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WARFARIN TO PREVENT THROMBOEMBOLISM IN CHRONIC ATRIAL FIBRILLATION
670 WARFARIN TO PREVENT THROMBOEMBOLISM IN CHRONIC ATRIAL FIBRILLATION
SiR,—In Dr Petersen and colleagues’ trial on the prevention of thromboembolism in chronic atrial fibrillation (the Copenhagen AFASAK study; Jan 28, p 175) the results were not analysed on an "intention-to-treat" basis. 5 thromboembolic complications were scored in the warfarin group, 20 in the aspirin group, and 21 in the placebo group. However, during the trial 126 patients (38%) in the warfarin group were withdrawn, compared with 44 (13%) in the aspirin group and 52 (15%) in the placebo group. 6 of the 126 patients withdrawn from the warfarin group had thromboembolic episodes. So, on an intention-to-treat basis the number of thromboembolic complications in the patients assigned to warfarin was 11 (5 + 6); the equivalent numbers for aspirin and for placebo are 21 (20 + 1) and 25 (21 + 4), respectively. A trend towards less thromboembolism in patients treated with warfarin remains, but the difference between warfarin and aspirin is not proven. We cannot, therefore, agree with the conclusion that it is "reasonable to recommend anticoagulation with warfarin for stroke prophylaxis in chronic AF".
PALLE PETERSEN GUDRUN BOYSEN
F. W. A. VERHEUGT T. W. GALEMA
1007MB Amsterdam, Netherlands
SIR,-Although the Copenhagen AFASAK study recorded thromboembolic complications less often in their warfarin-treated group (1-5%) than in the placebo group (6-2%) the conclusion that "it seems reasonable to recommend anticoagulation with warfarin for stroke prophylaxis in chronic (non-rheumatic) AF" is open to question. In a population-based study of isolated AF over three decades from the Mayo Clinic,’ the cumulative frequency of stroke on an actuarial basis at 15 years was only 13%, which is lower than the frequency in the warfarin-treated group in AFASAK. Furthermore, one must weigh the risk of anticoagulant therapy against the benefit. The complication rate of bleeding on anticoagulant therapy in the Copenhagen study, including 1 death and 1 case requiring blood transfusion, was 6-3%, which is much greater than the observed risk of thromboembolism. I agree that "studies on the effect of long-term anticoagulation are therefore still needed". Department of Medicine George Washington University Medical Center, Washington DC 23037, USA
TSUNG O. CHENG
Kopecky SL, Gersh BJ, McGoon MD, et al. The natural history of lone atrial fibrillation, a population-based study over three decades N Engl J Med 1987, 317: 669-74.
JOHN GODTFREDSEN
Department of Neurology, Rigghospitalet, DK-2100 Copenhagen, Denmark 1
Department of Cardiology, Free University Hospital,
1.
the study medication. On the basis of the AFASAK study we still find it reasonable to recommend warfarin treatment in patients with chronic AF. Professor Cheng states that the incidence of thromboembolic complications was 1 5% in our warfarin-treated group and 6-2% in the placebo group. This is not correct. The yearly incidence was 20% and 55%, respectively. Cheng compares our results with those of Kopecky and colleagues,’ who studied younger patients with isolated atrial fibrillation (AF), most of whom had paroxysmal AF. Our study was in older patients with chronic AF, which could explain the difference in the rate of thromboembolic complications between the two studies. Most of the bleeding complications were minor and the consequences were not comparable with those of thromboembolic complications.
