Efficacy and Safety Study of Apixaban for the Treatment of Deep Vein Thrombosis or Pulmonary Embolism
Sponsor
Bristol-Myers Squibb (Industry)
Overall Status
Completed
CT.gov ID
NCT00643201
Collaborator
Pfizer (Industry)
5,614
382
2
56
14.7
0.3
Study Details
Study Description
Brief Summary
The purpose of this study is to evaluate the effects of an investigational blood thinner, apixaban, in preventing venous thromboembolic (VTE) recurrence or death in patients with deep vein thrombosis (DVT) or pulmonary embolism (PE)
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 3 |
Study Design
Study Type:
Interventional
Actual Enrollment
:
5614 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
Double (Participant, Investigator)
Primary Purpose:
Treatment
Official Title:
A Safety and Efficacy Trial Evaluating the Use of Apixaban in the Treatment of Symptomatic Deep Vein Thrombosis and Pulmonary Embolism
Study Start Date
:
Jul 1, 2008
Actual Primary Completion Date
:
Mar 1, 2013
Actual Study Completion Date
:
Mar 1, 2013
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Active Comparator: Apixaban apixaban: tablets, oral, 10 milligram (mg) tablets, twice daily, for 7 days followed by apixaban 5 mg, twice daily, 6 months. |
Drug: Enoxaparin
solution, subcutaneous, 1 mg/kg Q12h until International normalized ratio (INR) ≥2.
Drug: warfarin
tablets, oral, dosing to target INR range between 2.0 - 3.0, once daily, 6 months
Other Names:
Drug: 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
|
| Experimental: Enoxaparin + Warfarin Enoxaparin: solution, subcutaneous, 1 mg/kg Q12h until international normalized ratio (INR) ≥2. |
Drug: Placebo for enoxaparin
solution, subcutaneous, 1 mg/kg Q12h until sham INR ≥2.
Drug: Placebo for warfarin
tablets, oral, dosing to target sham INR range between 2.0 - 3.0, once daily, 6 months
Drug: apixaban
tablets, oral, 10 mg tablets, twice daily, for 7 days followed by apixaban 5 mg, twice daily, 6 months
Other Names:
|
Outcome Measures
Primary Outcome Measures
- Incidence of Adjudicated Composite of Symptomatic, Recurrent Venous Thromboembolism (VTE) or VTE-Related Death During 6 Months of Treatment [Day 1 to Week 24 + 2 Days or 355 days (Discontinued Early)]
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).
Secondary Outcome Measures
- Incidence of Adjudicated Composite of Recurrent Symptomatic Venous Thromboembolism (VTE) or All-Cause Death [Day 1 up to 24 Weeks + 2 Days or 355 Days (Discontinued Early)]
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.
- Incidence of Adjudicated Composite of Recurrent Symptomatic VTE or Cardiovascular (CV)-Related Death [Day 1 up to 24 Weeks + 2 Days or 355 Days (Discontinued Early)]
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.
- Incidence of Adjudicated Composite of Recurrent Symptomatic VTE or VTE-related Death or Major Bleeding [Day 1 up to 24 Weeks + 2 Days or 355 Days (Discontinued Early)]
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
- Incidence of Adjudicated Composite of Recurrent Symptomatic VTE, Myocardial Infarction, Stroke, CV-related Death, Clinically Relevant Non-major (CRNM) Bleeding or Major Bleeding [Day 1 up to 24 Weeks + 2 Days or 355 Days (Discontinued Early)]
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).
- Incidence of Adjudicated Symptomatic Nonfatal Deep Vein Thrombosis (DVT) During the Intended Treatment Period [Day 1 up to 24 Weeks + 2 Days or 355 Days (Discontinued Early)]
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).
- Incidence of Adjudicated Symptomatic Nonfatal Pulmonary Embolism (PE) During the Intended Treatment Period [Day 1 to Week 24 + + 2 Days or 355 Days (Discontinued Early)]
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).
- Incidence of Adjudicated Venous Thromboembolism (VTE)-Related Death During the Intended Treatment Period [Day 1 to Week 24 + 2 Days or 355 Days (Discontinued Early)]
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).
- Incidence of Cardiovascular (CV)-Related Death Including VTE-related Death During the Intended Treatment Period [Day 1 to Week 24 + 2 Days or 355 Days (Discontinued Early)]
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).
- Incidence of All-Cause Death During the Intended Treatment Period [Day 1 to Week 24 + 2 Days or 355 Days (Discontinued Early)]
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).
- Incidence of Adjudicated Major Bleeding During the Treatment Period in Treated Participants [Day 1 to Week 24 + 2 Days or 355 Days (Discontinued Early)]
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.
- Incidence of Adjudicated Major/CRNM Bleeding During the Treatment Period in Treated Participants [Day 1 to Week 24 + 2 Days or 355 Days (Discontinued Early)]
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).
- Incidence of Adjudicated Clinically Relevant Non Major (CRNM) Bleeding During the Treatment Period in Treated Participants [Day 1 to Week 24 + 2 Days or 355 Days (Discontinued Early)]
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.
- Incidence of Adjudicated Minor Bleeding During the Treatment Period in Treated Participants [Day 1 to Week 24 + 2 Days or 355 Days (Discontinued Early)]
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.
- Incidence of Adjudicated Total Bleeding During the Treatment Period in Treated Participants [Day 1 to Week 24 + 2 Days or 355 Days (Discontinued Early)]
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.
- 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 [First dose to last dose of 24 Weeks + 2 days (AEs) or + 30 days (SAEs) or until drug discontinued]
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.
- Number of Treated Participants With Marked Abnormalities in Hematology Laboratory Tests [Day 1 to Week 24 + 2 Days or 355 Days (Discontinued Early)]
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.
- Number of Treated Participants With Marked Abnormalities in Electrolyte Laboratory Tests [Day 1 to Week 24 + 2 Days or 355 Days (Discontinued Early)]
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.
- Number of Treated Participants With Marked Abnormalities in Kidney and Liver Function Laboratory Tests [Day 1 to Week 24 + 2 Days or 355 Days (Discontinued Early)]
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.
- Number of Treated Participants With Marked Abnormalities in Creatine Kinase, Uric Acid, and Total Protein Laboratory Tests [Day 1 to Week 24 + 2 Days or 355 Days (Discontinued Early)]
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.
- Number of Treated Participants With Marked Abnormalities in Urinalysis Laboratory Tests [Day 1 to Week 24 + 2 Days or 355 Days (Discontinued Early)]
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.
