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A review of anticoagulation with warfarin in patients with nonvalvular atrial fibrillation
CLINICALTHERAPEUTICSWOL.23.NO.
IO,2001
A Review of Anticoagulation with Warfarin in Patients with Nonvalvular Atria1 Fibrillation
Ahmed H. Abdelhafz,
MBBCh, MSc, MRCP
Acute and Elderly Medicine, Northern Gene& England
Hospitul, Sh@eld,
South Yorkshire,
ABSTRACT Background: Warfarin therapy has proved safe and effective in a number of randomized controlled trials of stroke prophylaxis in patients with nonvalvular atria1 fibrillation (NVAF), reducing the risk of stroke in these patients by two thirds. However, participants in the clinical trials were carefully selected and younger than patients in actual clinical practice. Objective: This analysis sought to determine whether the results of clinical trials in patients with NVAF can be extrapolated to the general population seen in clinical practice. Methods: A MEDLINE search from 1966 to the present was used to identify observational trials of anticoagulation in patients with NVAF that addressed warfarin use, anticoagulation control, efticacy, and complications. The search terms used were atrialfihrillation and unticougulution. Results: Although warfarin prophylaxis against stroke in patients with NVAF appeared to be as well tolerated and effective in clinical practice as in clinical trials, it was generally underused, particularly in the elderly. Anticoagulation control was not as good in clinical practice as in clinical trials, although the rates of stroke and major bleeding were comparable. Conclusions: Judicious use of warfarin, tailored to individual stroke risk, seems to be a reasonable policy. Warfarin therapy increases quality-adjusted survival in patients at high risk for stroke, and it is recommended for medium-risk patients unless their risk of bleeding is high or their quality of life while taking warfarin would be poor. Patients at a low risk for stroke will have equivalent health outcomes and incur lower costs if treated with aspirin. Despite the increased risk of hemorrhage in elderly patients, the net benefit of warfarin therapy is greater in this age group because of the higher risk of stroke. Active involvement of patients and their caregivers in an anticoagulation service setting may improve outcomes of anticoagulation therapy.
Accepted
for publication
August 6, 2001.
Printed in the USA. Reproduction
1628
in whole or part is not permitted.
A.H. ABDELHAFIZ
Key words: atria1 fibrillation, anticoagulation, clinical practice, efficacy, safety. (C/in Thel: 2001;23:1628-1636)
INTRODUCTION Atria1 fibrillation (AF) is a major risk factor for stroke, increasing the risk 5-fold compared with that in individuals with normal sinus rhythm.’ Randomized controlled trials have shown that prophylactic treatment with warfarin decreases the risk of stroke by 60% to 70% in patients with nonvalvular AF (NVAF),2 and guidelines support the use of warfarin in these patients.3,4 The major benefit of warfarin is seen in patients at highest risk for strokethose aged >75 years and those of any age with such risk factors as hypertension, poor ventricular function, diabetes mellitus, or previous transient ischemic attack (TIA) or stroke.” Because of the highly selected nature of patients in randomized clinical trials, there is concern over whether the evidence from such trials can be applied to clinical practice.6 Most patients with NVAF who are screened for such trials are ultimately excluded (>90% in 1 tria17). Patients in clinical practice may have different baseline risks compared with patients in clinical trials or may respond differently to anticoagulant treatment. In addition, compliance and safety may be different in clinical practice than in the carefully selected, well-motivated, and closely monitored participants in clinical studies. It is in high-risk older patients that physicians most fear inducing bleeding complications through the use of anticoagulation. Therefore, underutilization of this effective therapy is a continuing problem in all age groups, but particularly in the elderly.”
This analysis sought to determine whether the results of the major clinical trials of stroke prophylaxis in patients with NVAF7,9-14 can be extrapolated to the lessselected patients seen in clinical practice. A MEDLINE search from 1966 to the present was used to identify the relevant clinical and observational trials of anticoagulation in NVAF that addressed warfarin use, anticoagulation control, efficacy, and complications. The search terms used were utrial jibrillution and anticoagulation.
UNDERUSE OF WARFARIN IN PATIENTS WITH NVAF Antithrombotic treatment is underused in patients admitted to the hospital with stroke. In a European observational study of 2 13 patients with NVAF consecutively admitted to 3 European centers for an acute stroke or TIA in 1997,1s 148 (69.5%) had known NVAF and 34 (16.0%) were receiving anticoagulation before the stroke. Of 137 patients eligible for oral anticoagulation, 108 (78.8%) did not receive this treatment. New-onset NVAF and contraindications to anticoagulation accounted for a minority of those who did not receive oral anticoagulation. In prospective surveys of medical admissions to a Scottish district general hospitall and a hospital in Birmingham, England, serving a multiracial population,t7 NVAF was present in 3% to 6% of patients. Antithrombotic treatment was underused in patients with NVAF despite the presence of clinical risk factors for stroke (hypertension, heart failure, previous thromboembolism). In 61 patients discharged from the hospital with a new diagnosis of NVAF, only 15 (25.0%) received a prescription for warfarin.i7 In the Scottish study,16 only 34% of patients who
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CLINICAL THERAPEUTICS””
were eligible for warfarin treatment had a contraindication to anticoagulation. In another study,lx retrospective analysis of the case notes of patients with NVAF showed that >SO% were not prescribed warfarin, despite the absence of contraindications. Warfarin was also underused in a prospective population-based observational study in 5201 patients with NVAF aged 270 years in 4 communities in the United StatesI In a subgroup analysis of 172 (4.1%) patients, warfarin was prescribed for only 63 (36.6%). Of the 109 participants not reporting warfarin use, 92 (84.4%) had 21 risk factor for stroke. In a study in 5888 community-dwelling adults aged 26.5 years,“’ warfarin use increased 4-fold from 1990 to 1996 (from 13% to 50%) among patients with NVAF (P < 0.001). However, in 1996, patients aged <80 years were 4 times more likely to be using warfarin than those aged 280 years (P < 0.001). In a recent evaluative study of factors influencing the decision to use anticoagulation, Cohen et al”’ found that warfarin use lagged behind the need. Age >80 years, language diff’culties, insufficient physician awareness of the benefit, and patient disability emerged as independent variables negatively influencing the use of warfarin. In contrast, a history of stroke and the availability of echocardiographic information, regardless of the findings, were associated with increased warfarin use.
