Trial Outcomes & Findings for Efficacy and Safety Study of Apixaban for the Treatment of Deep Vein Thrombosis or Pulmonary Embolism (NCT NCT00643201)

Last Updated: 2014-04-21

Results Overview

VTE: nonfatal deep vein thrombosis (DVT) or nonfatal pulmonary embolism (PE). All events were adjudicated by an ICAC blinded to treatment. DVT assessed by compression ultrasound and/or venography; PE assessed by spiral computed tomography scanning, pulmonary angiography, and/or ventilation/perfusion lung scan. Event rate (proportion of participants): n/N (n=number of participants with observation; N=total number of efficacy evaluable participants). Intended treatment period: longer of the dosing period plus 2 days (completed treatment) or 355 days (discontinued early). Composite endpoint: events at any time from randomization until end of intended treatment, regardless whether drug treatment was received. All randomized participants with a non-missing primary endpoint were summarized. Missing endpoint = outcomes which could not be documented on or after study Day 154. Participants were categorized to the assigned group regardless of the treatment actually received (intent-to-treat).

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

5614 participants

Primary outcome timeframe

Day 1 to Week 24 + 2 Days or 355 days (Discontinued Early)

Results posted on

2014-04-21

Participant Flow

First participant, first visit: 27 August 2008; Last participant, last visit: 12 March 2013.

5614 enrolled, 5395 randomized; Reasons for non-randomization: 173 did not meet inclusion/exclusion criteria; 12 withdrew consent; 5 had clinical reason to continue current treatment; 3 administrative reason by sponsor; 1 death; 1 adverse event (AE); 24 other reasons. 1 site (5 patients) excluded from analysis due to unconfirmed accuracy of data.

Participant milestones

Participant milestones
Measure	Apixaban apixaban: tablets, oral, 10 milligram (mg) tablets, twice daily, for 7 days followed by apixaban 5 mg, twice daily, 6 months. Placebo for enoxaparin: solution, subcutaneous, 1milligram per kilogram (mg/kg) every 12 hours until sham international normalized ratio (INR) greater than, equal to ( ≥) 2. Placebo for warfarin: tablets, oral, dosing to target sham INR range between 2.0 - 3.0, once daily, 6 months	Enoxaparin + Warfarin Enoxaparin: solution, subcutaneous, 1 mg/kg Q12h until INR ≥2. Warfarin: tablets, oral, dosing to target INR range between 2.0 - 3.0, once daily, 6 months Placebo for apixaban: tablets, oral, 10 mg tablets, twice daily, for 7 days followed by placebo for apixaban 5 mg tablets, twice daily, 6 months
Randomized, Completed 6 Months of Study STARTED	2691	2704
Randomized, Completed 6 Months of Study COMPLETED	2314	2291
Randomized, Completed 6 Months of Study NOT COMPLETED	377	413
Completed Study Follow Up STARTED	2617	2639
Completed Study Follow Up COMPLETED	2547	2560
Completed Study Follow Up NOT COMPLETED	70	79

Reasons for withdrawal

Reasons for withdrawal
Measure	Apixaban apixaban: tablets, oral, 10 milligram (mg) tablets, twice daily, for 7 days followed by apixaban 5 mg, twice daily, 6 months. Placebo for enoxaparin: solution, subcutaneous, 1milligram per kilogram (mg/kg) every 12 hours until sham international normalized ratio (INR) greater than, equal to ( ≥) 2. Placebo for warfarin: tablets, oral, dosing to target sham INR range between 2.0 - 3.0, once daily, 6 months	Enoxaparin + Warfarin Enoxaparin: solution, subcutaneous, 1 mg/kg Q12h until INR ≥2. Warfarin: tablets, oral, dosing to target INR range between 2.0 - 3.0, once daily, 6 months Placebo for apixaban: tablets, oral, 10 mg tablets, twice daily, for 7 days followed by placebo for apixaban 5 mg tablets, twice daily, 6 months
Randomized, Completed 6 Months of Study Death	20	26
Randomized, Completed 6 Months of Study Adverse Event	150	182
Randomized, Completed 6 Months of Study Withdrawal by Subject	49	49
Randomized, Completed 6 Months of Study Lost to Follow-up	14	14
Randomized, Completed 6 Months of Study Poor or non-compliance	20	23
Randomized, Completed 6 Months of Study Pregnancy	3	2
Randomized, Completed 6 Months of Study Fails to meet inclusion/exclusion	13	9
Randomized, Completed 6 Months of Study Administrative reason	1	1
Randomized, Completed 6 Months of Study Other	107	107
Completed Study Follow Up Death	28	34
Completed Study Follow Up Withdrawal by Subject	23	29
Completed Study Follow Up Lost to Follow-up	18	16
Completed Study Follow Up non-specified	1	0

Baseline Characteristics

Efficacy and Safety Study of Apixaban for the Treatment of Deep Vein Thrombosis or Pulmonary Embolism

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Apixaban n=2691 Participants apixaban: tablets, oral, 10 milligram (mg) tablets, twice daily, for 7 days followed by apixaban 5 mg, twice daily, 6 months. Placebo for enoxaparin: solution, subcutaneous, 1milligram per kilogram (mg/kg) every 12 hours until sham International normalized ratio (INR) greater than, equal to ( ≥) 2. Placebo for warfarin: tablets, oral, dosing to target sham INR range between 2.0 - 3.0, once daily, 6 months	Enoxaparin + Warfarin n=2704 Participants Enoxaparin: solution, subcutaneous, 1 mg/kg Q12h until INR ≥2. warfarin: tablets, oral, dosing to target INR range between 2.0 - 3.0, once daily, 6 months Placebo for apixaban: tablets, oral, 10 mg tablets, twice daily, for 7 days followed by placebo for apixaban 5 mg tablets, twice daily, 6 months	Total n=5395 Participants Total of all reporting groups
Region of Enrollment Russian Federation	178 participants n=5 Participants	174 participants n=7 Participants	352 participants n=5 Participants
Region of Enrollment Italy	167 participants n=5 Participants	169 participants n=7 Participants	336 participants n=5 Participants
Region of Enrollment India	101 participants n=5 Participants	99 participants n=7 Participants	200 participants n=5 Participants
Age, Continuous	57.2 years STANDARD_DEVIATION 15.98 • n=5 Participants	56.7 years STANDARD_DEVIATION 16.01 • n=7 Participants	56.9 years STANDARD_DEVIATION 16.00 • n=5 Participants
Age, Customized Less than (<) 65	1729 participants n=5 Participants	1762 participants n=7 Participants	3491 participants n=5 Participants
Age, Customized 65 to < 75	560 participants n=5 Participants	570 participants n=7 Participants	1130 participants n=5 Participants
Age, Customized Greater than, equal to (>=) 75	402 participants n=5 Participants	372 participants n=7 Participants	774 participants n=5 Participants
Sex: Female, Male Female	1122 Participants n=5 Participants	1106 Participants n=7 Participants	2228 Participants n=5 Participants
Sex: Female, Male Male	1569 Participants n=5 Participants	1598 Participants n=7 Participants	3167 Participants n=5 Participants
Race/Ethnicity, Customized White	2218 participants n=5 Participants	2243 participants n=7 Participants	4461 participants n=5 Participants
Race/Ethnicity, Customized Black or African American	106 participants n=5 Participants	98 participants n=7 Participants	204 participants n=5 Participants
Race/Ethnicity, Customized American Indian or Alaska Native	6 participants n=5 Participants	2 participants n=7 Participants	8 participants n=5 Participants
Race/Ethnicity, Customized Asian	227 participants n=5 Participants	226 participants n=7 Participants	453 participants n=5 Participants
Race/Ethnicity, Customized Other Race	89 participants n=5 Participants	85 participants n=7 Participants	174 participants n=5 Participants
Race/Ethnicity, Customized Race Not Reported	45 participants n=5 Participants	50 participants n=7 Participants	95 participants n=5 Participants
Race/Ethnicity, Customized Hispanic or Latino	20 participants n=5 Participants	18 participants n=7 Participants	38 participants n=5 Participants
Race/Ethnicity, Customized Not Hispanic or Latino	367 participants n=5 Participants	380 participants n=7 Participants	747 participants n=5 Participants
Race/Ethnicity, Customized Ethnicity Not Reported	2304 participants n=5 Participants	2306 participants n=7 Participants	4610 participants n=5 Participants
Region of Enrollment Portugal	10 participants n=5 Participants	9 participants n=7 Participants	19 participants n=5 Participants
Region of Enrollment United States	387 participants n=5 Participants	398 participants n=7 Participants	785 participants n=5 Participants
Region of Enrollment Hong Kong	2 participants n=5 Participants	1 participants n=7 Participants	3 participants n=5 Participants
Region of Enrollment Spain	56 participants n=5 Participants	51 participants n=7 Participants	107 participants n=5 Participants
Region of Enrollment Ukraine	213 participants n=5 Participants	211 participants n=7 Participants	424 participants n=5 Participants
Region of Enrollment Israel	162 participants n=5 Participants	163 participants n=7 Participants	325 participants n=5 Participants
Region of Enrollment France	140 participants n=5 Participants	149 participants n=7 Participants	289 participants n=5 Participants
Region of Enrollment Malaysia	0 participants n=5 Participants	2 participants n=7 Participants	2 participants n=5 Participants
Region of Enrollment Australia	56 participants n=5 Participants	64 participants n=7 Participants	120 participants n=5 Participants
Region of Enrollment Denmark	69 participants n=5 Participants	72 participants n=7 Participants	141 participants n=5 Participants
Region of Enrollment South Africa	70 participants n=5 Participants	77 participants n=7 Participants	147 participants n=5 Participants
Region of Enrollment China	113 participants n=5 Participants	114 participants n=7 Participants	227 participants n=5 Participants
Region of Enrollment Korea, Republic of	2 participants n=5 Participants	2 participants n=7 Participants	4 participants n=5 Participants
Region of Enrollment Austria	40 participants n=5 Participants	39 participants n=7 Participants	79 participants n=5 Participants
Region of Enrollment Czech Republic	140 participants n=5 Participants	134 participants n=7 Participants	274 participants n=5 Participants
Region of Enrollment Hungary	145 participants n=5 Participants	128 participants n=7 Participants	273 participants n=5 Participants
Region of Enrollment Mexico	59 participants n=5 Participants	57 participants n=7 Participants	116 participants n=5 Participants
Region of Enrollment Canada	147 participants n=5 Participants	152 participants n=7 Participants	299 participants n=5 Participants
Region of Enrollment Argentina	17 participants n=5 Participants	16 participants n=7 Participants	33 participants n=5 Participants
Region of Enrollment Poland	60 participants n=5 Participants	59 participants n=7 Participants	119 participants n=5 Participants
Region of Enrollment Brazil	77 participants n=5 Participants	81 participants n=7 Participants	158 participants n=5 Participants
Region of Enrollment Singapore	5 participants n=5 Participants	5 participants n=7 Participants	10 participants n=5 Participants
Region of Enrollment Romania	33 participants n=5 Participants	41 participants n=7 Participants	74 participants n=5 Participants
Region of Enrollment Norway	40 participants n=5 Participants	32 participants n=7 Participants	72 participants n=5 Participants
Region of Enrollment Germany	202 participants n=5 Participants	205 participants n=7 Participants	407 participants n=5 Participants
Qualifying index Venous Thromboembolic Embolism Provoked Index VTE	272 participants n=5 Participants	272 participants n=7 Participants	544 participants n=5 Participants
Qualifying index Venous Thromboembolic Embolism Unprovoked Index VTE	2416 participants n=5 Participants	2429 participants n=7 Participants	4845 participants n=5 Participants
Qualifying index Venous Thromboembolic Embolism Not Reported	3 participants n=5 Participants	3 participants n=7 Participants	6 participants n=5 Participants
Index Event Classification Proximal DVT	1778 participants n=5 Participants	1814 participants n=7 Participants	3592 participants n=5 Participants
Index Event Classification PE	913 participants n=5 Participants	890 participants n=7 Participants	1803 participants n=5 Participants
Index Event Classification Adjudicated Proximal DVT	1749 participants n=5 Participants	1783 participants n=7 Participants	3532 participants n=5 Participants
Index Event Classification Adjudicated PE	930 participants n=5 Participants	906 participants n=7 Participants	1836 participants n=5 Participants

