Vascular Development and Vessel Remodelling. Vittorio Pengo, Fabio Barbero,Alessandra Biasiolo, Cinzia Pegoraro, Franco Noventa 1,S.

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1 Schattauer GmbH, Stuttgart Vascular Development and Vessel Remodelling Prevention of thromboembolism in patients with mitral stenosis and associated atrial fibrillation: effectiveness of low intensity (INR target 2) oral anticoagulant treatment Vittorio Pengo, Fabio Barbero,Alessandra Biasiolo, Cinzia Pegoraro, Franco Noventa 1,S.Iliceto Clinical Cardiology,Thrombosis Centre and 1 5th Clinical Medicine, University of Padova, Padova, Italy Summary Mitral stenosis (MS) in association with atrial fibrillation (AF) is a clinical condition at high risk for systemic thromboembolism. Although oral anticoagulants greatly reduce the incidence of thromboembolism in these patients, the optimal intensity of treatment has never been tested in specific clinical trials, and current recommendations are derived from studies of nonrheumatic AF. In this study we tested the effectiveness of two different intensities. The study design was carried out as an open randomized prospective study in an anticoagulation clinic. We randomized 103 patients with MS and AF to a low (target INR = 2) or moderate (target INR = 3) anticoagulation regimen. The primary end points were systemic thromboembolism, major bleeding and vascular death. During a mean follow-up of 4.5 years, 1 systemic embolism occurred in the low intensity group (0.41 per 100 pt/yrs, Keywords Anticoagulants, mitral valve, atrial fibrillation CI ), and 1 minor stroke occurred in the moderate intensity group (0.40 per 100 pt/yrs, CI ; p = ns). Major bleeding occurred in 8 patients, with 3 in the low intensity (1.25 per 100 pt/yrs) and 5 in the moderate intensity group (2.0 per 100 pt/yrs, Incidence Rate Ratio 0.6, CI ; p = ns). Total events (systemic embolism, major bleeding and vascular death) occurred in 7 low intensity patients and 8 moderate intensity patients. As expected, minor bleeding was more frequent in the moderate intensity group of patients, who actually had more intense treatment and required closer monitoring of oral anticoagulant treatment. These data suggest that low intensity anticoagulation, as performed in an anticoagulation clinic, is effective and safe in high risk patients with MS and AF. Thromb Haemost 2003; 89: Introduction Mitral stenosis (MS) is a clinical condition frequently associated with systemic thromboembolism (TE) (1), the rate of which in untreated patients varies from 9-14% (2) to 25% (3). Impaired blood influx into the left ventricle through a restricted mitral valve orifice and atrial fibrillation (AF) are the main pathogenic causes of thrombus formation in the left atrium (4). Although several trials suggested the utility of oral anticoagulants in preventing systemic thromboembolism in rheumatic valve disease, none has been adequately controlled (3, 5, 6). Nevertheless, oral anticoagulation has become the treatment of choice in the absence of further prospective randomized clinical trials. Initially, the recommended intensity of treatment was aimed at maintaining the International Normalized Ratio (INR) at INR (7) or even higher (8); more recently, the British Society of Hematology (9) and the American College of Chest Physicians (10) recommended a lower intensity treatment aimed Correspondence to: Vittorio Pengo Clinica Cardiologica, Centro Trombosi Università di Padova, Ospedale Ex Busonera via Gattamelata 64 I Padova, Italy Tel.: , Fax vittorio.pengo@unipd.it Received September 11, 2002 Accepted after revision January 27, 2003