MONITORING AND CONTROL OF ANTICOAGULATION IN CLINICAL PRACTICE Low-intensity anticoagulation with warfarin (ie, international normalized ratio [INR] 2.0-3.0) is recommended for patients with NVAF. because this provides
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the same degree of protection against stroke as more intense anticoagulation (ie, higher INR) but has a lower risk for major bleeding. *? In a review of the medical records of patients with NVAF in clinical practice,?s monitoring was performed less frequently than in clinical trials (mean of 36.340.9 days vs 21-28 days in clinical trials) and the INR was within the target therapeutic range less often (50% of days vs 68% of days in clinical trials). Although the mean INR was within the target range on 68% of days in clinical trials, there was considerable variability (44%83%). 7,9-‘4 Patients in the Canadian Atria1 Fibrillation Anticoagulation study”’ and the Stroke Prevention in Atrial Fibrillation study’ had much smaller proportions of days within the target range (44% and 56%, respectively) compared with patients in other trials. In 2 recent studies,21,” the target INR was achieved on 48.0% and 57.8% of days, respectively.
Anticoagulation Services and Patient Involvement Anticoagulation services (ACS) have been cited as a means of improving the provision of anticoagulation,‘6~‘7 relieving the busy physician of the day-to-day details of anticoagulation management. The ACS manager (typically a pharmacist, physician’s assistant, nurse, or nurse-practitioner) is responsible for dosing changes, scheduling, patient education, and other aspects of anticoagulation therapy. Studies in patients with access to ACS have shown that the quality of warfarin treatment (measured in terms of [l] the proportion of eligible patients receiving warfarin, [2] the proportion of time the INR was in the target range, and [3] when an INR outside the target range occurred, the time until the next INR deter-
A.H. ABDELHAFIZ
mination was made) was higher and the INR remained within the target range for longer periods compared with conventionally managed anticoagulation (68% vs 58%, respectively; P < 0.001).28~29 In a randomized controlled trial,“” patient education in self-management of anticoagulation (intervention group) resulted in less deviation in the INR from the mean target at 3- and 6-month follow-up compared with the control group, who received no patient education (squared INR deviation, 0.59 intervention group vs 0.95 control group at 3 months [P < O.OOl]; 0.65 vs 0.83 at 6 months [P = 0.031). INR values of the intervention group were within the target range more often than those of the control group (P = 0.006). Treatmentrelated quality-of-life measures, particularly treatment satisfaction scores, were significantly higher in the intervention group compared with the control group. In a study of a telephone-based ACS3’ the rates of complications of anticoagulation appeared to be similar to those reported for conventional anticoagulation clinics. ACS may be more cost-effective than conventional anticoagulation management. In a study comparing anticoagulation delivered through usual medical care and through an ACS,” patients treated at an ACS had lower rates of significant bleeding (8.1% vs 35.0%; P < O.OOl), major to fatal bleeding (1.6% vs 3.9%; P < 0.05), and thromboembolic events (3.3% vs 11.8%; P < 0.05). The mortality rate was numerically lower in patients managed at an ACS (0% vs 2.9%) but the difference was not statistically significant. Significantly lower annual rates of warfarin-related hospitalizations (5% vs 19%; P < 0.001) and emergency department visits (6% vs 22%; P < 0.001) reduced annual health care costs by $132,086 per 100 patients.
Self-monitoring of prothrombin time (PT) and self-adjustment of the warfarin dosage were evaluated in a long-term study at a tertiary medical institution.“” Study patients monitored their PT on 2 153 occasions over a mean of 44.7 months, compared with 1608 PT measurements over a mean of 42.5 months in matched controls treated with conventional management. Over the study period, there were a mean 11.5 dosage changes per study patient, compared with 22.7 changes per control patient (P < 0.001). Study patients had a PT within the recommended therapeutic range in 88.6% of determinations (95% CI, 87.2-89.9) compared with 68.0% in matched controls (95% CI, 65.7-70.3; P < 0.001). In the investigators’ opinion, patients who measure their own PT and adjust their warfarin dosage accordingly can achieve therapeutic effectiveness at least as good as that seen in patients managed in a conventional anticoagulation clinic.
