The value of novel oral anticoagulants in rural Australia

The new agents offer important safety and convenience advantages, but need to win the confidence of clinicians and patients

For more than 60 years, vitamin K antagonists, such as warfarin, have been the only option for long term oral anticoagulation therapy. Although effective for preventing and treating thromboembolism, warfarin is underused because controlling coagulation time (as measured by the international normalised ratio [INR]) is complex, and because of concerns about the risk of bleeding.1 Even when warfarin therapy is carefully managed, the INR of some patients is frequently outside the target range. Poor warfarin therapy control is associated with an increased risk of thromboembolism and bleeding. More convenient and safer oral anticoagulants are urgently needed.2

Non-vitamin K antagonist (or novel) oral anticoagulants (NOACs), including dabigatran, rivaroxaban and apixaban, have been available in Australia for more than 5 years. In large randomised, controlled trials involving more than 70 000 patients with atrial fibrillation and more than 28 000 patients with venous thromboembolism, NOACs administered in fixed doses without routine coagulation monitoring were found to be at least as effective as warfarin, but with important safety advantages:3 they reduced the risk of intracranial bleeding by one-half, and of fatal bleeding by one-third.4 These results have been replicated in database studies collectively involving more than 500 000 patients,5 and have been accompanied by a progressive increase in the uptake of NOACs worldwide. The convenience and safety advantages of NOACs compared with warfarin make these agents particularly attractive in rural and remote settings, where undertreatment is common, access to INR testing facilities is limited, management of severe bleeding can be challenging, and health outcomes are inferior to those in urban areas.6

In this issue of the MJA, Bellinge and colleagues7 report the results of a retrospective cohort study examining the uptake of NOACs in rural Australia in the 2 years following their listing by the Pharmaceutical Benefits Scheme. Among 609 patients with principal diagnoses of atrial fibrillation or venous thromboembolism admitted to one of four hospitals in rural Western Australia during 1 January 2014 – 31 December 2015, NOACs, warfarin, and low molecular weight heparin were prescribed for 33.7%, 32.8% and 7.6% of patients respectively; 25.9% of patients, most with atrial fibrillation, received aspirin or no antithrombotic therapy. The choice between a NOAC or warfarin differed by indication: among patients with newly diagnosed atrial fibrillation, NOACs were prescribed more often than warfarin (33% v 24%); among those with pre-existing atrial fibrillation, NOACs and warfarin had been prescribed at similar rates prior to their being admitted to hospital, but NOACs were prescribed more frequently at discharge (38% v 27%); and among patients with a diagnosis of venous thromboembolism, warfarin was prescribed more often than a NOAC (48% v 29%). Distance from the patient’s local hospital also appeared to influence the choice of treatment; those who lived locally were more likely to receive warfarin than a NOAC (38% v 31%), while those living further away were more likely to be prescribed a NOAC (36% v 29%). With respect to clinical outcomes, NOACs were associated with lower rates of bleeding than warfarin (4% v 10%; P = 0.027), while efficacy was similar (5% v 4% of patients re-admitted to hospital because of a new transient ischaemic attack, ischaemic stroke, systemic arterial thromboembolism, or venous thromboembolism). However, the results were not adjusted for differences in baseline characteristics, which may have contributed to the observed differences.

The increasing uptake of NOACs for long term oral anticoagulation therapy and the preference for them over warfarin when treating rural patients who have recently diagnosed atrial fibrillation or live some distance from regional hospitals probably reflects recognition by clinicians and patients that they are more convenient and safer than warfarin. Nevertheless, major treatment gaps remain. Despite increases in the uptake of oral anticoagulants, one-third of rural patients with a clear indication for anticoagulation therapy received aspirin or no treatment, and warfarin was still widely prescribed. Aspirin is relatively ineffective for preventing stroke in patients with atrial fibrillation; warfarin is clearly superior to aspirin, but NOACs offer important safety advantages, even when compared with well controlled warfarin therapy.8

The NOACs provide an opportunity for further reducing the burden of preventable stroke and other thromboembolic events in rural and remote Australia. Although progress is being made, further improvements will require intensified efforts to educate physicians and patients about the evidence for their efficacy and superior safety, as well as about the particular advantages of NOACs in settings where medical care may be less accessible. The recent introduction of idarucizumab as a rapidly acting and highly effective reversal agent for dabigatran,9 and the future prospect of andexanet alfa as a specific reversal agent for factor Xa inhibitors10 may help to further improve the confidence of clinicians and patients in the value of NOACs for preventing and treating thromboembolism.