Rapid Responses to:
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Rapid Responses: Rapid Responses published:
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![[Read Rapid Response]](/icons/misc/sectionDOWN.gif)
anticoagulation in AF
- dr.manan vasenwala (2 November 2002)
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Evidence for Aspirin-Clopidogrel combination is lacking
- Abhimanyu Lal (5 November 2002)
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Warfarin induced skin necrosis
- Wasiq A Thiryayi (6 November 2002)
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Utilisation of anti-thrombotic prophylaxis in Atrial fibrillation - putting theory into practice
- Varadarajan Baskar, Srinivasa Rangan, Dominic F D'Costa (14 November 2002)
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Full risk stratification
- James M. Walker (22 November 2002)
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Risk stratification cannot simply be linked to choice of antithrombotic prophylaxis in AF
- Nicolaas L. J. Magis, Carel Bakx, Henk G.A. Mokkink (24 December 2002)
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Antithrombotic prophylaxis for non-valvular atrial fibrillation: the endless story
- Claudio Cimminiello, Claudio Cimminiello, Luigi santoro, Ornella Mastrogiacomo, and Angelo Bignamini (6 April 2003)
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dr.manan vasenwala, consultant-cardiologist (non-invasive) aligarh-202002. india
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quite often, the person most needing anticoagulation has contraindications either medical or social. the elderly patient,any unreliable patient, living alone or in rural setup where facilities of monitoring are not available is the usual scenario in my practice. one has to then improvise. aspirin is always easy to prescribe. minidose warfarin is a good idea, but not backed by evidence of efficacy. current thinking with ischaemic heart disease, is to combine aspirin with clopidogrel. in fact, formulations are already available in india with this combination to be given once a day. clopidogrel is relatively free of adverse effects compared to ticlopidine.it is also cheaper than other newer antiplatelet agents.direct thrombin inhibitors are expensive. whether benefits can be extrapolated to prevention of thromboembolism in AF is yet unknown. it is true that benefit of anticoagulation is less in the young, but so is true for the complications. the elderly are more prone to develope intra- cranial hemorrhage than the young. tight monitoring is more required in the elderly. the role of echocardiography cannot be underestimated. only by echocardiography can one detect structural heart disease like mitral- aortic-annulo calcification, lv dysfunction, valve diasease, left atrial enlargement or left atrial appendicular dysfunction. i think it is an important non-invasive investigation for risk stratification especially when warfarin is being considered in AF. younger patients (<65yrs) who have 'lone-fibrillation'with a normal echocardiogram have a low risk of thrombo-embolism. but until an echo is done this stratification would be incomplete. Competing interests: None declared |
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Abhimanyu Lal, Clinical Observer Derriford Hospital, Plymouth
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Dear Sirs, The rapid response to Lip et al article “ABC of antithrombotic therapy: Antithrombotic therapy for atrial fibrillation” [1], entitled “anticoagulation in AF” by Vasenwala, has discussed the use of aspirin- clopidogrel combinations for thromboprophylaxis in patients with atrial fibrillation (AF) [2]. Kamath et al have demonstrated that a combination of Aspirin and Clopidogrel is not effective in reducing the plasma indices of platelet activation and thrombogenesis in AF [3]. Furthermore, Muller et al in their study on aspirin-clopidogrel versus Warfarin in AF concluded that Aspirin–Clopidogrel combination was not effective in modulating the coagulation cascade in AF [4]. There is no doubt that Warfarin therapy does necessitate regular monitoring of INR and dose changes, which poses problem in various settings, as mentioned by Dr. Vasenwala. Early data with Ximelagatran, the new direct oral thrombin inhibitor (currently in phase III of trials) [5], are encouraging, and suggest that Ximelagatran can prove to be equal, if not superior, to Warfarin in efficacy in thromboprophylaxis for AF. Furthermore monitoring of its dose is not required. We believe that the evidence available at present therefore does not support the use of the Aspirin–Clopidogrel combination in preference to Warfarin in patients with atrial fibrillation. References: 1. Gregory Y H Lip, Robert G Hart, Dwayne S G Conway. ABC of antithrombotic therapy: Antithrombotic therapy for atrial fibrillation. BMJ 2002; 325: 1022-1025. 