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August 29, 2012 (Munich, Germany) — A new prespecified analysis of the ARISTOTLE
study has shown that the new oral anticoagulant apixaban (Eliquis, Bristol-Myers Squibb/Pfizer) was better than warfarin
at preventing the primary outcome, stroke or systemic embolism, in
atrial-fibrillation patients, regardless of renal function [1]. And
patients with kidney disease seemed to have the greatest reduction in
major bleeding with apixaban.
These findings are important, because patients with renal insufficiency pose a problem for any kind of anticoagulant treatment due to their increased risk for both thromboembolic and bleeding events. Up to 20% of those with AF have some renal dysfunction, making treatment decisions difficult in this patient group.
These new results suggest that "apixaban may be particularly suited to address the unmet need for more effective and safer stroke prevention in patients with AF and renal dysfunction," say Dr Stefan H Höhnloser (JW Goethe University, Frankfurt, Germany) and colleagues in their paper published online August 29, 2012 in the European Heart Journal. Höhnloser also reported the results today in a clinical trial and registry update session at the European Society of Cardiology (ESC) 2012 Congress.
In a commentary accompanying the paper [2], Dr Jan Steffel (University Hospital Zurich, Switzerland) and Dr Gerhard Hindricks (University of Leipzig–Heart Center, Germany) concur. "This new substudy of ARISTOTLE provides solid evidence for the superiority of apixaban in patients with atrial fibrillation and chronic kidney disease. In the light of these data, apixaban appears to be a very appealing option for these individuals." However, they caution that this conclusion does not necessarily extend to those with severe renal disease (estimated glomerular filtration rate [eGFR] of <30 mL/min), since they made up only 1.5% of the study population.
And discussant of the trial at the ESC meeting, Dr Keith AA Fox (University of Edinburgh, Scotland), agrees: "In my view, ARISTOTLE provides a treatment option and advantages over warfarin in patients with moderate renal dysfunction, a group that is currently suboptimally treated."
Doctors Torn Deciding on Anticoagulation in AF With Renal Impairment
The main ARISTOTLE results were first reported at the ESC meeting last year and published simultaneously in the New England Journal of Medicine; they were widely viewed as the "most positive" data among the major randomized trials comparing new oral anticoagulants with warfarin for prevention of stroke in AF. Despite this, the US FDA has failed to yet approve apixaban for this indication for reasons that remain unclear. Apixaban is not approved for AF in the European Union, either, although it was cleared for marketing there for prevention of venous thromboembolism.
Steffel and Hindricks say doctors are torn when having to decide whether or not--and if so, how--to anticoagulate patients with atrial fibrillation and renal insufficiency. A recent study has even shown, for instance, that the net clinical benefit of warfarin is unclear in patients with AF and renal disease.
To try to address this problem, Höhnloser and colleagues evaluated the ARISTOTLE data, comparing apixaban--which is partially excreted by the renal system--with warfarin in relation to renal function. They note that a reduced dose of apixaban (2.5 mg twice daily instead of the usual 5 mg twice daily) was given to patients with two of the following criteria: age >80 years, weight <60 kg, and serum creatinine >133 mmol/L (1.5 mg/dL).
There were 7518 patients (42%) with no renal dysfunction (eGFR of >80 mL/min), 7587 (42%) with eGFR between 50 and 80 mL/min, and 3017 (15%) with an eGFR of <50 mL/min.
The rate of cardiovascular events and bleeding was higher in those with impaired renal function (<80 mL/min), as would be expected.
"The present analysis represents the largest experience of anticoagulation therapy in patients with AF and impaired renal function, and the superiority of apixaban relative to warfarin for preventing stroke or systemic embolism was consistent, irrespective of degree of renal impairment," say the researchers.
Those With Worse Kidney Function Had the Least Major Bleeding on Apixaban
Apixaban was also associated with fewer major bleeding events across all ranges of eGFR, with the relative risk reduction in major bleeding being greater in patients with an eGFR of <50 mL/min (hazard ratio 0.50; 95% CI 0.38–0.66' interaction p=0.005].