PRIMARY outcome

Timeframe: Day 1 to Week 24 + 2 Days or 355 days (Discontinued Early)

Population: All randomized participants with a non-missing primary endpoint (n/N: 59/2609; 71/2635, in apixaban, enoxaparin/warfarin, respectively). Intent-to-treat population. Confidence interval (CI) for event rate calculated based on the Wald asymptotic confidence limits.

Outcome measures

Outcome measures
Measure	Apixaban n=2609 Participants Apixaban: tablets, oral, 10 mg tablets, twice daily, for 7 days followed by apixaban 5 mg, twice daily, 6 months Placebo for enoxaparin: solution, subcutaneous, 1 mg/kg Q12h until sham INR ≥2. Placebo for warfarin: tablets, oral, dosing to target sham INR range between 2.0 - 3.0, once daily, 6 months	Enoxaparin + Warfarin n=2635 Participants Enoxaparin: solution, subcutaneous, 1 mg/kg Q12h until INR ≥2 warfarin: tablets, oral, dosing to target INR range between 2.0 - 3.0, once daily, 6 months Placebo for apixaban: tablets, oral, 10 mg tablets, twice daily, for 7 days followed by placebo for apixaban 5 mg tablets, twice daily, 6 months
Incidence of Adjudicated Composite of Symptomatic, Recurrent Venous Thromboembolism (VTE) or VTE-Related Death During 6 Months of Treatment	0.0226 proportion of participants Interval 0.0169 to 0.0283	0.0269 proportion of participants Interval 0.0208 to 0.0331

SECONDARY outcome

Timeframe: Day 1 up to 24 Weeks + 2 Days or 355 Days (Discontinued Early)

Population: All randomized participants with non-missing secondary endpoint (n/N: 84/2609; 104/2635, in apixaban, enoxaparin/warfarin arms, respectively). Participants categorized to assigned arm, regardless of treatment actually received. Intent to Treat principle. Confidence interval (CI) for event rate calculated based on Wald asymptotic confidence limits.

VTE included: nonfatal DVT or nonfatal PE. All events were adjudicated by an ICAC blinded to treatment. DVT was assessed by compression ultrasound and/or venography; PE was assessed by spiral computed tomography scanning, pulmonary angiography, and/or ventilation/perfusion lung scan. Event rate (proportion of participants with event) calculated as n/N (n=number of participants with observation; N=total number of efficacy evaluable participants). Intended treatment period: longer of the dosing period plus 2 days (completed treatment) or 355 days (discontinued early). Composite endpoint included events at any time from randomization until end of the intended treatment period, regardless whether drug treatment was received, ie intent to treat (ITT) principle. Each participant scored as having an event only if they experienced one or more of the elements of the composite. Participants with missing endpoint information excluded.

Outcome measures

Outcome measures
Measure	Apixaban n=2609 Participants Apixaban: tablets, oral, 10 mg tablets, twice daily, for 7 days followed by apixaban 5 mg, twice daily, 6 months Placebo for enoxaparin: solution, subcutaneous, 1 mg/kg Q12h until sham INR ≥2. Placebo for warfarin: tablets, oral, dosing to target sham INR range between 2.0 - 3.0, once daily, 6 months	Enoxaparin + Warfarin n=2635 Participants Enoxaparin: solution, subcutaneous, 1 mg/kg Q12h until INR ≥2 warfarin: tablets, oral, dosing to target INR range between 2.0 - 3.0, once daily, 6 months Placebo for apixaban: tablets, oral, 10 mg tablets, twice daily, for 7 days followed by placebo for apixaban 5 mg tablets, twice daily, 6 months
Incidence of Adjudicated Composite of Recurrent Symptomatic Venous Thromboembolism (VTE) or All-Cause Death	0.0322 proportion of participants Interval 0.0254 to 0.039	0.0395 proportion of participants Interval 0.032 to 0.0469

SECONDARY outcome

Timeframe: Day 1 up to 24 Weeks + 2 Days or 355 Days (Discontinued Early)

Population: All randomized participants with non-missing secondary endpoint (n/N: 61/2609; 77/2635, in apixaban, enoxaparin/warfarin arms, respectively). Participants categorized to assigned arm, regardless of treatment actually received. Intent to Treat principle. CI for event rate calculated based on Wald asymptotic confidence limits.

VTE included: nonfatal DVT or nonfatal PE. All events were adjudicated by an ICAC blinded to treatment. DVT was assessed by compression ultrasound and/or venography; PE was assessed by spiral computed tomography scanning, pulmonary angiography, and/or ventilation/perfusion lung scan. Event rate (proportion of participants with event) calculated as n/N (n=number of participants with observation; N=total number of efficacy evaluable participants, participants with missing endpoint information excluded). Intended treatment period: longer of the dosing period plus 2 days (completed treatment) or 355 days (discontinued early). Composite endpoint included events at any time from randomization until end of the intended treatment period, regardless whether drug treatment was received, ie, ITT principle. Each participant scored as having an event only if the participant experienced one or more of the elements of the composite.