2. manan vasenwala: Anticoagulation in AF (BMJ, 2 Nov 2002). Rapid response to ABC of antithrombotic therapy: Antithrombotic therapy for atrial fibrillation. BMJ 2002; 325: 1022-1025. 3. Kamath S, Blann A D, Chin B S, Lip G Y. A prospective randomised trial of aspirin-clopidogrel combination therapy and dose-adjusted Warfarin on indices of thrombogenesis and platelet activation in atrial fibrillation. J Am Coll Cardiol. 2002 Aug 7;40(3):484-90. 4. Muller I, Massberg S, Zierhut W, Binz C, Schuster A, Rudiger-Von Hoch S, Braun S, Gawaz M. Effects of Aspirin and Clopidogrel versus Oral Anticoagulation on Platelet Function and on Coagulation in Patients with Nonvalvular Atrial Fibrillation (CLAFIB). Pathophysiol Haemost Thromb. 2002 May;32(1):16-24. 5. Hopfner R. Ximelagatran (Astra Zeneca). Curr Opin Investig Drugs. 2002 Feb;3(2):246-51. Competing interests: None declared |
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Wasiq A Thiryayi, House Officer in General Surgery Royal Albert Edward Infirmary, Wigan, WN1 2NN
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Warfarin, as part of the therapy and prophylaxis of atrial fibrillation and venous thromboembolism, is undoubtedly the most widely used oral anticoagulant. However, one can never discount the fact that this medical intervention is designed to create an artificial bleeding tendency and the trade-off between the risk of bleeding and that of thrombosis, seems to be best achieved at a target INR level of 2-3. Also, the risk of bleeding complications is documented to increase with prolonged duration of use. However, there is one particular baffling complication, which can manifest even after the first warfarin dose. Yet, not all are aware of warfarin induced skin necrosis. This adverse effect is based on the drug’s mechanism of action of inhibiting the Vitamin K dependent protein activation. It is not just native pro-coagulant proteins, factors II, VII, IX and X, but also native anticoagulant proteins, protein C and S, in particular, that depend on this step for activation. A shorter native anticoagulant protein half –life imbalances the equation, leading to a temporary excess of pro- coagulant proteins. And a paradoxical clotty state ensues thereafter. CLINICAL PRESENTATION:
Competing interests: None declared |
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Varadarajan Baskar, Clinical Lecturer in Diabetes New Cross Hospital, Wolverhampton WV10 0QP, United Kingdom, Srinivasa Rangan, Dominic F D'Costa
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Despite evidence (1), observational studies have consistently shown an apparent under use of antithrombotic drugs in patients with atrial fibrillation (AF) (2-4). We evaluated the utilisation rates of anti- thrombotic prophylaxis in chronic AF and whether there were differences between specialities in a hospital discharge setting over two consecutive years. Evaluation of 100 case records during each of the years showed 79% (1999) and 89% (2000) overall to be on appropriate prophylaxis based on their risk. While there was a trend towards more appropriate use of antithrombotic prophylaxis by the cardiologists (100%) compared to other physicians (80% general physicians and 81% care of the elderly physicians), this difference was statistically insignificant. The decision to use antithrombotic prophylaxis in patients with AF involves a careful consideration of potential benefits versus the risks. However, it has been recently shown that physicians and patients vary considerably in their weighting up of the potential outcomes associated with AF and its treatment, underlining the importance of incorporating patients’ preferences in decision making (5). Our results suggest risk stratification and implementation of recommendations can easily be performed in clinical practice. It may no longer be appropriate in governance terms to accept poor rates of antithrombotic use. Furthermore, risk reassessment on an annual basis is also important since age is one of the most important determinants of risk. However, in elderly patients, risk stratification can be difficult as small changes in a patients’ functional status can make anticoagulation unsafe and therefore in such cases regular and close follow-up is mandatory. References 1. Lip GYH, Hart RG, Conway DSG. ABC of antithrombotic therapy for atrial fibrillation. Br. Med J 2002; 325: 1022-25. 2. Sudlow M, Rodgers H, Kenny RA, Thomson R. Population based study of use of anticoagulants among patients with atrial fibrillation in the community. BMJ 1997; 314: 1529-1530. 3. Adhiyaman V, Kamalakannan D, Oke A, Shaw IU, White AD. Underutilisation of antithrombotic therapy in atrial fibrillation. J R Soc Med 2000;93:138- 140 4. Perez I, Melbourn A, Kalra L. Use of antithrombotic measure for stroke prevention in atrial fibrillation. Heart 1999;82:570-574. 5. Devereaux PJ, Anderson DR, Gardner MJ, Putnam W et al. Differences between perspectives of physicians and patients on anticoagulation in patients with atrial fibrillation: observational study. BMJ 2001;323:1-7. Competing interests: None declared |
