The Journals of Gerontology Series A: Biological Sciences and Medical Sciences 59:1339-1342 (2004)
© 2004 The Gerontological Society of America
Clinical Experience
Management of Oral Anticoagulant in Clinical Practice: A Retrospective Study of 187 Patients
Isabelle Mahé,
Anne-Sophie Grenard,
Nathalie Joyeux,
Charles Caulin and
Jean-François Bergmann
Department of Internal Medicine, Lariboisière University Hospital, Paris, France.
Address correspondence to Dr. Isabelle Mahé, Service Médecine A, Hôpital Lariboisière 2, rue Ambroise Paré, 75010 Paris, France. E-mail: isabelle.mahe{at}lrb.ap-hop-paris.fr
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Abstract
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Oral anticoagulant (OA) therapy is widely used in elderly patients because of the increase of indications with age (venous thromboembolism and atrial fibrillation). A particularity of France is to administer three different OAs (warfarin and more often fluindione or acenocoumarol). In an attempt to assess the particularities of managing all three OAs in elderly patients in clinical practice, we studied the modalities of anticoagulation of 187 consecutive OA therapy patients (mean age = 74.4 years) hospitalized in an Internal Medicine department (95 patients on OA at admission and 92 patients initiated on OA during hospitalization). Patients aged 75 years or older more often required a low dosage of OA than those aged younger than 75, irrespective of the OA (warfarin and more often fluindione or acenocoumarol). Ambulatory patients aged 75 years or older were more susceptible to receive acenocoumarol than were ambulatory patients younger than 75 years (respectively 30/67 vs 8/28, respectively), whereas fluindione was prescribed at the same frequency in ambulatory patients and hospitalized patients, regardless of age group (
75: 32/67; <75: 19/28). In hospitalized patients with OA induction, fluindione was prescribed as often in patients younger than 75 than in patients aged 75 years or older (40/47 vs 35/45, respectively). On admission, international normalized ratio was in the target range in 26 of the 95 patients (27.4%) and was >3 in 51 of the 95 patients (51.6%). OA therapy was stopped during hospitalization in 35 patients (36.8%). In conclusion, we have a picture of the practice of anticoagulation with three different OA therapies. Although it is usually recommended to prescribe long half-time OA therapy (
2), it appears that short half-time therapy such as acenocoumarol still represents an important number of OA prescriptions in France, especially in ambulatory and elderly patients. International normalized ratio is not in the target range as often as expected in clinical practice, and elderly patients require specific modalities of OA therapy management, such as half dose initiation, use of long-half-life OA, and close monitoring.
THE management of oral anticoagulant (OA) therapy is a critical issue, especially in elderly patients. An increasing number of older patients are candidates for and could benefit from OA therapy because indications such as atrial fibrillation and venous thromboembolism (1,2) increase with age, but elderly patients are considered at higher risk of bleeding during OA therapy (3).
A characteristic of France is to administer 3 different OA therapies (warfarin, fluindione, and acenocoumarol). They have widely different properties: half time = 40, 31, and 9 hours, respectively; time until a visible effect = 48–96 hours for warfarin and fluindione, 24–48 hours for acenocoumarol. (2). Acenocoumarol and fluindione are the most often used in France; warfarin is the most often used worldwide. The main objective of the study was to assess the particularities of the management of OA therapy in France, especially in elderly patients and to determine whether recommendations translate to clinical practice.
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PATIENTS AND METHODS
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From January 2000 until December 2001, consecutive patients aged 18 years or older hospitalized in the Internal Medicine Department of Lariboisière Hospital (Paris, France), and receiving OA therapy at admission and/or during hospitalization were retrospectively studied. Patients were ambulatory before hospitalization and were all admitted to the unit through the emergency room. The whole recruitment of our unit comes from emergency, admitting ambulatory patients, OA therapy was chosen by the physician in charge of the patient, without interaction with the present study. Baseline characteristics of the patients and the OA therapy they were receiving were systematically recorded. Patients underwent daily physical examination. Every day during hospitalization, current treatments and bleeding events were noted. All patients had blood drawn for measurement of complete blood count, platelets, prothrombin time, and international normalized ratio (INR). Patients were followed-up during and after hospitalization to determine the final maintenance dose, defined as the dose of OA resulting in two successive INRs in the target range (2,3).