Outcome measures

Outcome measures
Measure	Apixaban n=2609 Participants Apixaban: tablets, oral, 10 mg tablets, twice daily, for 7 days followed by apixaban 5 mg, twice daily, 6 months Placebo for enoxaparin: solution, subcutaneous, 1 mg/kg Q12h until sham INR ≥2. Placebo for warfarin: tablets, oral, dosing to target sham INR range between 2.0 - 3.0, once daily, 6 months	Enoxaparin + Warfarin n=2635 Participants Enoxaparin: solution, subcutaneous, 1 mg/kg Q12h until INR ≥2 warfarin: tablets, oral, dosing to target INR range between 2.0 - 3.0, once daily, 6 months Placebo for apixaban: tablets, oral, 10 mg tablets, twice daily, for 7 days followed by placebo for apixaban 5 mg tablets, twice daily, 6 months
Incidence of Adjudicated Composite of Recurrent Symptomatic VTE or Cardiovascular (CV)-Related Death	0.0234 proportion of participants Interval 0.0176 to 0.0292	0.0292 proportion of participants Interval 0.0228 to 0.0357

SECONDARY outcome

Timeframe: Day 1 up to 24 Weeks + 2 Days or 355 Days (Discontinued Early)

Population: Total number of participants in each randomized arm, excluded those with missing endpoint and included those not in the efficacy evaluable population with bleeding event which occurred during treatment (n/N: 73/2610; 118/2635). Confidence interval (CI) for event rate calculated based on Wald asymptotic confidence limits.

VTE included: nonfatal DVT or nonfatal PE. All events were adjudicated by an ICAC blinded to treatment. DVT assessed by compression ultrasound and/or venography; PE assessed by spiral computed tomography scanning, pulmonary angiography, and/or ventilation/perfusion lung scan. Major bleeding defined by International Society on Thrombosis and Haemostasis: acute, clinically overt bleeding associated with decrease in hemoglobin (Hgb) of 2 g/dL or more or bleeding leading to transfusion or bleeding in a critical site or bleeding that is fatal . Event rate (proportion of participants with event): n/N (n=number of participants with observation; N=Total number of participants, excluding those with missing endpoint and including those not in the efficacy evaluable population with a bleeding event that occurred during treatment period. Events included regardless of whether or not participant received treatment, ie, ITT principle

Outcome measures

Outcome measures
Measure	Apixaban n=2610 Participants Apixaban: tablets, oral, 10 mg tablets, twice daily, for 7 days followed by apixaban 5 mg, twice daily, 6 months Placebo for enoxaparin: solution, subcutaneous, 1 mg/kg Q12h until sham INR ≥2. Placebo for warfarin: tablets, oral, dosing to target sham INR range between 2.0 - 3.0, once daily, 6 months	Enoxaparin + Warfarin n=2635 Participants Enoxaparin: solution, subcutaneous, 1 mg/kg Q12h until INR ≥2 warfarin: tablets, oral, dosing to target INR range between 2.0 - 3.0, once daily, 6 months Placebo for apixaban: tablets, oral, 10 mg tablets, twice daily, for 7 days followed by placebo for apixaban 5 mg tablets, twice daily, 6 months
Incidence of Adjudicated Composite of Recurrent Symptomatic VTE or VTE-related Death or Major Bleeding	0.0280 proportion of participants Interval 0.0216 to 0.0343	0.0448 proportion of participants Interval 0.0369 to 0.0527

SECONDARY outcome

Timeframe: Day 1 up to 24 Weeks + 2 Days or 355 Days (Discontinued Early)

Population: Total number participants in each treatment group, excluded those with missing endpoint and included those not in the efficacy evaluable population with bleeding event which occurred during treatment (n/N: 183/2617; 333/2641). Events included as per ITT principle. CI for event rate calculated based on Wald asymptotic confidence limits.

VTE=Nonfatal DVT or nonfatal PE adjudicated by ICAC blinded to treatment. DVT: compression ultrasound and/or venography; PE: spiral computed tomography scanning, pulmonary angiography, and/or ventilation/perfusion lung scan. Major Bleeding = acute, clinically overt bleeding: decrease in Hgb of 2 g/dL or more or bleeding leading to transfusion or bleeding in a critical site or fatal bleeding. CRNM = acute clinically overt bleeding: compromising hemodynamics, leading to hospitalization, hematoma, epistasis \>5 minutes or repetitive, gingival bleeding, hematuria, macroscopic gastrointestinal hemorrhage, rectal blood loss, hemoptysis. n/N (n=number of participants with observation; N=Total number of participants, excluding those with missing endpoint and including those not in the efficacy evaluable population with a bleeding event that occurred during treatment period). Events included regardless of whether or not treatment was received (ITT).

Outcome measures

Outcome measures
Measure	Apixaban n=2617 Participants Apixaban: tablets, oral, 10 mg tablets, twice daily, for 7 days followed by apixaban 5 mg, twice daily, 6 months Placebo for enoxaparin: solution, subcutaneous, 1 mg/kg Q12h until sham INR ≥2. Placebo for warfarin: tablets, oral, dosing to target sham INR range between 2.0 - 3.0, once daily, 6 months	Enoxaparin + Warfarin n=2641 Participants Enoxaparin: solution, subcutaneous, 1 mg/kg Q12h until INR ≥2 warfarin: tablets, oral, dosing to target INR range between 2.0 - 3.0, once daily, 6 months Placebo for apixaban: tablets, oral, 10 mg tablets, twice daily, for 7 days followed by placebo for apixaban 5 mg tablets, twice daily, 6 months
Incidence of Adjudicated Composite of Recurrent Symptomatic VTE, Myocardial Infarction, Stroke, CV-related Death, Clinically Relevant Non-major (CRNM) Bleeding or Major Bleeding	0.0699 proportion of participants Interval 0.0602 to 0.0797	0.1261 proportion of participants Interval 0.1134 to 0.1387

SECONDARY outcome

Timeframe: Day 1 up to 24 Weeks + 2 Days or 355 Days (Discontinued Early)

Population: Total number of participants in each randomized arm (ITT), excluding those with missing endpoint (n/N: 22/2608; 35/2633). CI for event rate calculated based on Wald asymptotic confidence limits.

DVT adjudicated by an ICAC blinded to treatment. DVT evaluated by: compression ultrasound and/or venography. Includes events that occurred during the intended treatment period, regardless of whether the participant received study medication, intent to treat principle (ITT). Event rate (proportion of participants with event): n/N (n=number of participants with observation; N=Total number of participants, excluding those with missing endpoint). Intended treatment period: longer of the dosing period plus 2 days (completed treatment) or 355 days (discontinued early).

Outcome measures

Outcome measures
Measure	Apixaban n=2608 Participants Apixaban: tablets, oral, 10 mg tablets, twice daily, for 7 days followed by apixaban 5 mg, twice daily, 6 months Placebo for enoxaparin: solution, subcutaneous, 1 mg/kg Q12h until sham INR ≥2. Placebo for warfarin: tablets, oral, dosing to target sham INR range between 2.0 - 3.0, once daily, 6 months	Enoxaparin + Warfarin n=2633 Participants Enoxaparin: solution, subcutaneous, 1 mg/kg Q12h until INR ≥2 warfarin: tablets, oral, dosing to target INR range between 2.0 - 3.0, once daily, 6 months Placebo for apixaban: tablets, oral, 10 mg tablets, twice daily, for 7 days followed by placebo for apixaban 5 mg tablets, twice daily, 6 months
Incidence of Adjudicated Symptomatic Nonfatal Deep Vein Thrombosis (DVT) During the Intended Treatment Period	0.0084 proportion of participants Interval 0.0049 to 0.0119	0.0133 proportion of participants Interval 0.0089 to 0.0177

SECONDARY outcome

Timeframe: Day 1 to Week 24 + + 2 Days or 355 Days (Discontinued Early)

Population: Total number of participants in each randomized arm (ITT), excluding those with missing endpoint (n/N: 27/2606; 25/2632). CI for event rate calculated based on Wald asymptotic confidence limits.

PE adjudicated by an ICAC blinded to treatment. PE: spiral computed tomography scanning, pulmonary angiography, and/or ventilation/perfusion lung scan. Includes events that occurred during the intended treatment period, regardless of whether the participant received study medication (ITT principle). Event rate (proportion of participants with event): n/N (n=number of participants with observation; N=Total number of participants, excluding those with missing endpoint). Intended treatment period: longer of the dosing period plus 2 days (completed treatment) or 355 days (discontinued early).

Outcome measures

Outcome measures
Measure	Apixaban n=2606 Participants Apixaban: tablets, oral, 10 mg tablets, twice daily, for 7 days followed by apixaban 5 mg, twice daily, 6 months Placebo for enoxaparin: solution, subcutaneous, 1 mg/kg Q12h until sham INR ≥2. Placebo for warfarin: tablets, oral, dosing to target sham INR range between 2.0 - 3.0, once daily, 6 months	Enoxaparin + Warfarin n=2632 Participants Enoxaparin: solution, subcutaneous, 1 mg/kg Q12h until INR ≥2 warfarin: tablets, oral, dosing to target INR range between 2.0 - 3.0, once daily, 6 months Placebo for apixaban: tablets, oral, 10 mg tablets, twice daily, for 7 days followed by placebo for apixaban 5 mg tablets, twice daily, 6 months
Incidence of Adjudicated Symptomatic Nonfatal Pulmonary Embolism (PE) During the Intended Treatment Period	0.0104 proportion of participants Interval 0.0065 to 0.0142	0.0095 proportion of participants Interval 0.0058 to 0.0132

SECONDARY outcome

Timeframe: Day 1 to Week 24 + 2 Days or 355 Days (Discontinued Early)

Population: Total number of participants in respective treatment groups excluding participants with missing endpoint information. (n/N: 12/2608; 16/2630). CI for event rate calculated based on Wald asymptotic confidence limits.

