Asian Cardiovasc Thorac Ann 2000;8:11-14
© 2000 Asia Publishing EXchange Pte Ltd
Low-Dose Warfarin in Patients With Carbomedics Heart Valve Prostheses
Per V Andersen, MD,
Jan Aagaard, MD
Department of Cardiothoracic and Vascular Surgery
Odense University Hospital
Odense, Denmark
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For reprint information contact: Jan Aagaard, MD Tel: 45 6541 1853 Fax: 45 6591 6935 email: jan.aagaard{at}ouh.dk Department of Cardiothoracic and Vascular Surgery, Odense University Hospital, Odense C, DK-5000, Denmark.
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Abstract
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All patients who received a Carbomedics heart valve prosthesis were assessed retrospectively by interview regarding thromboembolic, hemorrhagic, or other valve-related events. In cases of such events, the patient's practitioner or cardiologist was interviewed. Hospital records were reviewed in cases of hospital admission. Included in the study were patients who had isolated replacement of the aortic or mitral valve in whom it was possible to collect all International Normalized Ratio values from discharge through follow-up. There were 148 patients with isolated aortic valve replacement and 56 with isolated mitral valve replacement. Bleeding events were 3 times more frequent than thromboembolic events. Based on our results we will apply an International Normalized Ratio between 2 and 2.5 for patients with a Carbomedics heart valve prosthesis in aortic position and ratios between 2.5 and 3 for those with a mitral valve prosthesis.
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Introduction
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The Carbomedics bileaflet prosthetic heart valve (Sulzer Carbomedics, Inc., Austin, TX, USA) became available in 1986 and approval for use in the USA was issued on September 30, 1993. Since 1986, more than 320,000 Carbomedics valves have been implanted and no structural failures have been reported. Thus, the Carbomedics valve prosthesis is highly reliable. Thromboembolic and hemorrhagic events are the most common complications related to mechanical valves. In these respects, the Carbomedics valve meets or exceeds the safety of other mechanical valves on the market.1–3 The latest generation of mechanical heart valves is not as thrombogenic as previous generations so there is a tendency towards lowering the degree of anticoagulation.4–7 With an International Normalized Ratio (INR) between 3 and 4, there is a risk of serious hemorrhagic events when the INR periodically exceeds 4. In a previous study of the Carbomedics heart valve by Aagaard and colleagues1 where a target INR between 3 and 4 was used, a low frequency of thromboembolic events and a relatively high frequency of hemorrhagic complications were found. A low level of anticoagulation has been advocated for the St. Jude Medical and Medtronic heart valves.4–7 We previously reduced the target INR for patients with Carbomedics valves to 2.5 to 3 and later to 2 to 3. This retrospective study was performed with the aim of relating thromboembolic and hemorrhagic events to INR in patients with a complete INR history from surgery through follow-up.
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Patients and Methods
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Patients who had undergone valve surgery with im-plantation of a Carbomedics heart valve prosthesis at our institution were assessed retrospectively. Aortic valve replacement was carried out in 202 patients and mitral valve replacement in 81. All patients were assessed initially, regardless of whether the operation was performed on an elective or emergency basis, whether it was a first time surgery or a reoperation, and whether concomitant surgery was undertaken. Hemodynamic evaluation was carried out by echocardiography and most patients also had intravascular investigations. The operative technique was standardized and included total cardiopulmonary bypass with mild to moderate hypo-thermia, cold blood cardioplegia, and a single period of aortic crossclamping. Anticoagulant treatment was started on the first postoperative day with subcutaneous heparin in the morning and warfarin tablets in the evening. The heparin dose was 5000 units 3 times daily. Warfarin dosage was based on the daily INR. Injection of heparin was continued until the INR exceeded 2.
After discharge from hospital, all patients were followed up by their local medical practitioner or cardiologist. Patients who were alive at follow-up had a telephone interview and some answered a written questionnaire. The patients were questioned about thromboembolic, hemorrhagic, and other valve-related events. In cases of such events, the practitioner or cardiologist was inter-viewed. Hospital records were reviewed in cases of hospital admission or death. An attempt was made to collect all INR records from primary discharge through follow-up for the whole patient population. Included in the study group were patients with an isolated aortic or isolated mitral valve replacement in whom it was possible to collect a complete set of INR values from discharge through follow-up. The characteristics of the 204 patients who fulfilled these criteria are shown in Table 1
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The INR values were separated into 7 time intervals. On the assumption that the variation of INR between two measurements was linear, a calculation of how many days each patient was at risk of thromboembolic or hemorrhagic events in each interval was made using a computer program designed for this purpose. In patients with a thrombo-embolic or hemorrhagic event, the INR was measured at the time of hospitalization. The INR at the time of the event was related to one of the 7 INR intervals and the events in each interval were counted. By comparing the number of events in each INR interval to the total INR intervals, the risk of thromboembolic or hemorrhagic events in each INR interval could be calculated. This method of calculating incidence rates for specific levels of anticoagulation was proposed by Rosendaal and colleagues.8
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Results
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Collection of a complete set of INR values together with clinical follow-up data was possible in 148 patients with isolated aortic valve replacement and in 56 patients with isolated mitral valve replacement. The relationship between INR and thromboembolic and hemorrhagic events is shown in Tables 2 and 3. There were 5 reports of thromboembolic events. Two patients suffered a major event with residual disability in 1 of them; both had undergone aortic valve replacement. Three patients each suffered a minor event without any lasting disability; all 3 had undergone mitral valve replacement. Both the mitral and aortic valve patients were in sinus rhythm. Linearized rates of thrombolic events are presented in Table 4.
