A Phase 3 interventional study of Enoxaparin + Placebo and Apixaban + Placebo in Deep Vein Thrombosis and Pulmonary Embolism, sponsored by Bristol-Myers Squibb. Completed at 107 sites in 13 countries. Open to participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2015-12-30.
Sponsored by Bristol-Myers Squibb · Phase 3, Interventional, and Prevention
The purpose of this study is to learn if apixaban can prevent blood clots in the leg (deep vein Thrombosis [DVT]) and lung (pulmonary embolism [PE]) that sometimes occur after knee replacement surgery and to learn how apixaban compares to enoxaparin (Lovenox®) for preventing these clots. The safety of apixaban will also be studied.
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Key Inclusion Criteria:
Key Exclusion Criteria:
\+ placebo
Drug: Enoxaparin + Placebo
\+ placebo
Drug: Apixaban + Placebo
Drug page: Enoxaparin sodium
Syringes + tablets, Subcutaneous + Oral, 30mg, twice daily, 12 day treatment period
Also known as: Lovenox®
Tablet + Syringes, Oral + subcutaneous, 2.5 mg, twice daily, 12 day treatment period
Event Rate of the Composite of Adjudicated Venous Thromboembolism (VTE) Events and All-Cause Death With Onset During the Intended Treatment Period - Primary Subjects
An Independent Central Adjudication Committee (ICAC) adjudicated all venograms, suspected symptomatic deep vein thrombosis (DVT) and pulmonary embolism (PE), acute clinically overt bleeding events, suspected thrombocytopenia, suspected acute MI, suspected acute stroke, and cause of death. Event rate was number of participants with the composite endpoint divided by the number of participants analyzed and reported as percentage (%). Surgery=Day 1; Randomization/Treatment started on Day of Surgery or the next day (Day 1 or Day 2). A mandatory bilateral ascending contrast venogram was performed on all participants after 12 days (±2 days) of study treatment. Intended Treatment Period=starts on the day of randomization; for treated participants, the period ends at the latter of 2 days after last dose of study drug or 14 days after the first dose of study drug; for randomized participants who were not treated, the period ends 14 days after randomization.
Time frame: From Day 1 or Day 2 to last dose, plus 2 days or 14 days post randomization
Event Rate for Participants With Major Bleeding, Clinically Relevant Non-Major Bleeding, Major or Clinically Relevant Non-Major Bleeding, Any Bleeding With Onset During the Treatment Period - Treated Population
ICAC adjudicated acute clinically overt bleeding events as per International Society on Thrombosis and Hemostasis (ISTH) guidelines modified for surgical patients. Event rate was number of participants with the composite endpoint divided by the number of participants analyzed (%). Clinically relevant (CR); Non-Major (N-M) Bleeding. Day 1=Day of surgery. Treatment started (first dose) day of surgery or next day. Treatment continued for 12 days.
Time frame: First dose of study drug to last dose, plus 2 days post last dose
Event Rate for Participants With Major Bleeding, Clinically Relevant (CR) Non-Major (N-M) Bleeding , Major or Clinically Relevant (CR) Non-Major (N-M) Bleeding, Any Bleeding With Onset During the Follow-Up Period
ICAC adjudicated acute clinically overt bleeding events as per International Society on Thrombosis and Hemostasis (ISTH) guidelines modified for surgical patients. Event rate was number of participants with the composite endpoint divided by the number of participants analyzed (%). Follow up Period was from the end of the treatment period (last dose) up to 60 days post last dose, Day 72.
Time frame: Last dose of study drug to Day 72 (60 days)
Event Rate of Composite of Adjudicated Proximal DVT, Non-Fatal PE and All-Cause Death With Onset During the Intended Treatment Period PE and All-cause Death During the Intended Treatment Period
A mandatory bilateral ascending contrast venogram was performed on all participants after 12 days (±2 days) of study treatment. An ICAC adjudicated all venograms, suspected proximal DVT and non-fatal PE, and all-cause of death. Event rate was number of participants with the composite endpoint divided by the number of participants analyzed and reported as percentage (%).
Time frame: From Day 1 or Day 2 to last dose, plus 2 days or 14 days post randomization
Event Rate of Adjudicated VTE / VTE-related Death With Onset During the Treatment Period
VTE / VTE-related death was defined as the combination of fatal or non-fatal PE, and symptomatic or asymptomatic DVT. A mandatory bilateral ascending contrast venogram was performed on all participants after 12 days (±2 days) of study treatment. An ICAC adjudicated all venograms, suspected symptomatic DVT and PE, and cause of death. Event rate was number of participants with the endpoint divided by the number of participant's analyzed (%).
Time frame: From Day 1 or Day 2 to last dose, plus 2 days or 14 days post randomization
Event Rate for Participants With Proximal DVT/Non-Fatal PE/ VTE-Related Death With Onset During the Intended Treatment Period
An ICAC adjudicated all venograms, suspected symptomatic DVT and PE, and cause of death. Event rate was number of participants with the endpoint divided by the number of participant's analyzed (%).
Time frame: From Day 1 or Day 2 to last dose, plus 2 days or 14 days post randomization
Event Rate for Total Participants With Adjudicated VTE/All-Cause Death With Onset During the Intended Treatment Period
ICAC adjudicated all venograms, suspected symptomatic DVT and PE, and cause of death. Event rate was number of participants with the endpoint divided by the number of participant's analyzed (%).
