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Patients with atrial fibrillation: factor Xa inhibitors versus vitamin K antagonists for preventing cerebral or systemic embolism


Anticoagulant treatment with vitamin K antagonists ( VKAs ) is aimed at preventing thromboembolic complications and has been the therapy of choice for most people with non-valvular atrial fibrillation ( AF ) for many decades. A new class of anticoagulants, the factor Xa inhibitors, appear to have several pharmacological and practical advantages over vitamin K antagonists.

Researchers have assessed the effectiveness and safety of treatment with factor Xa inhibitors versus VKAs for the prevention of cerebral or systemic embolic events in people with atrial fibrillation.

Randomised controlled trials that have directly compared the effects of long-term treatment ( more than four weeks ) with factor Xa inhibitors and VKAs for the prevention of cerebral and systemic embolism in patients with atrial fibrillation, were searched.
Patients with and without a previous stroke or TIA ( transient ischemic attack ) were included.

The primary efficacy outcome was the composite endpoint of all strokes and other systemic embolic events.

Researchers included data from 42,084 participants randomised into 10 trials. All participants had a confirmed diagnosis of atrial fibrillation ( or atrial flutter ) and were deemed by the randomising physician to be eligible for long-term anticoagulant treatment with a VKA ( Warfarin [ Coumadin ] ) with a target International Normalised Ratio ( INR ) of 2.0 to 3.0 in most patients.
The included trials directly compared dose-adjusted warfarin with either Apixaban, Betrixaban, Darexaban, Edoxaban, Idraparinux or Rivaroxaban.

Four trials were double-masked, five partially-masked ( that is different doses of factor Xa inhibitor administered double-masked and Warfarin administered open-label ) and one was open-label.
Median duration of follow-up ranged from 12 weeks to 1.9 years.

The composite primary efficacy endpoint of all strokes ( both ischaemic and haemorrhagic ) and non-central nervous systemic embolic events was reported in nine of the included studies ( 40,777 participants ).

The treatment with a factor Xa inhibitor significantly decreased the number of strokes and systemic embolic events compared with dose-adjusted Warfarin ( odds ratio, OR=0.81 ).

Researchers have also analysed both components of this composite endpoint separately: treatment with a factor Xa inhibitor significantly decreased both the number of ischaemic and haemorrhagic strokes ( OR=0.78 ) and the number of systemic embolic events ( OR=0.53 ).All of the included studies ( 42,078 participants ) reported the number of major bleedings.
Treatment with a factor Xa inhibitor has significantly reduced the number of major bleedings compared with Warfarin ( OR=0.89 ).
There was, however, statistically significant and high heterogeneity ( I² = 81% ) and an analysis using a random-effects model did not show a statistically significant decrease in the number of major bleedings ( OR=0.92 ).

The pre-specified sensitivity analysis excluding open-label studies showed that treatment with a factor Xa inhibitor significantly reduced the number of major bleedings compared with Warfarin ( OR=0.84 ) but moderate heterogeneity was still observed ( I² = 65% ).
A similar sensitivity analysis using a random-effects model did not show a statistically significant decrease in the number of major bleedings in patients treated with factor Xa inhibitors ( OR=0.78 ).
Part of the observed heterogeneity can thus be explained by the increased risk of major bleedings in the factor Xa treatment arm in the single included open-label study, which studied Idraparinux. Other heterogeneity might be explained by differences in baseline bleeding risks in the two largest trials of Apixaban and Rivaroxaban, included in this review.

Data on intracranial haemorrhages ( ICHs ) were reported in eight studies ( 39,638 participants ). Treatment with a factor Xa inhibitor significantly reduced the risk of ICH compared with Warfarin ( OR=0.56 ).

Researchers observed statistically significant heterogeneity ( I² = 60% ). The pre-specified sensitivity analysis excluding the open-label study showed that treatment with a factor Xa inhibitor significantly reduced the number of ICHs compared with Warfarin ( OR=0.51 ), without any sign of statistical heterogeneity ( I² = 0% ).

The number of patients who died from any cause was reported in six studies ( 38,924 participants ). Treatment with a factor Xa inhibitor significantly reduced the number of all-cause deaths compared with Warfarin ( OR=0.88 ).

In conclusion, factor Xa inhibitors significantly reduced the number of strokes and systemic embolic events compared with Warfarin in patients with atrial fibrillation.
Factor Xa inhibitors also seem to reduce the number of major bleedings and ICHs compared with Warfarin, though the evidence for a reduction of major bleedings is somewhat less robust.
There is currently no conclusive evidence to determine which factor Xa inhibitor is more effective and safer for long-term anticoagulant treatment of patients with atrial fibrillation as head-to-head studies of the different factor Xa inhibitors have not yet been performed. ( Xagena )

Bruins Slot KM, Berge E, Cochrane Database Syst Rev 2013;8:CD008980. doi: 10.1002/14651858.CD008980.pub2

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