EFFICACY AND COMPLICATIONS OF WARFARIN ANTICOAGULATION In a recent prospective observational study evaluating the effects of preventive anticoagulation in patients with NVAF in 2 practice settings in Montreal, Canada,‘4 22 1 patients with documented NVAF were followed for a mean of 27 months. There were 4 treatment groups: aspirin, warfarin, blended treatment (comprising patients who started on 1 active treatment and switched to the other or who switched treatments more than once), and no treatment. Patients were interviewed by telephone every 6 months, and reported events were confirmed through a review of patients’ charts. The investigators found that on average, study patients were older
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CLINICAL THERAPEUTICS”
(mean + SD age, 71.6 f 9.3 years) and had a higher prevalence of underlying heart disease (52.0%) than those in pooled data from randomized clinical trials. Thirty-one (14.0%) patients received aspirin, 87 (39.3%) received warfarin, 65 (29.4%) received blended treatment, and 38 (17.1%) received no treatment, for a total of 493.7 person-years of follow-up. Nineteen patients had a first stroke during the follow-up period: 4 (5.2% per year) in the aspirin group, 4 ( I .8%) in the warfarin group, 4 (5.3%) in the blended-treatment group, and 7 (5.9%) in the no-treatment group. Only warfarin treatment was associated with a significantly lower risk of stroke compared with no treatment (RR, 0.3 1; 95% CI, 0.09-l .OO). The rate of any bleeding per 100 person-years was not significantly different between treatment groups (aspirin 2.5%, warfarin 3.4%, blended treatment 3.5%) compared with no treatment (1.9%). The relative effect of warfarin anticoagulation for the prevention of stroke in these practice settings was equivalent to that in randomized trials (bleeding rate in clinical trials, 1.4%4.2%), although these patients were older and sicker.7,“m’4 In another 2-year, prospective cohort study in a clinical practice setting,j” 167 patients with NVAF and a high risk for stroke received anticoagulation to maintain an INR between 2.0 and 3.0. Rates of stroke and major hemorrhage were compared with pooled data from randomized controlled trials in similar patients. Compared with the pooled trial data, the study group was a mean of 7 years older (95% CI, 4-10 years) and included 33% more women. The incidence of stroke in the study group (2.0% per year; 95% Cl, 0.7%4.4%) was comparable to that in patients receiving warfarin in
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the pooled study data (1.4%; 95% CI, 0.8%-2.3%). The annual incidence of major and minor bleeding complications was not significantly different between the study group and patients included in the pooled data (major bleeding, 1.7% vs 1.6%, respectively; minor bleeding, 5.4% vs 9.2%). In a case-control analysis,‘(’ bleeding risk was evaluated in 121 adult patients taking warfarin who were hospitalized for intracranial hemorrhage (intracerebra1 hemorrhage, 77 [46% fatal]; subdural hemorrhage, 44 [20% fatal]). Each patient was matched to 3 randomly selected, age-matched outpatients. Prothrombin time ratio (PTR) was the predominant risk factor for intracranial hemorrhage. The risk for intracerebral hemorrhage doubled with each 0.5 increase in PTR over the entire range (OR, 2.1; 95% CI, I .4-2.9). The risk for subdural hemorrhage was unchanged over the PTR range from 1.0 to 2.0 but rose dramatically above 2.0 (-INR, 4.0). Age was the only other significant independent risk factor for subdural hemorrhage (OR. 2.0 per decade; 95% CI, I .3-3.1). Age was of borderline significance as a risk factor for intracerebral hemorrhage (OR, 1.3 per decade; 95% Cl, 1.0-1.6).
ANTICOAGULATION IN THE ELDERLY In an observational study of 3 12 elderly patients with NVAF in a large long-term care facility,j7 208 women and 104 men (mean 2 SD age, 84 + 7 years; range, 62-101 years) received anticoagulation with aspirin 325 mg/d (n = 187) or warfarin adjusted to maintain an INR between 2.0 and 3.0 (n = 125). The incidence of new thromboembolic stroke was compared
A.H. ABDELHAFIZ
in the 2 groups over 36 +- I7 months (range, l-99 months) of follow-up. Four patients (3.2%) stopped taking warfarin because of adverse effects, compared with 4 (2.1%) who stopped taking aspirin (P = NS). New thromboembolic stroke occurred in 27 of 67 (40.3%) warfarin patients with a previous stroke and 56 of 69 (81.2%) aspirin patients (P < 0.001). In patients with no previous stroke, new thromboembolic stroke occurred in 13 of 58 (22.4%) warfarin patients and 66 of 1 18 (55.9%) aspirin patients (P < 0.001). Overall, new thromboembolic stroke occurred in 40 of 125 (32.0%) warfarin patients and 122 of 187 (65.2%) aspirin patients (P < 0.001). Cox regression analysis showed that after controlling for other risk factors, patients taking warfarin had a 76% lower risk of developing a new thromboembolic stroke than those taking aspirin. A prospective, multicenter study’s examined whether warfarin treatment placed elderly patients at increased risk for complications. Rates of bleeding and thrombotic events were compared in 461 patients aged 275 years and 461 patients aged ~70 years matched for sex, warfarin indication, and treatment center. Total bleeding rates in the older and younger patients were 9.9% and 6.6% patientyears, respectively (P = NS), and rates of major bleeding were 2.1% and 1.1% (P = NS); 6 and 1 of the events (all intracranial bleeding) were fatal in the respective groups (RR, 6.4; P = 0.05). In the older patients, the bleeding rate was lower (4.5%) in those with an INR between 2.0 and 2.9. Rates of thrombotic events in the older and younger patients were 4.2% and 2.5% patient-years, respectively (P = NS). The rate of thrombotic events in older patients was lower (1.5%) in those with an INR between 2.0
and 2.9. The results indicated that an INR <2.0 did not preclude bleeding in the elderly or offer adequate protection against thrombotic events. The best-tolerated and most effective option in these elderly patients appeared to be moderate anticoagulation (INR 2.0-3.0).
COST CONSIDERATIONS Gage et al” studied the quality-adjusted survival and cost-effectiveness of warfarin anticoagulation compared with aspirin or no therapy in patients with NVAF with and without additional risk factors for stroke. In patients with NVAF and additional risk factors for stroke (high-risk group), warfarin therapy led to greater quality-adjusted survival and produced cost savings. In patients with NVAF and I additional risk factor for stroke (moderaterisk group), warfarin therapy cost $8000 per quality-adjusted life-year saved. In patients aged $65 years with NVAF alone (low-risk group), warfarin cost -$370,000 per quality-adjusted life-year saved compared with aspirin therapy, whereas in those aged 275 years with NVAF alone (moderate-risk group), warfarin cost $110,000 per quality-adjusted life-year saved. In patients who did not receive warfarin, aspirin was preferred to no therapy on the basis of both qualityadjusted survival and cost in all patients, regardless of the number of risk factors. The investigators concluded that treatment with warfarin was cost-effective in patients with NVAF and 21 additional risk factor for stroke, whereas in 65-year-old patients with NVAF but no other risk factors for stroke, using warfarin rather than aspirin would have minimal effect on quality-adjusted survival while increasing costs significantly.
