. We suggest that patients be seen at least twice in this defining month.
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ABSTRACT
INTRODUCTION
