(Stroke. 2002;33:322.)
© 2002 American Heart Association, Inc.
Letters to the Editor |
Diurnal Variation in the Intensity of Anticoagulation in Atrial Fibrillation
Cardiology Service, General Hospital of Alicante
Hematology Service, General Hospital of Alicante
Hematology Unit, General Hospital of San Vicente, Alicante, Spain
Hematology Service, General Hospital of Alicante
To the Editor:
We read with interest the letter by Lip et al1 about the diurnal variation in the onset of stroke in atrial fibrillation (AF), which reported the presence of a circadian rhythm in stroke onset among these patients, with a higher number of strokes taking place between 6 AM and 6 PM and fewer between midnight and 6 AM. Although it is not specified if this variation occurs in both anticoagulated patients and those who are not, it seems that it is also present in patients who were receiving anticoagulation in the moment the stroke took place.
It is known that the majority of cardiovascular events (myocardial infarction, sudden death, etc) follow a circadian pattern,2,3 with most events occurring early in the morning. We also know that AF increases the risk of systemic embolism and that individual risk depends on some clinical and echocardiographic features.4,5 It has been demonstrated that AF confers a hypercoagulable state.6,7 On the other hand, this hypercoagulable state has been associated with the presence of thrombus in the left atrial appendage.8 However, there has been little scientific interest in the study of a possible circadian pattern in the hypercoagulable state seen in AF. Li-Saw-Hee et al9 analyzed the circadian rhythm in some hemostatic factors in patients with chronic AF; they concluded that there was no significant diurnal variation in plasma levels of any of these factors and, thus, that the prothrombotic state in AF was persistent. Decousus et al10 suggested that there is a diurnal variation in the intensity of anticoagulation, even if intravenous heparin is administrated in a constant infusion. This variation in the intensity of anticoagulation together with the persistent hypercoagulable state in AF could be responsible for a different thromboembolic risk during the day, existing periods when protection against stroke would be insufficient.
To study the presence of circadian variations in the degree of anticoagulation, we measured the international normalized ratio (INR) in 21 patients with chronic AF at four different moments of the day (noon, 6 PM, 11 PM, and 8 AM). All these patients had received controlled anticoagulation therapy with acenocoumarol (once daily, at 6 PM), maintaining a consistent INR between therapeutic limits (INR=2.00 to 3.00) for at least 4 weeks. Oral anticoagulant therapy was monitored using an automated assay (ACL Futura, Instrumentation Laboratory Co.) with a bovine calcium thromboplastin (Pro-IL-Complex, ISI 1.02). Factor VII is one of the proteins inactivated by oral anticoagulants—as it has the shortest half-life of all of them (6 hours), its diurnal variation in response to anticoagulant therapy can be seen in a 24-hour period. We determined levels of factor VII using a clotting assay with factor VII deficient plasma and its activated form (factor VIIa; STACLOT VIIa-rTF, Diagnostica STAGO), both in an automated coagulometer (STA, Roche).
There was a diurnal variation in INR measurements in patients with AF, with lower levels at 11 PM and 8 AM compared with those at noon and 6 PM (paired-samples t test, P=0.046). The majority of our patients were anticoagulated correctly, with only 2 of the measurements (2.4%) under therapeutic range. There was also a circadian rhythm in factor VII and factor VIIa levels (see Table). Based on these results, it seems to be a period (between 11 PM and 8 AM) when the intensity of anticoagulation is lower (reflected by lower INR and higher levels of factor VII).
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To our knowledge, no studies have analyzed circadian variations in anticoagulation intensity in patients with AF. Our study demonstrates the existence of a circadian rhythm in the intensity of anticoagulation in these patients, with lower INR values at 11 PM and 8 AM; moreover, the levels of factor VII and factor VIIa (inactivated by oral anticoagulants) were higher in the same period. The lower intensity of anticoagulation during the night and in early morning together with the lack of diurnal variation in hemostatic factors that has been reported8 could explain a clustering in stroke occurrence in the morning and early evening, as shown by Lip et al.