Time frame: From Day 1 or Day 2 to last dose, plus 2 days or 14 days post randomization
Event Rate for Total Participants With VTE/ VTE-Related Death With Onset During the Intended Treatment Period
ICAC adjudicated all venograms, suspected symptomatic DVT and PE, and cause of death. VTE includes DVT and PE. Event rate was number of participants with the endpoint divided by the number of participant's analyzed (%).
Time frame: From Day 1 or Day 2 to last dose, plus 2 days or 14 days post randomization
Event Rate for Participants With All-Cause Death During the Intended Treatment Period
Event rate was number of participants with all-cause death divided by the number of participant's analyzed (%).
Time frame: From Day 1 or Day 2 to last dose, plus 2 days or 14 days post randomization
Event Rate for Participants With VTE-Related Death With Onset During the Intended Treatment Period
ICAC adjudicated cause of death. Event rate was number of participants with the endpoint divided by the number of participant's analyzed (%).
Time frame: From Day 1 or Day 2 to last dose, plus 2 days or 14 days post randomization
Event Rate for Participants With Symptomatic VTE/ All-Cause Death With Onset During the Intended Treatment Period
ICAC adjudicated suspected symptomatic DVT and PE, and cause of death. Event rate was number of participants with the endpoint divided by the number of participant's analyzed (%).
Time frame: From Day 1 or Day 2 to last dose, plus 2 days or 14 days post randomization
Event Rate for Participants With Symptomatic VTE/ VTE-Related Death With Onset During the Intended Treatment Period
ICAC adjudicated suspected symptomatic DVT and PE, and cause of death. Event rate was number of participants with the endpoint divided by the number of participant's analyzed (%).
Time frame: From Day 1 or Day 2 to last dose, plus 2 days or 14 days post randomization
Event Rate for Participants With VTE/Major Bleeding/All-Cause Death With Onset During the Intended Treatment Period
ICAC adjudicated VTE, acute clinically overt bleeding events, suspected thrombocytopenia, and cause of death. Event rate was number of participants with the composite endpoint divided by the number of participants analyzed (%).
Time frame: From Day 1 or Day 2 to last dose, plus 2 days or 14 days post randomization
Event Rate for Participants With PE (Fatal or Non-Fatal), DVT (All, Symptomatic Proximal, and Distal, Asymptomatic) With Onset During the Intended Treatment Period
An ICAC adjudicated all venograms, suspected symptomatic deep vein thrombosis (DVT) and pulmonary embolism (PE), acute clinically overt bleeding events, suspected thrombocytopenia, suspected acute MI, suspected acute stroke, and cause of death. Event rate was number of participants with the composite endpoint divided by the number of participants analyzed (%).
Time frame: From Day 1 or Day 2 to last dose, plus 2 days or 14 days post randomization
Event Rate for Participants With Proximal DVT, Distal DVT, Asymptomatic Proximal DVT, Asymptomatic Distal DVT With Onset During the Intended Treatment Period
ICAC adjudicated all venograms and suspected symptomatic DVT. Event rate was number of participants with the endpoint divided by the number of participant's analyzed (%).
Time frame: From Day 1 or Day 2 to last dose, plus 2 days or 14 days post randomization
Event Rate for Participants With Adjudicated Myocardial Infarction (MI) Acute Ischemic Stroke and Thromboembolic Events With Onset During the Treatment Period
ICAC adjudicated acute clinically overt bleeding events, suspected thrombocytopenia, suspected acute MI, suspected acute stroke per International Society on Thrombosis and Hemostasis (ISTH) guidelines modified for surgical patients. Event rate was number of participants with the composite endpoint divided by the number of participants analyzed (%).
Time frame: From first dose to last dose, plus 2 days (12 days, plus 2)
Event Rate of Adjudicated MI, Stroke, and Thrombocytopenia Events During the Follow-Up Period
A 60-day follow-up period started after the last dose of study drug and continued until the End of Study Visit on Day 72 (60 days ± 3 days, after the last dose of study drug). Event rate was number of participants with the endpoint divided by the number of participants analyzed (%). ICAC adjudicated acute clinically overt bleeding events, suspected thrombocytopenia, suspected acute MI, suspected acute stroke per ISTH guidelines modified for surgical patients.
Time frame: Post last dose of study drug to Day 72 (60 days)
Number of Participants With Serious Adverse Events (SAEs), Bleeding Adverse Events (AEs), AEs Leading to Discontinuation, and Deaths - Treated Population
AE=any new unfavorable symptom, sign, or disease or worsening of a preexisting condition that may not have a causal relationship with treatment. SAE=a medical event that at any dose results in death, persistent or significant disability/incapacity, or drug dependency/abuse; is life-threatening, an important medical event, or a congenital anomaly/birth defect; or requires or prolongs hospitalization.
Time frame: First dose to last dose, plus 2 days for AEs (12 + 2 days) or plus 30 days for SAEs (12 + 30 days)
Mean Change From Baseline in Systolic and Diastolic Blood Pressure During the Treatment Period
Treatment Period=the period from first dose of study drug through 2 days after discontinuation of study drug (12 + 2 days). Baseline=measurement prior to first dose of study drug. Blood pressures (BP) were measured during screening (pre-operative, post-operative) and in the treatment period on Days 1 (day of first dose), 2, 3, 4,12 (end of treatment). Systolic and diastolic pressures were measured in millimeters of mercury (mmHg).
Time frame: Baseline to last dose of study drug, plus 2 days
Mean Change From Baseline in Heart Rate During the Treatment Period
Treatment Period=the period from first dose of study drug through 2 days after discontinuation of study drug (12 + 2 days). Baseline=measurement prior to first dose of study drug. Heart rate was measured during screening (pre-operative, post-operative) and in the treatment period on Days 1 (day of first dose), 2, 3, 4,12 (end of treatment). Heart rate was measured in beats per minute (bpm).