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CLINICAL THERAPEUTICS*’
CONCLUSIONS Based on the available data, warfarin appears to be as well tolerated and effective in clinical practice as in clinical trials. The decision to use anticoagulation in patients with NVAF should be clinically based after careful assessment of patient eligibility and the appropriateness of anticoagulation. 4o Judicious use of warlarin, tailored to individual stroke risk, seems to be a reasonable policy. Warfarin therapy increases quality-adjusted survival in patients at high risk for stroke, and it is recommended for medium-risk patients unless their risk of bleeding is high or their quality of life while taking warfarin would be poor. Patients at low risk for stroke will have equivalent health outcomes and incur lower costs if treated with aspirin. Despite its efficacy, warfarin anticoagulation remains underused, particularly in the elderly. It is less expensive in the elderly than in younger patients, and age in itself is not a risk factor for bleeding complications. Despite the increased risk of hemorrhage due to multiple comorbidities and polypharmacy in elderly patients, the net benefit of warfarin therapy is greater in this age group than in younger patients because of the increased risk of stroke. In elderly patients, moderate anticoagulation (INR 2.0-3.0) seems to be better tolerated and more effective than other intensities of anticoagulation, which either are not effective (INR ~2.0) or are associated with an increased risk of bleeding (INR >3.0). More research is needed to clarify the relative importance of barriers to warfarin use associated with patients, physicians, and health care systems, making it possible to target future interventions more precisely. Active involvement of patients and
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their caregivers in an ACS setting help improve outcomes.
may
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2. Risk factors for stroke and efficacy of antithrombotic therapy in atria1 fibrillation. Analysis of pooled data from five randomized controlled trials. Arch lnterrz Med. 1994;154:1449-1457.
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DB, McCrory D, Barnett HJ, Feussner JR. Medical treatment for stroke prevention. Ann Intern Med. 1994; I2 I:4 I 53.
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in Atrial Fibrillation Study. Final results. Circulution. I99 I ;84: 527-539.
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KE, et al. Failure to prescribe warfarin to patients with nonrheumatic atrial fibrillation. J Gcn Intern Med. 1996; I I :I 13-720.
9. Petersen P, Boysen G, Godtfredsen
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IO. Connolly SJ, Laupacis A, Gent M, et al. Canadian Atria1 Fibrillation Anticoagulation (CAFA) study. J Am Co11 Cardiol. 1991;18:349-355. 11. Singer DE, Hughes RA, Cress DR, et al. The effect of aspirin on the risk of stroke in patients with nonrheumatic atria1 fibrillation. The BAATAF study. Am Heart J. 1992;124:1567-1573. 12. Ezekowitz MD, Bridgers SL, James KE, et al, for the Veterans Affairs Stroke Prevention in Nonrheumatic Atria1 Fibrillation Investigators. Warfarin in the prevention of stroke associated with nonrheumatic atria1 fibrillation. N Engl J Med. 1992;327: 1406-1412. 13. EAFT (European Atria1 Fibrillation Trial) Study Group. Secondary prevention in non-rheumatic atria1 fibrillation after transient ischaemic attack or minor stroke. Luncet. I993;342: 1255-1262. 14. Warfarin versus aspirin for prevention of thromboembolism in atrial fibrillation: Stroke Prevention in Atria1 Fibrillation II Study. Lancet. 1994;343:687-69 1. 15. Deplanque D, Corea for the SAFE 1 Study and atria1 fibrillation: treatment appropriate 1999;82;563-569.
F, Arquizan C, et al, Investigators. Stroke Is stroke prevention beforehand‘? Heart.
16. Lip GYH, Tean KN, Dunn FG. Treatment of atria1 fibrillation in a district general hospital. Br Heart J. 1994;7 1:92-95. 17. Zarifis J, Beevers DC, Lip GYH. A survey of acute admissions with atria1 fibrillation in a multiracial hospital population. C/in Sci. 1995;33(Suppl):34P-35P. Abstract. IX. Bath PM, Prasad A, Brown MM, MacGregor GA. Survey of use of anticoagulation in patients with atria1 fibrillation. Br Med J. 1993;307:1045.
19 White RH, McBurnie MA, Manolio T, et al. Oral anticoagulation in patients with atria1 fibrillation: Adherence with guidelines in an elderly cohort. Am J Med. 1999;106:165-171. 20
Smith NL, Psaty BM, Furberg CD, et al. Temporal trends in the use of anticoagulants among older adults with atria1 fibrillation. Arch Intern Med. 1999; 159: 15741578.
21 Cohen N, Almoznino-Sarafian D, Alon I, et al. Warfarin for stroke prevention still underused in atria1 fibrillation: Patterns of omission. Stroke. 2000;3 1: 12 17-1222. 22. Landefeld CS, Beyth RJ. Anticoagulantrelated bleeding: Clinical epidemiology, prediction, and prevention. Am J Med. 1993;95:315-328. 23. Gottlieb LK, Salem-Schatz S. Anticoagulation in atria1 fibrillation. Does efficacy in clinical trials translate into effectiveness in practice? Arch Intern Med. 1994; 154:1945-1953. 24. Hellemons BS, Langenberg M, Lodder J, et al. Primary prevention of arterial thromboembolism in non-rheumatic atria1 fibrillation in primary care: Randomised controlled trial comparing two intensities of coumarin with aspirin. Br Med J. 1999; 3 19:958-964. 25. Malik AK, Taylor AJ. Can warfarin randomized trials be reproduced in ‘real life”? Adherence to warfarin guidelines for intensity of anticoagulation in a universitybased warfarin clinic. South h4ed J. 2000; 93:58-61. 26. Ansell JE, Buttaro ML, Thomas OV, Knowlton CH, for the Anticoagulation Guidelines Task Force. Consensus guidelines for coordinated outpatient oral anticoagulation therapy management. Ann Pharmacothe,: 1997;3 I :604-615.