VTE-related death included: DVT-related death or PE-related death. All events were adjudicated by an ICAC blinded to treatment. DVT was assessed by compression ultrasound and/or venography; PE was assessed by spiral computed tomography scanning, pulmonary angiography, and/or ventilation/perfusion lung scan. Event rate (proportion of participants with event) calculated as n/N (n=number of participants with observation; N=total number of participants in respective treatment groups excluding participants with missing endpoint information). Intended treatment period: longer of the dosing period plus 2 days (completed treatment) or 355 days (discontinued early). Includes events that occur during the intended treatment period regardless of whether or not the participant received study medication (ITT principle).

Outcome measures

Outcome measures
Measure	Apixaban n=2608 Participants Apixaban: tablets, oral, 10 mg tablets, twice daily, for 7 days followed by apixaban 5 mg, twice daily, 6 months Placebo for enoxaparin: solution, subcutaneous, 1 mg/kg Q12h until sham INR ≥2. Placebo for warfarin: tablets, oral, dosing to target sham INR range between 2.0 - 3.0, once daily, 6 months	Enoxaparin + Warfarin n=2630 Participants Enoxaparin: solution, subcutaneous, 1 mg/kg Q12h until INR ≥2 warfarin: tablets, oral, dosing to target INR range between 2.0 - 3.0, once daily, 6 months Placebo for apixaban: tablets, oral, 10 mg tablets, twice daily, for 7 days followed by placebo for apixaban 5 mg tablets, twice daily, 6 months
Incidence of Adjudicated Venous Thromboembolism (VTE)-Related Death During the Intended Treatment Period	0.0046 proportion of participants Interval 0.002 to 0.0072	0.0061 proportion of participants Interval 0.0031 to 0.0091

SECONDARY outcome

Timeframe: Day 1 to Week 24 + 2 Days or 355 Days (Discontinued Early)

Population: Total number of participants in respective groups excluding those with missing endpoint information (n/N: 15/2608; 23/2630). CI for event rate calculated based on Wald asymptotic confidence limits.

VTE-related death included: DVT-related death or PE-related death. All events were adjudicated by an ICAC blinded to treatment. DVT assessed by compression ultrasound and/or venography; PE assessed by spiral computed tomography scanning, pulmonary angiography, and/or ventilation/perfusion lung scan. Event rate (proportion of participants with event) calculated as n/N (n=number of participants with observation; N=total number of participants in respective treatment groups excluding participants with missing endpoint information). Intended treatment period: longer of the dosing period plus 2 days (completed treatment) or 355 days (discontinued early). Includes events that occur during the intended treatment period regardless of whether or not the participant received study medication (ITT principle).

Outcome measures

Outcome measures
Measure	Apixaban n=2608 Participants Apixaban: tablets, oral, 10 mg tablets, twice daily, for 7 days followed by apixaban 5 mg, twice daily, 6 months Placebo for enoxaparin: solution, subcutaneous, 1 mg/kg Q12h until sham INR ≥2. Placebo for warfarin: tablets, oral, dosing to target sham INR range between 2.0 - 3.0, once daily, 6 months	Enoxaparin + Warfarin n=2630 Participants Enoxaparin: solution, subcutaneous, 1 mg/kg Q12h until INR ≥2 warfarin: tablets, oral, dosing to target INR range between 2.0 - 3.0, once daily, 6 months Placebo for apixaban: tablets, oral, 10 mg tablets, twice daily, for 7 days followed by placebo for apixaban 5 mg tablets, twice daily, 6 months
Incidence of Cardiovascular (CV)-Related Death Including VTE-related Death During the Intended Treatment Period	0.0058 proportion of participants Interval 0.0028 to 0.0087	0.0087 proportion of participants Interval 0.0052 to 0.0123

SECONDARY outcome

Timeframe: Day 1 to Week 24 + 2 Days or 355 Days (Discontinued Early)

Population: Total number of participants excluding those with missing endpoint (n/N: 41/2608; 52/2630). Events included regardless of whether or not participant received treatment, ie, ITT principle. CI for event rate calculated based on Wald asymptotic confidence limits.

Intended treatment period: longer of the dosing period plus 2 days (completed treatment) or 355 days (discontinued early). Includes events that occurred during the intended treatment period, regardless of whether the participant received study medication (ITT principle). Event rate (proportion of participants with event): n/N (n=number of participants with observation; N=Total number of participants, excluding those with missing endpoint information).

Outcome measures

Outcome measures
Measure	Apixaban n=2608 Participants Apixaban: tablets, oral, 10 mg tablets, twice daily, for 7 days followed by apixaban 5 mg, twice daily, 6 months Placebo for enoxaparin: solution, subcutaneous, 1 mg/kg Q12h until sham INR ≥2. Placebo for warfarin: tablets, oral, dosing to target sham INR range between 2.0 - 3.0, once daily, 6 months	Enoxaparin + Warfarin n=2630 Participants Enoxaparin: solution, subcutaneous, 1 mg/kg Q12h until INR ≥2 warfarin: tablets, oral, dosing to target INR range between 2.0 - 3.0, once daily, 6 months Placebo for apixaban: tablets, oral, 10 mg tablets, twice daily, for 7 days followed by placebo for apixaban 5 mg tablets, twice daily, 6 months
Incidence of All-Cause Death During the Intended Treatment Period	0.0157 proportion of participants Interval 0.0109 to 0.0205	0.0198 proportion of participants Interval 0.0145 to 0.0251

SECONDARY outcome

Timeframe: Day 1 to Week 24 + 2 Days or 355 Days (Discontinued Early)

Population: Total number of participants receiving at least one dose of study drug n/N: 15/2676; 49/2689, in apixaban and enoxaparin/warfarin groups, respectively. CI for event rate calculated based on Wald asymptotic confidence limits. Participants were categorized according to the actual treatment received.

All events were adjudicated by an ICAC blinded to treatment. Bleeding defined by International Society on Thrombosis and Haemostasis: Major Bleeding: acute, clinically overt bleeding: decrease in hemoglobin (hgb) of 2 g/dL or more or bleeding leading to transfusion or bleeding in a critical site or fatal bleeding. Event rate (proportion of participants with event): n/N (n=number of participants with observation; N=Total number of participants in respective treatment group (all participants who received at least one dose of study drug). Participants were categorized to the treatment group to which they were assigned unless incorrect study treatment was received throughout the study, in which case the participant was categorized according to the treatment received.

Outcome measures

Outcome measures
Measure	Apixaban n=2676 Participants Apixaban: tablets, oral, 10 mg tablets, twice daily, for 7 days followed by apixaban 5 mg, twice daily, 6 months Placebo for enoxaparin: solution, subcutaneous, 1 mg/kg Q12h until sham INR ≥2. Placebo for warfarin: tablets, oral, dosing to target sham INR range between 2.0 - 3.0, once daily, 6 months	Enoxaparin + Warfarin n=2689 Participants Enoxaparin: solution, subcutaneous, 1 mg/kg Q12h until INR ≥2 warfarin: tablets, oral, dosing to target INR range between 2.0 - 3.0, once daily, 6 months Placebo for apixaban: tablets, oral, 10 mg tablets, twice daily, for 7 days followed by placebo for apixaban 5 mg tablets, twice daily, 6 months
Incidence of Adjudicated Major Bleeding During the Treatment Period in Treated Participants	0.0056 proportion of participants Interval 0.0028 to 0.0084	0.0182 proportion of participants Interval 0.0132 to 0.0233

SECONDARY outcome

Timeframe: Day 1 to Week 24 + 2 Days or 355 Days (Discontinued Early)

Population: Total number of participants receiving at least one dose of study drug n/N: 115/2676; 261/2689, in apixaban and enoxaparin/warfarin groups, respectively. CI for event rate calculated based on Wald asymptotic confidence limits. Participants were categorized according to the actual treatment received.

Major Bleeding = acute, clinically overt bleeding: decrease in hemoglobin of 2 g/dL or more, or bleeding leading to transfusion, or bleeding in a critical site, or fatal bleeding. CRNM = acute clinically overt bleeding: compromising hemodynamics, leading to hospitalization, hematoma, epistasis \>5 minutes or repetitive, gingival bleeding, hematuria, macroscopic gastrointestinal hemorrhage, rectal blood loss, hemoptysis. Minor =: All acute clinically overt bleeding events not meeting the criteria for either major bleeding or CRNM. All events were adjudicated by an ICAC blinded to treatment. Total bleeding = any of major, or CRNM, or minor bleeding. Event rate (proportion of participants with event): n/N (n=number of participants with observation; N=Total number of treated (received at least 1 dose of study drug).