Time frame: Baseline to last dose of study drug, plus 2 days
Number of Participants With Hematology Laboratory Marked Abnormality During the Treatment Period
Treatment Period=the period from first dose of study drug through 2 days after discontinuation of study drug. Hematology profile was measured during screening (pre-operative, post-operative) and in the Treatment Period on Days 2, 3, 4, 12 (end of treatment). Upper limit of normal (ULN); lower limit of normal (LLN). Platelet Count low: \< 100,000/mm\^3 (or \< 100\*109 cells/L). Erythrocytes low: \< 0.75 \*pre-dose. Hemoglobin low: \> 2 g/dL decrease compared to pre-dose or Value ≤ 8 g/dL. Hematocrit low: \< 0.75\*pre-dose . Leukocytes: \< 0.75\*LLN or \> 1.25\* ULN, or if pre-dose \< LLN then use \< 0.8\*predose or \> ULN if pre-dose \> ULN then use \> 1.2\*predose or \< LLN. Lymphocytes (absolute): \< 0.750\*10\^3 cells/µL or \> 7.50\*10\^3 cells/ µL. Eosinophils (absolute) high: \> 0.750\*10\^3 cells/µL. Basophils(absolute) high: \> 400/mm\^3 (or \> 0.4\*103 cells/µL). Monocytes (absolute) high: \> 2000/mm\^3 (or \> 2\*103 cells/µL). Neutrophils(absolute) high: \< 1.0\*103 cells/µL.
Time frame: First dose to last dose of study drug (12 days), plus 2 days
Number of Participants With Liver and Kidney Function Chemistry Laboratory Marked Abnormalities During the Treatment Period
Treatment Period=the period from first dose of study drug through 2 days after discontinuation of study drug. Laboratory Chemistry profile was measured during screening (pre-operative, post-operative) and in the Treatment Period on Days 4, and 12 (end of treatment). Bilirubin (direct) high: \> 1.5\*ULN. Total bilirubin: : \> 2\*ULN, Alanine Aminotransferase (ALT) high: \> 3\*ULN. Alkaline Phosphatase (ALP): \> 2\*ULN. Aspartate Aminotransferase (AST): \> 3\*ULN. Creatinine: \> 1.5\*ULN.
Time frame: First dose to last dose of study drug (12 days), plus 2 days
Number of Participants With Electrolyte Chemistry Laboratory Marked Abnormalities During the Treatment Period
Laboratory Chemistry profile was measured during screening (pre-operative, post-operative) and in the Treatment Period on Days 4, and 12 (end of treatment). Potassium: \< 0.9\*LLN or \> 1.1\*ULN, or if pre-dose \< LLN then use \< 0.9\*predose or \> ULN if pre-dose \> ULN then use \> 1.1\*predose or \< LLN. Calcium: \< 0.8\*LLN or \> 1.2\*ULN, or if pre-dose \< LLN then use \< 0.75\*predose or \> ULN If pre-dose \> ULN then use \> 1.25\*predose or \< LLN. Chloride: \< 0.9\*LLN or \> 1.1\*ULN, or if pre-dose \< LLN then use \< 0.9\*predose or \> ULN if pre-dose \> ULN then use \> 1.1\*predose or \< LLN. Sodium: \< 0.95\*LLN or \> 1.05\*ULN, or if pre-dose \< LLN then use \< 0.95\*predose or \>ULN if pre-dose \> ULN then use \> 1.05\*predose or \< LLN. Bicarbonate: \< 0.75\*LLN or \> 1.25\*ULN, or if pre-dose \< LLN then use \< 0.75\*predose or \> ULN if pre-dose \> ULN then use \> 1.25\*predose or \< LLN.
Time frame: First dose to last dose of study drug (12 days), plus 2 days
Number of Participants With Other Chemistry Laboratory Marked Abnormalities During the Treatment Period
Treatment Period=the period from first dose of study drug through 2 days after discontinuation of study drug. Laboratory Chemistry profile was measured during screening (pre-operative, post-operative) and in the Treatment Period on Days 4, and 12 (end of treatment). Fasting Glucose: if pre-dose \< LLN then use \< 0.8\*predose; or \> ULN if pre-dose \> ULN then use \> 2.0\*predose or \<LLN. Total Protein: \< 0.9\*LLN or \> 1.1\*ULN, or if pre-dose \< LLN then use 0.9\*predose or \> ULN if pre-dose \> ULN then use 1.1\*predose or \< LLN. Uric Acid: \> 1.5\*ULN, or if pre-dose \> ULN then use \> 2\*predose. Creatine Kinase (CK): \> 5\*ULN.