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27. Hirsh J, Dalen JE, Deykin D, et al. Oral anticoagulants. Mechanism of action, clinical effectiveness, and optimal therapeutic range. Chest. 1995; IO8(Suppl 4):23 IS2468.
28. Samsa GP, Matchar DB, Goldstein LB, et al. Quality of anticoagulation management among patients with atrial fibrillation: Results of a review of medical records from 2 communities. Arch Intern Med. 2000; 160:967-973.
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34 Caro JJ, Flegel KM, Orejuela M, et al. Anticoagulant prophylaxis against stroke in atrial fibrillation: Effectiveness in actual practice. Corn Med Assoc J. 1999: I 6 I : 493-497. 35. Kalra L, Yu G, Perez I, et al. Prospective cohort study to determine if trial efficacy of anticoagulation for stroke prevention in atrial fibrillation translates into clinical effectiveness. Br Med J. 2000;320: I2361239.
29. Lesho EP, Michaud E, Asquith D. Do anticoagulation clinics treat patients more effectively than physicians‘? Arch Intern Med. 2000; 160:243. Editorial.
36. Hylek EM, Singer DE. Risk factors for intracranial hemorrhage in outpatients taking warfarin. Ann Intern Med. 1994:120: 897-902.
30. Sawicki PT, for the Working Group for the Study of Patient Self-Management of Oral Anticoagulation. A structured teaching and self-management program for patients receiving oral anticoagulation: A randomized controlled trial. JAMA. 1999; 281:145-150.
31. Moherman LJ, Kolar MM. Complication rates for a telephone-based anticoagulation service. Am J Health Syst Phorm. 1999;56: 1540-1542.
37. Aronow WS, Ahn C, Kronzon I, Gutstein H. Incidence of new thromboembolic stroke in persons 62 years and older with chronic atrial fibrillation treated with warfarin versus aspirin. J Am Geria/r SW. 1999;47:366-368. 38. Palareti G. Hirsh J. Legnani C, et al. Oral anticoagulation treatment in the elderly: A nested, prospective. case-control study. Arch Intern Med. 2000; I60:470478.
32. Chiquette E. Amato MC, Bussey HI. Comparison of an anticoagulation clinic with usual medical care: Anticoagulation control, patient outcomes, and health care costs. Arch Intern Med. 1998;158:16411647.
33. Ansell JE, Pate1 N, Ostrovsky
D, et al. Long-term patient self-management of oral anticoagulation. Arch intern Med. 1995;155:2185-2189.
39. Gage BF. Cardinalli AB, Albers GW. Owens DK. Cost-effectiveness of warfarin and aspirin for prophylaxis of stroke in patients with nonvalvular atrial fibrillation. JAMA. 1995;274: 1839-1845. 40. Kalra L, Perer I. Melbourn A. Risk assessment and anticoagulation for primary stroke prevention in atrial fibrillation. Stroke. 1999;30: I2 18-l 222.
Address correspondence to: A.H. Abdelhafiz, MBBCh, MSc, MRCP, Specialist Registrar, Acute and Elderly Medicine, Northern General Hospital, Harries Road, Sheffield, S Yorks, S.5 7AU, UK. E-mail: [email protected]
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IO,2001
A Review of Anticoagulation with Warfarin in Patients with Nonvalvular Atria1 Fibrillation
Ahmed H. Abdelhafz,
MBBCh, MSc, MRCP
Acute and Elderly Medicine, Northern Gene& England
Hospitul, Sh@eld,
South Yorkshire,
ABSTRACT Background: Warfarin therapy has proved safe and effective in a number of randomized controlled trials of stroke prophylaxis in patients with nonvalvular atria1 fibrillation (NVAF), reducing the risk of stroke in these patients by two thirds. However, participants in the clinical trials were carefully selected and younger than patients in actual clinical practice. Objective: This analysis sought to determine whether the results of clinical trials in patients with NVAF can be extrapolated to the general population seen in clinical practice. Methods: A MEDLINE search from 1966 to the present was used to identify observational trials of anticoagulation in patients with NVAF that addressed warfarin use, anticoagulation control, efticacy, and complications. The search terms used were atrialfihrillation and unticougulution. Results: Although warfarin prophylaxis against stroke in patients with NVAF appeared to be as well tolerated and effective in clinical practice as in clinical trials, it was generally underused, particularly in the elderly. Anticoagulation control was not as good in clinical practice as in clinical trials, although the rates of stroke and major bleeding were comparable. Conclusions: Judicious use of warfarin, tailored to individual stroke risk, seems to be a reasonable policy. Warfarin therapy increases quality-adjusted survival in patients at high risk for stroke, and it is recommended for medium-risk patients unless their risk of bleeding is high or their quality of life while taking warfarin would be poor. Patients at a low risk for stroke will have equivalent health outcomes and incur lower costs if treated with aspirin. Despite the increased risk of hemorrhage in elderly patients, the net benefit of warfarin therapy is greater in this age group because of the higher risk of stroke. Active involvement of patients and their caregivers in an anticoagulation service setting may improve outcomes of anticoagulation therapy.