ELLEN D. ANDERSON
BJØRN ANDERSEN
Kopecky SL, Gersh BJ, McGoon MD, et al The natural history of lone atnal fibrillation, a population-based study over three decades. N Engl J Med 1987, 317: 669-74
ANTINEUTROPHIL CYTOPLASMIC ANTIBODIES
SIR,-Mr Hoare and Mr Rhys Evans’
case report of subglottic antineutrophil cytoplasmic antibody (ANCA) (Dec 10, p 1360) serves to point out that this autoantibody is not specific just for classic Wegener’s granulomatosis. The subsequent criticism (Jan 7, p 53 and Feb 4, p 269) shows that the controversy is largely due to the lack of a satisfactory method for classifying vasculitic diseases. In fact, Wegener originally highlighted only a subgroup of vasculitides involving the upper respiratory tract associated with granuloma formation (Wegener called this "rhinogenic granulomatosis"). In our view the histopathological entity should be considered merely as one pole of a multidimensional spectrum of conditions. It is therefore important to keep an open mind in diagnosing vasculitic diseases which might not fit into a particular
stenosis with
defined category. While in broad terms we agree that two major immunofluorescence patterns exist for ANCA, it is still premature to identify the antigens involved. The 29 kD protein2 and myeloperoxidase3are but two of the antigens that have received most attention. By ELISA with human lactoferrin (Sigma) we can detect lactoferrin antibody consistently in a male patient, aged 74, who has a vasculitic disease with renal, pulmonary, and arthritic
*/These letters have been shown to Dr Petersen and colleagues, reply follows.-ED L. SiR,—There seems to be some ambiguity in the use of the intention-to-treat principle. The purpose is to avoid certain biases and to provide conclusions of a pragmatic type. The assumption in this approach is that reliable information is available on all patients. whose
We used "intention to treat" in respect of cases in the warfarin group where there were events before treatment began or after it had been temporarily withdrawn. Our approach is, if anything, "unfair" to warfarin. The trial design stipulated that the interim analyses (and thereby any decision to stop the study) should be based on analysis of patients on treatment, so we did not use the intention-to-treat principle in analysing events after patients had been withdrawn. However, the follow-up procedure allowed for an intention-to-treat model and we gave the data. 6, 1, and 4 patients in the warfarin, aspirin, and placebo groups, respectively, had thromboembolic complications after withdrawal. Intention-totreat analysis gives 11, 21, and 25 thromboembolic complications in the three groups, respectively (p 0-056). An obvious drawback to a group sequential design is that treatment comparisons based upon other than our primary criteria may be less likely to be significant. However, we are not surprised that some patients in the warfarin group had thromboembolic complications after withdrawal from
’-,0 -’ ..J’
"" ,
II
’- V""
re- ’" -’-
,
Lactoferrin ELISA.
=
Lactoferrin (•-•) or bovine serum albumin ( x - x ) were incubated with 1/25 dilution of serum from patient with lactofernn antibody, then placed on microtitre plate coated with lactoferrin. Conjugated anti-human IgG was added and after addition of the substrate, optical density (OD) was measured. (o - - - -o) 1/25 dilution of normal serum. =
SiR,—In Dr Petersen and colleagues’ trial on the prevention of thromboembolism in chronic atrial fibrillation (the Copenhagen AFASAK study; Jan 28, p 175) the results were not analysed on an "intention-to-treat" basis. 5 thromboembolic complications were scored in the warfarin group, 20 in the aspirin group, and 21 in the placebo group. However, during the trial 126 patients (38%) in the warfarin group were withdrawn, compared with 44 (13%) in the aspirin group and 52 (15%) in the placebo group. 6 of the 126 patients withdrawn from the warfarin group had thromboembolic episodes. So, on an intention-to-treat basis the number of thromboembolic complications in the patients assigned to warfarin was 11 (5 + 6); the equivalent numbers for aspirin and for placebo are 21 (20 + 1) and 25 (21 + 4), respectively. A trend towards less thromboembolism in patients treated with warfarin remains, but the difference between warfarin and aspirin is not proven. We cannot, therefore, agree with the conclusion that it is "reasonable to recommend anticoagulation with warfarin for stroke prophylaxis in chronic AF".
PALLE PETERSEN GUDRUN BOYSEN
F. W. A. VERHEUGT T. W. GALEMA
1007MB Amsterdam, Netherlands
SIR,-Although the Copenhagen AFASAK study recorded thromboembolic complications less often in their warfarin-treated group (1-5%) than in the placebo group (6-2%) the conclusion that "it seems reasonable to recommend anticoagulation with warfarin for stroke prophylaxis in chronic (non-rheumatic) AF" is open to question. In a population-based study of isolated AF over three decades from the Mayo Clinic,’ the cumulative frequency of stroke on an actuarial basis at 15 years was only 13%, which is lower than the frequency in the warfarin-treated group in AFASAK. Furthermore, one must weigh the risk of anticoagulant therapy against the benefit. The complication rate of bleeding on anticoagulant therapy in the Copenhagen study, including 1 death and 1 case requiring blood transfusion, was 6-3%, which is much greater than the observed risk of thromboembolism. I agree that "studies on the effect of long-term anticoagulation are therefore still needed". Department of Medicine George Washington University Medical Center, Washington DC 23037, USA
TSUNG O. CHENG
Kopecky SL, Gersh BJ, McGoon MD, et al. The natural history of lone atrial fibrillation, a population-based study over three decades N Engl J Med 1987, 317: 669-74.