We agree with the second aspect of their letter, which points to the underutilization of antithrombotic therapy in patients with AF. The efficacy of this therapy to prevent embolic events in high-risk patients has been demonstrated (advanced age, high blood pressure, heart failure, history of stroke, etc),4,11–13, with nearly 65% reduction in the incidence of stroke.14 In spite of this, several studies have showed that it is scarcely used.15–18 To analyze the use of this therapy in our community, we collected data about the use of antithrombotic therapy in 57 patients with chronic AF of 1506 consecutive patients who came to our emergency service on 8 aleatory days. Although all of them had at least one clinical or echocardiographic risk factor for stroke, only 47% were taking anticoagulation therapy (acenocoumarol) and 23% were taking aspirin; none of them were taking both acenocoumarol and aspirin. In the multivariate analysis, only 2 variables were associated with the use of anticoagulation: age (the use of acenocoumarol was significantly higher in younger patients) and the fact that the patient was visited by a cardiologist rather than by a general internist or a family physician. Risk factors such as hypertension, heart failure, history of stroke, and diabetes showed no relationship to the use of antithrombotic therapy, nor did other aspects studied such as sex, comorbidity (CIRS scale), left atrial diameter, and left ventricle ejection fraction.
To conclude, our study shows the presence of a diurnal variation in the intensity of anticoagulation in patients with AF who were under oral anticoagulation with acenocoumarol, with lower levels during the night and early morning. This could explain the higher number of strokes taking place during the morning and afternoon. On the other hand, and in accordance with other studies, we have found that antithrombotic therapy is scarcely used in patients with AF, even if they have risk factors for stroke.
References
1.
Lip GYH, Tan E, Lau C, Kamath S. Diurnal variation in stroke onset in atrial fibrillation. Stroke. 2001; 32: 1443.Letter.
2. Muller J, Stone P, Turi Z. Circadian variation in the frequency of acute myocardial infarction. N Engl J Med. 1985; 313: 1315–1322.[Abstract]
3. Muller J, Ludmer P, Willich S. Circadian variation in the frequency of sudden cardiac death. Circulation. 1987; 1: 131–138.
4.
Atrial Fibrillation Investigators. Risk factors for stroke and efficacy of antithrombotic therapy in atrial fibrillation: analysis of pooled data from five randomised controlled trials. Arch Intern Med. 1994; 154: 1449–1457.
5. Stroke Prevention in Atrial Fibrillation Investigators. Predictors of thromboembolism in atrial fibrillation, II: echocardiographic features of patients at risk. Ann Intern Med. 1992; 116: 6–12.
6. Lip GYH. Does atrial fibrillation confer a hypercoagulable state?. Lancet. 1995; 346: 1113–1114.[CrossRef][Medline] [Order article via Infotrieve]
7. Roldán V, Marín F, Marco P, Martinez JG, Calatayud R, Sogorb F. Hypofibrinolysis in atrial fibrillation. Am Heart J. 1998; 136: 956–960.[CrossRef][Medline] [Order article via Infotrieve]
8.
Heppell RM, Berkin KE, McLenachan JM, Davies JA. Haemostatic and haemodynamic abnormalities associated with left atrial thrombosis in non-rheumatic atrial fibrillation. Heart. 1997; 77: 407–411.
9.
Li-Saw-Hee FL, Blann AD, Lip GYH. A cross-sectional and diurnal study of thrombogenesis among patients with chronic atrial fibrillation. J Am Coll Cardiol. 2000; 35: 1926–1931.
10. Decousus HA, Croze M, Levi FA, Jaubert JG, Perpoint BM, De Bonadona JF, Reinberg A, Queneau PM. Circadian changes in anticoagulant effect of heparin infused at a constant rate. BMJ. 1985; 290: 341–344.
11.
The Stroke Prevention in Atrial Fibrillation Investigators. The stroke prevention in atrial fibrillation study: final results. Circulation. 1991; 84: 527–539.
12. 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: 1505–1511.[Abstract]
13. Petersen P, Boysen G, Godtfredsen J, Andersen ED, Andersen B. Placebo-controlled randomised trial of warfarin and aspirin for prevention of thromboembolic complications in chronic atrial fibrillation: the Copenhagen AFASAK study. Lancet. 1989; 1: 175–179.[Medline] [Order article via Infotrieve]
14.
Hart RG, Halperin JL. Atrial fibrillation and thromboembolism: a decade of progress in stroke prevention. Ann Intern Med. 1999; 131: 688–695.
15. White RH, McBurnie MA, Manolio T, Furberg CD, Gardin JM, Kittner SJ, Bovill E, Knepper L. Oral anticoagulation in patients with atrial fibrillation: adherence with guidelines in an elderly cohort. Am J Med. 1999; 106: 165–171.[CrossRef][Medline] [Order article via Infotrieve]
16.
