To the Editor: The recent position statement by the Warfarin Reversal Consensus Group provides clear and concise guidelines for a number of clinical scenarios related to the use of warfarin. 1 Unfortunately, it makes the general statement about the periprocedural management of warfarin in patients with atrial fibrillation (AF), “clinical experience suggests that bridging therapy is not required” [page 496]. Clinicians caring for patients with large ischaemic stroke in these circumstances may beg to differ.

Although studies of bridging therapy in patients with AF in the periprocedural period are lacking, there are data which suggest that there is a considerably higher risk of thromboembolism during this period than would be expected by simply calculating the risk for several days off anticoagulation therapy.2-4 My own study of such patients undergoing endoscopy found a stroke risk of up to 3% in those at high risk.2 Many of these strokes were severe. The prothrombotic periprocedural environment may be a factor here, although advanced age and vascular risk factors may also contribute. The outstanding risk factor, however, is a previous history of stroke,2 and this is also a major risk factor for perioperative stroke in patients without AF.5 I would suggest careful, individualised assessment of all patients, and judicious bridging therapy where possible for patients with AF who have a past history of stroke.

To the Editor: The recent position statement from the Warfarin Reversal Consensus Group provides a comprehensive, coherent and practical approach to warfarin reversal management. 1

In reviewing the position statement, and with particular reference to the paragraph about modifiers of warfarin response, we noted that the contribution of cytochrome P450 2C9 (CYP2C9) genotype to the response to warfarin was not addressed. There is debate in the current literature about the clinical utility of evaluating CYP 2C9 genotype in patients already taking or about to start warfarin therapy. Nonetheless, a significant body of evidence supports the contribution of CYP2C9 genetic variants as modifiers of response to warfarin therapy.

CYP2C9 is the enzyme principally involved in metabolising warfarin.2 Several studies have identified the presence of single nucleotide polymorphisms in the CYP2C9 gene resulting in the expression of two allelic variants of CYP2C9 (CYP2C9*2 and CYP2C9*3) that are associated with reduced enzymatic activity, impaired metabolism of and increased sensitivity to standard warfarin doses.2,3 The allelic frequency of the mutant genotypes is in excess of 21% in the white population2 (they occur at reduced frequencies in African American populations and are rare in Asian populations4). The presence of allelic variants (CYP2C9*2 and CYP2C9*3) with reduced enzymatic activity is closely correlated with increased bleeding complications.2,3 Thus, there is potential for a considerable clinical impact given the large number of patients taking warfarin.

We have identified an allelic frequency of CYP2C9*2 and CYP2C9*3 genotypes in an Australian population of patients attending an anticoagulant clinic comparable to that reported in the literature.2,3 We also identified international normalised ratios in excess of the target range in patients with the CYP2C9*2 or CYP2C9*3 genotype undergoing induction warfarin therapy with standard dosing regimens, relative to those who did not have these genotypes (personal, unpublished data, presented as: Cytochrome P450 CYP2C9 genotyping and warfarin induction therapy, presented at the 2004 Annual Scientific Meeting of the Haematology Society of Australia and New Zealand [Oct 17–20, Melbourne, Australia]).

Recent reports suggest that CYP2C9 genotyping before inducing warfarin therapy may avert bleeding complications.5 However, CYP2C9 genotyping is currently only available within research institutes and larger corporations with research and development facilities and does not attract a Medicare rebate. While simple and inexpensive, genetic CYP2C9 screening has yet to be proven cost effective. However, genotyping may be of benefit in averting over-anticoagulation in certain clinical scenarios. These include commencing warfarin therapy in “high risk” elderly patients; those in whom low-dose, long-term, low-testing-frequency warfarin regimens are being contemplated; and in other “high risk” patients, such as those with conditions affecting warfarin metabolism, including liver disease, and in those taking medications known to interact with the hepatic metabolism of warfarin.

To the Editor: The article by Baker et al was a timely review of managing anticoagulation therapy and balancing the risks of thrombosis and bleeding.1 However, in managing anticoagulation therapy before non-cardiac surgery in patients with mechanical cardiac valve prostheses, the suggested 5-day cessation of warfarin therapy, with only subcutaneous heparin cover, is not appropriate. I have had three patients with mechanical bileaflet mitral prostheses develop valve thrombosis while under this protocol, two with a fatal outcome. I have also had one patient with a mechanical bileaflet aortic valve develop a popliteal arterial embolus requiring thrombectomy, despite being treated according to the protocol.

The consequences of valve thrombosis and thromboembolism far outweigh the lesser complications of increased bruising or bleeding associated with non-cardiac surgery. To avoid the potentially devastating complications of valve thromboembolism associated with the routine cessation of warfarin therapy 5 days before surgery, warfarin ought to be continued to maintain an INR (international normalised ratio) of around 2.0, supplemented with subcutaneous heparin. Alternatively, full intravenous heparinisation can be used while ceasing warfarin treatment, and continued postoperatively until the INR is restored to the therapeutic level. Warfarin should never be reversed with vitamin K, except in cases of life-threatening haemorrhage.