JOHN GODTFREDSEN
Department of Neurology, Rigghospitalet, DK-2100 Copenhagen, Denmark 1
Department of Cardiology, Free University Hospital,
1.
the study medication. On the basis of the AFASAK study we still find it reasonable to recommend warfarin treatment in patients with chronic AF. Professor Cheng states that the incidence of thromboembolic complications was 1 5% in our warfarin-treated group and 6-2% in the placebo group. This is not correct. The yearly incidence was 20% and 55%, respectively. Cheng compares our results with those of Kopecky and colleagues,’ who studied younger patients with isolated atrial fibrillation (AF), most of whom had paroxysmal AF. Our study was in older patients with chronic AF, which could explain the difference in the rate of thromboembolic complications between the two studies. Most of the bleeding complications were minor and the consequences were not comparable with those of thromboembolic complications.
ELLEN D. ANDERSON
BJØRN ANDERSEN
Kopecky SL, Gersh BJ, McGoon MD, et al The natural history of lone atnal fibrillation, a population-based study over three decades. N Engl J Med 1987, 317: 669-74
ANTINEUTROPHIL CYTOPLASMIC ANTIBODIES
SIR,-Mr Hoare and Mr Rhys Evans’
case report of subglottic antineutrophil cytoplasmic antibody (ANCA) (Dec 10, p 1360) serves to point out that this autoantibody is not specific just for classic Wegener’s granulomatosis. The subsequent criticism (Jan 7, p 53 and Feb 4, p 269) shows that the controversy is largely due to the lack of a satisfactory method for classifying vasculitic diseases. In fact, Wegener originally highlighted only a subgroup of vasculitides involving the upper respiratory tract associated with granuloma formation (Wegener called this "rhinogenic granulomatosis"). In our view the histopathological entity should be considered merely as one pole of a multidimensional spectrum of conditions. It is therefore important to keep an open mind in diagnosing vasculitic diseases which might not fit into a particular
stenosis with
defined category. While in broad terms we agree that two major immunofluorescence patterns exist for ANCA, it is still premature to identify the antigens involved. The 29 kD protein2 and myeloperoxidase3are but two of the antigens that have received most attention. By ELISA with human lactoferrin (Sigma) we can detect lactoferrin antibody consistently in a male patient, aged 74, who has a vasculitic disease with renal, pulmonary, and arthritic
*/These letters have been shown to Dr Petersen and colleagues, reply follows.-ED L. SiR,—There seems to be some ambiguity in the use of the intention-to-treat principle. The purpose is to avoid certain biases and to provide conclusions of a pragmatic type. The assumption in this approach is that reliable information is available on all patients. whose
We used "intention to treat" in respect of cases in the warfarin group where there were events before treatment began or after it had been temporarily withdrawn. Our approach is, if anything, "unfair" to warfarin. The trial design stipulated that the interim analyses (and thereby any decision to stop the study) should be based on analysis of patients on treatment, so we did not use the intention-to-treat principle in analysing events after patients had been withdrawn. However, the follow-up procedure allowed for an intention-to-treat model and we gave the data. 6, 1, and 4 patients in the warfarin, aspirin, and placebo groups, respectively, had thromboembolic complications after withdrawal. Intention-totreat analysis gives 11, 21, and 25 thromboembolic complications in the three groups, respectively (p 0-056). An obvious drawback to a group sequential design is that treatment comparisons based upon other than our primary criteria may be less likely to be significant. However, we are not surprised that some patients in the warfarin group had thromboembolic complications after withdrawal from
’-,0 -’ ..J’
"" ,
II
’- V""
re- ’" -’-
,
Lactoferrin ELISA.
=
Lactoferrin (•-•) or bovine serum albumin ( x - x ) were incubated with 1/25 dilution of serum from patient with lactofernn antibody, then placed on microtitre plate coated with lactoferrin. Conjugated anti-human IgG was added and after addition of the substrate, optical density (OD) was measured. (o - - - -o) 1/25 dilution of normal serum. =