Eligibility Criteria
Criteria
Ages Eligible for Study:
18 Years
and Older
Sexes Eligible for Study:
All
Accepts Healthy Volunteers:
No
Inclusion Criteria:
-
Men and women ≥ 18 years of age
-
Clinical diagnosis of DVT or PE
Exclusion Criteria:
-
Contraindications for enoxaparin or warfarin
-
Active bleeding or high risk for serious bleeding
-
Short life expectancy
-
Uncontrolled high blood pressure
-
Significantly impaired kidney or liver function
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Alabama Clinical Therapeutics, Llc | Birmingham | Alabama | United States | 35235 |
| 2 | Horizon Research Group, Inc. | Mobile | Alabama | United States | 36608 |
| 3 | Fort Smith Lung Center | Fort Smith | Arkansas | United States | 72901 |
| 4 | University Of Arkansas For Medical Sciences | Little Rock | Arkansas | United States | 72205 |
| 5 | Beaver Medical Group | Banning | California | United States | 92220 |
| 6 | University Of California San Francisco-Fresno | Fresno | California | United States | 93701 |
| 7 | University Of California, Davis Medical Center | Sacramento | California | United States | 95817 |
| 8 | Chest Medicine & Critical Care Medical Gr. Inc. | San Diego | California | United States | 92123 |
| 9 | Stanford University Medical Center | Stanford | California | United States | 94305 |
| 10 | Harbor Ucla Medical Center | Torrance | California | United States | 90509 |
| 11 | New West Physicians | Golden | Colorado | United States | 80401 |
| 12 | Drogue Medical, Llc | Wheat Ridge | Colorado | United States | 80033 |
| 13 | Bridgeport Hospital | Bridgeport | Connecticut | United States | 06610 |
| 14 | Dept Of Internal Med, Sect Of Pulmonary & Critical Care Med | New Haven | Connecticut | United States | 06510 |
| 15 | George Washington University Medical Faculty Associates | Washington | District of Columbia | United States | 20037 |
| 16 | Bay Pines Va Healthcare Systems | Bay Pines | Florida | United States | 33744 |
| 17 | Daniel G. Lorch, Jr, Md, Cpi | Brandon | Florida | United States | 33511 |
| 18 | Research Alliance, Inc. | Clearwater | Florida | United States | 33756 |
| 19 | River City Clinical Research | Jacksonville | Florida | United States | 32207 |
| 20 | Pasadena Center For Medical Research | St. Petersburg | Florida | United States | 33707 |
| 21 | Tampa Clinical Research | Tampa | Florida | United States | 33624 |
| 22 | Office Of Michele S. Maholtz Md | Vero Beach | Florida | United States | 32960 |
| 23 | Cleveland Clinic Florida | Weston | Florida | United States | 33331 |
| 24 | Atlanta Pulmonary Group | Atlanta | Georgia | United States | 30342 |
| 25 | Atlanta Institute For Medical Research, Inc | Decatur | Georgia | United States | 30030 |
| 26 | Chatham Hospitalists | Savannah | Georgia | United States | 31405 |
| 27 | Gateway Cardiology. P.C | Jerseyville | Illinois | United States | 62052 |
| 28 | West Suburban Medical Center | Oak Park | Illinois | United States | 60302 |
| 29 | Infectious Disease Of Indiana Psc | Carmel | Indiana | United States | 46032 |
| 30 | Heartland Vascular Medicine And Surgery | Windsor Heights | Iowa | United States | 50324 |
| 31 | Kentucky Lung Clinic | Hazard | Kentucky | United States | 41701 |
| 32 | Univ. Of Kentucky Dept. Of Surgery | Lexington | Kentucky | United States | 40536 |
| 33 | Research Integrity, Llc | Owensboro | Kentucky | United States | 42303 |
| 34 | Pen Bay Medical Center | Rockport | Maine | United States | 04856 |
| 35 | Anne Arundel Medical Center | Annapolis | Maryland | United States | 21401 |
| 36 | R Adams Cowley Shock Trauma Center | Baltimore | Maryland | United States | 21201 |
| 37 | Medstar Research Health Institute | Baltimore | Maryland | United States | 21237 |
| 38 | Henry Ford Hospital | Detroit | Michigan | United States | 48202 |
| 39 | Hurley Medical Center | Flint | Michigan | United States | 48503 |
| 40 | Mississippi Medical Research, Llc | Picayune | Mississippi | United States | 39466 |
| 41 | University Of Missouri-Columbia | Columbia | Missouri | United States | 65212 |
| 42 | Veterans Affairs Medical Center | Kansas City | Missouri | United States | 64128 |
| 43 | Washington University School Of Medicine | St Louis | Missouri | United States | 63110 |
| 44 | St. John'S Mercy Medical Center | St. Louis | Missouri | United States | 63141 |
| 45 | Mercury Street Medical Group, Pllc | Butte | Montana | United States | 59701 |
| 46 | Great Falls Clinic, Llp | Great Falls | Montana | United States | 59405 |
| 47 | Internal Medical Associates Of Grand Island, P.C | Grand Island | Nebraska | United States | 68803 |
| 48 | Creighton University Medical Center | Omaha | Nebraska | United States | 68131 |
| 49 | Morristown Memorial Hospital | Morristown | New Jersey | United States | 07962 |
| 50 | Pulmonary & Critical Care Services, Pc | Albany | New York | United States | 12205 |
| 51 | Kaleida Health System | Buffalo | New York | United States | 14209 |
| 52 | Richmond University Medical Center | Staten Island | New York | United States | 10310 |
| 53 | New York Medical College | Valhalla | New York | United States | 10595 |
| 54 | Carolinas Medical Center | Charlotte | North Carolina | United States | 28203 |
| 55 | Duke University Medical Center | Durham | North Carolina | United States | 27710 |
| 56 | Rex Healthcare | Raleigh | North Carolina | United States | 27607 |
| 57 | Piedmont Healthcare/Research | Statesville | North Carolina | United States | 28625 |
| 58 | Wilmington Medical Research | Wilmington | North Carolina | United States | 28401 |
| 59 | Clinical Trials Of America, Inc. | Winston Salem | North Carolina | United States | 27103 |
| 60 | Altru Health System Clinic | Grand Forks | North Dakota | United States | 58201 |
| 61 | Huron Hospital | Cleveland | Ohio | United States | 44112 |
| 62 | Remington Davis Inc. | Columbus | Ohio | United States | 43215 |
| 63 | Oregon Health Science University | Portland | Oregon | United States | 97239 |
| 64 | Penn State Milton S. Hershey Medical Center | Hershey | Pennsylvania | United States | 17033 |
| 65 | Greenville Hospital System | Greenville | South Carolina | United States | 29615 |
| 66 | Palmetto Clinical Research | Summerville | South Carolina | United States | 29485 |
| 67 | Holston Medical Group | Bristol | Tennessee | United States | 37620 |
| 68 | Kore Cv Research | Jackson | Tennessee | United States | 38305 |
| 69 | Primecare Medical Group | Houston | Texas | United States | 77024 |
| 70 | Cancer Care Centers Of South Texas | San Antonio | Texas | United States | 78229 |
| 71 | University Of Utah Medical Center | Salt Lake City | Utah | United States | 84132 |
| 72 | Lake Washington Vascular, Pllc | Bellevue | Washington | United States | 98004 |
| 73 | Franciscan Research Center | Tacoma | Washington | United States | 98405 |
| 74 | Local Institution | Ciudad Autonoma De Buenos Aire | Buenos Aires | Argentina | C1180AAX |
| 75 | Local Institution | Rosario | Santa Fe | Argentina | 2000 |
| 76 | Local Institution | Rosario | Santa Fe | Argentina | S2000CVB |
| 77 | Local Institution | Rosario | Santa Fe | Argentina | S2000DSV |
| 78 | Local Institution | Buenos Aires | Argentina | C1280AEB | |
| 79 | Local Institution | Cordoba | Argentina | 5000 | |
| 80 | Local Institution | Corrientes | Argentina | 3400 | |