Outcome measures

Outcome measures
Measure	Apixaban n=2676 Participants Apixaban: tablets, oral, 10 mg tablets, twice daily, for 7 days followed by apixaban 5 mg, twice daily, 6 months Placebo for enoxaparin: solution, subcutaneous, 1 mg/kg Q12h until sham INR ≥2. Placebo for warfarin: tablets, oral, dosing to target sham INR range between 2.0 - 3.0, once daily, 6 months	Enoxaparin + Warfarin n=2689 Participants Enoxaparin: solution, subcutaneous, 1 mg/kg Q12h until INR ≥2 warfarin: tablets, oral, dosing to target INR range between 2.0 - 3.0, once daily, 6 months Placebo for apixaban: tablets, oral, 10 mg tablets, twice daily, for 7 days followed by placebo for apixaban 5 mg tablets, twice daily, 6 months
Incidence of Adjudicated Major/CRNM Bleeding During the Treatment Period in Treated Participants	0.0430 proportion of participants Interval 0.0353 to 0.0507	0.0971 proportion of participants Interval 0.0859 to 0.1083

SECONDARY outcome

Timeframe: Day 1 to Week 24 + 2 Days or 355 Days (Discontinued Early)

Population: Total number of participants receiving at least one dose of study drug n/N: 103/2676; 215/2689, in apixaban and enoxaparin/warfarin groups, respectively. CI for event rate calculated based on Wald asymptotic confidence limits. Participants were categorized according to the actual treatment received.

Bleeding defined by International Society on Thrombosis and Haemostasis: CRNM defined as acute clinically overt bleeding: compromising hemodynamics, leading to hospitalization, hematoma, epistasis \>5 minutes or repetitive, gingival bleeding, hematuria, macroscopic gastrointestinal hemorrhage, rectal blood loss, hemoptysis. All events were adjudicated by an ICAC blinded to treatment. Event rate (proportion of participants with event): calculated as n/N (n=number of participants with observation; N=Total number of participants in respective treatment group (all participants who received at least one dose of study drug). Participants were categorized to the treatment group to which they were assigned unless incorrect study treatment was received throughout the study, in which case the participant was categorized according to the treatment received.

Outcome measures

Outcome measures
Measure	Apixaban n=2676 Participants Apixaban: tablets, oral, 10 mg tablets, twice daily, for 7 days followed by apixaban 5 mg, twice daily, 6 months Placebo for enoxaparin: solution, subcutaneous, 1 mg/kg Q12h until sham INR ≥2. Placebo for warfarin: tablets, oral, dosing to target sham INR range between 2.0 - 3.0, once daily, 6 months	Enoxaparin + Warfarin n=2689 Participants Enoxaparin: solution, subcutaneous, 1 mg/kg Q12h until INR ≥2 warfarin: tablets, oral, dosing to target INR range between 2.0 - 3.0, once daily, 6 months Placebo for apixaban: tablets, oral, 10 mg tablets, twice daily, for 7 days followed by placebo for apixaban 5 mg tablets, twice daily, 6 months
Incidence of Adjudicated Clinically Relevant Non Major (CRNM) Bleeding During the Treatment Period in Treated Participants	0.0385 proportion of participants Interval 0.0312 to 0.0458	0.0800 proportion of participants Interval 0.0697 to 0.0902

SECONDARY outcome

Timeframe: Day 1 to Week 24 + 2 Days or 355 Days (Discontinued Early)

Population: Total number of participants receiving at least one dose of study drug n/N: 313/2676; 505/2689, in apixaban and enoxaparin/warfarin groups, respectively. CI for event rate calculated based on Wald asymptotic confidence limits. Participants were categorized according to the actual treatment received.

Bleeding defined by International Society on Thrombosis and Haemostasis: Minor bleeding: all acute clinically overt bleeding events not meeting the criteria for either major bleeding or CRNM. All events wre adjudicated by an ICAC blinded to treatment. Event rate (proportion of participants) calculated as n/N (n=number of participants with observation; N=Total number of participants in respective treatment group (all participants who received at least one dose of study drug). Participants were categorized to the treatment group to which they were assigned unless incorrect study treatment was received throughout the study, in which case the participant was categorized according to the treatment received.

Outcome measures

Outcome measures
Measure	Apixaban n=2676 Participants Apixaban: tablets, oral, 10 mg tablets, twice daily, for 7 days followed by apixaban 5 mg, twice daily, 6 months Placebo for enoxaparin: solution, subcutaneous, 1 mg/kg Q12h until sham INR ≥2. Placebo for warfarin: tablets, oral, dosing to target sham INR range between 2.0 - 3.0, once daily, 6 months	Enoxaparin + Warfarin n=2689 Participants Enoxaparin: solution, subcutaneous, 1 mg/kg Q12h until INR ≥2 warfarin: tablets, oral, dosing to target INR range between 2.0 - 3.0, once daily, 6 months Placebo for apixaban: tablets, oral, 10 mg tablets, twice daily, for 7 days followed by placebo for apixaban 5 mg tablets, twice daily, 6 months
Incidence of Adjudicated Minor Bleeding During the Treatment Period in Treated Participants	0.1170 proportion of participants Interval 0.1048 to 0.1291	0.1878 proportion of participants Interval 0.173 to 0.2026

SECONDARY outcome

Timeframe: Day 1 to Week 24 + 2 Days or 355 Days (Discontinued Early)

Population: Total number of participants receiving at least one dose of study drug n/N: 402/2676; 676/2689, in apixaban and enoxaparin/warfarin groups, respectively. CI for event rate calculated based on Wald asymptotic confidence limits. Participants were categorized according to the actual treatment received.

Bleeding defined by International Society on Thrombosis and Haemostasis: Total Bleeding defined as any of major, CRNM, or minor bleeding. All events were adjudicated by an ICAC blinded to treatment. Event rate (proportion of participants with event): n/N (n=number of participants with observation; N=Total number of participants in respective treatment group (all participants who received at least one dose of study drug). Participants were categorized to the treatment group to which they were assigned unless incorrect study treatment was received throughout the study, in which case the participant was categorized according to the treatment received.

Outcome measures

Outcome measures
Measure	Apixaban n=2676 Participants Apixaban: tablets, oral, 10 mg tablets, twice daily, for 7 days followed by apixaban 5 mg, twice daily, 6 months Placebo for enoxaparin: solution, subcutaneous, 1 mg/kg Q12h until sham INR ≥2. Placebo for warfarin: tablets, oral, dosing to target sham INR range between 2.0 - 3.0, once daily, 6 months	Enoxaparin + Warfarin n=2689 Participants Enoxaparin: solution, subcutaneous, 1 mg/kg Q12h until INR ≥2 warfarin: tablets, oral, dosing to target INR range between 2.0 - 3.0, once daily, 6 months Placebo for apixaban: tablets, oral, 10 mg tablets, twice daily, for 7 days followed by placebo for apixaban 5 mg tablets, twice daily, 6 months
Incidence of Adjudicated Total Bleeding During the Treatment Period in Treated Participants	0.1502 proportion of participants Interval 0.1367 to 0.1638	0.2514 proportion of participants Interval 0.235 to 0.2678

SECONDARY outcome

Timeframe: First dose to last dose of 24 Weeks + 2 days (AEs) or + 30 days (SAEs) or until drug discontinued

Population: Total number of participants receiving at least one dose of study drug. Participants were categorized according to the actual treatment received.

Treated Participants: all who received at least 1 dose of study drug. Participants categorized to the treatment group to which they were assigned unless incorrect study treatment was received throughout the study, in which case the participant was categorized according to treatment received. Included all SAEs and AEs with onset from first dose to last dose + 2 days (for AEs) or + 30 days (for SAEs); note; bleeding AEs and SAEs from first dose to last dose + 2 days included. Discontinuations due to AE included all AEs/SAEs from first dose until drug was discontinued. 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.