To examine whether the reduction in bleeding in patients with impaired renal function was due to the more frequent use of the lower apixaban dose (2.5 mg twice daily), two sensitivity analyses were conducted, first by adjusting for dose and second by excluding all patients on low-dose apixaban and repeating the analysis only in the patients on the standard dose. In both, the interaction between treatment and renal function remained statistically significant for major bleeding.
Steffel and Hindricks seem convinced by this analysis: "The finding of a statistically significant greater reduction in major bleeding in patients with impaired renal function implies a particularly pronounced benefit of apixaban compared with warfarin in this patient population," they observe.
Further Analysis Of Existing Studies Will Provide More Guidance
They then wonder, "Should every patient with atrial fibrillation and renal insufficiency hence be anticoagulated with apixaban?" and "How does apixaban compare with rivaroxaban and dabigatran in these patients?"
Unfortunately, comprehensive cross-trial comparisons with the other novel anticoagulants are impossible to perform, given--among other factors--the different study designs, different patient populations, and (partly)
different bleeding definitions, they state. But as all three
trials compared the respective novel agent with warfarin, it would be
interesting to compare matched subsets of patients from each trial;
"such data, however, are not yet available."
Nevertheless, data from large registries and from real-world use will provide additional evidence for further guidance, they note.
Höhnloser has served as a consultant, member of steering committee, or speaker for Bayer Healthcare, Bristol-Myers Squibb, Boehringer Ingelheim, Boston Scientific, Cardiome, Forest RI, Johnson & Johnson, Medtronic, Pfizer, Portola, Sanofi, and St Jude Medical. Disclosures for the coauthors are listed in the paper. Steffel has received consulting and/or speaker's fees from AstraZeneca, Bayer HealthCare, Boehringer Ingelheim, Bristol-Myers Squibb, and Pfizer and research support from Bayer Healthcare. Hindricks declared no conflicts of interest. Fox has received grant funding and honoraria from Sanofi, Lilly, Bayer, Johnson & Johnson, AstraZeneca and Boehringer Ingelheim.source medscape
These findings are important, because patients with renal insufficiency pose a problem for any kind of anticoagulant treatment due to their increased risk for both thromboembolic and bleeding events. Up to 20% of those with AF have some renal dysfunction, making treatment decisions difficult in this patient group.
These new results suggest that "apixaban may be particularly suited to address the unmet need for more effective and safer stroke prevention in patients with AF and renal dysfunction," say Dr Stefan H Höhnloser (JW Goethe University, Frankfurt, Germany) and colleagues in their paper published online August 29, 2012 in the European Heart Journal. Höhnloser also reported the results today in a clinical trial and registry update session at the European Society of Cardiology (ESC) 2012 Congress.
In a commentary accompanying the paper [2], Dr Jan Steffel (University Hospital Zurich, Switzerland) and Dr Gerhard Hindricks (University of Leipzig–Heart Center, Germany) concur. "This new substudy of ARISTOTLE provides solid evidence for the superiority of apixaban in patients with atrial fibrillation and chronic kidney disease. In the light of these data, apixaban appears to be a very appealing option for these individuals." However, they caution that this conclusion does not necessarily extend to those with severe renal disease (estimated glomerular filtration rate [eGFR] of <30 mL/min), since they made up only 1.5% of the study population.
And discussant of the trial at the ESC meeting, Dr Keith AA Fox (University of Edinburgh, Scotland), agrees: "In my view, ARISTOTLE provides a treatment option and advantages over warfarin in patients with moderate renal dysfunction, a group that is currently suboptimally treated."
Doctors Torn Deciding on Anticoagulation in AF With Renal Impairment
The main ARISTOTLE results were first reported at the ESC meeting last year and published simultaneously in the New England Journal of Medicine; they were widely viewed as the "most positive" data among the major randomized trials comparing new oral anticoagulants with warfarin for prevention of stroke in AF. Despite this, the US FDA has failed to yet approve apixaban for this indication for reasons that remain unclear. Apixaban is not approved for AF in the European Union, either, although it was cleared for marketing there for prevention of venous thromboembolism.