| 81 | Local Institution | Garran | Australian Capital Territory | Australia | 2605 |
| 82 | Local Institution | Concord | New South Wales | Australia | 2139 |
| 83 | Local Institution | Kogarah | New South Wales | Australia | 2217 |
| 84 | Local Institution | Lismore | New South Wales | Australia | 2480 |
| 85 | Local Institution | Randwick | New South Wales | Australia | 2031 |
| 86 | Local Institution | Herston | Queensland | Australia | 4029 |
| 87 | Local Institution | Adelaide | South Australia | Australia | 5000 |
| 88 | Local Institution | Bedford Park | South Australia | Australia | 5042 |
| 89 | Local Institution | Hobart | Tasmania | Australia | 7000 |
| 90 | Local Institution | Box Hill | Victoria | Australia | 3128 |
| 91 | Local Institution | Clayton | Victoria | Australia | 3168 |
| 92 | Local Institution | Ringwood East | Victoria | Australia | 3135 |
| 93 | Local Institution | Windsor | Victoria | Australia | 3181 |
| 94 | Local Institution | Perth | Western Australia | Australia | 6001 |
| 95 | Local Institution | Graz | Austria | 8036 | |
| 96 | Local Institution | Innsbruck | Austria | 6020 | |
| 97 | Local Institution | Vienna | Austria | 1090 | |
| 98 | Local Institution | Vienna | Austria | 1100 | |
| 99 | Local Institution | Vienna | Austria | 1140 | |
| 100 | Local Institution | Vienna | Austria | 1160 | |
| 101 | Local Institution | Wien | Austria | 1090 | |
| 102 | Local Institution | Belo Horizonte - Mg | Minas Gerais | Brazil | 30150 |
| 103 | Local Institution | Curitiba | Parana | Brazil | 80035 |
| 104 | Local Institution | Curitiba | Parana | Brazil | 80050 |
| 105 | Local Institution | Curitiba | Parana | Brazil | 80810 |
| 106 | Local Institution | Curitiba | Parana | Brazil | 81520 |
| 107 | Local Institution | Rio Janeiro | Rio De Janeiro | Brazil | 22280 |
| 108 | Local Institution | Port Alegre | Rio Grande Do Sul | Brazil | 90020 |
| 109 | Local Institution | Porto Alegre | Rio Grande Do Sul | Brazil | 90035 |
| 110 | Local Institution | Porto Alegre | Rio Grande Do Sul | Brazil | 90110 |
| 111 | Local Institution | Porto Alegre | Rio Grande Do Sul | Brazil | 90610 |
| 112 | Local Institution | Botucatu | Sao Paulo | Brazil | 18618 |
| 113 | Local Institution | Liberdade | Sao Paulo | Brazil | 01509 |
| 114 | Local Institution | Sao Jose Do Rio Preto | Sao Paulo | Brazil | 15090 |
| 115 | Local Institution | Sao Bernardo do Campo | SP | Brazil | 09715 |
| 116 | Local Institution | Rio De Janeiro | Brazil | 20551 | |
| 117 | Local Institution | Sao Paulo | Brazil | 01323 | |
| 118 | Local Institution | Sao Paulo | Brazil | 04005 | |
| 119 | Local Institution | Sao Paulo | Brazil | 04025 | |
| 120 | Local Institution | Sao Paulo | Brazil | 05403 | |
| 121 | Local Institution | Edmonton | Alberta | Canada | T5H 4B9 |
| 122 | Local Institution | Edmonton | Alberta | Canada | T6G 2B7 |
| 123 | Local Institution | Vancouver | British Columbia | Canada | V5Z 1M9 |
| 124 | Local Institution | Vancouver | British Columbia | Canada | V6Z 1Y6 |
| 125 | Local Institution | Victoria | British Columbia | Canada | V8R 6R5 |
| 126 | Local Institution | Winnipeg | Manitoba | Canada | R2H 2A6 |
| 127 | Local Institution | Saint John | New Brunswick | Canada | E2L 4L2 |
| 128 | Local Institution | Hamilton | Ontario | Canada | L8L 2X2 |
| 129 | Local Institution | Hamilton | Ontario | Canada | L8N 4A6 |
| 130 | Local Institution | Hamilton | Ontario | Canada | L8S 4K1 |
| 131 | Local Institution | Ottawa | Ontario | Canada | K1Y 4E9 |
| 132 | Local Institution | Toronto | Ontario | Canada | M5G 2C4 |
| 133 | Local Institution | Waterloo | Ontario | Canada | N2J 1C4 |
| 134 | Local Institution | Windsor | Ontario | Canada | N8X 5A6 |
| 135 | Local Institution | Greenfield Park | Quebec | Canada | J4V 2H1 |
| 136 | Local Institution | Montreal | Quebec | Canada | H1T 2M4 |
| 137 | Local Institution | St. Jerome | Quebec | Canada | J7Z 5T3 |
| 138 | Local Institution | Punta Arenas | Magallanes Antartica | Chile | 6212296 |
| 139 | Local Institution | Independencia | Metropolitana | Chile | XXXXX |
| 140 | Local Institution | Santiago | Metropolitana | Chile | 7600448 |
| 141 | Local Institution | Santiago | Metropolitana | Chile | 8330024 |
| 142 | Local Institution | Vina Del Mar | Valparaiso | Chile | 2520000 |
| 143 | Local Institution | Beijing | Beijing | China | 100020 |
| 144 | Local Institution | Beijing | Beijing | China | 100029 |
| 145 | Local Institution | Beijing | Beijing | China | 100032 |
| 146 | Local Institution | Beijing | Beijing | China | 100035 |
| 147 | Local Institution | Beijing | Beijing | China | 100037 |
| 148 | Local Institution | Beijing | Beijing | China | 100038 |
| 149 | Local Institution | Beijing | Beijing | China | 100053 |
| 150 | Local Institution | Beijing | Beijing | China | 100191 |
| 151 | Local Institution | Guangzhou | Guangdong | China | 510080 |
| 152 | Local Institution | Wuhan | Hubei | China | 430022 |
| 153 | Local Institution | Shengyang | Liaoning | China | 110004 |
| 154 | Local Institution | Shanghai | Shanghai | China | 200032 |
| 155 | Local Institution | Shanghai | Shanghai | China | 200127 |
| 156 | Local Institution | Hangzhou | Zhejiang | China | 130016 |
| 157 | Local Institution | Hangzhou | Zhejiang | China | 310016 |
| 158 | Local Institution | Xian | China | 710032 | |
| 159 | Local Institution | Hradec Kralove | Czech Republic | 500 05 | |
| 160 | Local Institution | Kladno | Czech Republic | 272 59 | |
| 161 | Local Institution | Litomysl | Czech Republic | 570 14 | |
| 162 | Local Institution | Mestec Kralove | Czech Republic | 289 03 | |
| 163 | Local Institution | Ostrava Vitkovice | Czech Republic | 703 84 | |
| 164 | Local Institution | Ostrava | Czech Republic | 708 52 | |
| 165 | Local Institution | Praha 10 | Czech Republic | 100 34 | |
| 166 | Local Institution | Praha 1 | Czech Republic | 110 00 | |
| 167 | Local Institution | Praha 1 | Czech Republic | 118 33 | |
| 168 | Local Institution | Praha 2 | Czech Republic | 128 08 | |
| 169 | Local Institution | Usti Nad Labem | Czech Republic | 401 13 | |
| 170 | Local Institution | Usti Nad Orlici | Czech Republic | 562 18 | |
| 171 | Local Institution | Arhus C | Denmark | 8000 | |
| 172 | Local Institution | Hellerup | Denmark | 2900 | |
| 173 | Local Institution | Herning | Denmark | 7400 | |
| 174 | Local Institution | Hilleroed | Denmark | 3400 | |
| 175 | Local Institution | Horsens | Denmark | 8700 | |
| 176 | Local Institution | Naestved | Denmark | 4700 | |
| 177 | Local Institution | Silkeborg | Denmark | 8600 | |
| 178 | Local Institution | Angers | France | 49000 | |
| 179 | Local Institution | Arras | France | 62022 | |
| 180 | Local Institution | Besancon | France | 25000 | |
| 181 | Local Institution | Clamart | France | 92141 | |
| 182 | Local Institution | Clermont-Ferrand Cedex 01 | France | 63003 | |
| 183 | Local Institution | Dijon | France | 21079 | |
| 184 | Local Institution | Grenoble Cedex 9 | France | 38043 | |
| 185 | Local Institution | Langres Cedex | France | 52206 | |
| 186 | Local Institution | Le Kremlin-Bicetre | France | 94275 | |
| 187 | Local Institution | Lille Cedex | France | 59020 | |
| 188 | Local Institution | Limoges Cedex | France | 87042 | |
| 189 | Local Institution | Nantes | France | 44093 | |