Time frame: First dose to last dose of study drug (12 days), plus 2 days
| Milestone | Apixaban 2.5mg BID | Enoxaparin 30 mg SC Injection q 12 Hours |
|---|---|---|
| Started | 1599 | 1596 |
| Completed | 1509 | 1489 |
| Not completed | 90 | 107 |
| Withdrew: Death | 1 | 1 |
| Withdrew: Adverse event | 60 | 58 |
| Withdrew: Withdrawal by subject | 18 | 37 |
| Withdrew: Lost to follow-up | 0 | 1 |
| Withdrew: No longer meets study criteria | 1 | 2 |
| Withdrew: Administrative reason by sponsor | 1 | 0 |
| Withdrew: Non-specified | 9 | 8 |
| Milestone | Apixaban 2.5mg BID | Enoxaparin 30 mg SC Injection q 12 Hours |
|---|---|---|
| Started | 1553 | 1533 |
| Completed | 1492 | 1461 |
| Not completed | 61 | 72 |
| Withdrew: Withdrawal by subject | 17 | 19 |
| Withdrew: Death | 0 | 2 |
| Withdrew: Lost to follow-up | 38 | 39 |
| Withdrew: Non-specified | 6 | 12 |
An Independent Central Adjudication Committee (ICAC) adjudicated all venograms, suspected symptomatic deep vein thrombosis (DVT) and pulmonary embolism (PE), acute clinically overt bleeding events, suspected thrombocytopenia, suspected acute MI, suspected acute stroke, and cause of death. Event rate was number of participants with the composite endpoint divided by the number of participants analyzed and reported as percentage (%). Surgery=Day 1; Randomization/Treatment started on Day of Surgery or the next day (Day 1 or Day 2). A mandatory bilateral ascending contrast venogram was performed on all participants after 12 days (±2 days) of study treatment. Intended Treatment Period=starts on the day of randomization; for treated participants, the period ends at the latter of 2 days after last dose of study drug or 14 days after the first dose of study drug; for randomized participants who were not treated, the period ends 14 days after randomization.
| percentage of participants | Apixaban 2.5mg BID | Enoxaparin 30 mg SC Injection q 12 Hours |
|---|---|---|
| Event Rate of the Composite of Adjudicated Venous Thromboembolism (VTE) Events and All-Cause Death With Onset During the Intended Treatment Period - Primary Subjects | 8.99 (7.47 to 10.79) | 8.85 (7.33 to 10.66) |
A mandatory bilateral ascending contrast venogram was performed on all participants after 12 days (±2 days) of study treatment. An ICAC adjudicated all venograms, suspected proximal DVT and non-fatal PE, and all-cause of death. Event rate was number of participants with the composite endpoint divided by the number of participants analyzed and reported as percentage (%).
| percentage of participants | Apixaban 2.5mg BID | Enoxaparin 30 mg SC Injection q 12 Hours |
|---|---|---|
| Event Rate of Composite of Adjudicated Proximal DVT, Non-Fatal PE and All-Cause Death With Onset During the Intended Treatment Period PE and All-cause Death During the Intended Treatment Period | 2.05 (1.39 to 3.01) | 1.64 (1.06 to 2.55) |
VTE / VTE-related death was defined as the combination of fatal or non-fatal PE, and symptomatic or asymptomatic DVT. A mandatory bilateral ascending contrast venogram was performed on all participants after 12 days (±2 days) of study treatment. An ICAC adjudicated all venograms, suspected symptomatic DVT and PE, and cause of death. Event rate was number of participants with the endpoint divided by the number of participant's analyzed (%).
| percentage of participants | Apixaban 2.5mg BID | Enoxaparin 30 mg SC Injection q 12 Hours |
|---|---|---|
| Event Rate of Adjudicated VTE / VTE-related Death With Onset During the Treatment Period | 8.91 (7.40 to 10.71) | 8.61 (7.10 to 10.40) |
An ICAC adjudicated all venograms, suspected symptomatic DVT and PE, and cause of death. Event rate was number of participants with the endpoint divided by the number of participant's analyzed (%).
| percentage of participants | Apixaban 2.5mg BID | Enoxaparin 30 mg SC Injection q 12 Hours |
|---|---|---|
| Event Rate for Participants With Proximal DVT/Non-Fatal PE/ VTE-Related Death With Onset During the Intended Treatment Period | 1.97 (1.33 to 2.92) | 1.40 (0.86 to 2.26) |
ICAC adjudicated all venograms, suspected symptomatic DVT and PE, and cause of death. Event rate was number of participants with the endpoint divided by the number of participant's analyzed (%).
| percentage of participants | Apixaban 2.5mg BID | Enoxaparin 30 mg SC Injection q 12 Hours |
|---|---|---|
| Event Rate for Total Participants With Adjudicated VTE/All-Cause Death With Onset During the Intended Treatment Period | 2.13 (1.46 to 3.10) | 1.97 (1.32 to 2.94) |
ICAC adjudicated all venograms, suspected symptomatic DVT and PE, and cause of death. VTE includes DVT and PE. Event rate was number of participants with the endpoint divided by the number of participant's analyzed (%).
| percentage of participants | Apixaban 2.5mg BID | Enoxaparin 30 mg SC Injection q 12 Hours |
|---|---|---|
| Event Rate for Total Participants With VTE/ VTE-Related Death With Onset During the Intended Treatment Period | 2.05 (1.39 to 3.01) | 1.73 (1.12 to 2.65) |
Event rate was number of participants with all-cause death divided by the number of participant's analyzed (%).
| percentage of participants | Apixaban 2.5mg BID | Enoxaparin 30 mg SC Injection q 12 Hours |
|---|---|---|
| Event Rate for Participants With All-Cause Death During the Intended Treatment Period | 0.19 (0.04 to 0.59) | 0.19 (0.04 to 0.59) |
ICAC adjudicated cause of death. Event rate was number of participants with the endpoint divided by the number of participant's analyzed (%).
| percentage of participants | Apixaban 2.5mg BID | Enoxaparin 30 mg SC Injection q 12 Hours |
|---|---|---|
| Event Rate for Participants With VTE-Related Death With Onset During the Intended Treatment Period | 0.13 (0.00 to 0.49) | 0.00 (0.00 to 0.30) |
ICAC adjudicated suspected symptomatic DVT and PE, and cause of death. Event rate was number of participants with the endpoint divided by the number of participant's analyzed (%).
