Issue 13 / 15 April 2013

A STRAIGHTFORWARD answer for patients about stroke prevention in atrial fibrillation is no closer as debate comparing the new anticoagulant dabigatran with warfarin continues.

For the third time since 2011, dabigatran has been recommended for Pharmaceutical Benefits Scheme (PBS) listing for first-line stroke prevention therapy in patients with non-valvular atrial fibrillation (AF), despite continued conjecture about the drug’s safety, efficacy and marketing.

It was recommended for PBS funding in March 2011, before the federal government set up the Review of Anticoagulation Therapies in Atrial Fibrillation on 30 September, 2011. (1)

Since then, it has been given Pharmaceutical Benefits Advisory Committee (PBAC) approval in July 2012 and again last month.

Two articles in the latest issue of the MJA take different views on dabigatran. (2) (3)

The first raises concerns about the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) trial, including selection bias, co-interventions, adverse events, generalisability, and the importance of patient selection, plus lack of reversibility in overdose. (4)

The authors were also critical of the drug’s maker, Boehringer Ingelheim for its aggressive marketing, which targeted GPs.

“The tale of dabigatran sounds some cautionary notes about proper critical appraisal of new randomised controlled trials, care in deciding on the generalisability of results, judicious screening of patients and lessons about the politics around increasingly lucrative drugs”, the authors wrote.

The second MJA article defended RE-LY saying that, compared with warfarin, dabigatran produced “reductions in ischaemic stroke (one-third) and haemorrhagic stroke (one-half) that were statistically significant and clinically important”.

“Regulators have approved dabigatran in more than 75 countries, including Australia, and guidelines suggest the new oral anticoagulants are preferable to warfarin for most patients with non-valvular AF”, the authors wrote.

Dr Evan Ackermann, chair of the Royal Australian College of General Practitioners National Standing Committee on Quality, said he had concerns about the way Boehringer Ingelheim may have influenced the approval system.

“They organised the trial, ran it, interpreted it and after one approval from the PBAC, they targeted GPs and suddenly there were 20 000 Australians on dabigatran”, Dr Ackermann told MJA InSight.

“The product familiarisation program [PFP] for dabigatran was introduced when there were still a lot of questions about safety”, he said. “It was inappropriate and we said so.”

Dr Ackermann said although many safety issues had been appropriately resolved, there were still concerns about dabigatran’s place in AF therapy. “Is it a first-line therapy or second? These questions haven’t been resolved.”

Dr Rob Creek, medical director for Boehringer Ingelheim in Australia, said the government’s review of anticoagulation found that only 40%–60% of AF patients who are appropriate for anticoagulation therapy actually received warfarin.

“The dabigatran PFP was undertaken in response to this defined clinical need and met the requirements of both the Medicines Australia Code of Conduct and Commonwealth legislation”, he said.

“It was initiated only after both Therapeutic Goods Administration [TGA] registration and a positive PBAC recommendation were granted, at a time when confirmation of a PBS listing could be expected within 6 months of a positive PBAC recommendation.”

The government’s reluctance to act on the PBAC recommendation may have set a dangerous precedent, says the doctor who was national coordinator of the RE-LY trial.

Associate Professor John Amerena, of the department of medicine at Deakin University, said the drug had now been in front of the PBAC three times and had been recommended three times. “Again it will be down to the Health Minister’s discretion as to whether dabigatran is funded.”

The PBAC has predicted that the cost to the PBS from dabigatran would be “greater than $100 million in Year 5”, with more than 200 000 patients a year expected to take the drug. (5)

“The whole process has been politicised, which sets a precedent”, Professor Amerena said.

Professor Amerena said both MJA papers presented valid points but that “the truth probably lies somewhere in between”.

“Nobody is suggesting that everyone on warfarin should be transferred to dabigatran. People who are stable on warfarin should stay on it”, he said.

A spokesman for Minister for Health Tanya Plibersek said the PBAC outcomes would be published on the PBS website on 26 April.

“We make no apology for thoroughly assessing the effectiveness and cost-effectiveness of new drugs”, the spokesman said. “Based on the results of a large trial, dabigatran represents a safe, efficacious and cost-effective therapy for some ‘at risk’ patients.”

He said the TGA has issued safety alerts for dabigatran advising caution when prescribing for some patients, particularly the elderly and those with reduced kidney function. (6)

– Cate Swannell

1. MJA 2013; 198 (7): 356-357
2. MJA 2013; 198 (7): 358-359
3. Department of Health and Ageing: Review of Anticoagulation Therapies in Atrial Fibrillation
4. ClinicalTrials.gov: Randomized Evaluation of Long Term Anticoagulant Therapy (RE-LY) With Dabigatran Etexilate
5. PBAC Public Summary Document; March 2011
6. TGA alerts February 2013

Posted 15 April 2013

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7 thoughts on “Dabigatran debate rages

  1. John Stokes says:

    This is essentially an issue about informed consent. Many patients put on this medication have not had informed consent. How many have been told there is no antidote? Why have not the opinions of A&E Specialists, Anaesthetists and Intensivists who have to care for bleeding patients been explored? In the rush to market and use this drug a few important issues have been ignored.

  2. Anonymous says:

    Two Questions:
    1. Should an anticoagulation drug likely to used very widely that has no reversal agent be approved for first-line treatment?
    2. Have the direct and indirect payments by the promoter to those involved in the approval process been fully declared?

  3. Jon Phipps says:

    This is too dangerous for oldies that fall or fracture or have other bleeding risks compared to warfarin which is hard enough to reverse in a hurry.

  4. David De Leacy says:

    1. This drug was inappropriately marketed by the drug company before its true role on anticoagulation was established as stated above. Elderly people with kidney impairment have died unneccesarily due to uncontolled haemorrhage.
    2. Why has it taken until February 2013 for the TGA to act with warnings?
    3. Professor Amerena, all rational debate about the appropriate and safe release of drugs into the ‘marketplace’ ceased in the late 1980s/early 1990s with the rise of free enterprise monetarism and deregulation and is now totally political eg Mr Rudd/Ms Roxon in cabinet releasing or not releasing drugs depending on non-medical/pharmacological factors. Vociferous and powerfully agggressive lobbying groups and drug companies are now allowed under business law to directly approach politicians and the public to spruik their wares. Regulated and independent arms-length assessment processes established after the thalidomide disaster of the 1960s have gone out the door and it is now a free for all. Since the Harvard School of Business usurped the Harvard School of Medicine from the 1970s/1980s onwards, all drug releases are intrinsically political (dollars equals patients equals votes). eg. AIDs drugs, Herceptin, Glivec etc etc. Dabigatran is just the latest cab off the rank.

  5. Anonymous says:

    Once a drug is approved by the Advisory Committee for Prescription Medicines it is available for use in patients. It is appropriate for the sponsor to inform prescribers about the availability of this new medication.

    If it does not get PBS listing, it may still be available for patients for whom it is well suited and who tolerate it and can afford it

  6. Anonymous says:

    “Once a drug is approved by the Advisory Committee for Prescription Medicines it is available for use in patients.”

    The Advisory Committee for Prescription Medicines does not approve anything – it is an advisory committee only. It is the TGA that approves the registration of medicines.

  7. 142342@amamember says:

    This drug is a prime example of pharmaceutical company corruption with money being the bottom line. It blows me away that the TGA actually approved a medication that can’t be monitored, has no reversing agent and can result in life threatening bleeding. I am aware of two dabigatran related deaths, solely related to the inability to quickly reverse this agent. Presently there is a class action against Boehringer Ingelheim in the USA and I hope that that pay dearly for their greed!

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