| 190 | Local Institution | Paris | France | 75004 | |
| 191 | Local Institution | Paris | France | 75010 | |
| 192 | Local Institution | Pierre Benite | France | 69495 | |
| 193 | Local Institution | Saint-Priest En Jarez | France | 42270 | |
| 194 | Local Institution | Toulouse cedex 9 | France | 31059 | |
| 195 | Local Institution | Vernon | France | 27200 | |
| 196 | Local Institution | Berlin | Germany | 10117 | |
| 197 | Local Institution | Berlin | Germany | 10787 | |
| 198 | Local Institution | Berlin | Germany | 12559 | |
| 199 | Local Institution | Berlin | Germany | 14050 | |
| 200 | Local Institution | Bochum | Germany | 44791 | |
| 201 | Local Institution | Cologne | Germany | 50937 | |
| 202 | Local Institution | Dortmund | Germany | 44137 | |
| 203 | Local Institution | Dresden | Germany | 01067 | |
| 204 | Local Institution | Dresden | Germany | 01307 | |
| 205 | Local Institution | Frankfurt | Germany | 60596 | |
| 206 | Local Institution | Gottingen | Germany | 37075 | |
| 207 | Local Institution | Karlsbad | Germany | 76307 | |
| 208 | Local Institution | Ludwigshafen | Germany | 67063 | |
| 209 | Local Institution | Mannheim | Germany | 68161 | |
| 210 | Local Institution | Mannheim | Germany | 68163 | |
| 211 | Local Institution | Munchen | Germany | 80331 | |
| 212 | Local Institution | Munich | Germany | 80336 | |
| 213 | Local Institution | Pokfulman | Hong Kong | XXXXX | |
| 214 | Local Institution | Shatin, N.T | Hong Kong | ||
| 215 | Local Institution | Budapest | Hungary | 1032 | |
| 216 | Local Institution | Budapest | Hungary | 1097 | |
| 217 | Local Institution | Budapest | Hungary | 1125 | |
| 218 | Local Institution | Gyula | Hungary | 5700 | |
| 219 | Local Institution | Kecskemet | Hungary | 6000 | |
| 220 | Local Institution | Miskolc | Hungary | 3501 | |
| 221 | Local Institution | Mosonmagyarovar | Hungary | 9200 | |
| 222 | Local Institution | Szekesfehervar | Hungary | 8000 | |
| 223 | Local Institution | Zalaegerszeg | Hungary | 8900 | |
| 224 | Local Institution | Hyderabad | Andhra Pradesh | India | 500 082 |
| 225 | Local Institution | Hyderabad | Andhra Pradesh | India | 500034 |
| 226 | Local Institution | Ahmedabad | Gujarat | India | 380006 |
| 227 | Local Institution | Gurgaon | Haryana | India | 122001 |
| 228 | Local Institution | Bangalore | Karnataka | India | 560054 |
| 229 | Local Institution | Bengaluru | Karnataka | India | 560017 |
| 230 | Local Institution | Manipal | Karnataka | India | 576104 |
| 231 | Local Institution | Pune | Maharashtra | India | 411001 |
| 232 | Local Institution | Mohali | Punjab | India | 160062 |
| 233 | Local Institution | Ludhiana | Tagore Nagar | India | 141001 |
| 234 | Local Institution | Chennai | Tamil Nadu | India | 600 006 |
| 235 | Local Institution | Bangalore | India | 560052 | |
| 236 | Local Institution | Bangalore | India | 560099 | |
| 237 | Local Institution | Pune | India | 411001 | |
| 238 | Local Institution | Tiberias | Lower Galillee | Israel | 15208 |
| 239 | Local Institution | Afula | Israel | 18101 | |
| 240 | Local Institution | Ashkelon | Israel | 78278 | |
| 241 | Local Institution | Hadera | Israel | 38101 | |
| 242 | Local Institution | Haifa | Israel | 31048 | |
| 243 | Local Institution | Haifa | Israel | 31096 | |
| 244 | Local Institution | Holon | Israel | 58100 | |
| 245 | Local Institution | Jerusalem | Israel | 91031 | |
| 246 | Local Institution | Jerusalem | Israel | 91120 | |
| 247 | Local Institution | Kfar Saba | Israel | 44281 | |
| 248 | Local Institution | Nahariya | Israel | 22100 | |
| 249 | Local Institution | Petach-Tikva | Israel | 49100 | |
| 250 | Local Institution | Rehovot | Israel | 76100 | |
| 251 | Local Institution | Safed | Israel | 13100 | |
| 252 | Local Institution | Tel Aviv | Israel | 64239 | |
| 253 | Local Institution | Tel Hashomer | Israel | 52621 | |
| 254 | Local Institution | Bologna | Italy | 40138 | |
| 255 | Local Institution | Castelfranco Veneto (Tv) | Italy | 31033 | |
| 256 | Local Institution | Chieti Scalo | Italy | 66013 | |
| 257 | Local Institution | Cosenza | Italy | 87100 | |
| 258 | Local Institution | Milano | Italy | 20132 | |
| 259 | Local Institution | Padova | Italy | 35128 | |
| 260 | Local Institution | Palermo | Italy | 90127 | |
| 261 | Local Institution | Pavia | Italy | 27100 | |
| 262 | Local Institution | Piacenza | Italy | 29100 | |
| 263 | Local Institution | Pisa | Italy | 56124 | |
| 264 | Local Institution | Reggio Emilia | Italy | 42100 | |
| 265 | Local Institution | Rome | Italy | 00168 | |
| 266 | Local Institution | Rozzano (Mi) | Italy | 20089 | |
| 267 | Local Institution | San Daniele Del Friuli (Ud) | Italy | 33038 | |
| 268 | Local Institution | Vicenza | Italy | 36100 | |
| 269 | Local Institution | Vittorio Veneto (Tv) | Italy | 31029 | |
| 270 | Local Institution | Busan | Korea, Republic of | 602-702 | |
| 271 | Local Institution | Seoul | Korea, Republic of | 120752 | |
| 272 | Local Institution | Seoul | Korea, Republic of | 137-040 | |
| 273 | Local Institution | Seoul | Korea, Republic of | 138736 | |
| 274 | Local Institution | Georgetown | Penang | Malaysia | 10350 |
| 275 | Local Institution | Ipoh | Perak | Malaysia | 30990 |
| 276 | Local Institution | Kuala Lumpur | Malaysia | 50586 | |
| 277 | Local Institution | Melaka | Malaysia | 75400 | |
| 278 | Local Institution | Tijuana | Baja California | Mexico | 22500 |
| 279 | Local Institution | Leon | Guanajuato | Mexico | 37320 |
| 280 | Local Institution | Guadalajara | Jalisco | Mexico | 44280 |
| 281 | Local Institution | Zapopan | Jalisco | Mexico | 45170 |
| 282 | Local Institution | Zapopan | Jalisco | Mexico | 45200 |
| 283 | Local Institution | Monterrey | Nuevo Leon | Mexico | 64000 |
| 284 | Local Institution | Monterrey | Nuevo Leon | Mexico | 64718 |
| 285 | Local Institution | Xalapa | Veracruz | Mexico | 91020 |
| 286 | Local Institution | Aguascalientes | Mexico | 20230 | |
| 287 | Local Institution | Durango | Mexico | 34080 | |
| 288 | Local Institution | Alesund | Norway | 6017 | |
| 289 | Local Institution | Fredrikstad | Norway | 1606 | |
| 290 | Local Institution | Gjettum | Norway | 1346 | |
| 291 | Local Institution | Gjovik | Norway | 2819 | |
| 292 | Local Institution | Hamar | Norway | 2318 | |
| 293 | Local Institution | Oslo | Norway | 0319 | |
| 294 | Local Institution | Oslo | Norway | 0407 | |
| 295 | Local Institution | Oslo | Norway | 0456 | |
| 296 | Local Institution | Trondheim | Norway | 7006 | |
| 297 | Local Institution | Tynset | Norway | 2500 | |
| 298 | Local Institution | Bialystok | Poland | 15-276 | |
| 299 | Local Institution | Bydgoszcz | Poland | 85-168 | |
| 300 | Local Institution | Bydgoszcz | Poland | 85-681 | |
| 301 | Local Institution | Gdansk | Poland | 80-803 | |
| 302 | Local Institution | Gdynia | Poland | 81-348 | |
| 303 | Local Institution | Lodz | Poland | 90-153 | |
| 304 | Local Institution | Lublin | Poland | 20-081 | |
| 305 | Local Institution | Lublin | Poland | 20-718 | |
| 306 | Local Institution | Poznan | Poland | 61-848 | |
| 307 | Local Institution | Przeworsk | Poland | 37-200 | |
| 308 | Local Institution | Szczecin | Poland | 70-111 | |
| 309 | Local Institution | Warsawa | Poland | 02-776 | |
| 310 | Local Institution | Warsaw | Poland | 02-005 | |