Outcome measures

Outcome measures
Measure	Apixaban n=2676 Participants Apixaban: tablets, oral, 10 mg tablets, twice daily, for 7 days followed by apixaban 5 mg, twice daily, 6 months Placebo for enoxaparin: solution, subcutaneous, 1 mg/kg Q12h until sham INR ≥2. Placebo for warfarin: tablets, oral, dosing to target sham INR range between 2.0 - 3.0, once daily, 6 months	Enoxaparin + Warfarin n=2689 Participants Enoxaparin: solution, subcutaneous, 1 mg/kg Q12h until INR ≥2 warfarin: tablets, oral, dosing to target INR range between 2.0 - 3.0, once daily, 6 months Placebo for apixaban: tablets, oral, 10 mg tablets, twice daily, for 7 days followed by placebo for apixaban 5 mg tablets, twice daily, 6 months
Number of Participants With Adverse Events (AEs), Serious AEs (SAEs), Bleeding AEs, Discontinuations Due to AEs and Death During the Treatment Period in Treated Participants AE	1795 participants	1923 participants
Number of Participants With Adverse Events (AEs), Serious AEs (SAEs), Bleeding AEs, Discontinuations Due to AEs and Death During the Treatment Period in Treated Participants SAE	417 participants	410 participants
Number of Participants With Adverse Events (AEs), Serious AEs (SAEs), Bleeding AEs, Discontinuations Due to AEs and Death During the Treatment Period in Treated Participants Bleeding AE or SAE	415 participants	695 participants
Number of Participants With Adverse Events (AEs), Serious AEs (SAEs), Bleeding AEs, Discontinuations Due to AEs and Death During the Treatment Period in Treated Participants Discontinued Due to AE or SAE	162 participants	199 participants
Number of Participants With Adverse Events (AEs), Serious AEs (SAEs), Bleeding AEs, Discontinuations Due to AEs and Death During the Treatment Period in Treated Participants Death	37 participants	44 participants

SECONDARY outcome

Timeframe: Day 1 to Week 24 + 2 Days or 355 Days (Discontinued Early)

Population: N=Treated participants who received at least one dose of study drug and had non-missing laboratory measurements.

Lower limit of normal (LLN). Upper limit of normal (ULN). Pre-therapy (PreRx). Absolute (Abs) neutrophil count, bands + neutrophils (ANC). Cells per microliter (c/µL). Grams per deciliter (g/dL). Cells per Liter (c/L). Millimeter (MM). White blood cells: \< 0.75\*LLN, \> 1.25\*ULN; Hemoglobin: \<= 11.5 g/dL (males), \<= 9.5 g/dL (females); Hematocrit: \<= 37% (males), \<= 32% (females); Erythrocytes: \<0.75\*10\^6 c/µL\*PreRx; Platelet count: \< 75\*10\^9 c/L, \> 700\*10\^9 c/L; ANC: \< 1.00\*10\^3 c/µL; Abs eosinophils: \> 0.750\*10\^3 c/µL; Abs Basophils: \> 400/MM\^3; Abs Monocytes\> 2000/MM\^3; Abs Lymphocytes: \< 0.750\*10\*3 c/ µL, \> 7.5\*10\^3 c/ µL.

Outcome measures

Outcome measures
Measure	Apixaban n=2599 Participants Apixaban: tablets, oral, 10 mg tablets, twice daily, for 7 days followed by apixaban 5 mg, twice daily, 6 months Placebo for enoxaparin: solution, subcutaneous, 1 mg/kg Q12h until sham INR ≥2. Placebo for warfarin: tablets, oral, dosing to target sham INR range between 2.0 - 3.0, once daily, 6 months	Enoxaparin + Warfarin n=2593 Participants Enoxaparin: solution, subcutaneous, 1 mg/kg Q12h until INR ≥2 warfarin: tablets, oral, dosing to target INR range between 2.0 - 3.0, once daily, 6 months Placebo for apixaban: tablets, oral, 10 mg tablets, twice daily, for 7 days followed by placebo for apixaban 5 mg tablets, twice daily, 6 months
Number of Treated Participants With Marked Abnormalities in Hematology Laboratory Tests Erthrocytes Low (N=2599, 2593)	23 participants	17 participants
Number of Treated Participants With Marked Abnormalities in Hematology Laboratory Tests Hematocrit Low (N=2588, 2587)	26 participants	20 participants
Number of Treated Participants With Marked Abnormalities in Hematology Laboratory Tests Hemoglobin Low (N=2599, 2593)	96 participants	101 participants
Number of Treated Participants With Marked Abnormalities in Hematology Laboratory Tests Platelet Count Low (N=2594, 2589)	23 participants	13 participants
Number of Treated Participants With Marked Abnormalities in Hematology Laboratory Tests Leukocytes Low (N=2528, 2519)	41 participants	41 participants
Number of Treated Participants With Marked Abnormalities in Hematology Laboratory Tests Leukocytes High (N=2528, 2519)	26 participants	15 participants
Number of Treated Participants With Marked Abnormalities in Hematology Laboratory Tests Absolute Basophils High (N=2594,2589)	1 participants	2 participants
Number of Treated Participants With Marked Abnormalities in Hematology Laboratory Tests Absolute Eosinophils High (N=2594,2589)	84 participants	79 participants
Number of Treated Participants With Marked Abnormalities in Hematology Laboratory Tests Absolute Lyphocytes Low (N=2594,2589)	94 participants	76 participants
Number of Treated Participants With Marked Abnormalities in Hematology Laboratory Tests Absolute Lyphocytes High (N=2594,2589)	4 participants	3 participants
Number of Treated Participants With Marked Abnormalities in Hematology Laboratory Tests Absolute Monocytes High (N=2594,2589)	1 participants	2 participants
Number of Treated Participants With Marked Abnormalities in Hematology Laboratory Tests Absolute Neutrophils Low (N=2594,2589)	9 participants	20 participants

SECONDARY outcome

Timeframe: Day 1 to Week 24 + 2 Days or 355 Days (Discontinued Early)

Population: N=Treated participants who received at least one dose of study drug and had non-missing laboratory measurements.

Bicarbonate milliequivalents/Liter (mEq/L) Low/High: \< 0.75\*LLN or \> 1.25\*ULN, or if pre-dose \< LLN then use \< 0.75\*pre-dose or \> ULN if pre-dose \> ULN then use \> 1.25\*pre-dose or \< LLN; Serum Calcium mg/dL Low/High: \< 0.8\*LLN or \> 1.2\*ULN, or if pre-dose \< LLN then use \< 0.75\*pre-dose or \> ULN if pre-dose \> ULN then use \> 1.25\*pre-dose or \< LLN; Serum Chloride mEq/L: \< 0.9\*LLN or \> 1.1\*ULN, or if pre-dose \< LLN then use \< 0.9\*pre-dose or \> ULN if pre-dose \> ULN then use \> 1.1\*pre-dose or \< LLN; Serum Potassium mEq/L: \< 0.9\*LLN or \> 1.1\*ULN, or if pre-dose \< LLN then use \< 0.9\*pre-dose or \> ULN if pre-dose \> ULN then use \> 1.1\*pre-dose or \< LLN; Serum Sodium mEq/L: \< 0.95\*LLN or \> 1.05\*ULN, or if pre-dose \< LLN then use \< 0.95\*pre-dose or \> ULN if pre-dose \> ULN then use \> 1.05\*pre-dose or \< LLN.

Outcome measures

Outcome measures
Measure	Apixaban n=2601 Participants Apixaban: tablets, oral, 10 mg tablets, twice daily, for 7 days followed by apixaban 5 mg, twice daily, 6 months Placebo for enoxaparin: solution, subcutaneous, 1 mg/kg Q12h until sham INR ≥2. Placebo for warfarin: tablets, oral, dosing to target sham INR range between 2.0 - 3.0, once daily, 6 months	Enoxaparin + Warfarin n=2596 Participants Enoxaparin: solution, subcutaneous, 1 mg/kg Q12h until INR ≥2 warfarin: tablets, oral, dosing to target INR range between 2.0 - 3.0, once daily, 6 months Placebo for apixaban: tablets, oral, 10 mg tablets, twice daily, for 7 days followed by placebo for apixaban 5 mg tablets, twice daily, 6 months
Number of Treated Participants With Marked Abnormalities in Electrolyte Laboratory Tests Bicarbonate Low (N=2600,2593)	44 participants	31 participants
Number of Treated Participants With Marked Abnormalities in Electrolyte Laboratory Tests Bicarbonate High (N=2600,2593)	17 participants	11 participants
Number of Treated Participants With Marked Abnormalities in Electrolyte Laboratory Tests Total Calcium Low (N=2601,2596)	3 participants	10 participants
Number of Treated Participants With Marked Abnormalities in Electrolyte Laboratory Tests Total Calcium High (N=2601,2596)	12 participants	11 participants
Number of Treated Participants With Marked Abnormalities in Electrolyte Laboratory Tests Chloride Low Total Calcium Low (N=2601,2596)	5 participants	3 participants
Number of Treated Participants With Marked Abnormalities in Electrolyte Laboratory Tests Chloride Low Total Calcium High (N=2601,2596)	0 participants	1 participants
Number of Treated Participants With Marked Abnormalities in Electrolyte Laboratory Tests Potassium Low (N=2601,2596)	26 participants	22 participants
Number of Treated Participants With Marked Abnormalities in Electrolyte Laboratory Tests Potassium High (N=2601,2596)	19 participants	22 participants
Number of Treated Participants With Marked Abnormalities in Electrolyte Laboratory Tests Sodium Low (N=2601,2596)	4 participants	4 participants

SECONDARY outcome

Timeframe: Day 1 to Week 24 + 2 Days or 355 Days (Discontinued Early)

Population: N=Treated participants who received at least one dose of study drug and had non-missing laboratory measurements.

