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Development of apixaban: a novel anticoagulant for prevention of stroke in patients with atrial fibrillation.

Hanna MS, Mohan P, Knabb R, Gupta E, Frost C, Lawrence JH - Ann. N. Y. Acad. Sci. (2014)

Bottom Line: The factor Xa inhibitor apixaban is one of the novel anticoagulants to emerge as alternatives to long-standing standards of care that include low-molecular-weight heparin and warfarin.Twice-daily dosing of apixaban, rather than once daily, was chosen to lower peak concentrations and reduce fluctuations between peak and trough levels.In the AVERROES study of patients who were unsuitable for warfarin therapy, apixaban was superior to aspirin in reducing the risk of stroke or systemic embolism (SSE), without a significant increase in major bleeding (MB).

View Article: PubMed Central - PubMed

Affiliation: Global Clinical Research, Research & Development, Bristol-Myers Squibb Company, Princeton, New Jersey.

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Relative efficacy and safety of apixaban compared with warfarin as a function of center-based time-in-therapeutic range (TTR) in the phase III trial for stroke prevention in AF (ARISTOTLE trial). As previously described, a center-based TTR was calculated for each investigative site in the trial and comparisons of outcomes on apixaban and warfarin were made at each site.37 For each level of center-based TTR from 1% to 80% on the y-axis, an HR for apixaban versus warfarin was calculated from all sites with a TTR greater than or equal to each value on the y-axis. The bolded curves are the HRs for the efficacy and safety outcomes on apixaban versus warfarin at each level of TTR; also shown are the 95% CIs. The estimated HR remains below unity for both efficacy and bleeding; this suggests a persistent benefit of apixaban over warfarin over a wide range of TTR values. The dashed vertical line at a TTR = 70% indicates the site level mean TTR above which European Society of Cardiology guidelines27,37 consider warfarin to be well controlled. Overall in ARISTOTLE, 75% of sites had a TTR >60%, 50% of sites had a TTR ≥66%, and 25% of sites had a TTR ≥71%. At sites in the United States, the overall TTR was 72%.37
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fig03: Relative efficacy and safety of apixaban compared with warfarin as a function of center-based time-in-therapeutic range (TTR) in the phase III trial for stroke prevention in AF (ARISTOTLE trial). As previously described, a center-based TTR was calculated for each investigative site in the trial and comparisons of outcomes on apixaban and warfarin were made at each site.37 For each level of center-based TTR from 1% to 80% on the y-axis, an HR for apixaban versus warfarin was calculated from all sites with a TTR greater than or equal to each value on the y-axis. The bolded curves are the HRs for the efficacy and safety outcomes on apixaban versus warfarin at each level of TTR; also shown are the 95% CIs. The estimated HR remains below unity for both efficacy and bleeding; this suggests a persistent benefit of apixaban over warfarin over a wide range of TTR values. The dashed vertical line at a TTR = 70% indicates the site level mean TTR above which European Society of Cardiology guidelines27,37 consider warfarin to be well controlled. Overall in ARISTOTLE, 75% of sites had a TTR >60%, 50% of sites had a TTR ≥66%, and 25% of sites had a TTR ≥71%. At sites in the United States, the overall TTR was 72%.37

Mentions: Another way to analyze this relationship is as a continuous curve rather than in quartiles. The HR and 95% CI can be plotted for key outcomes across a range of INR control by analyzing the results of subjects from sites where TTR exceeds the specified cutoff. The curves for both SSE and ISTH MB appear in Figure3.37 In both cases, the estimate for the HR and 95% CI were favorable for apixaban, with stability across a wide range of TTRs up to about 80% TTR. Above that value, the very few numbers of events and small numbers of patients in this group (only 9.3% of treated patients achieved a TTR of ≥80%) cause the analysis to break down. These findings provide further evidence that even across a wide range of very good INR control, apixaban is superior to warfarin.