| 311 | Local Institution | Warszawa | Poland | 01-138 | |
| 312 | Local Institution | Wroclaw | Poland | 50-981 | |
| 313 | Local Institution | Wroclaw | Poland | 51-124 | |
| 314 | Local Institution | Coimbra | Portugal | 3004-548 | |
| 315 | Local Institution | Guarda | Portugal | 6301-857 | |
| 316 | Local Institution | Lisboa | Portugal | 1169-050 | |
| 317 | Local Institution | Lisboa | Portugal | 1769-001 | |
| 318 | Local Institution | San Juan | Puerto Rico | 00921 | |
| 319 | Local Institution | Baia Mare | Romania | 430031 | |
| 320 | Local Institution | Bucharest | Romania | 022328 | |
| 321 | Local Institution | Bucharest | Romania | 030171 | |
| 322 | Local Institution | Bucharest | Romania | 050098 | |
| 323 | Local Institution | Targu Mures | Romania | 540136 | |
| 324 | Local Institution | Arkhangelsk | Russian Federation | 163045 | |
| 325 | Local Institution | Chelyabinsk | Russian Federation | 454136 | |
| 326 | Local Institution | Kazan | Russian Federation | 420101 | |
| 327 | Local Institution | Moscow | Russian Federation | 109386 | |
| 328 | Local Institution | Moscow | Russian Federation | 111539 | |
| 329 | Local Institution | Moscow | Russian Federation | 115093 | |
| 330 | Local Institution | Moscow | Russian Federation | 115280 | |
| 331 | Local Institution | Moscow | Russian Federation | 117292 | |
| 332 | Local Institution | Moscow | Russian Federation | 119049 | |
| 333 | Local Institution | Moscow | Russian Federation | 121359 | |
| 334 | Local Institution | Moscow | Russian Federation | 121552 | |
| 335 | Local Institution | Moscow | Russian Federation | 127473 | |
| 336 | Local Institution | Novosibirsk | Russian Federation | 630090 | |
| 337 | Local Institution | Rostov-On Don | Russian Federation | 344022 | |
| 338 | Local Institution | Ryazan | Russian Federation | 390026 | |
| 339 | Local Institution | Saint Petersburg | Russian Federation | 192242 | |
| 340 | Local Institution | Saint Petersburg | Russian Federation | 197022 | |
| 341 | Local Institution | Saint-Petersburg | Russian Federation | 196247 | |
| 342 | Local Institution | Saint-Petersburg | Russian Federation | 197341 | |
| 343 | Local Institution | Saint-Petersburg | Russian Federation | 199106 | |
| 344 | Local Institution | Saratov | Russian Federation | 410012 | |
| 345 | Local Institution | St Petersburg | Russian Federation | 194044 | |
| 346 | Local Institution | Yaroslavl | Russian Federation | 150062 | |
| 347 | Local Institution | Singapore | Singapore | 169608 | |
| 348 | Local Institution | Singapore | Singapore | 308433 | |
| 349 | Local Institution | Singapore | Singapore | 529889 | |
| 350 | Local Institution | Bioemfontein | Free State | South Africa | 9301 |
| 351 | Local Institution | Centurion | Gauteng | South Africa | 0157 |
| 352 | Local Institution | Parktown | Gauteng | South Africa | 2193 |
| 353 | Local Institution | Pretoria | Gauteng | South Africa | 0084 |
| 354 | Local Institution | Durban | Kwa Zulu Natal | South Africa | 4001 |
| 355 | Local Institution | Pietermaritzburg | Kwa Zulu Natal | South Africa | 3201 |
| 356 | Local Institution | Bellville | Western Cape | South Africa | 7530 |
| 357 | Local Institution | George | Western Cape | South Africa | 6529 |
| 358 | Local Institution | Somerset West | Western Cape | South Africa | 7130 |
| 359 | Local Institution | Worcester | Western Cape | South Africa | 6850 |
| 360 | Local Institution | Torrevieja | Alicante | Spain | 03186 |
| 361 | Local Institution | Getafe | Spain | 28905 | |
| 362 | Local Institution | L'Hospitalet De Llobregat | Spain | 08907 | |
| 363 | Local Institution | Leon | Spain | 24008 | |
| 364 | Local Institution | Madrid | Spain | 28007 | |
| 365 | Local Institution | Madrid | Spain | 28029 | |
| 366 | Local Institution | Madrid | Spain | 28041 | |
| 367 | Local Institution | Malaga | Spain | 29010 | |
| 368 | Local Institution | Mourente | Spain | 36071 | |
| 369 | Local Institution | Tarragona | Spain | 43007 | |
| 370 | Local Institution | Chernihiv | Ukraine | 14034 | |
| 371 | Local Institution | Dnipropetrovsk | Ukraine | 49000 | |
| 372 | Local Institution | Donetsk | Ukraine | 83045 | |
| 373 | Local Institution | Ivano-Frankivsk | Ukraine | 76008 | |
| 374 | Local Institution | Ivano-Frankivsk | Ukraine | 76018 | |
| 375 | Local Institution | Kharkiv | Ukraine | 61018 | |
| 376 | Local Institution | Kyiv | Ukraine | 03680 | |
| 377 | Local Institution | Lviv | Ukraine | 79010 | |
| 378 | Local Institution | Odesa | Ukraine | 65117 | |
| 379 | Local Institution | Ternopil | Ukraine | 46000 | |
| 380 | Local Institution | Vinnytsia | Ukraine | 21018 | |
| 381 | Local Institution | Zaporizhzhia | Ukraine | 69035 | |
| 382 | Local Institution | Livingston | West Lothian | United Kingdom | EH54 7BH |
Sponsors and Collaborators
- Bristol-Myers Squibb
- Pfizer
Investigators
- Study Director: Bristol-Myers Squibb, Bristol-Myers Squibb
Study Documents (Full-Text)
None provided.More Information
Additional Information:
Publications
None provided.Responsible Party:
Bristol-Myers Squibb
ClinicalTrials.gov Identifier:
NCT00643201
Other Study ID Numbers:
- CV185-056
- EUDRACT: 2007-007867-25
First Posted:
Mar 26, 2008
Last Update Posted:
Apr 21, 2014
Last Verified:
Apr 1, 2014
Additional relevant MeSH terms:
Study Results
Participant Flow
| Recruitment Details | First participant, first visit: 27 August 2008; Last participant, last visit: 12 March 2013. |
|---|---|
| Pre-assignment Detail | 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. |
| Arm/Group Title | Apixaban | Enoxaparin + Warfarin |
|---|---|---|
| Arm/Group Description | 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: 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 |
| Period Title: Randomized, Completed 6 Months of Study | ||
| STARTED | 2691 | 2704 |
| COMPLETED | 2314 | 2291 |
| NOT COMPLETED | 377 | 413 |
| Period Title: Randomized, Completed 6 Months of Study | ||
| STARTED | 2617 | 2639 |
| COMPLETED | 2547 | 2560 |
| NOT COMPLETED | 70 | 79 |
Baseline Characteristics
| Arm/Group Title | Apixaban | Enoxaparin + Warfarin | Total |
|---|---|---|---|
| Arm/Group Description | 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: 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 of all reporting groups |
| Overall Participants | 2691 | 2704 | 5395 |
| Age (years) [Mean (Standard Deviation) ] | |||
| Mean (Standard Deviation) [years] |
57.2
(15.98)
|
56.7
(16.01)
|
56.9
(16.00)
|
| Age, Customized (participants) [Number] | |||
| Less than (<) 65 |
1729
64.3%
|
1762
65.2%
|
3491
64.7%
|
| 65 to < 75 |
560
20.8%
|
570
21.1%
|
1130
20.9%
|
| Greater than, equal to (>=) 75 |
402
14.9%
|
372
13.8%
|
774
14.3%
|
| Sex: Female, Male (Count of Participants) | |||
| Female |
1122
41.7%
|
1106
40.9%
|
2228
41.3%
|
| Male |
1569
58.3%
|
1598
59.1%
|
3167
58.7%
|
| Race/Ethnicity, Customized (participants) [Number] | |||
| White |
2218
82.4%
|
2243
83%
|
4461
82.7%
|
| Black or African American |
106
3.9%
|
98
3.6%
|
204
3.8%
|
| American Indian or Alaska Native |
6
0.2%
|
2
0.1%
|
8
0.1%
|
| Asian |
227
8.4%
|
226
8.4%
|
453
8.4%
|
| Other Race |
89
3.3%
|
85
3.1%
|
174
3.2%
|
| Race Not Reported |
45
1.7%
|
50
1.8%
|
95
1.8%
|
| Hispanic or Latino |
20
0.7%
|
18
0.7%
|
38
0.7%
|