Blood urea nitrogen (BUN), milligrams/deciliter (mg/dL), units per liter (U/L). BUN mg/dL High: \> 1.5\*ULN; Creatinine mg/dL: \> 1.5\*ULN; Alanine aminotransferase (ALT) U/L: \> 3\*ULN; Aspartate aminotransferase (AST) U/L: \> 3\*ULN; Alkaline phosphatase U/L: \> 2\*ULN; Bilirubin Direct mg/dL: \> 1.5\*ULN; Bilirubin Total mg/dL: \> 2\*ULN.

Outcome measures

Outcome measures
Measure	Apixaban n=2601 Participants Apixaban: tablets, oral, 10 mg tablets, twice daily, for 7 days followed by apixaban 5 mg, twice daily, 6 months Placebo for enoxaparin: solution, subcutaneous, 1 mg/kg Q12h until sham INR ≥2. Placebo for warfarin: tablets, oral, dosing to target sham INR range between 2.0 - 3.0, once daily, 6 months	Enoxaparin + Warfarin n=2598 Participants Enoxaparin: solution, subcutaneous, 1 mg/kg Q12h until INR ≥2 warfarin: tablets, oral, dosing to target INR range between 2.0 - 3.0, once daily, 6 months Placebo for apixaban: tablets, oral, 10 mg tablets, twice daily, for 7 days followed by placebo for apixaban 5 mg tablets, twice daily, 6 months
Number of Treated Participants With Marked Abnormalities in Kidney and Liver Function Laboratory Tests BUN High (N=517, 523)	2 participants	7 participants
Number of Treated Participants With Marked Abnormalities in Kidney and Liver Function Laboratory Tests Creatinine High (N=2601, 2596)	47 participants	37 participants
Number of Treated Participants With Marked Abnormalities in Kidney and Liver Function Laboratory Tests ALT High (N=2601, 2598)	52 participants	145 participants
Number of Treated Participants With Marked Abnormalities in Kidney and Liver Function Laboratory Tests ALP High (N=2601, 2598)	35 participants	27 participants
Number of Treated Participants With Marked Abnormalities in Kidney and Liver Function Laboratory Tests AST High (N=2601, 2598)	40 participants	40 participants
Number of Treated Participants With Marked Abnormalities in Kidney and Liver Function Laboratory Tests Direct Bilirubin High (N=2601, 2593)	28 participants	21 participants
Number of Treated Participants With Marked Abnormalities in Kidney and Liver Function Laboratory Tests Total Bilirubin High (N=2601, 2597)	8 participants	7 participants

SECONDARY outcome

Timeframe: Day 1 to Week 24 + 2 Days or 355 Days (Discontinued Early)

Population: N=Treated participants who received at least one dose of study drug and had non-missing laboratory measurements.

Creatine kinase High: \>5\*ULN Units/Liter (U/L); Total Protein High/Low: \< 0.9 \*LLN or \> 1.1\*ULN, or if pre-dose \< LLN then use 0.9\* pre-dose or \> ULN if pre-dose \> ULN then use 1.1 \*pre-dose or \<LLN; Uric acid High: \> 1.5\* ULN, or if pre-dose \> ULN then use \> 2 \*pre-dose.

Outcome measures

Outcome measures
Measure	Apixaban n=2601 Participants Apixaban: tablets, oral, 10 mg tablets, twice daily, for 7 days followed by apixaban 5 mg, twice daily, 6 months Placebo for enoxaparin: solution, subcutaneous, 1 mg/kg Q12h until sham INR ≥2. Placebo for warfarin: tablets, oral, dosing to target sham INR range between 2.0 - 3.0, once daily, 6 months	Enoxaparin + Warfarin n=2596 Participants Enoxaparin: solution, subcutaneous, 1 mg/kg Q12h until INR ≥2 warfarin: tablets, oral, dosing to target INR range between 2.0 - 3.0, once daily, 6 months Placebo for apixaban: tablets, oral, 10 mg tablets, twice daily, for 7 days followed by placebo for apixaban 5 mg tablets, twice daily, 6 months
Number of Treated Participants With Marked Abnormalities in Creatine Kinase, Uric Acid, and Total Protein Laboratory Tests Creatine Kinase High (N=2601, 2596)	20 participants	24 participants
Number of Treated Participants With Marked Abnormalities in Creatine Kinase, Uric Acid, and Total Protein Laboratory Tests Uric Acid High (N=2601, 2596)	6 participants	3 participants
Number of Treated Participants With Marked Abnormalities in Creatine Kinase, Uric Acid, and Total Protein Laboratory Tests Total Protein Low (N=2601, 2596)	15 participants	16 participants
Number of Treated Participants With Marked Abnormalities in Creatine Kinase, Uric Acid, and Total Protein Laboratory Tests Total Protein High (N=2601, 2596)	0 participants	0 participants

SECONDARY outcome

Timeframe: Day 1 to Week 24 + 2 Days or 355 Days (Discontinued Early)

Population: N=Treated participants who received at least one dose of study drug and had non-missing laboratory measurements.

All tests in urine: Glucose: If missing pre-dose use ≥ 2, or if value ≥ 4, or if pre-dose = 0 or 0.5 use ≥ 2, or if pre-dose = 1 use ≥ 3, or if pre-dose = 2 or 3 use ≥ 4; Protein: If missing pre-dose use ≥ 2, or if value ≥ 4, or if pre-dose = 0 or 0.5 use ≥ 2, or if pre-dose = 1 use ≥ 3, or if pre-dose = 2 or 3 use ≥ 4; Blood: If missing pre-dose use ≥ 2, or if value ≥ 4, or if pre-dose = 0 or 0.5 use ≥ 2, or if pre-dose = 1 use ≥ 3, or if pre-dose = 2 or 3 use ≥ 4; Leukocyte esterase: If missing pre-dose use ≥ 2, or if value ≥ 4, or if pre-dose = 0 or 0.5 use ≥ 2, or if pre-dose = 1 use ≥ 3, or if pre-dose = 2 or 3 use ≥ 4;Red blood cells (RBC): If missing pre-dose use ≥ 2, or if value ≥ 4, or if pre-dose = 0 or 0.5 use ≥ 2, or if pre-dose = 1 use ≥ 3, or if pre-dose = 2 or 3 use ≥ 4; White blood cells (WBC): If missing pre-dose use ≥ 2, or if value ≥ 4, or if pre-dose = 0 or 0.5 use ≥ 2, or if pre-dose = 1 use ≥ 3, or if pre-dose = 2 or 3 use ≥ 4.

Outcome measures

Outcome measures
Measure	Apixaban n=1685 Participants Apixaban: tablets, oral, 10 mg tablets, twice daily, for 7 days followed by apixaban 5 mg, twice daily, 6 months Placebo for enoxaparin: solution, subcutaneous, 1 mg/kg Q12h until sham INR ≥2. Placebo for warfarin: tablets, oral, dosing to target sham INR range between 2.0 - 3.0, once daily, 6 months	Enoxaparin + Warfarin n=1719 Participants Enoxaparin: solution, subcutaneous, 1 mg/kg Q12h until INR ≥2 warfarin: tablets, oral, dosing to target INR range between 2.0 - 3.0, once daily, 6 months Placebo for apixaban: tablets, oral, 10 mg tablets, twice daily, for 7 days followed by placebo for apixaban 5 mg tablets, twice daily, 6 months
Number of Treated Participants With Marked Abnormalities in Urinalysis Laboratory Tests Blood in Urine High (N=2289, 2273)	85 participants	127 participants
Number of Treated Participants With Marked Abnormalities in Urinalysis Laboratory Tests Glucose in Urine High (N=2289, 2273)	46 participants	31 participants
Number of Treated Participants With Marked Abnormalities in Urinalysis Laboratory Tests Leukocyte Esterase in Urine High (N=2289, 2273)	105 participants	102 participants
Number of Treated Participants With Marked Abnormalities in Urinalysis Laboratory Tests Protein in Urine High (N=2289, 2273)	41 participants	50 participants
Number of Treated Participants With Marked Abnormalities in Urinalysis Laboratory Tests RBC + WBC in Urine High (N=1685, 1719)	359 participants	361 participants
Number of Treated Participants With Marked Abnormalities in Urinalysis Laboratory Tests RBC in Urine High (N=1293, 1389)	111 participants	140 participants
Number of Treated Participants With Marked Abnormalities in Urinalysis Laboratory Tests WBC in Urine High (N=1354, 1361)	274 participants	263 participants

Adverse Events

Apixaban

Serious events: 417 serious events

Other events: 1014 other events

Deaths: 0 deaths

Enoxaparin/Warfarin

Serious events: 410 serious events

Other events: 1207 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Additional Information

Bristol-Myers Squibb Study Director

Bristol-Myers Squibb

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee Bristol-Myers Squibb Co. agreements with investigators vary; constant is our right to embargo communications regarding trial results prior to public release for a period ≤60 days from submittal for review. We will not prohibit investigators from publishing, but will prohibit the disclosure of previously undisclosed confidential information other than study results, and request postponement of single-center publications until after disclosure of the clinical trial's primary publication.
Publication restrictions are in place

