Study Highlights Benefits of Newer Anticoagulants

Liam Davenport

July 05, 2018

Direct oral anticoagulants (DOACs), in particular apixaban, reduce the risk of major bleeds in comparison with warfarin in both patients with and without atrial fibrillation (AF), say UK researchers in findings that should provide reassurance over the safety of the drugs.

Unlike warfarin, DOACs do not require regular testing to check blood levels and have consequently been increasingly used as an alternative to the older drug.

However, while previous clinical trials have suggested that DOACs have a comparable or lower risk of bleeding to warfarin, they have typically been tested only in carefully selected patients.

Moreover, the majority of observational studies comparing the DOACs with warfarin have focused only on patients with AF.

As Yana Vinogradova, research fellow, Division of Primary Care, University of Nottingham, and colleagues point out, this "represents only half of anticoagulant users".

Anticoagulant Analysis

The current analysis therefore included more than 195,000 patients receiving anticoagulants, of whom almost half did not have AF, and almost a third were taking drugs other than warfarin.

The results, published online by the BMJ on 4th July, showed that apixaban was associated with a lower risk of major, brain and gastric bleeds in patients with and without AF versus warfarin.

While the risk of major brain bleeds was reduced with dabigatran in AF patients and rivaroxaban in non-AF patients versus warfarin, rivaroxaban and low-dose apixaban were linked to an increased risk of death.

While acknowledging the limitations of their analysis, the team writes: "Our study has shown that the risk of major bleeding is lower in patients taking apixaban regardless of the reason for prescribing."

They add: "Our results give an initial, reassuring, indication of the risk patterns for all patients taking anticoagulants, with respect to those prescribed apixaban."

To examine the risks and benefits of DOACs versus warfarin in a real-world setting, the team gathered data from the QResearch and Clinical Practice Research Datalink primary care databases, both of which are representative of the UK population.

They focused on patients aged 21–99 who were prescribed warfarin, dabigatran, rivaroxaban, and apixaban between 2011 and 2016, excluding those who had any anticoagulant prescription in the previous 12 months.

They were linked at the patient level to hospital admissions data, as well as mortality data provided by the Office for National Statistics (ONS), with the primary outcomes major bleeding leading to hospital admission or death.

In addition, secondary outcomes included ischaemic stroke, venous thromboembolism, and all-cause mortality, with all analyses adjusted for demographic and clinical variables, including ethnicity, smoking status, alcohol use, deprivation, bleeding disorders and cancer, among others.

A total of 196,061 patients from both databases were included in the study, including 132,231 on warfarin, 7744 who were taking dabigatran, 37,863 receiving rivaroxaban and 18,223 prescribed apixaban.

Study Results

Overall, 103,270 (53%) of the patients were diagnosed with AF, while the remaining 92,791 (47%) were taking anticoagulants for other conditions.

Compared with warfarin, apixaban was associated with a reduction in the risk of major bleeding and intracranial bleeding in patients with AF, at an adjusted hazard ratio (HR) of 0.66 and 0.40, respectively.

In patients without AF, apixaban was, compared with warfarin, associated with a reduced risk of major bleeding, at an HR of 0.60, any gastrointestinal bleeding, at an HR of 0.55, and upper gastrointestinal bleeding (0.55).

Dabigatran was associated with a decreased risk of intracranial bleeding versus warfarin in patients with AF (HR 0.45), while rivaroxaban was associated with a reduced risk of intracranial bleeding versus warfarin in non-AF patients (HR 0.54).

Rivaroxaban was linked to an increased risk of all-cause mortality versus warfarin in both patients with AF (HR 1.19) and those without AF (HR 1.51). Interestingly, low-dose apixaban was also associated with an increased mortality risk in AF and non-AF patients, at HR of 1.27 and 1.34, respectively.

Closer Monitoring

The team writes that these observations may reflect "the closer monitoring of patients undergoing treatment with warfarin" or underlying comorbidities affecting prescribing choices.

The team calculates that, overall, apixaban had the lowest number needed to treat over 6 months to avoid one extra major bleed versus warfarin, at 182 AF patients and 138 non-AF patients.

Rivaroxaban had the lowest number needed to harm to observe one extra death versus warfarin over 6 months, at 202 AF patients and 61 non-AF patients.

Noting that their study provides evidence on the outcomes with anticoagulants in patients without AF, they highlight that "this group, however, includes patients undergoing preventative treatment for venous thromboembolism or ischaemic stroke after hip or knee replacements, fractures, or other operations and studying this group in detail would require further splitting".

This work has been supported by National Institute for Health Research (NIHR) with a School for Primary Care Research (SPCR) round 11 grant (reference number 304). This paper presents independent research funded by the NIHR SPCR.

Julia Hippisley-Cox is professor of clinical epidemiology at the University of Nottingham and unpaid director of QResearch, a not-for-profit organisation which is a joint partnership between the University of Nottingham and EMIS (commercial IT supplier for 60% of general practices in the UK). She is also a paid director of ClinRisk Limited, which produces open and closed source software to ensure the reliable and updatable implementation of clinical risk algorithms (including QRISK2) within clinical computer systems to help improve patient care. No other conflicts declared.

BMJ 2018;362:k2505 doi: 10.1136/bmj.k2505. Full text.

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