| Not Hispanic or Latino |
367
13.6%
|
380
14.1%
|
747
13.8%
|
| Ethnicity Not Reported |
2304
85.6%
|
2306
85.3%
|
4610
85.4%
|
| Region of Enrollment (participants) [Number] | |||
| Portugal |
10
0.4%
|
9
0.3%
|
19
0.4%
|
| United States |
387
14.4%
|
398
14.7%
|
785
14.6%
|
| Hong Kong |
2
0.1%
|
1
0%
|
3
0.1%
|
| Spain |
56
2.1%
|
51
1.9%
|
107
2%
|
| Ukraine |
213
7.9%
|
211
7.8%
|
424
7.9%
|
| Israel |
162
6%
|
163
6%
|
325
6%
|
| Russian Federation |
178
6.6%
|
174
6.4%
|
352
6.5%
|
| Italy |
167
6.2%
|
169
6.3%
|
336
6.2%
|
| India |
101
3.8%
|
99
3.7%
|
200
3.7%
|
| France |
140
5.2%
|
149
5.5%
|
289
5.4%
|
| Malaysia |
0
0%
|
2
0.1%
|
2
0%
|
| Australia |
56
2.1%
|
64
2.4%
|
120
2.2%
|
| Denmark |
69
2.6%
|
72
2.7%
|
141
2.6%
|
| South Africa |
70
2.6%
|
77
2.8%
|
147
2.7%
|
| China |
113
4.2%
|
114
4.2%
|
227
4.2%
|
| Korea, Republic of |
2
0.1%
|
2
0.1%
|
4
0.1%
|
| Austria |
40
1.5%
|
39
1.4%
|
79
1.5%
|
| Czech Republic |
140
5.2%
|
134
5%
|
274
5.1%
|
| Hungary |
145
5.4%
|
128
4.7%
|
273
5.1%
|
| Mexico |
59
2.2%
|
57
2.1%
|
116
2.2%
|
| Canada |
147
5.5%
|
152
5.6%
|
299
5.5%
|
| Argentina |
17
0.6%
|
16
0.6%
|
33
0.6%
|
| Poland |
60
2.2%
|
59
2.2%
|
119
2.2%
|
| Brazil |
77
2.9%
|
81
3%
|
158
2.9%
|
| Singapore |
5
0.2%
|
5
0.2%
|
10
0.2%
|
| Romania |
33
1.2%
|
41
1.5%
|
74
1.4%
|
| Norway |
40
1.5%
|
32
1.2%
|
72
1.3%
|
| Germany |
202
7.5%
|
205
7.6%
|
407
7.5%
|
| Qualifying index Venous Thromboembolic Embolism (participants) [Number] | |||
| Provoked Index VTE |
272
10.1%
|
272
10.1%
|
544
10.1%
|
| Unprovoked Index VTE |
2416
89.8%
|
2429
89.8%
|
4845
89.8%
|
| Not Reported |
3
0.1%
|
3
0.1%
|
6
0.1%
|
| Index Event Classification (participants) [Number] | |||
| Proximal DVT |
1778
66.1%
|
1814
67.1%
|
3592
66.6%
|
| PE |
913
33.9%
|
890
32.9%
|
1803
33.4%
|
| Adjudicated Proximal DVT |
1749
65%
|
1783
65.9%
|
3532
65.5%
|
| Adjudicated PE |
930
34.6%
|
906
33.5%
|
1836
34%
|
Outcome Measures
| Title | Incidence of Adjudicated Composite of Symptomatic, Recurrent Venous Thromboembolism (VTE) or VTE-Related Death During 6 Months of Treatment |
|---|---|
| Description | 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). |
| Time Frame | Day 1 to Week 24 + 2 Days or 355 days (Discontinued Early) |
Outcome Measure Data
| Analysis Population Description |
|---|
| 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. |
| Arm/Group Title | Apixaban | Enoxaparin + Warfarin |
|---|---|---|
| Arm/Group Description | 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: 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 |
| Measure Participants | 2609 | 2635 |
| Number (95% Confidence Interval) [proportion of participants] |
0.0226
0%
|
0.0269
0%
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Apixaban, Enoxaparin + Warfarin |
|---|---|---|
| Comments | Hypothesis that apixaban was non-inferior to enoxaparin/warfarin therapy in preventing the recurrence of VTE (nonfatal DVT or nonfatal PE)/VTE-related death. | |
| Type of Statistical Test | Non-Inferiority or Equivalence | |
| Comments | Statistical Testing: non-inferiority tested at 1-sided α=0.025 with margin of 1.8. Demonstration of non-inferiority using both relative risk (RR) (margin = 1.8) and risk difference (RD) (margin = 0.035) were required to achieve the primary objective. | |
| Statistical Test of Hypothesis | p-Value | <0.0001 |
| Comments | This is the first test in a sequential testing sequence. p-value calculated based on the Yanagawa-Tango-Hiejima test stratified by index event strata for non-inferiority. Tested at 1-sided α=0.025 | |
| Method | Yanagawa-Tango-Hiejima | |
| Comments | For a successful trial; rejection of the null hypotheses for both RR and RD was required. | |
| Method of Estimation | Estimation Parameter | Risk Ratio (RR) |
| Estimated Value | 0.8390 | |
| Confidence Interval |
(2-Sided) 95% 0.5965 to 1.1802 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
Statistical Analysis 2
| Statistical Analysis Overview | Comparison Group Selection | Apixaban, Enoxaparin + Warfarin |
|---|---|---|
| Comments | Hypothesis that apixaban was non-inferior to enoxaparin/warfarin therapy in preventing the recurrence of VTE (nonfatal DVT or nonfatalPE)/VTE-related death as measured by risk difference. | |
| Type of Statistical Test | Non-Inferiority or Equivalence | |
| Comments | Statistical Testing; non-inferiority tested at 1-sided α=0.025. If non-inferiority demonstrated for both RR and RD, the primary objective was achieved. | |
| Statistical Test of Hypothesis | p-Value | <0.0001 |
| Comments | Yanagawa-Tango-Hiejima test statistic for risk difference (RD). | |
| Method | Yanagawa-Tango-Hiejima | |
| Comments | ||
| Method of Estimation | Estimation Parameter | Risk Difference (RD) |
| Estimated Value | -0.0044 | |
| Confidence Interval |
(2-Sided) 95% -0.0128 to 0.0040 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
Statistical Analysis 3
| Statistical Analysis Overview | Comparison Group Selection | Apixaban, Enoxaparin + Warfarin |
|---|---|---|
| Comments | Hypothesis of apixaban therapy being superior to enoxaparin/warfarin therapy for the adjudicated endpoint. Inferential testing required demonstration of non-inferiority using both RR and RD plus demonstration of superiority for major bleeding. | |
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.3128 |
| Comments | Tested at 2-sided α=0.05 significance. Further inferential statistical testing halted due to failure to reject the null hypothesis of equivalence for VTE/VTE-related death. | |
| Method | Cochran-Mantel-Haenszel | |
| Comments | Relative risk, CI, and p-value were calculated based on CMH test stratified by index event strata. | |
| Method of Estimation | Estimation Parameter | Risk Ratio (RR) |
| Estimated Value | 0.8390 | |
| Confidence Interval |
(2-Sided) 95% 0.5965 to 1.1802 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
| Title | Incidence of Adjudicated Composite of Recurrent Symptomatic Venous Thromboembolism (VTE) or All-Cause Death |
|---|---|
| Description | 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. |
| Time Frame | Day 1 up to 24 Weeks + 2 Days or 355 Days (Discontinued Early) |
Outcome Measure Data
| Analysis Population Description |
|---|
| 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. |
| Arm/Group Title | Apixaban | Enoxaparin + Warfarin |
|---|---|---|
| Arm/Group Description | 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: 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 |
| Measure Participants | 2609 | 2635 |
| Number (95% Confidence Interval) [proportion of participants] |
0.0322
0%
|
0.0395
0%
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Apixaban, Enoxaparin + Warfarin |
|---|---|---|
| Comments | Exploratory hypothesis of apixaban therapy being superior to enoxaparin/warfarin therapy for the adjudicated endpoint. | |
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.1554 |
| Comments | The test was stratified by index event strata using alpha=0.05 level of significance. Analysis was performed on the secondary efficacy dataset; there was no imputation of missing data. | |
| Method | Cochran-Mantel-Haenszel | |
| Comments | Nominal p-value is reported. | |
| Method of Estimation | Estimation Parameter | Risk Ratio (RR) |
