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

Incidence of Adjudicated Composite of Recurrent Symptomatic VTE or Cardiovascular (CV)-Related Death

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.

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

Incidence of Adjudicated Composite of Recurrent Symptomatic VTE or VTE-related Death or Major Bleeding

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

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

Incidence of Adjudicated Composite of Recurrent Symptomatic VTE, Myocardial Infarction, Stroke, CV-related Death, Clinically Relevant Non-major (CRNM) Bleeding or Major Bleeding

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).

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

Incidence of Adjudicated Symptomatic Nonfatal Deep Vein Thrombosis (DVT) During the Intended Treatment Period

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).

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

Incidence of Adjudicated Symptomatic Nonfatal Pulmonary Embolism (PE) During the Intended Treatment Period

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).

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

Incidence of Adjudicated Venous Thromboembolism (VTE)-Related Death During the Intended Treatment Period

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).

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

Incidence of Cardiovascular (CV)-Related Death Including VTE-related Death During the Intended Treatment Period

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).

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

Incidence of All-Cause Death During the Intended Treatment Period

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).

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

Incidence of Adjudicated Major Bleeding During the Treatment Period in Treated Participants

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.

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

Incidence of Adjudicated Major/CRNM Bleeding During the Treatment Period in Treated Participants

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).

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

Incidence of Adjudicated Clinically Relevant Non Major (CRNM) Bleeding During the Treatment Period in Treated Participants

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.

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

Incidence of Adjudicated Minor Bleeding During the Treatment Period in Treated Participants

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.

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

Incidence of Adjudicated Total Bleeding During the Treatment Period in Treated Participants

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.

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

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

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.

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

Number of Treated Participants With Marked Abnormalities in Hematology Laboratory Tests

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.

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

Number of Treated Participants With Marked Abnormalities in Electrolyte Laboratory Tests

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.

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

Number of Treated Participants With Marked Abnormalities in Kidney and Liver Function Laboratory Tests

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.

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

Number of Treated Participants With Marked Abnormalities in Creatine Kinase, Uric Acid, and Total Protein Laboratory Tests

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.

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

Number of Treated Participants With Marked Abnormalities in Urinalysis Laboratory Tests

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.

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