Apropos of the therapeutic INR ranges generally recommended for mechanical cardiac valve replacements, the current generation of prostheses does not require the anticoagulation intensity of the older style prostheses.2,3 Lower intensity anticoagulation is sufficient to prevent thromboembolism at decreased risk of haemorrhagic complications.4 My personal practice for patients with bileaflet mechanical prostheses is to maintain an INR of 2.0–2.5 for aortic valves, and 2.5–3.0 for mitral valves. The higher intensity for mitral prostheses relates to potential increased thrombogenicity because of lower leaflet opening pressures, as well as the common association of left atrial dilatation and atrial fibrillation.

To the Editor: A middle-aged woman with atrial fibrillation had her warfarin therapy stopped for 2 days before dental extraction. She had a catastrophic stroke and is now a plaintiff. I was asked if her medical management accorded with common practice.

At the October 2004 Annual Conference of the Royal Australian College of General Practitioners, I conducted a straw poll of 20 experienced GPs, of whom 18 said they would stop warfarin for between 2 and 4 days before a dental extraction. Some of these GPs regarded a dental extraction as elective surgery and pointed me to authoritative (but slightly ambiguous) sources to back up their view. 1,2 However, a review of the medical and dental literature shows that this is an example of common practice lagging behind clinical evidence.

The first controlled trial of dental extraction in patients on warfarin therapy was conducted in 1983.3 It showed that it was not necessary to cease warfarin prophylaxis for patients whose international normalised ratio (INR) was within the normal therapeutic range. Since then, two major literature reviews have confirmed these conclusions.4,5 A recent Australian review on warfarin reversal expresses a similar point of view.6 The incidence of a serious embolic complication from stopping therapy with warfarin is 1%, and this is three times more likely to occur than bleeding complications in patients whose warfarin therapy was continued.4 Furthermore, a stroke is a catastrophic event, while a bleeding tooth socket is simply messy and usually easily controlled.

An authoritative review and position statement on warfarin therapy and dental procedures from the Australasian Society of Thrombosis and Haemostasis may be the catalyst required to align common practice with clinical evidence.

In reply: We thank Blacker for his constructive and helpful comments. Our recommendations on bridging therapy in patients with atrial fibrillation were for patients with chronic atrial fibrillation who had not previously had a thromboembolic event.1 We do agree with Blacker that extreme care needs to be exercised in patients with atrial fibrillation and a previous thromboembolism. These patients should be managed along the same lines as patients who are at relatively high risk of recurrent thromboembolism. We also wish to emphasise that it is extremely important to assess each individual patient carefully, and to use the consensus guidelines as guiding principles, and not apply them blindly.

Dear and his colleagues correctly point out that there are several published studies that have confirmed increased warfarin sensitivity in allelic variants of the cytochrome P450 2C9 (CYP2C9) enzyme. Polymorphisms associated with reduced enzymatic activity have been reported to be associated with increased warfarin sensitivity. They suggest that determining the genotype of individuals before commencing warfarin therapy may be of benefit in reducing the incidence of over-anticoagulation in a select group of patients. We do not believe that this approach is currently practical or possible. From a practical point of view we recognise several reasons why patients become over-anticoagulated when treated with warfarin. In our article we discussed several important modifiers that contribute to an individual’s sensitivity to warfarin. While we agree that polymorphisms of the CYP2C9 gene on its own have been linked with increased sensitivity to warfarin, we are not aware of any studies showing a synergistic interaction of the polymorphism with other clinically recognised causes of increased warfarin sensitivity. Furthermore, we are not aware of any properly conducted studies that have attempted to address the clinical or economic viability of screening for CYP2C9 polymorphisms in patients for whom warfarin therapy is planned. Finally, the time required to obtain the results of this investigation would preclude its application in the routine management of patients who require warfarin therapy.

The letter by Lubicz highlights the difficulties encountered in bridging anticoagulant therapy in patients with prosthetic valves. As pointed out in our article, the management of these patients is controversial and mostly anecdotal.1 We believe that the recommendations in our article are useful for most patients, but would like to emphasise the need to consult with the relevant experts in order to avoid bleeding or thrombosis. We would not recommend routine full therapeutic anticoagulation therapy with heparin immediately after surgery, or the combined use of warfarin at any international normalised ratio (INR) with subcutaneous heparin before surgery. Such approaches are more likely to cause confusion and predispose the patients to either bleeding or the risk of thrombosis. Patients with prosthetic valves require careful handling, and involving experts in their management is critical.

Kamien’s comments are important and illustrate the difficulties in changing entrenched practices. We hope that our recommendations will go some way to improving the way we manage patients on warfarin therapy who are about to undergo surgery.