| Estimated Value | 0.8151 | |
| Confidence Interval |
(2-Sided) 95% 0.6146 to 1.0812 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
| Title | Incidence of Adjudicated Composite of Recurrent Symptomatic VTE or Cardiovascular (CV)-Related Death |
|---|---|
| Description | 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) |
Outcome Measure Data
| Analysis Population Description |
|---|
| 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. |
| Arm/Group Title | Apixaban | Enoxaparin + Warfarin |
|---|---|---|
| Arm/Group Description | 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: 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 |
| Measure Participants | 2609 | 2635 |
| Number (95% Confidence Interval) [proportion of participants] |
0.0234
0%
|
0.0292
0%
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Apixaban, Enoxaparin + Warfarin |
|---|---|---|
| Comments | Exploratory hypothesis of apixaban therapy being superior to enoxaparin/warfarin therapy for the adjudicated endpoint. | |
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.1848 |
| Comments | The test was stratified by index event strata using alpha=0.05 level of significance. . Nominal p-value is reported. | |
| Method | Cochran-Mantel-Haenszel | |
| Comments | Analysis was performed on the secondary efficacy dataset; there was no imputation of missing data. | |
| Method of Estimation | Estimation Parameter | Risk Ratio (RR) |
| Estimated Value | 0.7994 | |
| Confidence Interval |
(2-Sided) 95% 0.5737 to 1.1137 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
| Title | Incidence of Adjudicated Composite of Recurrent Symptomatic VTE or VTE-related Death or Major Bleeding |
|---|---|
| Description | 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) |
Outcome Measure Data
| Analysis Population Description |
|---|
| 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. |
| Arm/Group Title | Apixaban | Enoxaparin + Warfarin |
|---|---|---|
| Arm/Group Description | 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: 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 |
| Measure Participants | 2610 | 2635 |
| Number (95% Confidence Interval) [proportion of participants] |
0.0280
0%
|
0.0448
0%
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Apixaban, Enoxaparin + Warfarin |
|---|---|---|
| Comments | Exploratory hypothesis of apixaban therapy being superior to enoxaparin/warfarin therapy for the adjudicated endpoint. | |
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.0011 |
| Comments | The test was stratified by index event strata using alpha=0.05 level of significance. Nominal p-value is reported. | |
| Method | Cochran-Mantel-Haenszel | |
| Comments | ||
| Method of Estimation | Estimation Parameter | Risk Ratio (RR) |
| Estimated Value | 0.6236 | |
| Confidence Interval |
(2-Sided) 95% 0.4682 to 0.8306 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
| Title | Incidence of Adjudicated Composite of Recurrent Symptomatic VTE, Myocardial Infarction, Stroke, CV-related Death, Clinically Relevant Non-major (CRNM) Bleeding or Major Bleeding |
|---|---|
| Description | 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) |
Outcome Measure Data
| Analysis Population Description |
|---|
| 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. |
| Arm/Group Title | Apixaban | Enoxaparin + Warfarin |
|---|---|---|
| Arm/Group Description | 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: 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 |
| Measure Participants | 2617 | 2641 |
| Number (95% Confidence Interval) [proportion of participants] |
0.0699
0%
|
0.1261
0%
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Apixaban, Enoxaparin + Warfarin |
|---|---|---|
| Comments | Exploratory hypothesis of apixaban therapy being superior to enoxaparin/warfarin therapy for the adjudicated endpoint. | |
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | <0.0001 |
| Comments | The test was stratified by index event strata using alpha=0.05 level of significance. Nominal p-value is reported. | |
| Method | Cochran-Mantel-Haenszel | |
| Comments | ||
| Method of Estimation | Estimation Parameter | Risk Ratio (RR) |
| Estimated Value | 0.5532 | |
| Confidence Interval |
(2-Sided) 95% 0.4658 to 0.6569 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
| Title | Incidence of Adjudicated Symptomatic Nonfatal Deep Vein Thrombosis (DVT) During the Intended Treatment Period |
|---|---|
| Description | 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) |
Outcome Measure Data
| Analysis Population Description |
|---|
| 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. |
| Arm/Group Title | Apixaban | Enoxaparin + Warfarin |
|---|---|---|
| Arm/Group Description | 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: 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 |
| Measure Participants | 2608 | 2633 |
| Number (95% Confidence Interval) [proportion of participants] |
0.0084
0%
|
0.0133
0%
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Apixaban, Enoxaparin + Warfarin |
|---|---|---|
| Comments | Exploratory hypothesis of apixaban therapy being superior to enoxaparin/warfarin therapy for the adjudicated endpoint. | |
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Risk Ratio (RR) |
| Estimated Value | 0.6347 | |
| Confidence Interval |
(2-Sided) 95% 0.3735 to 1.0787 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | Relative Risk and CI was calculated based on CMH test stratified by index event strata. | |
| Title | Incidence of Adjudicated Symptomatic Nonfatal Pulmonary Embolism (PE) During the Intended Treatment Period |
|---|---|
| Description | 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) |
Outcome Measure Data
| Analysis Population Description |
|---|
| 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. |
| Arm/Group Title | Apixaban | Enoxaparin + Warfarin |
|---|---|---|
| Arm/Group Description | 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: 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 |
| Measure Participants | 2606 | 2632 |
| Number (95% Confidence Interval) [proportion of participants] |
0.0104
0%
|
0.0095
0%
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Apixaban, Enoxaparin + Warfarin |
|---|---|---|
| Comments | Exploratory hypothesis of apixaban therapy being superior to enoxaparin/warfarin therapy for the adjudicated endpoint. | |
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Risk Ratio (RR) |
| Estimated Value | 1.0935 | |
| Confidence Interval |
(2-Sided) 95% 0.6363 to 1.8793 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | Relative Risk and CI was calculated based on CMH test stratified by index event strata. | |
| Title | Incidence of Adjudicated Venous Thromboembolism (VTE)-Related Death During the Intended Treatment Period |
|---|---|
| Description | 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) |
Outcome Measure Data
| Analysis Population Description |
|---|
| 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. |
| Arm/Group Title | Apixaban | Enoxaparin + Warfarin |
|---|---|---|
| Arm/Group Description | 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: 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 |
| Measure Participants | 2608 | 2630 |