| percentage of participants | Apixaban 2.5mg BID | Enoxaparin 30 mg SC Injection q 12 Hours |
|---|---|---|
| Event Rate for Participants With Symptomatic VTE/ All-Cause Death With Onset During the Intended Treatment Period | 1.25 (0.80 to 1.94) | 1.00 (0.61 to 1.64) |
ICAC adjudicated suspected symptomatic DVT and PE, and cause of death. Event rate was number of participants with the endpoint divided by the number of participant's analyzed (%).
| percentage of participants | Apixaban 2.5mg BID | Enoxaparin 30 mg SC Injection q 12 Hours |
|---|---|---|
| Event Rate for Participants With Symptomatic VTE/ VTE-Related Death With Onset During the Intended Treatment Period | 1.19 (0.75 to 1.87) | 0.81 (0.46 to 1.41) |
ICAC adjudicated VTE, acute clinically overt bleeding events, suspected thrombocytopenia, and cause of death. Event rate was number of participants with the composite endpoint divided by the number of participants analyzed (%).
| percentage of participants | Apixaban 2.5mg BID | Enoxaparin 30 mg SC Injection q 12 Hours |
|---|---|---|
| Event Rate for Participants With VTE/Major Bleeding/All-Cause Death With Onset During the Intended Treatment Period | 9.90 (8.31 to 11.76) | 10.60 (8.95 to 12.54) |
An ICAC adjudicated all venograms, suspected symptomatic deep vein thrombosis (DVT) and pulmonary embolism (PE), acute clinically overt bleeding events, suspected thrombocytopenia, suspected acute MI, suspected acute stroke, and cause of death. Event rate was number of participants with the composite endpoint divided by the number of participants analyzed (%).
| percentage of participants | Apixaban 2.5mg BID | Enoxaparin 30 mg SC Injection q 12 Hours |
|---|---|---|
| PE (Fatal or Non-Fatal) (n=1599, 1596) | 1.00 (0.61 to 1.64) | 0.44 (0.20 to 0.93) |
| Non-Fatal PE (n=1599, 1596) | 0.88 (0.51 to 1.49) | 0.44 (0.20 to 0.93) |
| All DVT n=1142, 1122 | 7.79 (6.37 to 9.51) | 8.20 (6.73 to 9.97) |
| Symptomatic DVT (n=1599, 1596) | 0.19 (0.04 to 0.59) | 0.44 (0.20 to 0.93) |
| Asymptomatic DVT (n=1139,1115) | 7.55 (6.15 to 9.25) | 7.62 (6.20 to 9.35) |
| Symptomatic Proximal DVT (n=1599,1596) | 0.13 (0.00 to 0.49) | 0.19 (0.04 to 0.59) |
| Symptomatic Distal DVT (n=1599,1596) | 0.06 (0.00 to 0.40) | 0.38 (0.15 to 0.85) |
ICAC adjudicated all venograms and suspected symptomatic DVT. Event rate was number of participants with the endpoint divided by the number of participant's analyzed (%).
| percentage of participants | Apixaban 2.5mg BID | Enoxaparin 30 mg SC Injection q 12 Hours |
|---|---|---|
| Proximal DVT (n=1254, 1207) | 0.72 (0.36 to 1.39) | 0.91 (0.49 to 1.65) |
| Distal DVT (n=1146, 1133) | 7.24 (5.88 to 8.91) | 8.03 (6.58 to 9.78) |
| Asymptomatic Proximal DVT (n=1252, 1204) | 0.56 (0.25 to 1.18) | 0.66 (0.32 to 1.34) |
| Asymptomatic Distal DVT (n=1145, 1127) | 7.16 (5.80 to 8.82) | 7.54 (6.14 to 9.25) |
ICAC adjudicated acute clinically overt bleeding events, suspected thrombocytopenia, suspected acute MI, suspected acute stroke per International Society on Thrombosis and Hemostasis (ISTH) guidelines modified for surgical patients. Event rate was number of participants with the composite endpoint divided by the number of participants analyzed (%).
| percentage of participants | Apixaban 2.5mg BID | Enoxaparin 30 mg SC Injection q 12 Hours |
|---|---|---|
| MI/Stroke | 0.06 (0.00 to 0.40) | 0.31 (0.11 to 0.77) |
| MI | 0.06 (0.00 to 0.40) | 0.25 (0.08 to 0.68) |
| Stroke | 0.00 (0.00 to 0.30) | 0.13 (0.01 to 0.50) |
| Thrombocytopenia | 0.00 (0.00 to 0.30) | 0.13 (0.01 to 0.50) |
ICAC adjudicated acute clinically overt bleeding events as per International Society on Thrombosis and Hemostasis (ISTH) guidelines modified for surgical patients. Event rate was number of participants with the composite endpoint divided by the number of participants analyzed (%). Clinically relevant (CR); Non-Major (N-M) Bleeding. Day 1=Day of surgery. Treatment started (first dose) day of surgery or next day. Treatment continued for 12 days.