2 Anticoagulants in mitral stenosis 761 at maintaining the INR between 2.0 and 3.0. However, these recommendations were not derived from specific studies but rather from extrapolation of the results of large randomized studies in patients with nonvalvular atrial fibrillation. These studies have reported three different therapeutic INR ranges to be effective for stroke prevention: (11), (12), and (13). Moreover, in a group of patients who underwent tissue valve replacement, a range of 2.0 to 2.25 was also effective in preventing thromboembolism (14). Given that a broad range of INR values appears effective in related clinical settings and that the intensity of treatment in patients with MS has never been properly assessed, we prospectively evaluated the effectiveness and safety of two regimens of oral anticoagulant treatment, i.e. low-intensity (target INR = 2) and moderate intensity (target INR = 3). Materials and methods This randomized open-labelled study was initiated in 1991 after approval by local health institutions. Informed consent was obtained from each patient. Patients Patients considered for this study were diagnosed by means of doppler echocardiography or angiography (15, 16) and mitral valve area was calculated according to the pressure half-time method (17). Mitral stenosis was considered mild, moderate and severe when mitral valve area was 2 cm 2, <2 cm 2 and >1 cm 2, and 1 cm 2, respectively. Mitral regurgitation was graded with the use of the color Doppler-jet area method (18). Exclusion criteria comprised the following: a) inability to obtain informed consent; b) poor compliance to oral anticoagulant treatment; c) previous major bleeding (19); d) heart failure (New York Heart Association class III-IV); h) antiplatelet therapy if not suspended 1 week before; i) life expectancy of less than 12 months; j) planned cardioversion. Randomization and follow-up Enrolled patients were randomly allocated into 2 groups: Group L received oral anticoagulants (warfarin or acenocoumalol) to maintain the INR at a target value of 2.0 (low intensity treatment), and Group M to maintain the INR at a target value of 3.0 (moderate intensity treatment). Patients were randomized in blocks of 10 using a computer program. Surveillance of oral anticoagulant treatment was performed following the guidelines provided by the Italian Federation of Anticoagulation Clinics (20). Patients were considered to have dropped out of the study if therapy was interrupted for more than 1 month, if an exclusion criterion or an indication for standard oral anticoagulant treatment arose during the study, or if the patient was transferred to another center. Patients lost to follow-up were censored at the time of their last study visit. Events Primary outcome events were ischemic stroke, defined as sudden neurological deficit lasting >24 h in the absence of cerebral hemorrhage at neuroimaging; peripheral or visceral embolism, defined as the occurrence of acute ischemia documented by angiography or surgery in the absence of atherosclerotic occlusive disease; cerebral hemorrhage, documented at neuroimaging; major bleeding as previously defined (19); and vascular death, defined as a death in which a nonvascular cause was not clearly documented. The INR was defined as temporally related to an outcome event if it was measured at the time of the event or during the preceding 8 days. Secondary outcome events were acute myocardial infarction characterized by typical chest pain, electrocardiogram changes and significant increase in cardiac enzymes, and total mortality. Primary and secondary end-points were evaluated by a neurologist and a cardiologist unaware of the treatment group. The method of Rosendaal et al. (21) was used to evaluate the achieved intensity of anticoagulation in the two groups. Statistical analysis Patients with MS and AF on oral anticoagulants have a rate of thromboembolism as low as 0.7%/yr (22); considering the low number of patients with this clinical condition, a classical equivalence study exploring the efficacy and safety of two intensity treatments would require enrolment of a large number of subjects. To explore the efficacy of two different intensities of oral anticoagulant treatment we randomly assigned these patients to two treatment groups (low or medium intensity anticoagulation) for a cumulative follow-up period of at least 200 pt/yrs per group with the objective of describing the rate of thromboembolism in comparison to data obtained in randomized trials on nonrheumatic atrial fibrillation. The incidence of thromboembolic and hemorrhagic events was considered stable with time and therefore event rates were expressed as incidence rate and relative (Poisson) confidence intervals; event rates were then compared by means of incidence rate ratios (23). Mean INR values and mean weekly warfarin dosage in the two groups were compared by Student s t test for continuous variables. Results From March 1991 to March 1997, 135 patients referred to Padova s Thrombosis Centre with MS were assessed for eligibility. Twenty-eight were excluded for the following reasons: unavailability for regular follow-up (n = 13); previous major bleeding while on oral anticoagulant treatment (n = 5); congestive heart failure (n = 5); programmed DC electric cardioversion (n = 4); life expectancy of less than 12 months (n = 1). The remaining 107 patients were randomly assigned to low intensity (group L, target INR = 2) anticoagulation treatment (n = 52)

3 762 Pengo, et al. Table 1: Characteristics of patients with mitral stenosis at randomization Principal outcome events No difference in primary outcome events was evident, as 2 episodes of systemic thromboembolism were recorded, consisting of 1 peripheral embolism in group L (0.4 per 100 pt/yrs, CI ) and 1 minor stroke in group M (0.4 per 100 pt/yrs, CI ; p = ns); the related INR were 2.4 and 2.1, respectively. Figure 1 shows incidence rates and corresponding confidence intervals in the two arms in comparison with results of 5 randomised clinical trials on nonrheumatic atrial fibrillation. Major bleeding occurred in 8 patients, 3 in group L (1.25 per 100 pt/yrs, CI ) and 5 in group M (2.0 per 100 pt/yrs, CI ). The incidence rate ratio of major bleeding was 0.6 (CI , p = ns). There were 3 cases of intracranial bleeding, all in group M (two of which were fatal); the related INRs at presentation were 2.6, 3.9 and 3.5. Vascular death occurred in 5 patients, 3 in group L (1.25 per 100 pt/yrs, CI ) and 2 in group M (0.8 per 100 pt/yrs, CI ; p = ns). Total outcome events occurred in 7 patients in group L and 8 in group M. Other events One patient in group L suffered an acute myocardial infarction and subsequently underwent mitral valve substitution and aortocoronary by-pass surgery. Five patients, 3 in group L (1,25 per 100 pt/yrs) and 2 in group M (0.8 per 100 pt/yrs), died of nonvascular death. Twenty-seven minor bleeding events were recorded in group L (11.5 per 100 pt/yrs) and 77 in group M (31.2 per 100 pt/yrs); the incidence rate ratio was statistically significant (0.35, CI ; p <0.001). or to the moderate intensity treatment (group M, target INR = 3, n = 55). The study was terminated in March Patients showed comparable baseline characteristics (Table 1). Total follow-up was 485 years (240 for group L and 245 for group M) with a mean follow-up of 4.5 years. Twelve patients dropped out; of these, 6 patients (3 in each group) were followed in other centers, 4 patients (3 in group L and 1 in group M) suspended oral anticoagulant treatment after effective non programmed cardioversion, 1 patient in group L dropped out due to a relative contraindication to treatment (acute pancreatitis), 1 patient in group M dropped out after the target INR was reduced for recurrent metrorrhagia. Sixteen patients (7 in group L and 9 in group M) terminated the study prior to surgical substitution of a mitral heart valve with a mechanical prosthesis. No patients were lost to follow-up. Quality of oral anticoagulant treatment Patients in group L had 3302 INR determinations and dose prescriptions (as a mean, one every 26 days) while patients in group M had 4177 INR determinations and dose prescriptions (as a mean, one every 21 days). Fig. 2 shows that the achieved intensity of treatment in the two groups was actually different. Patients in the target 2 group spent 74% of the time at an INR between 1.5 and 2.5, while patients in the target 3 group spent Figure 1: Incidence rates of systemic thromboembolism and corresponding confidence intervals in the two studied arms (Target 2,Target 3) in comparison with results of 5 randomised clinical trials on nonrheumatic atrial fibrillation.the BAATAF and SPINAF studies did not consider peripheral thromboembolism as primary end-point.

