March 7, 2012 (Birmingham, United Kingdom) — A new "real-world" analysis finds that all of the new oral anticoagulant agents — apixaban (Eliquis, Pfizer/Bristol-Myers Squibb), dabigatran (Pradaxa, Boehringer Ingelheim), and rivaroxaban (Xarelto, Bayer) — have a greater net clinical benefit than warfarin in patients with atrial fibrillation (AF) who are at high risk of stroke (CHA2DS2-VASc score of 2 or more) [1]. The report was published in the March 2012 issue of Thrombosis and Haemostasis.
In those AF patients at low or intermediate risk of stroke, there appear to be some subtle differences between the novel agents, lead author Dr Amitava Banerjee (University of Birmingham Centre for Cardiovascular Sciences, UK) told heartwire . But he cautioned that it is impossible to properly compare and contrast the three on the basis of this new analysis, because of the way it was conducted.
"We extrapolated, using the available trials in the new agents, what we thought would happen in a real-world cohort of patients on warfarin vs not on warfarin. All the trials have looked at slightly different patients with slightly different outcomes and slightly different times, so we're not comparing apples with apples. We can't clearly say that one is better than the other" in the absence of head-to-head trials, he stresses. But until more data are available in the coming years, "this is our best guestimate; it's as good as we can get," he notes.
In an accompanying editorial [2], Dr Samuel Z Goldhaber (Brigham and Women's Hospital, Boston, MA), says that Banerjee et al have taken a "unique approach" toward dissecting the facts surrounding warfarin and novel anticoagulants and comparing them with no anticoagulant treatment in a Danish cohort. [They] are to be commended."
But he also warns that this study "does not guide us as to which specific novel oral anticoagulant should be used in an individual patient. Such distinctions and drug-patient alignments cannot be extrapolated from the raw data in the current analysis."
New agents "particularly better" at higher CHA2DS2-VASc scores
Of the three agents, dabigatran has been on the market longest for the prevention of stroke in patients with AF. Recently, however, there have been concerns that this new agent has been used too freely, particularly in old and frail patients and those with poor renal function, resulting in bleeding events. There are also questions about a possible increase in MI with dabigatran. Rivaroxaban was recently approved in the US for prevention of stroke in AF patients on the basis of the ROCKET-AF trial, as well as in the EU; apixaban is under consideration for this indication in the US, with a decision expected by the end of June this year.
Banerjee et al performed their new analysis to help inform the decision-making process when all these novel agents become available. Using data on those with nonvalvular AF from the Danish National Patient Registry, they calculated the net clinical benefit, balancing ischemic stroke against intracranial hemorrhage, on the basis of the recent clinical-trial outcome data for the new anticoagulants.
"We've assumed that these new drugs would perform just as they did in the trials in this cohort of Danish patients," explains Banerjee. "For all three, we can say they are significantly better than warfarin at all levels of CHA2DS2-VASc, but they are particularly better at the higher scores."In those at low risk (CHA2DS2-VASc score of 0) — "who traditionally we would have avoided using warfarin in at all," says Banerjee, the results show that apixaban and dabigatran 110 mg twice daily had a positive net clinical benefit.
And in those at intermediate risk (CHA2DS2-VASc=1), "the net clinical benefit is particularly favorable with apixaban and both doses of dabigatran [110 mg and 150 mg twice daily]," he says.
For the high-risk patients, "if you look at the Forest plots, you'll see that the confidence intervals are similar for apixaban, dabigatran, and rivaroxaban, so in clinical terms it means that all three novel agents can be expected, from the trial evidence, to have at least as good a benefit as warfarin in terms of stroke prevention and have less risk of intracranial hemorrhage by our model. So I would use one of these, rather than warfarin, given current data."
Best estimate for now; longer-term data needed
However, Banerjee stresses, "We need longer-term data; we've only got a year or two of follow-up maximum on any of these agents, whereas we've got patients on warfarin for 10 to 20 years. We're going to find out more about things like MI and bleeding with dabigatran as the data emerge, but this is the best that we can do at the moment."