| percentage of participants | Apixaban 2.5mg BID | Enoxaparin 30 mg SC Injection q 12 Hours |
|---|---|---|
| Major Bleeding (n=1596, 1588) | 0.69 (0.37 to 1.25) | 1.39 (0.91 to 2.11) |
| CR N-M Bleeding (n=1596, 1588) | 2.19 (1.58 to 3.05) | 2.96 (2.23 to 3.93) |
| Major or CR N-M Bleeding(n=1596, 1588) | 2.88 (2.16 to 3.84) | 4.28 (3.39 to 5.41) |
| Any Bleeding (n=1596, 1588) | 5.33 (4.33 to 6.55) | 6.80 (5.66 to 8.16) |
ICAC adjudicated acute clinically overt bleeding events as per International Society on Thrombosis and Hemostasis (ISTH) guidelines modified for surgical patients. Event rate was number of participants with the composite endpoint divided by the number of participants analyzed (%). Follow up Period was from the end of the treatment period (last dose) up to 60 days post last dose, Day 72.
| percentage of participants | Apixaban 2.5mg BID | Enoxaparin 30 mg SC Injection q 12 Hours |
|---|---|---|
| Major Bleeding (n=1563, 1553) | 0.13 (0.01 to 0.51) | 0.13 (0.01 to 0.51) |
| CR N-M Bleeding (n=1563, 1553) | 0.26 (0.08 to 0.69) | 0.45 (0.20 to 0.96) |
| Major or CR N-M Bleeding (n=1563, 1553) | 0.38 (0.16 to 0.86) | 0.58 (0.29 to 1.12) |
| Any Bleeding (n=1563, 1553) | 0.90 (0.52 to 1.52) | 1.29 (0.83 to 2.00) |
A 60-day follow-up period started after the last dose of study drug and continued until the End of Study Visit on Day 72 (60 days ± 3 days, after the last dose of study drug). Event rate was number of participants with the endpoint divided by the number of participants analyzed (%). ICAC adjudicated acute clinically overt bleeding events, suspected thrombocytopenia, suspected acute MI, suspected acute stroke per ISTH guidelines modified for surgical patients.
| percentage of participants | Apixaban 2.5mg BID | Enoxaparin 30 mg SC Injection q 12 Hours |
|---|---|---|
| MI/Stroke | 0.06 (0.00 to 0.41) | 0.06 (0.00 to 0.41) |
| MI | 0.06 (0.00 to 0.41) | 0.06 (0.00 to 0.41) |
| Stroke | 0.00 (0.00 to 0.30) | 0.00 (0.00 to 0.31) |
| Thrombocytopenia | 0.00 (0.00 to 0.30) | 0.00 (0.00 to 0.31) |
AE=any new unfavorable symptom, sign, or disease or worsening of a preexisting condition that may not have a causal relationship with treatment. SAE=a medical event that at any dose results in death, persistent or significant disability/incapacity, or drug dependency/abuse; is life-threatening, an important medical event, or a congenital anomaly/birth defect; or requires or prolongs hospitalization.
| participants | Apixaban 2.5mg BID | Enoxaparin 30 mg SC Injection q 12 Hours |
|---|---|---|
| SAE | 123 | 123 |
| Bleeding AE | 110 | 144 |
| AEs leading to discontinuation | 60 | 58 |
| Deaths | 3 | 5 |
Treatment Period=the period from first dose of study drug through 2 days after discontinuation of study drug (12 + 2 days). Baseline=measurement prior to first dose of study drug. Blood pressures (BP) were measured during screening (pre-operative, post-operative) and in the treatment period on Days 1 (day of first dose), 2, 3, 4,12 (end of treatment). Systolic and diastolic pressures were measured in millimeters of mercury (mmHg).
| mmHg | Apixaban 2.5mg BID | Enoxaparin 30 mg SC Injection q 12 Hours |
|---|---|---|
| Diastolic BP Day 1 (n=240, 237) | -0.4 ± 0.741 | -0.9 ± 0.738 |
| Diastolic BP Day 2 (n=1577, 1574) | 1.7 ± 0.301 | 1.5 ± 0.305 |
| Diastolic BP Day 3 (n=1489,1498) | 2.3 ± 0.322 | 2.1 ± 0.321 |
| Diastolic BP Day 4 (n=127,134) | 0.6 ± 1.217 | 0.3 ± 1.104 |
| Diastolic BP Day 12 (n=1495,1463) | 7.3 ± 0.342 | 7.5 ± 0.343 |
| Systolic BP Day 1 (n=240,237) | 1.5 ± 1.189 | -0.7 ± 1.303 |
| Systolic BP Day 2 (n=1577,1574) | 5.4 ± 0.505 | 4.2 ± 0.518 |
| Systolic BP Day 3 (n=1489,1498) | 4.7 ± 0.536 | 4.3 ± 0.555 |
| Systolic BP Day 4 (n=127,134) | 2.8 ± 2.129 | 1.4 ± 1.871 |
| Systolic BP Day 12 (n=1495,1463) | 9.1 ± 0.543 | 8.9 ± 0.562 |
Treatment Period=the period from first dose of study drug through 2 days after discontinuation of study drug (12 + 2 days). Baseline=measurement prior to first dose of study drug. Heart rate was measured during screening (pre-operative, post-operative) and in the treatment period on Days 1 (day of first dose), 2, 3, 4,12 (end of treatment). Heart rate was measured in beats per minute (bpm).