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RESULTS
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Between January 1, 1999 and December 31, 2000, 187 patients were retrospectively included (85 men, 102 women, mean age: 74.4 (±15.4 years). They were hospitalized for the following reasons: cardiovascular disease (n = 59), venous thromboembolism (n = 47), neurologic disease (n = 26), infectious disease (n = 17), bleeding events (n = 14), other (neoplasic, pulmonary) (n = 21). Baseline clinical features are presented in Table 1. Of the 187 patients, 95 were receiving OA therapy before hospitalization and 92 were initiated on OA therapy during hospitalization. Before hospitalization, OA therapy was acenocoumarol (23%), fluindione (67.4%), and warfarin (9.6%) (Table 1). On admission, INR was in the target range in 27.4% of the 95 inpatients on OA (9/28 patients younger than 75 and 16/67 patients aged 75 years or older) and >3 in 51.6% (14/28 patients younger than 75 and 37/67 patients aged 75 years or older) of the 95 inpatients on OA (Table 2). OA therapy was stopped during hospitalization in 35 subjects (36.8%). The reasons for withdrawal were the following: major bleeding (n = 9), death (n = 5), exploration of bleeding (n = 2), existence of a contraindication to OA therapy (cirrhosis, frequent falls, lack of observance) (n = 6), end of duration of therapy (n = 5), cognitive impairment (n = 6), and no indication (n = 2).
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Table 2. International Normalized Ratio (INR) of Patients on Oral Anticoagulant (OA) at Entrance According to Age and Oral Anticoagulant Therapy.
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Some differences between patient and treatment characteristics were observed. Fluindione was the most frequently prescribed OA, both in ambulatory and hospitalized patients (51/95 vs 75/92, respectively); acenocoumarol was used most of the time in ambulatory patients (38/95 ambulatory vs 5/92 hospitalized), and warfarin represented the minority of prescriptions (5/95 vs 12/92 in ambulatory and hospitalized patients, respectively). In addition, ambulatory patients aged 75 years or older were more likely to receive acenocoumarol than were ambulatory patients younger than 75 years (30/67 vs 8/28, respectively), whereas ambulatory patients younger than 75 or aged 75 years or older were as likely to receive fluindione (19/28 vs 32/67, respectively) as hospitalized patients younger than 75 or aged 75 years or older (40/47 vs 35/45, respectively). In hospitalized patients with OA induction, fluindione was prescribed as often in patients younger than 75 as in patients aged 75 years or older (40/47 vs 35/45, respectively). Patients aged 75 years or older required a low dose of OA (fluindione, acenocoumarol, or warfarin) to reach the target range of INR more often than did patients younger than 75 (68.6% vs 26.8%). Significantly more patients aged 75 or older required a low dose in comparison to patients younger than 75 (p <.0001) (Table 3).
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DISCUSSION
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This observational study paints a picture of the modalities and particularities of OA therapy in France (for ambulatory and hospitalized patients). Three OAs are available: fluindione is the most widely used OA, before acenocoumarol and warfarin. Although it is usually recommended that physicians prescribe long half-time OA therapy (2), it appears that short half-time therapy such as acenocoumarol still represents a large number of OA prescriptions in France, especially in ambulatory and elderly patients. Consequently, our study presents data about the practical use of fluindione and acenocoumarol, whereas the literature talks almost only about warfarin. For a long time acenocoumarol was preferred in France because of its short half-time, which allowed it to reach the target range more quickly and, in the case of overanticoagulation, to recover the basal state more quickly. It is now recognized that OAs with long half-times have to be preferred because of their more stable anticoagulations; in France, fluindione is the most used since modalities of prescription are taught in medical schools. This is not the case for warfarin, although all clinical studies have been performed with this drug.
All patients were followed up with consultations and/or by telephone. We observed that subjects aged 75 years or older required a lower dose of OA to reach their target INR. The reduction of the maintenance dose for those patients aged 75 years or older was observed with all three OAs in our study. This finding suggests that data available about warfarin (4,5) can be extended to other OAs. Hylek (4) reported that the average dose required to maintain a therapeutic range decreased by 11% per decade of patient age. Similarly, Fihn and colleagues (5) reported that patients aged 80 years or older required a warfarin dose that was one-third to one-half the size of that given to patients younger than 50 years: 6.3 mg in patients younger than 50, 5.4 mg in patients 50–59, 4.8 mg in patients 60–69, 4.2 mg in patients 70–79, and 3.3 mg in patients aged 80 or older.