Accepted
for publication
August 6, 2001.
Printed in the USA. Reproduction
1628
in whole or part is not permitted.
A.H. ABDELHAFIZ
Key words: atria1 fibrillation, anticoagulation, clinical practice, efficacy, safety. (C/in Thel: 2001;23:1628-1636)
INTRODUCTION Atria1 fibrillation (AF) is a major risk factor for stroke, increasing the risk 5-fold compared with that in individuals with normal sinus rhythm.’ Randomized controlled trials have shown that prophylactic treatment with warfarin decreases the risk of stroke by 60% to 70% in patients with nonvalvular AF (NVAF),2 and guidelines support the use of warfarin in these patients.3,4 The major benefit of warfarin is seen in patients at highest risk for strokethose aged >75 years and those of any age with such risk factors as hypertension, poor ventricular function, diabetes mellitus, or previous transient ischemic attack (TIA) or stroke.” Because of the highly selected nature of patients in randomized clinical trials, there is concern over whether the evidence from such trials can be applied to clinical practice.6 Most patients with NVAF who are screened for such trials are ultimately excluded (>90% in 1 tria17). Patients in clinical practice may have different baseline risks compared with patients in clinical trials or may respond differently to anticoagulant treatment. In addition, compliance and safety may be different in clinical practice than in the carefully selected, well-motivated, and closely monitored participants in clinical studies. It is in high-risk older patients that physicians most fear inducing bleeding complications through the use of anticoagulation. Therefore, underutilization of this effective therapy is a continuing problem in all age groups, but particularly in the elderly.”
This analysis sought to determine whether the results of the major clinical trials of stroke prophylaxis in patients with NVAF7,9-14 can be extrapolated to the lessselected patients seen in clinical practice. A MEDLINE search from 1966 to the present was used to identify the relevant clinical and observational trials of anticoagulation in NVAF that addressed warfarin use, anticoagulation control, efficacy, and complications. The search terms used were utrial jibrillution and anticoagulation.
UNDERUSE OF WARFARIN IN PATIENTS WITH NVAF Antithrombotic treatment is underused in patients admitted to the hospital with stroke. In a European observational study of 2 13 patients with NVAF consecutively admitted to 3 European centers for an acute stroke or TIA in 1997,1s 148 (69.5%) had known NVAF and 34 (16.0%) were receiving anticoagulation before the stroke. Of 137 patients eligible for oral anticoagulation, 108 (78.8%) did not receive this treatment. New-onset NVAF and contraindications to anticoagulation accounted for a minority of those who did not receive oral anticoagulation. In prospective surveys of medical admissions to a Scottish district general hospitall and a hospital in Birmingham, England, serving a multiracial population,t7 NVAF was present in 3% to 6% of patients. Antithrombotic treatment was underused in patients with NVAF despite the presence of clinical risk factors for stroke (hypertension, heart failure, previous thromboembolism). In 61 patients discharged from the hospital with a new diagnosis of NVAF, only 15 (25.0%) received a prescription for warfarin.i7 In the Scottish study,16 only 34% of patients who
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were eligible for warfarin treatment had a contraindication to anticoagulation. In another study,lx retrospective analysis of the case notes of patients with NVAF showed that >SO% were not prescribed warfarin, despite the absence of contraindications. Warfarin was also underused in a prospective population-based observational study in 5201 patients with NVAF aged 270 years in 4 communities in the United StatesI In a subgroup analysis of 172 (4.1%) patients, warfarin was prescribed for only 63 (36.6%). Of the 109 participants not reporting warfarin use, 92 (84.4%) had 21 risk factor for stroke. In a study in 5888 community-dwelling adults aged 26.5 years,“’ warfarin use increased 4-fold from 1990 to 1996 (from 13% to 50%) among patients with NVAF (P < 0.001). However, in 1996, patients aged <80 years were 4 times more likely to be using warfarin than those aged 280 years (P < 0.001). In a recent evaluative study of factors influencing the decision to use anticoagulation, Cohen et al”’ found that warfarin use lagged behind the need. Age >80 years, language diff’culties, insufficient physician awareness of the benefit, and patient disability emerged as independent variables negatively influencing the use of warfarin. In contrast, a history of stroke and the availability of echocardiographic information, regardless of the findings, were associated with increased warfarin use.
MONITORING AND CONTROL OF ANTICOAGULATION IN CLINICAL PRACTICE Low-intensity anticoagulation with warfarin (ie, international normalized ratio [INR] 2.0-3.0) is recommended for patients with NVAF. because this provides
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the same degree of protection against stroke as more intense anticoagulation (ie, higher INR) but has a lower risk for major bleeding. *? In a review of the medical records of patients with NVAF in clinical practice,?s monitoring was performed less frequently than in clinical trials (mean of 36.340.9 days vs 21-28 days in clinical trials) and the INR was within the target therapeutic range less often (50% of days vs 68% of days in clinical trials). Although the mean INR was within the target range on 68% of days in clinical trials, there was considerable variability (44%83%). 7,9-‘4 Patients in the Canadian Atria1 Fibrillation Anticoagulation study”’ and the Stroke Prevention in Atrial Fibrillation study’ had much smaller proportions of days within the target range (44% and 56%, respectively) compared with patients in other trials. In 2 recent studies,21,” the target INR was achieved on 48.0% and 57.8% of days, respectively.
