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`and Bristol's ARIS10TLE Study Finds the Golden Mean of Antic...
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`http://www.forbes.com/sites/larryhusten/201 l/08/28/pfizer-and-bristo
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`Forbes
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`Contributor
`Lauy Hysten,
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`rm e medical journaMst covering cardiology news.
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`PHARMA & HEALTHCARE I B/28/2011 C 2:08AM I 3,733 views
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`Pfizer and Bristol's ARISTOTLE
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`Study Finds the Golden Mean of
`Anticoagulation
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`In ancient Greece the philosopher Aristotle
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`l was the desirable
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`thought thJ•.goldm:iJnE.\ll
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`middle between two extremes, one of excess
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`and the other of deficiency. In cardiology,
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`apixaban may be the golden mean of
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`anticoagulation, achieving the ideal balance
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`of reduced strokes and deaths without
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`causing any additional bleeding
`complications.
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`The Apixaban for Reduction in Stroke and
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`Other Thromboembolic Events in Atrial
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`Fibrillation (ARISTOTLE) study compared
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`warlarin to apixaban (5 mg twice daily) in
`Chris Granger and Lars Wallentin at the
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`18,201 patients with AF and at least one
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`ESC Press Conference
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`additional risk factor for stroke. The
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`overachieving trial demonstrated that
`apixaban (Eliquis, Pfizer and Bristol-Myers Squibb) was not only noninferior
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`to warfarin in efficacy, it was superior. Further, treatment with apixaban
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`resulted in a statistically significant reduction in mortality, and reduced the
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`risk of major bleeding. The results of ARISTOTLE were presented by
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`Christopher Granger on Sunday morning at the European Society of
`ously in the Nw.
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`Cardiology meeting in Paris and llllblifil1ed simultane
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`England Journal Q/Medicine.
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`Here are the key details:
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`After 1.8 years of followup, stroke or systemic embolism (the primary
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`endpoint) occurred in 212 out of 9120 apixaban-treated patients versus 265
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`out of 9081 warlarin-treated patients:
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`• Yearly rate: 1.27% in the 11pixaban group versus 1.60% in the warfarin group (HR
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`0.79, CI 0.66-0.95, p<o.001 for noninferiority, p=o.01 for superiority)
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`Major bleeding occurred in 327 of the apixaban-treated patients versus 462
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`of the warlarin-treated patients.
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`• Yearly rate: 2.13% versus 3.09% (HR 0.69, CI 0.60-0.80, p<o.001
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`11/28/2012 6:1
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`BMS 2006
`MYLAN v. BMS
`IPR2018-00892
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`http://www.fortJes.com/sites/larryhusten/2011/08/28/pfizer-and-bristo
`and Bristol's ARISTOTLE Study Finds the Golden Mean of Antic...
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`Death occurred in 603 apixaban-treated patients versus 669 warfarin­
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`treated patients.
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`• Yearly rate: 3.52% versus 3.94% (HR 0.89, CI 0.80-0.99, p=o.047)
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`• Yearly rate of death from cardiovascular causes: 1.80% versus 2.02% (HR 0.89, CI
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`0.76-1.04)
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`Hemorrhagic stroke occurred in 40 apixaban-treated patients versus 78
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`warfarin-treated patients.
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`• Yearly rate: 0.24% versus 0.47% per year (HR 0.51, Cl 0.35-0.75, p<o.001)
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`Ischemic or uncertain stroke occurred in 162 apixaban-treated patients
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`versus 175 warfarin-treated patients.
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`• Yearly rate: 0.97% per year vs 1.05%, HR 0.92, CI o. 74-1.13, p=o-42)
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`Stroke, systemic embolism, MI, or death from any cause occurred in
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`810 apixaban-treated patients versus 906 warfarin-treated patients.