| bpm | Apixaban 2.5mg BID | Enoxaparin 30 mg SC Injection q 12 Hours |
|---|---|---|
| Heart Rate Day 1 (n=240,237) | 2.3 ± 0.761 | 2.7 ± 0.761 |
| Heart Rate Day 2 (n=1575,1574) | 4.6 ± 0.312 | 4.5 ± 0.317 |
| Heart Rate Day 3 (n=1490,1498) | 4.5 ± 0.334 | 5.0 ± 0.344 |
| Heart Rate Day 4 (n=127,134) | 7.6 ± 1.365 | 9.4 ± 1.320 |
| Heart Rate Day 12 (n=1495, 1462) | -0.3 ± 0.361 | -0.1 ± 0.375 |
Treatment Period=the period from first dose of study drug through 2 days after discontinuation of study drug. Hematology profile was measured during screening (pre-operative, post-operative) and in the Treatment Period on Days 2, 3, 4, 12 (end of treatment). Upper limit of normal (ULN); lower limit of normal (LLN). Platelet Count low: \< 100,000/mm\^3 (or \< 100\*109 cells/L). Erythrocytes low: \< 0.75 \*pre-dose. Hemoglobin low: \> 2 g/dL decrease compared to pre-dose or Value ≤ 8 g/dL. Hematocrit low: \< 0.75\*pre-dose . Leukocytes: \< 0.75\*LLN or \> 1.25\* ULN, or if pre-dose \< LLN then use \< 0.8\*predose or \> ULN if pre-dose \> ULN then use \> 1.2\*predose or \< LLN. Lymphocytes (absolute): \< 0.750\*10\^3 cells/µL or \> 7.50\*10\^3 cells/ µL. Eosinophils (absolute) high: \> 0.750\*10\^3 cells/µL. Basophils(absolute) high: \> 400/mm\^3 (or \> 0.4\*103 cells/µL). Monocytes (absolute) high: \> 2000/mm\^3 (or \> 2\*103 cells/µL). Neutrophils(absolute) high: \< 1.0\*103 cells/µL.
| participants | Apixaban 2.5mg BID | Enoxaparin 30 mg SC Injection q 12 Hours |
|---|---|---|
| Hemoglobin low (n=1561,1549) | 386 | 392 |
| Hematocrit low (n=1558,1547) | 135 | 157 |
| Platelet count low (n=1556,1543) | 6 | 9 |
| Erythrocytes low (n=1557,1547) | 130 | 149 |
| Leukocytes low(n=1583,1572) | 8 | 11 |
| Leukocytes high(n=1583,1572) | 214 | 210 |
| Basophils high (n=1577, 1564) | 0 | 2 |
| Eosinophils high (n=1577, 1564) | 32 | 13 |
| Lymphocytes low (n=1577,1564) | 125 | 117 |
| Lymphocytes high (n=1577,1564) | 2 | 4 |
| Monocytes high (n=1577,1564) | 4 | 4 |
| Neutrophils low (n=1577,1564) | 4 | 5 |
Treatment Period=the period from first dose of study drug through 2 days after discontinuation of study drug. Laboratory Chemistry profile was measured during screening (pre-operative, post-operative) and in the Treatment Period on Days 4, and 12 (end of treatment). Bilirubin (direct) high: \> 1.5\*ULN. Total bilirubin: : \> 2\*ULN, Alanine Aminotransferase (ALT) high: \> 3\*ULN. Alkaline Phosphatase (ALP): \> 2\*ULN. Aspartate Aminotransferase (AST): \> 3\*ULN. Creatinine: \> 1.5\*ULN.
| participants | Apixaban 2.5mg BID | Enoxaparin 30 mg SC Injection q 12 Hours |
|---|---|---|
| ALP high (n=1573,1563) | 42 | 55 |
| ALT high (n=1573,1562) | 33 | 45 |
| AST high (n=1573,1562) | 29 | 40 |
| Bilirubin direct high (n=1563,1553) | 63 | 54 |
| Bilirubin total high(n=1572,1562) | 2 | 8 |
| Creatinine high (n=1569,1562) | 17 | 28 |
Laboratory Chemistry profile was measured during screening (pre-operative, post-operative) and in the Treatment Period on Days 4, and 12 (end of treatment). Potassium: \< 0.9\*LLN or \> 1.1\*ULN, or if pre-dose \< LLN then use \< 0.9\*predose or \> ULN if pre-dose \> ULN then use \> 1.1\*predose or \< LLN. Calcium: \< 0.8\*LLN or \> 1.2\*ULN, or if pre-dose \< LLN then use \< 0.75\*predose or \> ULN If pre-dose \> ULN then use \> 1.25\*predose or \< LLN. Chloride: \< 0.9\*LLN or \> 1.1\*ULN, or if pre-dose \< LLN then use \< 0.9\*predose or \> ULN if pre-dose \> ULN then use \> 1.1\*predose or \< LLN. Sodium: \< 0.95\*LLN or \> 1.05\*ULN, or if pre-dose \< LLN then use \< 0.95\*predose or \>ULN if pre-dose \> ULN then use \> 1.05\*predose or \< LLN. Bicarbonate: \< 0.75\*LLN or \> 1.25\*ULN, or if pre-dose \< LLN then use \< 0.75\*predose or \> ULN if pre-dose \> ULN then use \> 1.25\*predose or \< LLN.