Anticoagulation Services and Patient Involvement Anticoagulation services (ACS) have been cited as a means of improving the provision of anticoagulation,‘6~‘7 relieving the busy physician of the day-to-day details of anticoagulation management. The ACS manager (typically a pharmacist, physician’s assistant, nurse, or nurse-practitioner) is responsible for dosing changes, scheduling, patient education, and other aspects of anticoagulation therapy. Studies in patients with access to ACS have shown that the quality of warfarin treatment (measured in terms of [l] the proportion of eligible patients receiving warfarin, [2] the proportion of time the INR was in the target range, and [3] when an INR outside the target range occurred, the time until the next INR deter-
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mination was made) was higher and the INR remained within the target range for longer periods compared with conventionally managed anticoagulation (68% vs 58%, respectively; P < 0.001).28~29 In a randomized controlled trial,“” patient education in self-management of anticoagulation (intervention group) resulted in less deviation in the INR from the mean target at 3- and 6-month follow-up compared with the control group, who received no patient education (squared INR deviation, 0.59 intervention group vs 0.95 control group at 3 months [P < O.OOl]; 0.65 vs 0.83 at 6 months [P = 0.031). INR values of the intervention group were within the target range more often than those of the control group (P = 0.006). Treatmentrelated quality-of-life measures, particularly treatment satisfaction scores, were significantly higher in the intervention group compared with the control group. In a study of a telephone-based ACS3’ the rates of complications of anticoagulation appeared to be similar to those reported for conventional anticoagulation clinics. ACS may be more cost-effective than conventional anticoagulation management. In a study comparing anticoagulation delivered through usual medical care and through an ACS,” patients treated at an ACS had lower rates of significant bleeding (8.1% vs 35.0%; P < O.OOl), major to fatal bleeding (1.6% vs 3.9%; P < 0.05), and thromboembolic events (3.3% vs 11.8%; P < 0.05). The mortality rate was numerically lower in patients managed at an ACS (0% vs 2.9%) but the difference was not statistically significant. Significantly lower annual rates of warfarin-related hospitalizations (5% vs 19%; P < 0.001) and emergency department visits (6% vs 22%; P < 0.001) reduced annual health care costs by $132,086 per 100 patients.
Self-monitoring of prothrombin time (PT) and self-adjustment of the warfarin dosage were evaluated in a long-term study at a tertiary medical institution.“” Study patients monitored their PT on 2 153 occasions over a mean of 44.7 months, compared with 1608 PT measurements over a mean of 42.5 months in matched controls treated with conventional management. Over the study period, there were a mean 11.5 dosage changes per study patient, compared with 22.7 changes per control patient (P < 0.001). Study patients had a PT within the recommended therapeutic range in 88.6% of determinations (95% CI, 87.2-89.9) compared with 68.0% in matched controls (95% CI, 65.7-70.3; P < 0.001). In the investigators’ opinion, patients who measure their own PT and adjust their warfarin dosage accordingly can achieve therapeutic effectiveness at least as good as that seen in patients managed in a conventional anticoagulation clinic.
EFFICACY AND COMPLICATIONS OF WARFARIN ANTICOAGULATION In a recent prospective observational study evaluating the effects of preventive anticoagulation in patients with NVAF in 2 practice settings in Montreal, Canada,‘4 22 1 patients with documented NVAF were followed for a mean of 27 months. There were 4 treatment groups: aspirin, warfarin, blended treatment (comprising patients who started on 1 active treatment and switched to the other or who switched treatments more than once), and no treatment. Patients were interviewed by telephone every 6 months, and reported events were confirmed through a review of patients’ charts. The investigators found that on average, study patients were older
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(mean + SD age, 71.6 f 9.3 years) and had a higher prevalence of underlying heart disease (52.0%) than those in pooled data from randomized clinical trials. Thirty-one (14.0%) patients received aspirin, 87 (39.3%) received warfarin, 65 (29.4%) received blended treatment, and 38 (17.1%) received no treatment, for a total of 493.7 person-years of follow-up. Nineteen patients had a first stroke during the follow-up period: 4 (5.2% per year) in the aspirin group, 4 ( I .8%) in the warfarin group, 4 (5.3%) in the blended-treatment group, and 7 (5.9%) in the no-treatment group. Only warfarin treatment was associated with a significantly lower risk of stroke compared with no treatment (RR, 0.3 1; 95% CI, 0.09-l .OO). The rate of any bleeding per 100 person-years was not significantly different between treatment groups (aspirin 2.5%, warfarin 3.4%, blended treatment 3.5%) compared with no treatment (1.9%). The relative effect of warfarin anticoagulation for the prevention of stroke in these practice settings was equivalent to that in randomized trials (bleeding rate in clinical trials, 1.4%4.2%), although these patients were older and sicker.7,“m’4 In another 2-year, prospective cohort study in a clinical practice setting,j” 167 patients with NVAF and a high risk for stroke received anticoagulation to maintain an INR between 2.0 and 3.0. Rates of stroke and major hemorrhage were compared with pooled data from randomized controlled trials in similar patients. Compared with the pooled trial data, the study group was a mean of 7 years older (95% CI, 4-10 years) and included 33% more women. The incidence of stroke in the study group (2.0% per year; 95% Cl, 0.7%4.4%) was comparable to that in patients receiving warfarin in
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the pooled study data (1.4%; 95% CI, 0.8%-2.3%). The annual incidence of major and minor bleeding complications was not significantly different between the study group and patients included in the pooled data (major bleeding, 1.7% vs 1.6%, respectively; minor bleeding, 5.4% vs 9.2%). In a case-control analysis,‘(’ bleeding risk was evaluated in 121 adult patients taking warfarin who were hospitalized for intracranial hemorrhage (intracerebra1 hemorrhage, 77 [46% fatal]; subdural hemorrhage, 44 [20% fatal]). Each patient was matched to 3 randomly selected, age-matched outpatients. Prothrombin time ratio (PTR) was the predominant risk factor for intracranial hemorrhage. The risk for intracerebral hemorrhage doubled with each 0.5 increase in PTR over the entire range (OR, 2.1; 95% CI, I .4-2.9). The risk for subdural hemorrhage was unchanged over the PTR range from 1.0 to 2.0 but rose dramatically above 2.0 (-INR, 4.0). Age was the only other significant independent risk factor for subdural hemorrhage (OR. 2.0 per decade; 95% CI, I .3-3.1). Age was of borderline significance as a risk factor for intracerebral hemorrhage (OR, 1.3 per decade; 95% Cl, 1.0-1.6).