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`• Yearly rate: 4.85% versus 5.49%, HR o.88, p=o.01
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`The results were consistent across a broad range of subgroups. Of note, there
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`were no significant differences between geographic regions. There was a
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`greater reduction in major bleeding associated with apixaban in nondiabetics
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`compared to diabetics {p=o.003 for interaction) and in patients with
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`moderate or severe renal impairment compared to those with mild or no renal
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`impairment ((p=o.03 for interaction).
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`The investigators calculated that for every 1000 patients treated with
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`apixaban instead of warfarin for 1. 8 years
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`• stroke would be avoided in 6 patients,
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`• major bleeding would be avoided in 15 patients, and
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`• death would be avoided in 8 patients.
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`Comparing their results with the RE-LY trial of dabigatran, the authors wrote
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`that apixaban "appears to combine the advantages of each of the two doses of
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`dabigatran, with both a greater overall reduction in the rate of stroke and a
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`lower rate of bleeding than the rates with warfarin." They also noted that in
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`the ROCKET AF trial rivaroxaban lowered intracranial hemorrahge and fatal
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`bleeding but was not better than warfarin in other major bleeding. They listed
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`possible reasons for the differences in trials of the three drugs: "differences in
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`and pharmacodyn amic properties of
`the doses of drugs, the pharmacokinetic
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`the drugs, patient populations, or other features of the clinical-trial design."
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`They also noted that the 3 novel anticoagulants (apixaban, dabigatran, and
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`rivaroxaban) have all demonstrated a lower risk of hemorrhagic stroke
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`compared to warfarin, suggesting "a specfic risk associated with warfarin,
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`possibly related to its inhibition of multiple coagulation factors or interaction
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`between warfarin and tissue factor VIia complexes in the brain."
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`In.an.W..:.G9mp�nyim� �di.twia.J, Jessica Mega called
`the ARISTOTLE results
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`"impressive" and wrote that "a new era of anticoagulation in patients with
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`atrial fibrillation appears to be emerging." She said that all three newer
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`anticoagulants significantly reduce hemorrhagic stroke and have similar
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`effects on mortality, though the difference in mortality was significant only in
`ARISTOTLE. The three drugs, she writes, "have been shown to have a more
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`favorable bleeding profile than warfarin and are at least as efficacious."
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`11/28/2012 6:•
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`and Bristol's ARIS'IOTLE Study Finds the Golden Mean of Antic...
`http://www.forbes.com/sites/lanyhusten/2011/08/28/pfizer-and-bristo
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`In an interview, Christopher Granger, the first author of the study, said that
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`the investigators felt "as though we hit the sweet spot" with the drug in the
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`trial, achieving greater efficacy in preventing stroke while also producing a
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`"really remarkable reduction in major bleeding, and all with a drug that's
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`really very well tolerated" and that has produced "no real safety signal."
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`In addition, Granger said that the results in the United States appear to be
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`consistent with the overall trial, although a detailed analys is has not yet been
`performed.
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`Granger speculated that after the forthcoming ENGAGE AF=TIMI 48 trial
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`with edoxaban, "there will not be another large trial with a a warfarin
`comparator."
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`At the ESC press conference for ARISTOTLE, Lars Wallentin presented
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`results of the trial stratified by the time in the therapeutic range (TTR).
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`Although the benefits of apixaban were more pronounced in centers with poor
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`INR control, apixaban was still beneficial in centers that had good INR
`control.
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`Click here to download the press release from Bristol-Myers Squibb and
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`Pfizer:
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`08�1811.ARISTOTLE.ESC Data.Rele,t�.e <;opy
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`This article is available online at:
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`h tip: I I www.for h<:s. <:<1m/sl. tes/l a.rrvhus tmi/20 l l/08i28/.l)fiz,�r-t1 ud-bl'istols-:n·fal.otl,,-stu d \' -
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`fi11ds-tl1e--gold,,n-m�,an-of-,ft11ti,,o.igulaiio11,,2/
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`11/28/2012 6:•
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