Limits...
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.

Show MeSH

Related in: MedlinePlus

Efficacy and bleeding outcomes in the phase II dose-ranging trial of apixaban for prevention of VTE following elective knee replacement surgery (APROPOS trial). Three total daily dose levels of apixaban were tested (5, 10, 20 mg), administered either qd (5 mg qd, 10 mg qd, 20 mg qd) or in divided doses bid (2.5 mg bid, 5 mg bid, 10 mg bid). Reflecting clinical practice patterns in the United States, two comparators were tested: enoxaparin 30 mg bid (subcutaneous administration) and warfarin (target INR range of 2–3). The phase III dose studied in trials for prevention of VTE was 2.5 mg bid, and the phase III dose studied in trials for stroke prevention in AF was 5 mg bid. Modified, with permission, from Lassen et al.15
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4260137&req=5

fig01: Efficacy and bleeding outcomes in the phase II dose-ranging trial of apixaban for prevention of VTE following elective knee replacement surgery (APROPOS trial). Three total daily dose levels of apixaban were tested (5, 10, 20 mg), administered either qd (5 mg qd, 10 mg qd, 20 mg qd) or in divided doses bid (2.5 mg bid, 5 mg bid, 10 mg bid). Reflecting clinical practice patterns in the United States, two comparators were tested: enoxaparin 30 mg bid (subcutaneous administration) and warfarin (target INR range of 2–3). The phase III dose studied in trials for prevention of VTE was 2.5 mg bid, and the phase III dose studied in trials for stroke prevention in AF was 5 mg bid. Modified, with permission, from Lassen et al.15

Mentions: It was not practical to conduct dose-ranging phase II studies for apixaban in all indications. For stroke prevention and risk reduction in AF, for example, event rates are so low that the ability to discriminate between doses would only be possible with studies that are the same size as a typical phase III trial. Dose selection in each of the phase III apixaban trials was intended to optimize the benefit–risk profile for the target patient population. To inform dosing in subsequent trials, a dose-ranging eight-arm phase II study was conducted in patients undergoing elective knee replacement surgery, including three qd apixaban arms, three bid apixaban arms, and two comparator arms: enoxaparin 30 mg subcutaneous bid and warfarin (international normalized ratio (INR) 2–3).15 In a surgical setting, (1) the efficacy end point, a composite of deep vein thrombosis (DVT), pulmonary embolism, or related death, occurs in orthopedic surgery patients with substantially greater frequency than stroke in AF patients, and (2) the frequency of clinically important bleeding is sufficiently high to assess dose dependence. In all six apixaban arms, the efficacy event rate was lower than both comparator arms; and in the 2.5 mg bid and 5 mg qd apixaban arms, the bleeding rate was lower than in either of the comparator arms. For each of three total daily doses of apixaban (5, 10, and 20 mg), the bid dose had a lower efficacy event rate than did the qd dose (Fig.1).15 This observation is supported by an additional exposure–response analysis (Fig. S1) that showed greater avoidance of thrombotic or bleeding events with bid dosing compared with qd dosing.16 On the basis of these studies, an apixaban dose of 2.5 mg bid was selected for phase III studies for the prevention of VTE following elective hip or knee replacement surgery.17–19


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)

Efficacy and bleeding outcomes in the phase II dose-ranging trial of apixaban for prevention of VTE following elective knee replacement surgery (APROPOS trial). Three total daily dose levels of apixaban were tested (5, 10, 20 mg), administered either qd (5 mg qd, 10 mg qd, 20 mg qd) or in divided doses bid (2.5 mg bid, 5 mg bid, 10 mg bid). Reflecting clinical practice patterns in the United States, two comparators were tested: enoxaparin 30 mg bid (subcutaneous administration) and warfarin (target INR range of 2–3). The phase III dose studied in trials for prevention of VTE was 2.5 mg bid, and the phase III dose studied in trials for stroke prevention in AF was 5 mg bid. Modified, with permission, from Lassen et al.15
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4260137&req=5

fig01: Efficacy and bleeding outcomes in the phase II dose-ranging trial of apixaban for prevention of VTE following elective knee replacement surgery (APROPOS trial). Three total daily dose levels of apixaban were tested (5, 10, 20 mg), administered either qd (5 mg qd, 10 mg qd, 20 mg qd) or in divided doses bid (2.5 mg bid, 5 mg bid, 10 mg bid). Reflecting clinical practice patterns in the United States, two comparators were tested: enoxaparin 30 mg bid (subcutaneous administration) and warfarin (target INR range of 2–3). The phase III dose studied in trials for prevention of VTE was 2.5 mg bid, and the phase III dose studied in trials for stroke prevention in AF was 5 mg bid. Modified, with permission, from Lassen et al.15
Mentions: It was not practical to conduct dose-ranging phase II studies for apixaban in all indications. For stroke prevention and risk reduction in AF, for example, event rates are so low that the ability to discriminate between doses would only be possible with studies that are the same size as a typical phase III trial. Dose selection in each of the phase III apixaban trials was intended to optimize the benefit–risk profile for the target patient population. To inform dosing in subsequent trials, a dose-ranging eight-arm phase II study was conducted in patients undergoing elective knee replacement surgery, including three qd apixaban arms, three bid apixaban arms, and two comparator arms: enoxaparin 30 mg subcutaneous bid and warfarin (international normalized ratio (INR) 2–3).15 In a surgical setting, (1) the efficacy end point, a composite of deep vein thrombosis (DVT), pulmonary embolism, or related death, occurs in orthopedic surgery patients with substantially greater frequency than stroke in AF patients, and (2) the frequency of clinically important bleeding is sufficiently high to assess dose dependence. In all six apixaban arms, the efficacy event rate was lower than both comparator arms; and in the 2.5 mg bid and 5 mg qd apixaban arms, the bleeding rate was lower than in either of the comparator arms. For each of three total daily doses of apixaban (5, 10, and 20 mg), the bid dose had a lower efficacy event rate than did the qd dose (Fig.1).15 This observation is supported by an additional exposure–response analysis (Fig. S1) that showed greater avoidance of thrombotic or bleeding events with bid dosing compared with qd dosing.16 On the basis of these studies, an apixaban dose of 2.5 mg bid was selected for phase III studies for the prevention of VTE following elective hip or knee replacement surgery.17–19

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