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Table 2. Thromboembolic and Hemorrhagic Events in Relation to International Normalized Ratio in 148 Patients After Aortic Valve Replacement
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Table 3. Thromboembolic and Hemorrhagic Events in Relation to International Normalized Ratio in 56 Patients After Mitral Valve Replacement
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Fourteen patients each suffered one anticoagulant-related bleeding event. The events were all registered as major since they led to hospital admission but they were nonfatal in all cases. Linearized rates of anticoagulant-related bleeding events are given in Table 4
. No patient developed thrombosis of the valve. There were 11 deaths in the study patients; 5 cardiac and 6 noncardiac. None of the cardiac deaths was valve-related.
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Discussion
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All mechanical heart valve prosthesis are thrombogenic and anticoagulant treatment is mandatory to reduce the risk of thromboembolic events. With anticoagulants, there is always a risk of hemorrhagic events when anticoa-gulation becomes too intense. The optimal INR is under debate and different ranges of INR have been proposed. In 1990, the British Society of Haematology recommended an INR between 3 and 4.5 but in 1992, the American College of Chest Physicians recommended a range of 2.5 to 3.5.9–11 These recommendations were based on com-parison of the risk of thromboembolic and hemorrhagic events in different groups with different intended INR levels. INR recommendations are complicated by the fact that up to 40% of the time, the INR is outside the intended range.9,12,13
In a study by Cannegieter and colleagues,9 the risks of thromboembolic and hemorrhagic events were calculated in different groups of achieved levels of INR and an optimal INR between 3 and 4 was found. Only 20% of the implanted valves were tilting disc or bileaflet valves. The rest were older valve types with a 10 times higher risk of thromboembolic or hemorrhagic events compared to the tilting disc or bileaflet types (when the INR was between 2 and 2.9). In a multicenter trail, patients were randomized to two different ranges of intended INR (2 to 3 and 3 to 4.5).14 Ninety-five percent of these low-risk patients had a St. Jude or Omnicarbon valve implanted in the aortic position. The risk of thromboembolic events was the same in both groups but there was a significantly lower risk of hemorrhage in the group with an INR between 2 and 3. Horstkotte and colleagues4 found a low INR caused only a marginal increase in the rate of embolism but a highly significant decrease in the rate of bleeding. Thus, a target INR of 2.5 to 3 was recommended for patients with a St. Jude Medical valve in the aortic position and for low-risk patients with a St. Jude Medical valve in the mitral position. Aspirin in addition to oral anti-coagulants, was shown to diminish the rate of throm-boembolic events in patients with mechanical heart valves but the risk of bleeding was greater.15
In this retrospective study of the Carbomedics heart valve prosthesis, bleeding events were 3 times more frequent than thromboembolic events. Half of the bleeding events were serious and more serious than the thromboembolic events. Thromboembolic events were few even though the time the patients spent at risk with an INR below 2 was 13 times longer than the time with values above 4.7. Thromboembolic events were most frequent within the ideal INR range, which was not unexpected since the majority of patient-years were within this range. The study further showed that the risk of bleeding increased when the INR was above 3. Eight (64%) of the hemorrhagic events occurred when the INR was above 4.7. These 8 events correspond to 42% of the total number of thromboembolic and hemorrhagic events.
In all patients, there is a fluctuation of INR. Therefore, the therapeutic INR level should have an upper and lower safety margin to avoid or diminish serious hemorrhagic and thromboembolic complications. Based on our results, we will continue to aim for an INR between 2 and 3 for the Carbomedics heart valve prosthesis and tend to keep patients with aortic valve prostheses between 2 and 2.5 since the event rate within this INR range was not greater than in the background population. Patients with a mitral valve prostheses should be kept within an INR range of 2.5 to 3. In patients with specific bleeding or throm-bogenicity characteristics, an individualized INR is advocated. When a safe self-management anticoagulation-monitoring system becomes available, the fluctuations of INR should be diminished along with the complication rates. A package consisting of a valve prosthesis and a self-management anticoagulation-monitoring system may be available in the future.
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References
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Abstract
Introduction
