Safety issues highlighted with newer oral anticoagulant drugs

Researchers discover that dabigatran, rivaroxaban and apixaban carry varying risks of adverse drug reactions, suggesting that they are not interchangeable.

The new oral anticoagulant drugs Dabigatran, Rivaroxaban and Apixaban pills and pill boxes

Analysis of ‘real-life’ data comparing newer direct oral anticoagulants with warfarin has identified adverse drug reactions (ADRs) ‘not previously associated’ with the new treatments, including hip fracture.

Direct oral anticoagulants, such as dabigatran, rivaroxaban and apixaban, are becoming increasingly popular alternatives to warfarin in patients with atrial fibrillation owing to their ability to produce similar effects without the need for regular coagulation monitoring.

While their findings confirm earlier work suggesting a reduced risk of intracranial bleed but increased risk of gastrointestinal bleed with the newer drugs, the researchers say they also identified important differences between them, which need looking at in more detail.

The research team from the University of Bologna, Italy, scanned data on almost 33,000 suspected ADRs listed in the World Health Organization database, known as VigiBase.

More than two thirds (69%) of the identified case reports were classed as ‘serious’, with the biggest proportion (32%) occurring in men over the age of 65 years.

Reporting the results in the British Journal of Clinical Pharmacology
(online, 10 January 2017), the team found that gastrointestinal haemorrhage was more likely to occur with the newer agents compared with warfarin (reporting odds ratio 1.6), but similar numbers of reports for cerebral haemorrhage (reporting odds ratio 0.31).

The researchers analysed the data to identify the ADRs that were the most significant. Among the 105 ADRs they found to be worthy of further investigation, dabagitran was reported most frequently.

They also discovered that rivaroxaban (541 cases) and dabigatran (1,707 cases) were statistically more likely to be linked to a gastrointestinal bleed compared with warfarin, but that apixaban was not, suggesting it could be a possible first-line treatment in patients at high risk of gastrointestinal bleed.

Rivaroxaban was the only direct oral anticoagulant to show a positive association with intracranial haemorrhage compared with warfarin — a finding which has also been reported in previous clinical trials.

The results showed apparent differences in the risk of cardiac events between the treatments, including a higher risk of heart attack with rivaroxaban, which the researchers say need to be clarified in further studies.

The researchers also report that their analyses highlighted some issues that had not been reported before, including ‘a very high number’ of musculoskeletal disorders associated with the newer treatments, as well as differences in the risk of renal problems between the drugs.

Dabigatran in particular was found to be statistically associated with hip fracture, the researchers point out, while apixaban seemed to have “a better safety profile” among the newer anticoagulants.

Study leader Domenico Motola, assistant professor in pharmacology at the Department of Medical and Surgical Sciences at the University of Bologna, says the team’s analysis further strengthens existing knowledge on the benefit-risk ratios of newer anticoagulants.

“Our data suggest that direct oral anticoagulants are not interchangeable, as several differences emerged in the rate and type of adverse drug reactions between one drug and another.”

Commenting on the study, Steve Glynn, specialist principal pharmacist at NHS Greater Glasgow and Clyde, says there are “subtle differences” between the drugs and it was important to look in depth at the evidence.

“This is the latest of a series of real-life studies of these drugs that have been published in recent years and they each come up with a slightly different result,” he explains.

He points out that most prescribers probably had a favourite direct oral anticoagulant but there would be circumstances when an alternative drug would be more appropriate for a particular patient. “And sometimes it might be that warfarin is the best choice,” he adds.

Source: Courtesy of Helen Williams

Helen Williams, consultant pharmacist for cardiovascular disease for the NHS Southwark clinical commissioning group, says underlying diseases may contribute to adverse drug reactions, therefore this data should be interpreted carefully

Also commenting, Helen Williams, consultant pharmacist for cardiovascular disease for the NHS Southwark clinical commissioning group, says: “Care needs to be taken when interpreting this data as it does not take into account patients underlying diseases which could contribute to the reported ADRs.”

While Lucy Wilkinson, senior cardiac nurse at the British Heart Foundation, says: “There are around 1.2 million people living with atrial fibrillation (AF) in the UK, making it the most common abnormal heart rhythm.

“Living with AF increases your risk of stroke by four or five times, so anti-coagulant medication is important for many to help reduce this risk,” she adds. “We welcome more research into the risks and benefits of both anti-coagulant choices to ensure the best treatment for AF patients.”


[1] Monaco L, Biagi C, Conti V et al. Safety profile of the direct oral anticoagulants: an analysis of the WHO database of adverse drug reactions. British Journal of Clinical Pharmacology 2017. doi: 10.1111/bcp.13234

Last updated
The Pharmaceutical Journal, PJ, January 2017, Vol 298, No 7897;298(7897):DOI:10.1211/PJ.2017.20202191

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