It is recommended that warfarin be initiated with the average maintenance dose, usually <5 mg in elderly patients because of their increased pharmacodynamic response (6,7). This increased sensitivity to warfarin associated with advancing age remains unexplained, even if the clearance of warfarin decreases with age (1,2). It does not seem to be imputable to INR variability, as Fihn and colleagues (5) observed a clear consistency of the mean prothrombin time ratio over time in patients as old as 80 years of age. Elderly patients did not appear to be more difficult to manage (5). It must be noted that the increased sensitivity to the effects of warfarin in older patients may occur both in the early induction period and then during the maintenance phase of therapy (8,9).
There are few clinical data about acenocoumarol, probably because it is used mostly in France, whereas most international studies have been performed with warfarin. Gadisseur and colleagues (10) investigated whether the anticoagulation control (percentage of time within the therapeutic range) of acenocoumarol and phenprocoumon in 456 patients with 7245 INR checks yielded 230 patient-years. Quality of OA control was higher with phenprocoumon (number of INR checks in the therapeutic range = 42.7% vs 36.5%), whereas the incidence of severe bleeding complications was similar (0.04/patient/year vs 0.03/patient/year). In a second study with data from 22,178 patients of whom 72% were treated with acenocoumarol (11), patients on phenprocoumon were significantly more often in the therapeutic range as compared to those on acenocoumarol (50% vs 43%); in addition, patients on phenprocoumon required fewer monitoring visits and had more stable anticoagulation. In addition, in a prospective cohort study (12), patients on acenocoumarol had an increased risk of having an INR > 6 compared to patients on phenprocoumon.
OA therapy is widely used, especially in elderly patients, because indications increase with age. Although the expected benefits of OA therapy are greater in elderly patients due to the increased underlying thromboembolic risk, they are often denied OA therapy because of doctors' and patients' fear of increased bleeding risk. In our cohort, the proportion of patients aged 75 years or older allows us to assess the particularities of OA management in this specific population and to compare these particularities to younger subjects. Mean age was 74.4, and the two main indications were atrial fibrillation and venous thromboembolism, as found in all observational studies (2). At entrance in the unit, INR was in the therapeutic range in only 27% of patients, and was >3 in 51.6% of patients, especially in the elderly patients. These results in our cohort are difficult to extrapolate, because when they enter the unit, patients have an acute condition which could change their anticoagulation state. Other authors also noticed a low proportion of patients receiving OA therapy in the target INR (slightly higher), although patients were closely monitored. Laackie and colleagues (13) reported that, in a cohort of 18 patients (mean age = 82 y; target INR = 2–3) followed by the Geriatric Ambulatory Program for 2 years, 51% of INR responses were therapeutic, 35% were subtherapeutic, and 14% were supratherapeutic. It is of critical importance to maintain INR in the target range, because an INR > 3 is a risk factor for bleeding (1–5,14,15) and the risk of intracranial hemorrhage in patients receiving warfarin increases exponentially at INR values > 4 (14). The bleeding risk associated with an INR from 3 to 4.5 is threefold the risk associated with an INR between 2 and 2.5 (15). The optimal target INR in all anticoagulated patients appears to be 2–3 because INR < 2 do not preclude bleeding, even in elderly patients, and do not protect from thrombotic events (1).
We are aware of the limits of our study. It is retrospective and monocentric; the allocation of OA therapy was not randomized. However, our study reflects usual clinical conditions, and the patient sample was large and diverse. The patients in our study reflect the target population of OA therapy (mean age = 78 years), with comorbid conditions, and the clinical practice conditions of OA monitoring. Patients admitted for bleeding illustrate the deficiency of OA management.
In practice, specific modalities of OA management should be applied when treating elderly patients, such as choice of an OA with a long half-time, half-dose initial administration, and close monitoring to avoid overdose (INR > 3) and/or undesirable therapeutic associations (4). Elderly patients should be monitored more carefully to maximize their time in the therapeutic range (grade 2C) (2).
Conclusion
Our study illustrates the difficulties of OA management in clinical practice and the gap between recommendations and practice in choosing a long-half-time OA, adapting the induction dosage of OA therapy in elderly patients, maintaining the INR in the target range, and monitoring therapy duration. Elderly patients require close monitoring because they require lower doses of OA to reach the target INR. A major way to achieve better management of OA therapy is to educate patients, so that results of clinical trials may translate to clinical practice.
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Acknowledgments
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This study was presented during the XIXth Congress of The International Society on Thrombosis and Haemostasis, Birmingham, U.K., July 13–19, 2003.
Received May 10, 2004
Accepted May 17, 2004
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References
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Abstract
Patients and Methods