Steffel and Hindricks say doctors are torn when having to decide whether or not--and if so, how--to anticoagulate patients with atrial fibrillation and renal insufficiency. A recent study has even shown, for instance, that the net clinical benefit of warfarin is unclear in patients with AF and renal disease.
ARISTOTLE provides a treatment option and
advantages over warfarin in patients with moderate renal dysfunction, a
group that is currently suboptimally treated.
And the initial enthusiasm associated with the novel anticoagulants--such as dabigatran (Pradaxa, Boehringer Ingelheim) and rivaroxaban
(Xarelto, Bayer/Johnson & Johnson)--"was dampened shortly after
their introduction, when reports of major hemorrhages surfaced," they
note. "Indeed, it quickly became clear that especially dabigatran, which
is 80% renally cleared, has a significant potential for severe bleeding
in patients with reduced renal function."To try to address this problem, Höhnloser and colleagues evaluated the ARISTOTLE data, comparing apixaban--which is partially excreted by the renal system--with warfarin in relation to renal function. They note that a reduced dose of apixaban (2.5 mg twice daily instead of the usual 5 mg twice daily) was given to patients with two of the following criteria: age >80 years, weight <60 kg, and serum creatinine >133 mmol/L (1.5 mg/dL).
There were 7518 patients (42%) with no renal dysfunction (eGFR of >80 mL/min), 7587 (42%) with eGFR between 50 and 80 mL/min, and 3017 (15%) with an eGFR of <50 mL/min.
The rate of cardiovascular events and bleeding was higher in those with impaired renal function (<80 mL/min), as would be expected.
"The present analysis represents the largest experience of anticoagulation therapy in patients with AF and impaired renal function, and the superiority of apixaban relative to warfarin for preventing stroke or systemic embolism was consistent, irrespective of degree of renal impairment," say the researchers.
Those With Worse Kidney Function Had the Least Major Bleeding on Apixaban
Apixaban was also associated with fewer major bleeding events across all ranges of eGFR, with the relative risk reduction in major bleeding being greater in patients with an eGFR of <50 mL/min (hazard ratio 0.50; 95% CI 0.38–0.66' interaction p=0.005].
To examine whether the reduction in bleeding in patients with impaired renal function was due to the more frequent use of the lower apixaban dose (2.5 mg twice daily), two sensitivity analyses were conducted, first by adjusting for dose and second by excluding all patients on low-dose apixaban and repeating the analysis only in the patients on the standard dose. In both, the interaction between treatment and renal function remained statistically significant for major bleeding.
Steffel and Hindricks seem convinced by this analysis: "The finding of a statistically significant greater reduction in major bleeding in patients with impaired renal function implies a particularly pronounced benefit of apixaban compared with warfarin in this patient population," they observe.
Further Analysis Of Existing Studies Will Provide More Guidance
They then wonder, "Should every patient with atrial fibrillation and renal insufficiency hence be anticoagulated with apixaban?" and "How does apixaban compare with rivaroxaban and dabigatran in these patients?"
Unfortunately, comprehensive cross-trial comparisons with the other novel anticoagulants are impossible to perform, given--among other factors--the different study designs, different patient populations, and (partly)
Nevertheless, data from large registries and from real-world use will provide additional evidence for further guidance, they note.
Höhnloser has served as a consultant, member of steering committee, or speaker for Bayer Healthcare, Bristol-Myers Squibb, Boehringer Ingelheim, Boston Scientific, Cardiome, Forest RI, Johnson & Johnson, Medtronic, Pfizer, Portola, Sanofi, and St Jude Medical. Disclosures for the coauthors are listed in the paper. Steffel has received consulting and/or speaker's fees from AstraZeneca, Bayer HealthCare, Boehringer Ingelheim, Bristol-Myers Squibb, and Pfizer and research support from Bayer Healthcare. Hindricks declared no conflicts of interest. Fox has received grant funding and honoraria from Sanofi, Lilly, Bayer, Johnson & Johnson, AstraZeneca and Boehringer Ingelheim.source medscape
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