Send letter to journal:
Re: Low-intensity vitamin K antagonists in preference to aspirin for low risk patients with NVAF

Dear Editor,

Given the fact that abnormalities of coagulation rather than platelet abnormalities are the one which predominate in atrial fibrillation (AF)(1)(2), it seems more plausible to rely on low-intensity anticoagulation along the lines of BAATAF(3) and SPINAF(4) rather than on aspirin(1) when managing patients with non valvar atrial fibrillation (NVAF) deemed to be at low risk of thromboembolism. The principal shortcoming of BAATAF and SPNAF, rendering those trials potentially inapplicable to current practice, is that they relied on prothrombin time ratios (PTR) as opposed to INR, and the conversion factor from PTR to INR was, at best, only an approximation. Another potential drawback is the finding that, among patients taking warfarin, an INR of 1.5-1.9 at admission was associated with a mortality rate similar to that for an INR of less than 1.5, but this can be countered by the argument that Hylek et al did not adress this issue specifically in relation to low-risk NVAF patients(5). What we now need is a new trial specifically recruiting low risk NVAF patients (low risk criteria to include absence of previous embolic phenomena) where low intensity anticoagulation, using INR, will be compared with aspirin. In such a trial, in addition to categorising patients as being either at low risk or at high risk of thromboembolism, the risk/benefit profile of VKA might be further enhanced by profiling those patients for CYP2C9 genetic variants so as to evaluate warfarin-related haemorrhagic risk(6).

Yours sincerely

OMP Jolobe

References

(1) Lip GYH and Boos CJ Antithrombotic treatment in atrial fibrillation Heart 2006:92:155-61.

(2) Stein B., Foster V., Halperin JL et al Antithrombotic therapy in cardiac disease: an emerging approach based on pathogenesis and risk Circulation 1989:80:1501-13.

(3) The Boston Area Anticoagulation Trial for Atrial Fibrillation(BAATAF) Investigators The effect of low-dose warfarin on the risk of stroke in patients with non -rheumatic atrial fibrillation New England Journal of Medicine 1990:323:1505-11.

(4)Ezekowitz MD., Bridges SL., James KE et al Warfarin in the prevention of stroke associated with non-rheumatic atrial fibrillation(SPINAF) New England Journal of Medicine 1992:327:1406-12.

(5) Hylek EM., Go AS., Chang Y., et al Effect of intensity of oral anticoagulation on stroke severity and mortality in atrial fibrillation New England Journal of Medicine 2003:349:1019-26.

Send letter to journal:
Re: Antithrombotic treatment in atrial fibrillation

Dear Editor,

Given the fact that BAATAF conferred a relative risk reduction of 86%, and SPINAF conferred a relative risk reduction of 79% for embolic complications of non valvular atrial fibrillation(NVAF) utilising INR ranges of 1.5-2.7, and 1.4-2.8, respectively(1)(2), in a population presumably comprising, not only NVAF patients at high risk of embolic complications, but also those at low risk, the hypothesis that now needs to be tested is whether the risk/benefit ratio of Vitamin K Antagonists (VKA) might be favourably modified by utilising a comparable target INR range in NVAF patients deemed to be at low risk of embolic complications.

The other unresolved issue is one also adressed by the authors, namely, the initiation of anticoagulant therapy when a patient with atrial fibrillation presents with non-haemorrhagic embolic stroke, given the occasional occurence of haemorrhagic transformation (with accompanying clinical deterioration) within the first 8 days of presentation even in the case of initially small embolic infarcts(3). The dilemna is that, whilst haemorrhagic transformation within 14 days is significantly commoner (p<0.0001) among heparinised patients with embolic infarcts than among their non-heparinised counterparts, recurrence of ischaemic (presumably embolic) stroke during that time frame is also significantly less common (p<0.001) in the heparinised group than in their non-heparinised counterparts(4). This dilemna is compounded by the fact that, by definition, patients presenting with embolic complications belong to the high-risk category, justifying, on the basis of clinical trial evidence, a target INR in the range 2.5-4.0(5). What is even more potentially intriguing is whether the analogy of aspirin resistance applies to some of these high-risk patients, justifying a target INR of 3.0-4.0 as opposed to 2.0-3.0 in order to confer complete prophylaxis.

A nationwide questionnaire of anticoagulant clinics might reveal cases of either native valve rheumatic atrial fibrillation or NVAF where extracerebral embolic complications occured despite anticoagulation within the INR range of 2.0-3.0. I encountered one such case (with native valve rheumatic atrial fibrillation) during my 19 years as NHS consultant, leading me to assume, rightly or wrongly, that some patients with native valve rheumatic atrial fibrillation (in particular those with mitral stenosis) might be more fully protected by utilising a target INR of 3.0-4.0.

OMP Jolobe

References

(1) The Boston Area Anticoagulant Trial for Atrial Fibrillation(BAATAF) Investigators The effect of low-dose warfarin on the risk of stroke in patients with non rheumatic atrial fibrillation. N Engl J Med 1990;323:1505-11

(2) Ezekowitz MD, bridgers SL, James KE et al Warfarin in the prevention of stroke associated with non rheumatic atrial fibrillation(SPINAF) N Enlg J Med 1992;327:1406-12.

(3) Cerebral Embolism Study Group Immediate anticoagulation of embolic stroke: brain hemorrhage and management options Stroke 1984;15:779-89.

(4) Saxena R., Lewis S., Berge E et al for the International Stroke trial collaborative Group Risk of early death and recurrent stroke and the effect of heparin in 3619 patients with acute iscemic stroke and atrial fibrillation in the internationnal stroke trial. Stroke 2001;32:2333-