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James M. Walker, Associate, Internal Medicine Chief Medical Information Officer Geisinger Health System 100 N. Academy Ave. Danville, PA 17822 USA
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The SPAF investigators demonstrated that patients with atrial fibrillation can be risk-stratified as having between a 1.5% to 9.0% per year risk of bleeding (1). Surely the standard of care is that every patient should have their risk of stroke and of bleeding on warfarin estimated and discussed with them (with updates whenever a clinical event or birthday changes either estimate). Since this is not humanly possible, improved electronic medical records will be necessary to prompt the elicitation and input of the required information, calculate the risk estimates, and update the estimates automatically (as well as recording the patient's decision). 1. SPAF Investigators (1996). "Bleeding during antithrombotic therapy in patients with atrial fibrillation." Arch Intern Med 156: 409. Competing interests: None declared |
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Nicolaas L. J. Magis, general practitioner Department of Vocational Training for General Practitioners, UMCN, PO Box 9101, 6500 HB Nijmegen, NL, Carel Bakx, Henk G.A. Mokkink
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Risk stratification cannot simply be linked to choice of antithrombotic prophylaxis in atrial fibrillation EDITOR – The clinical review by Lip et al1 was about the different aspects of antithrombotic therapy in atrial fibrillation, as well as the considerations involved in the decision making process. We disagree with Lip when he states that the benefits of anticoagulant therapy are greater for elderly patients, while young patients at a relative low risk have less to gain from full dose anticoagulation as there may be little difference between the number of strokes prevented and the number of haemorrhagic complications. There seems a misconception about the use of risk stratification schemes. While their use in assessing risk has been generally accepted, there is no clear proof that high-risk patients are better off with anticoagulants while low-risk patients are better off with aspirin. We conducted a review of all randomised controlled trials directly comparing anticoagulants and aspirin or other platelet inhibitors as antithrombotic prophylaxis in atrial fibrillation. Seven trials met our criteria: AFASAK (’89)2, BAATAF (’92)3, EAFT (’93)4, SPAF II (’94)5, SIFA (’97)6, AFASAK II (’98)7, and PATAF (’99)8. There were marked differences between these trials in selecting patients, dosage of aspirin, range of INR, duration of follow-up, and most importantly in the choice of primary endpoints (some involving only thrombo-embolic complications, others involving both thrombo-embolic and haemorrhagic complications). Three trials (AFASAK, BAATAF and EAFT) showed that treatment with anticoagulants gave significantly better results than treatment with aspirin. Four trials (SPAF II, SIFA, AFASAK II and PATAF) showed no significant difference. Only in the SPAF II trial subgroup analysis was done based on risk stratification: the population was divided into two groups, one younger than 75 years, one older. The trial showed that there were significantly more bleeding complications in the older group. The primary endpoints of this study were ischaemic stroke and systemic embolism. Both the group younger than 75 years (RR 0,67, 95% CI 0,34-1,3, p=0,24) and the group older than 75 years (RR 0,73, 95% CI 0,37-1,5, p=0,39) showed no significantly better results with anticoagulants. Therefore, the assumption that people at higher risk because of their age benefit more from treatment with anticoagulants was not confirmed. Since age is only one of many risk factors, we would recommend more trials that use risk stratification schemes to divide the trial population into risk categories, in order to compare anticoagulants and aspirin within a low, intermediate and high risk group. The assumption that high risk groups, mostly seen by general practitioners, benefit more from anticoagulants in comparison with low risk groups needs further investigation. Nicolaas LJ Magis, general practitioner nicmagis@hotmail.com Carel Bakx, general practitioner Henk GA Mokkink, methodologist Department of Vocational Training for General Practitioners, University Medical Centre Nijmegen PO Box 9101, 6500 HB Nijmegen, Netherlands 1 Lip GYH, Hart RG, Conway DSG. ABC of antithrombotic therapy: Antithrombotic therapy for atrial fibrillation. BMJ 2002;325:1022-1025 2 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;1:175-9. 