Analysis: Can warfarin alternatives fulfil their promise?

The headlines were impressive. ‘£2.50 a day pill to beat stroke’. ‘First new anti-stroke treatment in 50 years’. Such was the coverage that greeted the first of several new oral anticoagulants (NOACs) to be approved by NICE last year.

The hope was that they would leave warfarin for the rats, but the reality has been quite different. Prescribing data suggest the newer drugs are largely being reserved for patients who are unsuitable for warfarin, with CCG leaders complaining of ‘huge cost implications’.

The latest blow is last month’s publication of data from the RE-ALIGN study, which was halted early because of an excess risk of bleeding in mechanical heart valve patients on dabigatran compared with warfarin. So where do all the conflicting messages on cost and safety leave GPs?

Early hope

After 50 years of waiting for an alternative to warfarin, three came along at once.

The 2009 RE-LY trial of dabigatran showed 150mg of the drug could significantly reduce the risk of stroke or systemic embolism in patients with atrial fibrillation by 34% over and above warfarin. Then in 2011 the ARISTOTLE trial showed similar results for apixaban and the ROCKET-AF trial reported that rivaroxaban was ‘non-inferior’ to warfarin.

The stage was set for a revolution in the management of stroke risk in AF. But almost immediately the cracks began to show.

When NICE gave the green light in March 2012 for GPs to prescribe dabigatran for stroke prevention in AF, it simultaneously dismissed an appeal by NHS Salford, which had argued approval would bust its drugs budget.

NICE ruled any potential budgetary impact dabigatran might have was ‘not a matter with which the appraisal committee was or could be concerned’. Based on a pack price of £75.60 plus VAT, NICE estimated an £18,900 cost per QALY for dabigatran – below the £20,000 threshold used to declare a treatment a cost-effective use of NHS resources.

While not disputing the cost-effectiveness, PCTs such as Salford were concerned about the affordability of a drug they said could cost an estimated £900-£1,000 per patient per year.

As a 2011 Drug and Therapeutics Bulletin review pointed out, this is around double the cost of warfarin, which, even including the cost of monitoring, is only £426 per patient per year.

CCG restrictions

As Pulse reported at the time, shadow CCGs were quick to warn that switching patients en masse could push up overall primary care prescribing spending by as much as 20% – although the price of dabigatran was subsequently reduced. Many said they would restrict its use to those unsuitable for warfarin.

Rivaroxaban was also approved by NICE for stroke prevention in AF patients in May 2012, followed by apixaban earlier this year.

A Pulse analysis of NHS primary care prescribing data showed a 14-fold increase in the use of NOACs in 2012 compared with 2011. But there was also a 9% rise in the use of warfarin, leading experts to conclude that the newer anticoagulants were indeed being reserved for patients unable to take warfarin.

Dr Matthew Fay, a GP in Shipley, West Yorkshire and a medical adviser to the Atrial Fibrillation Association, says: ‘First, warfarin is a highly effective medication. NOACs are in a market where they are as good as an incredibly good drug.

‘Second, they are deemed to be very expensive. Even though NICE’s technical appraisal shows they are cost-effective,
it doesn’t mean that they’re affordable. CCGs seem to be following the PCT attitude and restricting them.’

NHS Mid Essex CCG – where warfarin remains the drug of choice for anticoagulation in AF – is a case in point. CCG chair and clinical lead Dr Lisa Harrod-Rothwell says: ‘We’re the eighth-lowest funded CCG in the country and in a hugely challenging financial situation. Any transition from one system to another, where the rewards will be reaped at some point down the line, is very difficult for us.’

Dr Donal Hynes, co-vice chair of the NHS Alliance and a GP in Bridgwater, Somerset, says switching patients from warfarin to the NOACs will be complicated. ‘Some of the warfarin clinics have been put out to tender, so you’d need to wind down the contracts for them before you can move a single patient over to the newer drugs. That process may take a while.

‘Also, not every patient is suitable to be switched so you will always have a small number of patients on warfarin and will need to maintain a service for them – which suddenly becomes very non-cost-effective. A lot of CCGs have taken the decision for now to leave it up to GPs to switch patients at their own pace rather than saving millions all in one go.’

Safety concerns

Clinical considerations then come into play; despite impressive efficacy data for the NOACs, UK clinical experience of their use is very limited and trial reports have had mixed results.

The Medicines and Healthcare products Regulatory Agency clarified the contraindications and monitoring requirements for switching patients to dabigatran last year, after an international review of data on the risks of haemorrhage. But a recent ‘real world’ study found ‘no evidence’ of an excess of bleeding events with dabigatran compared with warfarin.

A spokesperson for Boehringer Ingelheim – manufacturer of dabigatran – said the RE-ALIGN study in patients with mechanical heart values was halted early because interim results showed an ‘imbalance’ in bleeding complications between dabigatran and warfarin. Dabigatran is now contraindicated in this group of patients.

But Dr Fay says most of the evidence for NOACs is positive and predicts GP use of the drugs will gradually rise. ‘Both clinicians and patients seem wary of the lack of experience in the British clinical community regarding their use, but this will change. I think it will be a slow burn.’

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