| participants | Apixaban 2.5mg BID | Enoxaparin 30 mg SC Injection q 12 Hours |
|---|---|---|
| Calcium low (n=1569,1562) | 1 | 5 |
| Calcium high (n=1569,1562) | 0 | 1 |
| Chloride low (n=1568,1562) | 11 | 17 |
| Chloride high (n=1568,1562) | 0 | 1 |
| Bicarbonate low (n=1568,1561) | 11 | 13 |
| Potassium low(n=1568,1559) | 54 | 56 |
| Potassium high(n=1568,1559) | 26 | 20 |
| Sodium low (n=1568,1562) | 23 | 39 |
| Sodium high (n=1568,1562) | 2 | 0 |
Treatment Period=the period from first dose of study drug through 2 days after discontinuation of study drug. Laboratory Chemistry profile was measured during screening (pre-operative, post-operative) and in the Treatment Period on Days 4, and 12 (end of treatment). Fasting Glucose: if pre-dose \< LLN then use \< 0.8\*predose; or \> ULN if pre-dose \> ULN then use \> 2.0\*predose or \<LLN. Total Protein: \< 0.9\*LLN or \> 1.1\*ULN, or if pre-dose \< LLN then use 0.9\*predose or \> ULN if pre-dose \> ULN then use 1.1\*predose or \< LLN. Uric Acid: \> 1.5\*ULN, or if pre-dose \> ULN then use \> 2\*predose. Creatine Kinase (CK): \> 5\*ULN.
| participants | Apixaban 2.5mg BID | Enoxaparin 30 mg SC Injection q 12 Hours |
|---|---|---|
| Fasting Glucose low (n=611, 579) | 8 | 5 |
| Fasting Glucose high (n=611, 579) | 54 | 28 |
| Total Protein low (n=1568,1562) | 527 | 513 |
| CK high (n=1573,1563) | 52 | 45 |
| Uric Acid high (n=1567,1562) | 22 | 12 |
Collected over First dose to last dose, plus 2 days for AEs or plus 30 days for SAEs.. Non-serious events are listed at a 5% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| Apixaban 2.5mg BID | — | 123/1,596 (7.7%) | 713/1,596 (44.7%) |
| Enoxaparin 30 mg SC Injection q 12 Hours | — | 123/1,588 (7.7%) | 741/1,588 (46.7%) |
| Event | Apixaban 2.5mg BID | Enoxaparin 30 mg SC Injection q 12 Hours |
|---|---|---|
| Pulmonary embolismRespiratory, thoracic and mediastinal disorders | 19/1596 | 9/1588 |
| Deep vein thrombosisVascular disorders | 6/1596 | 10/1588 |
| Atrial fibrillationCardiac disorders | 3/1596 | 5/1588 |
| Gastrointestinal haemorrhageGastrointestinal disorders | 2/1596 | 5/1588 |
| AnaemiaBlood and lymphatic system disorders | 5/1596 | 2/1588 |
| Cerebrovascular accidentNervous system disorders | 0/1596 | 4/1588 |
| HaematomaVascular disorders | 3/1596 | 4/1588 |
| Myocardial infarctionCardiac disorders | 2/1596 | 4/1588 |
| Wound infectionInfections and infestations | 4/1596 | 2/1588 |
| CellulitisInfections and infestations | 4/1596 | 2/1588 |
| Event | Apixaban 2.5mg BID | Enoxaparin 30 mg SC Injection q 12 Hours |
|---|---|---|
| NauseaGastrointestinal disorders | 208/1596 | 241/1588 |
| ConstipationGastrointestinal disorders | 227/1596 | 234/1588 |
| Oedema peripheralGeneral disorders | 131/1596 | 153/1588 |
| PyrexiaGeneral disorders | 137/1596 | 149/1588 |
| Deep vein thrombosisVascular disorders | 127/1596 | 113/1588 |
| DizzinessNervous system disorders | 103/1596 | 88/1588 |
| VomitingGastrointestinal disorders | 99/1596 | 102/1588 |
| InsomniaPsychiatric disorders | 77/1596 | 86/1588 |
| Pain in extremityMusculoskeletal and connective tissue disorders | 84/1596 | 77/1588 |
Randomized participants were summarized.
| Age, Continuous(years) | Apixaban 2.5mg BID | Enoxaparin 30 mg SC Injection q 12 Hours | Total |
|---|---|---|---|
| Mean | 65.9 ± 9.26 | 65.7 ± 9.22 | 65.8 ± 9.24 |
| Age, Customized(participants) | Apixaban 2.5mg BID | Enoxaparin 30 mg SC Injection q 12 Hours | Total |
|---|---|---|---|
| Less than(<) 65 years | 697 | 691 | 1388 |
| Greater than, equal to (>=) 65 and < 75 years | 593 | 610 | 1203 |
| >=75 years | 309 | 295 | 604 |
| Sex: Female, Male(Participants) | Apixaban 2.5mg BID | Enoxaparin 30 mg SC Injection q 12 Hours | Total |
|---|---|---|---|
| Female | 997 | 986 | 1983 |
| Male | 602 | 610 | 1212 |
| Region of Enrollment(participants) | Apixaban 2.5mg BID | Enoxaparin 30 mg SC Injection q 12 Hours | Total |
|---|---|---|---|
| Argentina | 43 | 43 | 86 |
| Russian Federation | 15 | 13 | 28 |
| Hungary | 28 | 26 | 54 |
| United States | 464 | 474 | 938 |
| Canada | 554 | 548 | 1102 |
| Sweden | 66 | 68 | 134 |
| Turkey | 12 | 10 | 22 |
| Denmark | 87 | 89 | 176 |
| Brazil | 42 | 39 | 81 |
| Poland | 35 | 35 | 70 |
| Mexico | 138 | 138 | 276 |
| Israel | 44 | 42 | 86 |
| Australia | 50 | 54 | 104 |
| Norway | 21 | 17 | 38 |
Showing the first 100 of 107 sites across 13 countries.
The record gives a start of Nov 2006, a primary completion of May 2008 and a completion of May 2008. It does not say whether these dates are actual or estimated.
Results were first posted in Dec 2015, 7 years 7 months after primary completion.
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