To the Editor: I appreciated Brukner’s perspective on treatment of venous thromboembolism (VTE),1 but I do feel some additional considerations and clarifications are in order.

Quotes from Kearon2 and Kearon and colleagues3 about the duration of therapy are missing an important caveat. The suggestion for longer duration and possibly “indefinite” anticoagulant therapy after a first deep vein thrombosis or pulmonary embolism is in reference to unprovoked VTE. Brukner1 mentions a plane flight from China to Australia 3 days before he experienced a symptomatic pulmonary embolism. According to guidelines issued by the American College of Chest Physicians, such a flight (although I cannot comment with certainty on its duration) is likely to represent a reversible minor risk factor for VTE — “prolonged travel (eg, > 8 h)”.3

Indeed, Kearon2 and the authors of a related research article to which he refers4 make the important distinction between provoked and unprovoked VTE. Kearon comments:

Additional factors and preferences are also important when considering prolonged anticoagulant therapy for individual patients. For instance, I can empathise with the 25-year-old who wants to discontinue warfarin therapy after 6 months following a first unprovoked VTE — another 50 years of warfarin therapy might seem a disheartening burden. And certainly we must take into account other variables that may increase a patient’s risk of bleeding complications while receiving warfarin therapy, such as older age, the presence of other acute or chronic illnesses and the use of other medications, particularly antiplatelet therapy.3

For someone such as Brukner,1 who claims that his anxiety about a recurrence of VTE is reduced by staying on warfarin therapy, I would probably say, “That’s OK by me, as long as you are aware of the risks and implications of provoked and unprovoked VTE”. For other patients with unprovoked VTE who may not want to continue indefinite anticoagulant therapy, there are other management options worth discussing. First, there is the possibility of further risk stratification for VTE recurrence by testing D-dimer levels. This strategy is receiving considerable study and validation as a useful tool for predicting VTE recurrence.5,6 Second, for patients who refuse to continue warfarin therapy but would consider other therapies for reducing their risk of having a recurrence of VTE, I would suggest taking a daily low dose of vitamin E, which has shown some benefit in reducing VTE.7 Finally, the ASPIRE (Aspirin to Prevent Recurrent Venous Thromboembolism) Trial, which is currently underway, should provide a definitive answer as to whether aspirin is a safe and effective option for secondary VTE prevention. If the trial supports the use of aspirin for this purpose, it would offer another VTE risk-reduction option for those who prefer not to take warfarin indefinitely.8

To the Editor: Brukner’s personal perspective in a recent issue of the Journal highlights the inherent difficulty of managing patients taking warfarin.1 Although Brukner advocates life-long warfarin therapy for patients who have experienced a pulmonary embolism, we believe few clinicians would be willing to expose their patients to the increased risk of haemorrhage associated with long-term warfarin therapy, especially if a transient risk factor for venous thromboembolism (VTE) existed (such as frequent air travel, in Brukner’s case).

There is an abundance of conjecture regarding the appropriate duration of warfarin therapy for VTE, with guidelines and clinical intuition often differing. But it is possible that, in the future, decisions about the appropriate duration of warfarin therapy may be guided by the use of pharmacogenetics. Pharmacogenetics gives clinicians an insight into how a patient’s genetic profile affects his or her ability to metabolise drugs, thereby allowing doctors to better tailor the dose and duration of the patient’s medications.

In the case of warfarin, metabolism of S-warfarin (the more potent enantiomer in the racemic warfarin mixture) occurs via the cytochrome P450 system, specifically enzyme CYP2C9.2 Studies have shown that patients who metabolise warfarin normally are homozygous for the wild-type allele CYP2C9*1, whereas patients with polymorphisms in the CYP2C9 allele have reduced warfarin metabolism and increased risk of bleeding.3 The anticoagulation effect of warfarin actually occurs via inhibition of the C1 subunit of the vitamin K 2,3-epoxide reductase complex (VKORC1).4 Numerous polymorphisms have been identified in VKORC1, and it is speculated that VKORC1 polymorphisms alone may account for a significant proportion of response variability to warfarin.4

Validated algorithms have been developed to combine information on a patient’s CYP2C9 and VKORC1 genotypes with factors such as age and body surface area to identify an appropriate warfarin regimen.5 Although the pharmacogenetic information required to employ this algorithm has not been assessed for cost-effectiveness, it is quite possible that clinicians will be able to use such pharmacogenetic information to their advantage in the future. This would allow doctors to identify with greater precision which patients are likely to benefit from warfarin (and how much is required, for how long), rather than relying on equivocal evidence and clinical intuition alone.