Development of apixaban: a novel anticoagulant for prevention of stroke in patients with atrial fibrillation.

Hanna MS, Mohan P, Knabb R, Gupta E, Frost C, Lawrence JH - Ann. N. Y. Acad. Sci. (2014)

Relative efficacy and safety of apixaban compared with warfarin as a function of center-based time-in-therapeutic range (TTR) in the phase III trial for stroke prevention in AF (ARISTOTLE trial). As previously described, a center-based TTR was calculated for each investigative site in the trial and comparisons of outcomes on apixaban and warfarin were made at each site.37 For each level of center-based TTR from 1% to 80% on the y-axis, an HR for apixaban versus warfarin was calculated from all sites with a TTR greater than or equal to each value on the y-axis. The bolded curves are the HRs for the efficacy and safety outcomes on apixaban versus warfarin at each level of TTR; also shown are the 95% CIs. The estimated HR remains below unity for both efficacy and bleeding; this suggests a persistent benefit of apixaban over warfarin over a wide range of TTR values. The dashed vertical line at a TTR = 70% indicates the site level mean TTR above which European Society of Cardiology guidelines27,37 consider warfarin to be well controlled. Overall in ARISTOTLE, 75% of sites had a TTR >60%, 50% of sites had a TTR ≥66%, and 25% of sites had a TTR ≥71%. At sites in the United States, the overall TTR was 72%.37
© Copyright Policy - open-access
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4260137&req=5

fig03: Relative efficacy and safety of apixaban compared with warfarin as a function of center-based time-in-therapeutic range (TTR) in the phase III trial for stroke prevention in AF (ARISTOTLE trial). As previously described, a center-based TTR was calculated for each investigative site in the trial and comparisons of outcomes on apixaban and warfarin were made at each site.37 For each level of center-based TTR from 1% to 80% on the y-axis, an HR for apixaban versus warfarin was calculated from all sites with a TTR greater than or equal to each value on the y-axis. The bolded curves are the HRs for the efficacy and safety outcomes on apixaban versus warfarin at each level of TTR; also shown are the 95% CIs. The estimated HR remains below unity for both efficacy and bleeding; this suggests a persistent benefit of apixaban over warfarin over a wide range of TTR values. The dashed vertical line at a TTR = 70% indicates the site level mean TTR above which European Society of Cardiology guidelines27,37 consider warfarin to be well controlled. Overall in ARISTOTLE, 75% of sites had a TTR >60%, 50% of sites had a TTR ≥66%, and 25% of sites had a TTR ≥71%. At sites in the United States, the overall TTR was 72%.37
Mentions: Another way to analyze this relationship is as a continuous curve rather than in quartiles. The HR and 95% CI can be plotted for key outcomes across a range of INR control by analyzing the results of subjects from sites where TTR exceeds the specified cutoff. The curves for both SSE and ISTH MB appear in Figure3.37 In both cases, the estimate for the HR and 95% CI were favorable for apixaban, with stability across a wide range of TTRs up to about 80% TTR. Above that value, the very few numbers of events and small numbers of patients in this group (only 9.3% of treated patients achieved a TTR of ≥80%) cause the analysis to break down. These findings provide further evidence that even across a wide range of very good INR control, apixaban is superior to warfarin.

Bottom Line: The factor Xa inhibitor apixaban is one of the novel anticoagulants to emerge as alternatives to long-standing standards of care that include low-molecular-weight heparin and warfarin.Twice-daily dosing of apixaban, rather than once daily, was chosen to lower peak concentrations and reduce fluctuations between peak and trough levels.In the AVERROES study of patients who were unsuitable for warfarin therapy, apixaban was superior to aspirin in reducing the risk of stroke or systemic embolism (SSE), without a significant increase in major bleeding (MB).

View Article: PubMed Central - PubMed

Affiliation: Global Clinical Research, Research & Development, Bristol-Myers Squibb Company, Princeton, New Jersey.

Show MeSH
Related in: MedlinePlus