Oral Anticoagulant Therapy in Patients with Nonrheumatic Atrial Fibrillation and Risk of Bleeding

Vittorio Pengo; Cristina Legnani; Franco Noventa; Gualtiero Palareti; the ISCOAT; on behalf of

doi:10.1055/s-0037-1615599

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2001; 85(03): 418-422
DOI: 10.1055/s-0037-1615599

Review Article

Schattauer GmbH

Oral Anticoagulant Therapy in Patients with Nonrheumatic Atrial Fibrillation and Risk of Bleeding

A Multicenter Inception Cohort Study

Vittorio Pengo

¹Department of Clinical and Experimental Medicine, Cardiology Section, University of Padova, Italy

,

Cristina Legnani

²Department of Angiology and Blood Coagulation, University Hospital S. Orsola-Malpighi, Bologna, Italy

,

Franco Noventa

¹Department of Clinical and Experimental Medicine, Cardiology Section, University of Padova, Italy

,

Gualtiero Palareti

²Department of Angiology and Blood Coagulation, University Hospital S. Orsola-Malpighi, Bologna, Italy

,

the ISCOAT

› Author Affiliations

Abstract

Summary

Oral anticoagulants (OA) are the drug of choice for stroke prevention in patients with non-rheumatic atrial fibrillation (NRAF). This clear benefit/risk ratio comes from several randomized clinical trials (RCT) in which highly selected patients were strictly monitored. The aim of this study was to ascertain whether the safety of OA was also obtained outside the setting of clinical trials in consecutive patients starting treatment and routinely followed at Italian anticoagulation clinics. A total of 433 patients with NRAF were enrolled in the ISCOAT study and followed up for a mean of 1.4 years. Two patients (0.3% per year) suffered from a complete non-fatal ischemic stroke, 8 patients (1.3% per year) died of thrombosis-related vascular death, and 11 patients (11 events, 1.8% per year) suffered from major bleedings (2 fatal). Major bleeding occurred more frequently in patients >75 years of age (6 events, 5.1% per year) than in younger patients (5 events, 1.0% per year).

The cumulative incidence of major bleeding in patients over 75 years of age (10.8%; 95% CI, 1.8-19.8) was significantly higher than in younger patients (2.8%; 95% CI, 0.3-5.3, p = 0.006). Major primary bleeding unrelated to organic lesions (7 patients, 1 male and 6 females) occurred in 5 elderly patients (>75 years old) with a cumulative incidence (9.6%; 95% CI 0.8-18.4) significantly higher than in younger patients (1.2%; 95% CI, 0-3.0, p = 0.0003). Univariate analysis revealed a higher frequency of major primary bleeding in females, in diabetic patients and in in those who had suffered a previous thromboembolic event. Multivariate analysis revealed that only age grater than 75 years was independently related to major primary bleedings (RR 6.6; 95% CI 1.2-37, p = 0.032). Minor bleedings (n = 27) were not more frequent in elderly patients (6% vs 4% per year, p = ns). Patients were kept at optimal intensity of treatment for 63% of the time. These data confirm the efficacy of OA but identify elderly patients as a high risk group of major bleeding.