ANTICOAGULATION IN THE ELDERLY In an observational study of 3 12 elderly patients with NVAF in a large long-term care facility,j7 208 women and 104 men (mean 2 SD age, 84 + 7 years; range, 62-101 years) received anticoagulation with aspirin 325 mg/d (n = 187) or warfarin adjusted to maintain an INR between 2.0 and 3.0 (n = 125). The incidence of new thromboembolic stroke was compared
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in the 2 groups over 36 +- I7 months (range, l-99 months) of follow-up. Four patients (3.2%) stopped taking warfarin because of adverse effects, compared with 4 (2.1%) who stopped taking aspirin (P = NS). New thromboembolic stroke occurred in 27 of 67 (40.3%) warfarin patients with a previous stroke and 56 of 69 (81.2%) aspirin patients (P < 0.001). In patients with no previous stroke, new thromboembolic stroke occurred in 13 of 58 (22.4%) warfarin patients and 66 of 1 18 (55.9%) aspirin patients (P < 0.001). Overall, new thromboembolic stroke occurred in 40 of 125 (32.0%) warfarin patients and 122 of 187 (65.2%) aspirin patients (P < 0.001). Cox regression analysis showed that after controlling for other risk factors, patients taking warfarin had a 76% lower risk of developing a new thromboembolic stroke than those taking aspirin. A prospective, multicenter study’s examined whether warfarin treatment placed elderly patients at increased risk for complications. Rates of bleeding and thrombotic events were compared in 461 patients aged 275 years and 461 patients aged ~70 years matched for sex, warfarin indication, and treatment center. Total bleeding rates in the older and younger patients were 9.9% and 6.6% patientyears, respectively (P = NS), and rates of major bleeding were 2.1% and 1.1% (P = NS); 6 and 1 of the events (all intracranial bleeding) were fatal in the respective groups (RR, 6.4; P = 0.05). In the older patients, the bleeding rate was lower (4.5%) in those with an INR between 2.0 and 2.9. Rates of thrombotic events in the older and younger patients were 4.2% and 2.5% patient-years, respectively (P = NS). The rate of thrombotic events in older patients was lower (1.5%) in those with an INR between 2.0
and 2.9. The results indicated that an INR <2.0 did not preclude bleeding in the elderly or offer adequate protection against thrombotic events. The best-tolerated and most effective option in these elderly patients appeared to be moderate anticoagulation (INR 2.0-3.0).
COST CONSIDERATIONS Gage et al” studied the quality-adjusted survival and cost-effectiveness of warfarin anticoagulation compared with aspirin or no therapy in patients with NVAF with and without additional risk factors for stroke. In patients with NVAF and additional risk factors for stroke (high-risk group), warfarin therapy led to greater quality-adjusted survival and produced cost savings. In patients with NVAF and I additional risk factor for stroke (moderaterisk group), warfarin therapy cost $8000 per quality-adjusted life-year saved. In patients aged $65 years with NVAF alone (low-risk group), warfarin cost -$370,000 per quality-adjusted life-year saved compared with aspirin therapy, whereas in those aged 275 years with NVAF alone (moderate-risk group), warfarin cost $110,000 per quality-adjusted life-year saved. In patients who did not receive warfarin, aspirin was preferred to no therapy on the basis of both qualityadjusted survival and cost in all patients, regardless of the number of risk factors. The investigators concluded that treatment with warfarin was cost-effective in patients with NVAF and 21 additional risk factor for stroke, whereas in 65-year-old patients with NVAF but no other risk factors for stroke, using warfarin rather than aspirin would have minimal effect on quality-adjusted survival while increasing costs significantly.
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CONCLUSIONS Based on the available data, warfarin appears to be as well tolerated and effective in clinical practice as in clinical trials. The decision to use anticoagulation in patients with NVAF should be clinically based after careful assessment of patient eligibility and the appropriateness of anticoagulation. 4o Judicious use of warlarin, tailored to individual stroke risk, seems to be a reasonable policy. Warfarin therapy increases quality-adjusted survival in patients at high risk for stroke, and it is recommended for medium-risk patients unless their risk of bleeding is high or their quality of life while taking warfarin would be poor. Patients at low risk for stroke will have equivalent health outcomes and incur lower costs if treated with aspirin. Despite its efficacy, warfarin anticoagulation remains underused, particularly in the elderly. It is less expensive in the elderly than in younger patients, and age in itself is not a risk factor for bleeding complications. Despite the increased risk of hemorrhage due to multiple comorbidities and polypharmacy in elderly patients, the net benefit of warfarin therapy is greater in this age group than in younger patients because of the increased risk of stroke. In elderly patients, moderate anticoagulation (INR 2.0-3.0) seems to be better tolerated and more effective than other intensities of anticoagulation, which either are not effective (INR ~2.0) or are associated with an increased risk of bleeding (INR >3.0). More research is needed to clarify the relative importance of barriers to warfarin use associated with patients, physicians, and health care systems, making it possible to target future interventions more precisely. Active involvement of patients and
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their caregivers in an ACS setting help improve outcomes.
may
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Address correspondence to: A.H. Abdelhafiz, MBBCh, MSc, MRCP, Specialist Registrar, Acute and Elderly Medicine, Northern General Hospital, Harries Road, Sheffield, S Yorks, S.5 7AU, UK. E-mail: [email protected]
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