Stafford RS, Singer DE. Recent national patterns of warfarin use in atrial fibrillation. Circulation. 1998; 97: 1231–1233.
17.
Bungard TJ, Ghali WA, Teo KK, McAlister FA, Tsuyuki RT. Why do patients with atrial fibrillation not receive warfarin? Arch Intern Med. 2000; 160: 41–46.
18.
Cage BF, Boechler M, Doggette AL, Fortune G, Flaker GC, Rich MW, Radford MJ. Adverse outcomes and predictors of underuse of antithrombotic therapy in Medicare beneficiaries with chronic atrial fibrillation. Stroke. 2000; 31: 822–827.
University Department of Medicine, City Hospital, Birmingham B18 7QH, England UK
Response
We thank Garcia et al for their interest in our letter on diurnal variation in stroke among patients with atrial fibrillation (AF). Their proposal on a diurnal variation in INR intensity, with lower INR levels at 11 PM and 8 AM, and higher factor VII levels, when compared with levels at noon and 6 PM, would be consistent with our observations.
We would also agree with their second point that antithrombotic therapy is underutilized in patients with AF, despite the presence of stroke risk factors. While the evidence is there, and "high-risk" groups can be identified who would benefit most from warfarin,1 there still remains considerable variation in the management of AF among consultant physicians2 and more recently, among accident and emergency (A&E) department clinicians.3
Observations from the latter survey of 124 A&E consultants in England3 are important, as A&E consultants were more likely to initiate treatment only if the patient with AF had signs of shock or heart failure, but when patients had other associated medical problems, they were more likely to be referred directly to the "on-call" medical team. There was also a general reluctance to start anticoagulation in the A&E department, this being seen as something best handled by the medical team, and differences in opinion over how long AF should have persisted for anticoagulation to be necessary in the context of electrical cardioversion. Given the current view of A&E as the "front line" of medical management, it makes it even more important that A&E clinicians should at least initiate management of patients with AF and be prepared to manage them for some time in the A&E department.
A final point relates to the patients’ perceptions of AF, their understanding of the disease, and the risks/benefits of antithrombotic therapy. In the West Birmingham Atrial Fibrillation Project, we have recently shown that many patients with AF possess very limited knowledge of AF as well as its consequences and therapy; furthermore there were significant differences between the different ethnic groups (Caucasian, Afro-Caribbean, Indo-Asian) in terms of their knowledge of the risks, actions, and benefits of warfarin as well as AF itself.4
We recently extended this study to a small pilot survey of 36 patients (11 men; mean age 73 years, SD 6) with AF in Kuala Lumpur, Malaysia; 75% were Chinese, 19% Malay, and 6% Indian. The commonest comorbid factors were hypertension (31%), heart failure (19%), and ischemic heart disease (14%). When these AF patients were asked whether they knew what condition they had, 72% reported "don’t know," while other responses included "heart condition" (17%), and "fast/irregular heartbeat" in 8%. Only 1 patient could specify that the condition was "atrial fibrillation." When asked about the seriousness of their condition, only 30% regarded AF as "serious," with 36% considering AF as "not serious," and 34% "did not know." Only 8% of respondents knew that AF led to an increased risk of stroke, and 36% said that warfarin use did not pose any risk(s). The majority (58%) considered that fate/God had the most control over their health. Only 16 patients (44%) were taking warfarin (despite risk factors in most of them), and 81% of these did so "because their doctor told them to." Given the paucity of literature from non-Caucasian populations with AF, these observations from a Malaysian AF patient population are broadly in keeping with our observations from Birmingham, England—highlighting the need for greater patient education and improvement in their understanding of this common but potentially serious cardiac arrhythmia.
References
1. Lip GYH. Thromboprophylaxis for atrial fibrillation. Lancet. 1999; 353: 4–6.[CrossRef][Medline] [Order article via Infotrieve]
2.
Lip GYH, Zarifis J, Watson RD, Beevers DG. Physician variation in the management of patients with atrial fibrillation. Heart. 1996; 75: 200–205.
3.
Williams E, Ansari M, Lip GYH. Management of atrial fibrillation in the accident and emergency department: a survey of accident and emergency consultants. Q J Med. 2001; 94: 609–614.
4.
Lip GYH, Kamath S, Jafri M, Mohammed A, Bareford D. Ethnic differences in patient perceptions of atrial fibrillation and anticoagulation therapy: the West Birmingham Atrial Fibrillation Project. Stroke. 2002; 33: 238–242.
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