Keywords

Oral anticoagulants - atrial fibrillation - bleeding

Full Text

References

References
1 Wolf PA, Abbott RD, Kannel WB. Atrial fibrillation as an independent factor for stroke: the Framingham study. Stroke 1991; 22: 983-8.
2 Phillips SJ, Whisnan JP, O’Fallon WM, Freye RL. Prevalence of cardiovascular diseases and diabetes mellitus in residents of Rochester, Minnesota. Mayo Clin Proc 1990; 65: 344-59.
3 Petersen P, Boysen G, Godtredsen Andersen ED, Andersen B. Placebo-controlled, randomized trial of warfarin and aspirin for prevention of thromboembolic complications in chronic atrial fibrillation. Lancet 1989; 1: 175-9.
4 Atrial Fibrillation Study Group Investigators.. Stroke prevention in atrial fibrillation study. Final results. Circulation 1991; 84: 527-39.
5 The Boston Area Anticoagulation Trial For Atrial Fibrillation Investigators.. The effect of low-dose warfarin on the risk of stroke in patients with non-rheumatic atrial fibrillation. N Engl J Med 1990; 323: 1505-11.
6 Connolly SJ, Laupacis A, Gent M, Roberts RS, Cairns JA, Joyner C. Canadian atrial fibrillation study. J Am Coll Cardiol 1991; 18: 349-55.
7 Ezekowitz MD, Bridgers SL, James KE, Carliner NH, Colling CL, Gornick CC, Krause-Steinraue H, Kurtzke JF, Nazarian SM, Radford MJ, Rickles FR, Shabetal R, Deykin D. Warfarin in the prevention of stroke associated with nonrheumatic atrial fibrillation. N Engl J Med 1992; 327: 1406-12.
8 EAFT Study Group.. European Atrial Fibrillation Trial: secondary prevention of vascular events in patients with non-rheumatic atrial fibrillation and a recent transient ischaemic attack or minor ischaemic stroke. Lancet 1993; 342: 1255-62.
9 Albers GW, Yim JM, Belew KM. et al. Status of antithrombotic therapy in patients with atrial fibrillation in university hospitals. Arch Intern Med 1996; 156: 2311-6.
10 Munschauer FE, Priore RL, Hens M, Castilone A. Thromboembolism prophylaxis in chronic atrial fibrillation. Practice patterns in community and tertiary care hospitals. Stroke 1997; 28: 72-6.
11 Gurevitz JH, Monette J, Ronchon PA, Eckler MA, Avorn J. Atrial fibrillation and stroke prevention with warfarin in the long-term care setting. Arch Intern Med 1987; 157: 978-84.
12 Palareti G, Leali N, Coccheri S, Poggi M, Manotti C, D’Angelo A, Pengo V, Erba N, Moia M, Ciavarella N, Devoto G, Berrettini M, Musolesi S. Bleeding complications of oral anticoagulant treatment: an inception-cohort, prospective collaboratory study (ISCOAT). Lancet 1996; 348: 423-8.
13 Stroke Prevention in Atrial Fibrillation Investigators.. Warfarin versus aspirin for prevention of thromboembolism in atrial fibrillation: Stroke Prevention in Atrial Fibrillation II Study. Lancet 1994; 343: 687-91.
14 Fihn SD, Callaghan CM, Martin DC. et al. The risk for and the severity of bleeding complications in elderly patients treated with warfarin. Ann Intern Med 1996; 124: 970-9.
15 Tripodi A, Chantarangkul V, Akkawat B, Clerici M, Mannucci PM. A partial factor V deficiency in anticoagulated lyophilized plasmas has been identified as a cause of the International Normalized Ratio discrepancy in the external quality control scheme. Thromb Res 1995; 78: 283-92.
16 Rosendaal FR, Cannegieter SC, van der Meer FJM, Briët E. A method to determine the optimal intensity of oral anticoagulant therapy. Thromb Haemost 1993; 69: 236-9.
17 Sahai H, Kurshid A. Statistics in epidemiology: methods, techniques and applications. CRC Press; 1996
18 Kaplan EL, Meier P. Nonparametric estimation from incomplete observation. J Am Stat Assoc 1958; 53: 457-81.
19 Mantel N. Evaluation of survival data and two new rank order statistics arising in its consideration. Cancer Chemother Rep 1966; 50: 163-70.
20 Pengo V, Zasso A, Barbero F, Banzato A, Nante G, Parissenti L, John N, Novente F, Dalla Volta S. Effectiveness of fixed mini-dose warfarin in the prevention of thromboembolism and vascular death in nonrheumatic atrial fibrillation. Am J Cardiol 1998; 82: 433-7.
21 Atrial Fibrillation Investigators.. Risk factors for stroke and efficacy of anti-thrombotic therapy in atrial fibrillation: analysis of pooled data from five randomized controlled trials. Arch Intern Med 1994; 154: 1449-57.
22 Stroke Prevention in Atrial Fibrillation Investigators.. Adjusted-dose warfarin versus low-intensity, fixed-dose warfarin plus aspirin for high risk patients with atrial fibrillation: Stroke Prevention in Atrial Fibrillation III randomized clinical trial. Lancet 1996; 348: 633-8.
23 Hylek EM, Skates SJ, Sheehan MA, Singer DE. An analysis of the lowest effective intensity of prophylactic anticoagulation for patients with non-rheumatic atrial fibrillation. N Engl J Med 1996; 335: 540-6.
24 Gullov AL, Keofoed BG, Petersen P. et al. Fixed mini-dose warfarin and aspirin alone and in combination versus adjusted-dose warfarin for the stroke prevention in atrial fibrillation; second Copenhagen Atrial Fibrillation, Aspirin and Anticoagulation study (the AFASAK2 study). Arch Intern Med 1998; 158: 1513-21.
25 Hart RG. Intensity of anticoagulation to prevent stroke in patients with atrial fibrillation (letter). Ann Intern Med 1998; 128: 408.
26 Sheffield JVL, Larson EB. Intensity of anticoagulation to prevent stroke in patients with atrial fibrillation. Ann Inten Med 1998; 128: 408.
27 Laupacis A, Albers GW, Dalen JE, Dunn MI, Jacobson AK, Singer D. Antithrombotic therapy in atrial fibrillation. Chest 1998; 114 suppl 579S-89S.
28 Cortelazzo S, Finazzi G, Viero P, Galli M, Remuzzi A, Parenzan L, Barbui T. Thrombotic and hemorrhagic complications in patients with mechanical heart valve prosthesis attending an anticoagulation clinic. Thromb Haemost 1993; 69: 316-20.
29 Palareti G, Poggi M, Guazzaloca G, Savino A, Coccheri S. Assessment of mental ability in elderly anticoagulated patients; its reduction is associated with a less satisfactory quality of treatment. Blood Coagul Fibrinolysis 1997; 8: 411-7.
30 Hellemons BSP, Langenberg M, Lodder J, Vermeer F, Shouten HJA, Lemmens TH, van Ree JW, Knottnerus JA. Primary prevention of arterial thromboembolism in non-rheumatic atrial fibrillation in primary care: randomized controlled trial comparing two intensities of coumarin with aspirin. BMJ 1999; 319: 958-64.