Thrombolysis review controversy

LEADING neurologists have condemned an Australasian College for Emergency Medicine decision to fund its own analysis of thrombolysis for acute stroke, which the college claims would be free of the conflicts of interest that plague existing guidance on the treatment.

The Australasian College for Emergency Medicine (ACEM) is inviting proposals for consultants to analyse the published literature on thrombolysis in acute ischaemic stroke, which it has refused to endorse as a standard of care. (1)

Professor Yusuf Nagree, chair of the ACEM Scientific Committee, said unlike reviews published to date, its analysis would be “uniquely independent”.

“We are trying to find researchers who have no preconceived views or biases”, he told MJA InSight. An expert advisory panel would also be established to support the project, including an emergency physician, neurologist, GP, public health expert and lay person.

A Cochrane review published earlier this year found thrombolytic therapy significantly reduced death and dependency rates at 3‒6 months after stroke, and that this overall benefit was apparent despite an increase in symptomatic intracranial haemorrhage and deaths at 7‒10 days. (2)

However, Professor Nagree argued the review may have been undermined by conflicts of interest among its authors, who reported receiving payments from Boehringer Ingelheim, manufacturer of the recombinant tissue plasminogen activator alteplase.

He cited a review of the 20 most cited articles on stroke thrombolysis, which found 85% disclosed pharmaceutical sponsorship. (3)

Professor Nagree said there were several methodological flaws with the major trials to date, including the subjectivity of functional outcomes and selective allocation of patients to the intervention and placebo groups. “Of the 12 trials looking at the efficacy of thrombolysis for stroke to date, only two showed a benefit.”

He described the college’s current position on stroke thrombolysis as “very neutral”.

“We have said that it is a potentially beneficial intervention for acute ischaemic stroke, but because of conflicting evidence, it cannot be considered a standard of care”, he told MJA InSight.

“There are significant risks associated with thrombolysis, including intracranial haemorrhage and early death.”

He predicted the review would be published by mid 2015.

“If thrombolysis is shown to be effective we have got a big issue with rural hospitals where the therapy is not well established as it is in the cities”, Professor Nagree said. “But if the findings are negative, then our tertiary hospitals will have to relook at what they’re currently doing.”

However, leading neurologists have lambasted the project as a naive publicity stunt, raising concerns that it could lead to patients forgoing potentially life-saving therapy.

Professor Christopher Levi, stroke neurologist and director of Clinical Research and Translation, Hunter New England Local Health District, said that around the world thrombolysis was the guidelines-recommended therapy for acute ischaemic stroke in appropriately selected patients.

“There are hundreds of doctors behind these guidelines. To imply that these people are acting as part of a conspiracy and are tainted is the medical equivalent of the climate science sceptics”, Professor Levi told MJA InSight.

He said it would be virtually impossible for the college to conduct a review free of conflicts of interest. “If you don’t have a conflict you don’t have an interest — what matters is how those potential conflicts and interests are managed.

Professor Levi said some hospitals had introduced models of care that bypassed unsupportive emergency departments to ensure appropriate patients received thrombolysis for ischaemic stroke. “In some places, patients are seen directly from the ambulance by neurologists or stroke physicians now.”

He said neurologists and stroke physicians were well positioned to weigh up the risks and benefits of thrombolytic therapy as they dealt with patients both in the acute phase and in the long term, monitoring their recovery.

Professor Craig Anderson, professor of stroke medicine and clinical neuroscience medicine at The George Institute for Global Health in Sydney, said there was a “clear net benefit from thrombolysis in ischaemic stroke, dependent on the time and location of the clot in the brain and size of the ischaemic lesion”.

Professor Levi told MJA InSight that currently 5%‒7% of Australians who had an ischaemic stroke received thrombolysis, while among those who present to hospital within the critical 3.5-hour window, the rate was around 25%.

He said a realistic goal was for 20%‒25% of all ischaemic stroke patients to receive thrombolysis through enhancing the ambulance system’s capacity to respond quickly and through appropriate patient selection.

However, a major challenge was overcoming the entrenched opposition to stroke thrombolysis among some doctors, he said.

1. ACEM 2014; Request for Proposal: Review of stroke thrombolysis
2. Cochrane Database Syst Rev 2014; (7): CD000213; Online 29 July
3. West J Emerg Med 2011; 12: 435-441

(Photo: Zephyr / Science Photo Library)