Restriction type: OTHER

Measure	Apixaban n=2676 participants at risk Apixaban: tablets, oral, 10 mg tablets, twice daily, for 7 days followed by apixaban 5 mg, twice daily, 6 months Placebo for enoxaparin: solution, subcutaneous, 1 mg/kg Q12h until sham INR ≥2 Placebo for warfarin: tablets, oral, dosing to target sham INR range between 2.0 - 3.0, once daily, 6 months	Enoxaparin/Warfarin n=2689 participants at risk Enoxaparin: solution, subcutaneous, 1 mg/kg Q12h until INR ≥2 warfarin: tablets, oral, dosing to target INR range between 2.0 - 3.0, once daily, 6 months Placebo for apixaban: tablets, oral, 10 mg tablets, twice daily, for 7 days followed by placebo for apixaban 5 mg tablets, twice daily, 6 months
Gastrointestinal disorders CONSTIPATION	2.7% 73/2676 • Day 1 up to 24 Weeks + 2 Days or 355 Days (for those participants who discontinued early)/	3.2% 87/2689 • Day 1 up to 24 Weeks + 2 Days or 355 Days (for those participants who discontinued early)/
Gastrointestinal disorders DIARRHOEA	3.7% 100/2676 • Day 1 up to 24 Weeks + 2 Days or 355 Days (for those participants who discontinued early)/	3.9% 106/2689 • Day 1 up to 24 Weeks + 2 Days or 355 Days (for those participants who discontinued early)/
Gastrointestinal disorders NAUSEA	3.0% 81/2676 • Day 1 up to 24 Weeks + 2 Days or 355 Days (for those participants who discontinued early)/	3.9% 106/2689 • Day 1 up to 24 Weeks + 2 Days or 355 Days (for those participants who discontinued early)/
Gastrointestinal disorders VOMITING	1.9% 50/2676 • Day 1 up to 24 Weeks + 2 Days or 355 Days (for those participants who discontinued early)/	2.6% 69/2689 • Day 1 up to 24 Weeks + 2 Days or 355 Days (for those participants who discontinued early)/
General disorders FATIGUE	2.2% 58/2676 • Day 1 up to 24 Weeks + 2 Days or 355 Days (for those participants who discontinued early)/	1.9% 50/2689 • Day 1 up to 24 Weeks + 2 Days or 355 Days (for those participants who discontinued early)/
General disorders OEDEMA PERIPHERAL	3.5% 93/2676 • Day 1 up to 24 Weeks + 2 Days or 355 Days (for those participants who discontinued early)/	4.1% 111/2689 • Day 1 up to 24 Weeks + 2 Days or 355 Days (for those participants who discontinued early)/
General disorders PYREXIA	2.0% 54/2676 • Day 1 up to 24 Weeks + 2 Days or 355 Days (for those participants who discontinued early)/	2.1% 56/2689 • Day 1 up to 24 Weeks + 2 Days or 355 Days (for those participants who discontinued early)/
Infections and infestations BRONCHITIS	1.9% 51/2676 • Day 1 up to 24 Weeks + 2 Days or 355 Days (for those participants who discontinued early)/	2.1% 56/2689 • Day 1 up to 24 Weeks + 2 Days or 355 Days (for those participants who discontinued early)/
Infections and infestations NASOPHARYNGITIS	3.9% 104/2676 • Day 1 up to 24 Weeks + 2 Days or 355 Days (for those participants who discontinued early)/	3.6% 98/2689 • Day 1 up to 24 Weeks + 2 Days or 355 Days (for those participants who discontinued early)/
Infections and infestations URINARY TRACT INFECTION	3.4% 92/2676 • Day 1 up to 24 Weeks + 2 Days or 355 Days (for those participants who discontinued early)/	3.0% 82/2689 • Day 1 up to 24 Weeks + 2 Days or 355 Days (for those participants who discontinued early)/
Injury, poisoning and procedural complications CONTUSION	1.8% 48/2676 • Day 1 up to 24 Weeks + 2 Days or 355 Days (for those participants who discontinued early)/	3.6% 97/2689 • Day 1 up to 24 Weeks + 2 Days or 355 Days (for those participants who discontinued early)/
Investigations ALANINE AMINOTRANSFERASE INCREASED	1.1% 30/2676 • Day 1 up to 24 Weeks + 2 Days or 355 Days (for those participants who discontinued early)/	3.9% 105/2689 • Day 1 up to 24 Weeks + 2 Days or 355 Days (for those participants who discontinued early)/
Investigations BLOOD CREATINE PHOSPHOKINASE INCREASED	1.2% 33/2676 • Day 1 up to 24 Weeks + 2 Days or 355 Days (for those participants who discontinued early)/	2.9% 78/2689 • Day 1 up to 24 Weeks + 2 Days or 355 Days (for those participants who discontinued early)/
Investigations GAMMA-GLUTAMYLTRANSFERASE INCREASED	1.4% 38/2676 • Day 1 up to 24 Weeks + 2 Days or 355 Days (for those participants who discontinued early)/	2.1% 56/2689 • Day 1 up to 24 Weeks + 2 Days or 355 Days (for those participants who discontinued early)/
Metabolism and nutrition disorders HYPERCHOLESTEROLAEMIA	1.0% 28/2676 • Day 1 up to 24 Weeks + 2 Days or 355 Days (for those participants who discontinued early)/	2.0% 55/2689 • Day 1 up to 24 Weeks + 2 Days or 355 Days (for those participants who discontinued early)/
Musculoskeletal and connective tissue disorders ARTHRALGIA	2.8% 74/2676 • Day 1 up to 24 Weeks + 2 Days or 355 Days (for those participants who discontinued early)/	3.1% 84/2689 • Day 1 up to 24 Weeks + 2 Days or 355 Days (for those participants who discontinued early)/
Musculoskeletal and connective tissue disorders BACK PAIN	3.0% 80/2676 • Day 1 up to 24 Weeks + 2 Days or 355 Days (for those participants who discontinued early)/	3.2% 87/2689 • Day 1 up to 24 Weeks + 2 Days or 355 Days (for those participants who discontinued early)/
Musculoskeletal and connective tissue disorders PAIN IN EXTREMITY	4.4% 119/2676 • Day 1 up to 24 Weeks + 2 Days or 355 Days (for those participants who discontinued early)/	4.8% 130/2689 • Day 1 up to 24 Weeks + 2 Days or 355 Days (for those participants who discontinued early)/
Nervous system disorders DIZZINESS	2.5% 66/2676 • Day 1 up to 24 Weeks + 2 Days or 355 Days (for those participants who discontinued early)/	2.6% 69/2689 • Day 1 up to 24 Weeks + 2 Days or 355 Days (for those participants who discontinued early)/
Nervous system disorders HEADACHE	6.3% 169/2676 • Day 1 up to 24 Weeks + 2 Days or 355 Days (for those participants who discontinued early)/	6.2% 167/2689 • Day 1 up to 24 Weeks + 2 Days or 355 Days (for those participants who discontinued early)/
Renal and urinary disorders HAEMATURIA	1.5% 41/2676 • Day 1 up to 24 Weeks + 2 Days or 355 Days (for those participants who discontinued early)/	3.4% 91/2689 • Day 1 up to 24 Weeks + 2 Days or 355 Days (for those participants who discontinued early)/
Respiratory, thoracic and mediastinal disorders COUGH	2.3% 61/2676 • Day 1 up to 24 Weeks + 2 Days or 355 Days (for those participants who discontinued early)/	2.2% 58/2689 • Day 1 up to 24 Weeks + 2 Days or 355 Days (for those participants who discontinued early)/
Respiratory, thoracic and mediastinal disorders DYSPNOEA	2.4% 64/2676 • Day 1 up to 24 Weeks + 2 Days or 355 Days (for those participants who discontinued early)/	2.7% 73/2689 • Day 1 up to 24 Weeks + 2 Days or 355 Days (for those participants who discontinued early)/
Respiratory, thoracic and mediastinal disorders EPISTAXIS	2.9% 77/2676 • Day 1 up to 24 Weeks + 2 Days or 355 Days (for those participants who discontinued early)/	5.4% 144/2689 • Day 1 up to 24 Weeks + 2 Days or 355 Days (for those participants who discontinued early)/
Vascular disorders HAEMATOMA	1.3% 34/2676 • Day 1 up to 24 Weeks + 2 Days or 355 Days (for those participants who discontinued early)/	2.7% 72/2689 • Day 1 up to 24 Weeks + 2 Days or 355 Days (for those participants who discontinued early)/
Vascular disorders HYPERTENSION	2.6% 70/2676 • Day 1 up to 24 Weeks + 2 Days or 355 Days (for those participants who discontinued early)/	2.5% 68/2689 • Day 1 up to 24 Weeks + 2 Days or 355 Days (for those participants who discontinued early)/