3 Singer DE, Hughes RA, Gress DR, Sheehan MA, Oertel LB, Maraventano SW, et al. The effect of aspirin on the risk of stroke in patients with nonreumatic atrial fibrillation: The BAATAF study. American Heart Journal 1992;124:1567-73. 4 EAFT (European Atrial Fibrillation Trial) Study Group. Secondary prevention in non-rheumatic atrial fibrillation after transient ischaemic attack or minor stroke. Lancet 1993;342:1255-62. 5 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. 6 Morocutti C, Amabile G, Fattapposta F, Nicolosi A, Matteoli S, Trappolini M, et al. Indobufen Versus Warfarin in the Secondary Prevention of Major Vascular Events in Nonrheumatic Atrial Fibrillation. Stroke 1997;28:1015-21. 7 Gulløv AL, Koefoed BG, Petersen P, Pedersen TS, Andersen ED, Godtfredsen J, et al. Fixed minidose warfarin and aspirin alone and in combination vs adjusted-dose warfarin for stroke prevention in atrial fibrillation; Second Copenhagen Atrial Fibrillation, Aspirin and Anticoagulation Study. Arch Intern Med 1998;158:1521. 8 Hellemons BSP, Langenberg M, Lodder J, Vermeer F, Schouten HJA, Lemmens Th et al. Primary prevention of arterial thromboembolism in non- rheumatic atrial fibrillation in primary care: randomised controlled trial comparing two intensities of coumarin with aspirin. BMJ 1999;319:958-64. Competing interests: None declared |
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Claudio Cimminiello, Chief Department of Medicine - Vimercate Hospital - Milan ITALY Vimercate Hospital-via C Battisti 22-20059-Vimercate (MILAN), Claudio Cimminiello, Luigi santoro, Ornella Mastrogiacomo, and Angelo Bignamini
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Antithrombotic prophylaxis for non-valvular atrial
fibrillation (NVAF) is the subject of endless debate. After the controversies
raised by Taylor's overview on the comparison between oral anticoagulants and
antiplatelet agents (1), there is the risk that the recent review by Lip et
al (2) may cause additional misunderstandings. This paper states that indobufen,
a cox-inhibitor antiplatelet agent, is as effective as warfarin on the basis
of a single small secondary prevention trial (3). Moreover, Lip and coworkers
also mention the study by Hart et al (4), a meta-analysis including 5 trials
that resulted in the superiority of warfarin over aspirin. Unfortunately, a
degree of generalization has to be introduced into overviews and meta-analyses,
which often prevents the achievement of a clear-cut outcome. This is the case
of the overviews reported so far on antithrombotic prophylaxis in NVAF. They
did not clarify definitely the true extent of the benefit of anticoagulant therapy
across categories of patients at different risk, so that no firm conclusion
can be reached regarding the risk/benefit ratio of this kind of therapy.
Figure 1 - Comparison of warfarin vs antiplatelet agents on the outcome "any stroke"; overall comparison and separate comparisons for primary and secondary prevention studies
Figure 2 - Comparison of warfarin vs antiplatelet agents on the combined outcome "death for any reason or non-fatal ischaemic stroke "; overall comparison and separate comparisons for primary and secondary prevention studies Recent studies (6) have highlighted the lack of marked
platelet activation in patients with NVAF and suggest that this factor may not
play an important role in the pathogenesis of thromboembolism in NVAF. However,
the source of emboli in the ischemic events that occur in NVAF patients has
not been established. The weaker protection afforded by cox-inhibitor antiplatelet
agents as compared to warfarin could also be related to the low efficacy of
these agent in the reduction of the risk of stroke.
Competing interests: Claudio Cimminiello is member of the steering committeee of the MATCH trial (Management of ATHerothrombosis with Clopidogrel in High-risk patients with stroke) and received fees from Sanofi-Synthelabo |
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