4 Anticoagulants in mitral stenosis 763 Figure 2: Percent of patient-time among the INR categories in the low intensity (target 2) and in the moderate intensity (target 3) groups. 51% of the time at an INR between 2.5 and 3.5.The mean INR value in group L was 2.14 ± 0.64 SD (median INR = 2.01); this value was significantly lower than that found in group M (mean INR value 2.76 ± 0.93, p <0.0001; median INR = 2.66). The mean weekly warfarin dosage was accordingly lower in group L (25.5 ± 8.9 SD mg/week) than in group M (28.4 ± 11.2 SD mg/week, p <0.0001). Discussion Mitral stenosis is a clinical condition associated with high risk of systemic embolism, which is the presenting feature of the disease in 12.4% of cases (2). The incidence of systemic emboli is seven times greater with the development of atrial fibrillation (24), with a prevalence of systemic emboli at autopsy of 41% (25). Early studies demonstrated that oral anticoagulant treatment dramatically reduces systemic embolism in patients with mitral valve diseases (26). Although never evaluated in a randomised trial, there was little doubt regarding the effectiveness of oral anticoagulation in reducing systemic embolism in these patients. Non randomised studies, in fact, showed a decrease in systemic embolism from 9.8% to 3.4% per patient-year (24) in the 1960s; the incidence of systemic thromboembolism further decreased to 0.8% per patient year in a series of 217 patients treated over a 9.5-year period (3). This figure is consistent with that found in the present study (0.4% per patient year) and with those reported in both retrospective (0.7%) (22) and randomized prospective studies of patients with atrial fibrillation (0.41% and 0.90%, respectively) (13, 27) who are at lower risk. In a recent multicenter inception cohort study of patients with atrial fibrillation treated with oral anticoagulants at an INR range of 2.0 to 3.0 or 2.0 to 3.5, the rate of systemic thromboembolism was 0.3% per patient year (28). The incidence of thromboembolism rose to 3.7% when ineffective low doses warfarin were used (29). Therefore, in the present study, the rate of systemic thromboembolism in high risk patients treated with low intensity oral anticoagulant treatment should be considered satisfactory and does not differ from that obtained in the moderate intensity group. On the other hand all 3 episodes of cerebral bleeding occurred in the moderate intensity group of patients, who spent a longer time at high intensity anticoagulation. We know that the bleeding risk is much higher for INR values above 5.0, and significantly increases even at INR values above 3.0 (19). A further advantage of low intensity anticoagulant treatment in these patients is the lower frequency of INR determinations and lower rate of minor bleeding events, both of which might contribute to improving the patients quality of life and compliance. The principal limitation of the present study is that the sample size was not calculated to allow evaluation of the equivalence between the two therapeutic regimens. Nevertheless, the cumulative follow-up was sufficiently long to postulate near equivalence in terms of systemic thromboembolism. In conclusion a low intensity of oral anticoagulant treatment (target INR = 2) might be preferred in patients with MS and AF as incidence rates and confidence intervals for thromboembolic complications are the same as those obtained with a moderate intensity and in line with those obtained in clinical trials dealing with a condition at much lower risk. Moreover, the lower number of major bleeding events and less frequent controls appear to favour a less intense treatment. We do not know, however, if these results can be extrapolated to routine care for anticoagulated patients, as they were obtained in the setting of an anticoagulation clinic within a cardiology department. Abbreviations MS = Mitral Stenosis AF = Atrial Fibrillation TE = Tromboembolism INR = International Normalized Ratio

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