Goldhaber agrees: "The present results do not guide us about unanticipated risks of the novel agents that might be detected with longitudinal programs of intensified pharmacovigilance."
Banerjee has no conflicts of interest; disclosures for the coauthors are listed in the paper. Goldhaber has no relevant disclosures; he is the author of Clotblog on theheart.org.
In those AF patients at low or intermediate risk of stroke, there appear to be some subtle differences between the novel agents, lead author Dr Amitava Banerjee (University of Birmingham Centre for Cardiovascular Sciences, UK) told heartwire . But he cautioned that it is impossible to properly compare and contrast the three on the basis of this new analysis, because of the way it was conducted.
"We extrapolated, using the available trials in the new agents, what we thought would happen in a real-world cohort of patients on warfarin vs not on warfarin. All the trials have looked at slightly different patients with slightly different outcomes and slightly different times, so we're not comparing apples with apples. We can't clearly say that one is better than the other" in the absence of head-to-head trials, he stresses. But until more data are available in the coming years, "this is our best guestimate; it's as good as we can get," he notes.
In an accompanying editorial [2], Dr Samuel Z Goldhaber (Brigham and Women's Hospital, Boston, MA), says that Banerjee et al have taken a "unique approach" toward dissecting the facts surrounding warfarin and novel anticoagulants and comparing them with no anticoagulant treatment in a Danish cohort. [They] are to be commended."
But he also warns that this study "does not guide us as to which specific novel oral anticoagulant should be used in an individual patient. Such distinctions and drug-patient alignments cannot be extrapolated from the raw data in the current analysis."
New agents "particularly better" at higher CHA2DS2-VASc scores
Of the three agents, dabigatran has been on the market longest for the prevention of stroke in patients with AF. Recently, however, there have been concerns that this new agent has been used too freely, particularly in old and frail patients and those with poor renal function, resulting in bleeding events. There are also questions about a possible increase in MI with dabigatran. Rivaroxaban was recently approved in the US for prevention of stroke in AF patients on the basis of the ROCKET-AF trial, as well as in the EU; apixaban is under consideration for this indication in the US, with a decision expected by the end of June this year.
Banerjee et al performed their new analysis to help inform the decision-making process when all these novel agents become available. Using data on those with nonvalvular AF from the Danish National Patient Registry, they calculated the net clinical benefit, balancing ischemic stroke against intracranial hemorrhage, on the basis of the recent clinical-trial outcome data for the new anticoagulants.
"We've assumed that these new drugs would perform just as they did in the trials in this cohort of Danish patients," explains Banerjee. "For all three, we can say they are significantly better than warfarin at all levels of CHA2DS2-VASc, but they are particularly better at the higher scores."In those at low risk (CHA2DS2-VASc score of 0) — "who traditionally we would have avoided using warfarin in at all," says Banerjee, the results show that apixaban and dabigatran 110 mg twice daily had a positive net clinical benefit.
And in those at intermediate risk (CHA2DS2-VASc=1), "the net clinical benefit is particularly favorable with apixaban and both doses of dabigatran [110 mg and 150 mg twice daily]," he says.
For the high-risk patients, "if you look at the Forest plots, you'll see that the confidence intervals are similar for apixaban, dabigatran, and rivaroxaban, so in clinical terms it means that all three novel agents can be expected, from the trial evidence, to have at least as good a benefit as warfarin in terms of stroke prevention and have less risk of intracranial hemorrhage by our model. So I would use one of these, rather than warfarin, given current data."
Best estimate for now; longer-term data needed
However, Banerjee stresses, "We need longer-term data; we've only got a year or two of follow-up maximum on any of these agents, whereas we've got patients on warfarin for 10 to 20 years. We're going to find out more about things like MI and bleeding with dabigatran as the data emerge, but this is the best that we can do at the moment."
Goldhaber agrees: "The present results do not guide us about unanticipated risks of the novel agents that might be detected with longitudinal programs of intensified pharmacovigilance."
Banerjee has no conflicts of interest; disclosures for the coauthors are listed in the paper. Goldhaber has no relevant disclosures; he is the author of Clotblog on theheart.org.
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