| Number (95% Confidence Interval) [proportion of participants] |
0.0046
0%
|
0.0061
0%
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Apixaban, Enoxaparin + Warfarin |
|---|---|---|
| Comments | Exploratory hypothesis of apixaban therapy being superior to enoxaparin/warfarin therapy for the adjudicated endpoint. | |
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Risk Ratio (RR) |
| Estimated Value | 0.7521 | |
| Confidence Interval |
(2-Sided) 95% 0.3560 to 1.5889 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | Relative Risk and CI was calculated based on CMH test stratified by index event strata. | |
| Title | Incidence of Cardiovascular (CV)-Related Death Including VTE-related Death During the Intended Treatment Period |
|---|---|
| Description | 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) |
Outcome Measure Data
| Analysis Population Description |
|---|
| 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. |
| Arm/Group Title | Apixaban | Enoxaparin + Warfarin |
|---|---|---|
| Arm/Group Description | 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: 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 |
| Measure Participants | 2608 | 2630 |
| Number (95% Confidence Interval) [proportion of participants] |
0.0058
0%
|
0.0087
0%
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Apixaban, Enoxaparin + Warfarin |
|---|---|---|
| Comments | Exploratory hypothesis of apixaban therapy being superior to enoxaparin/warfarin therapy for the adjudicated endpoint. | |
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Risk Ratio (RR) |
| Estimated Value | 0.6539 | |
| Confidence Interval |
(2-Sided) 95% 0.3419 to 1.2508 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | Relative Risk and CI was calculated based on CMH test stratified by index event strata. | |
| Title | Incidence of All-Cause Death During the Intended Treatment Period |
|---|---|
| Description | 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) |
Outcome Measure Data
| Analysis Population Description |
|---|
| 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. |
| Arm/Group Title | Apixaban | Enoxaparin + Warfarin |
|---|---|---|
| Arm/Group Description | 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: 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 |
| Measure Participants | 2608 | 2630 |
| Number (95% Confidence Interval) [proportion of participants] |
0.0157
0%
|
0.0198
0%
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Apixaban, Enoxaparin + Warfarin |
|---|---|---|
| Comments | Exploratory hypothesis of apixaban therapy being superior to enoxaparin/warfarin therapy for the adjudicated endpoint. | |
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Risk Ratio (RR) |
| Estimated Value | 0.7934 | |
| Confidence Interval |
(2-Sided) 95% 0.5287 to 1.1906 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | Relative Risk and CI was calculated based on CMH test stratified by index event strata. | |
| Title | Incidence of Adjudicated Major Bleeding During the Treatment Period in Treated Participants |
|---|---|
| Description | 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) |
Outcome Measure Data
| Analysis Population Description |
|---|
| 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. |
| Arm/Group Title | Apixaban | Enoxaparin + Warfarin |
|---|---|---|
| Arm/Group Description | 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: 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 |
| Measure Participants | 2676 | 2689 |
| Number (95% Confidence Interval) [proportion of participants] |
0.0056
0%
|
0.0182
0%
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Apixaban, Enoxaparin + Warfarin |
|---|---|---|
| Comments | Hypothesis: apixaban therapy being superior to enoxaparin/warfarin therapy for the adjudicated endpoint. As per the hierarchical statistical testing cascade, inferential testing for adjudicated major bleeding occurred because non-inferiority for VTE/VTE-related death (Primary efficacy endpoint) was demonstrated earlier. Rejection of the null hypothesis for equivalence for major bleeding allowed inferential testing for superiority of VTE/VTE-related death. | |
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | <0.0001 |
| Comments | p-value calculated on the CMH test stratified by index event strata. | |
| Method | Cochran-Mantel-Haenszel | |
| Comments | ||
| Method of Estimation | Estimation Parameter | Risk Ratio (RR) |
| Estimated Value | 0.3070 | |
| Confidence Interval |
(2-Sided) 95% 0.1728 to 0.5452 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | Relative risk and CI were calculated based on CMH test stratified by index event strata. | |
| Title | Incidence of Adjudicated Major/CRNM Bleeding During the Treatment Period in Treated Participants |
|---|---|
| Description | 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) |
Outcome Measure Data
| Analysis Population Description |
|---|
| 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. |
| Arm/Group Title | Apixaban | Enoxaparin + Warfarin |
|---|---|---|
| Arm/Group Description | 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: 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 |
| Measure Participants | 2676 | 2689 |
| Number (95% Confidence Interval) [proportion of participants] |
0.0430
0%
|
0.0971
0%
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Apixaban, Enoxaparin + Warfarin |
|---|---|---|
| Comments | Exploratory hypothesis of apixaban therapy being superior to enoxaparin/warfarin therapy for the adjudicated endpoint. Inferential testing was not conducted because the null hypothesis pertaining to superiority for VTE/VTE-related death was not rejected. | |
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | <0.0001 |
| Comments | Tested at 2-sided alpha=0.05 significance. | |
| Method | Cochran-Mantel-Haenszel | |
| Comments | Nominal p-value is reported. | |
| Method of Estimation | Estimation Parameter | Risk Ratio (RR) |
| Estimated Value | 0.4410 | |
| Confidence Interval |
(2-Sided) 95% 0.3566 to 0.5453 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | Relative Risk and CI was calculated based on CMH test stratified by index event strata. | |
| Title | Incidence of Adjudicated Clinically Relevant Non Major (CRNM) Bleeding During the Treatment Period in Treated Participants |
|---|---|
| Description | 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) |
Outcome Measure Data
| Analysis Population Description |
|---|
| 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. |
| Arm/Group Title | Apixaban | Enoxaparin + Warfarin |
|---|---|---|
| Arm/Group Description | 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: 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 |
| Measure Participants | 2676 | 2689 |
| Number (95% Confidence Interval) [proportion of participants] |
0.0385
0%
|
0.0800
0%
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Apixaban, Enoxaparin + Warfarin |
|---|---|---|
| Comments | Exploratory hypothesis of apixaban therapy being superior to enoxaparin/warfarin therapy for the adjudicated endpoint. | |
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | <0.0001 |
| Comments | Tested at 2-sided alpha=0.05 significance. | |
| Method | Cochran-Mantel-Haenszel | |
| Comments | Nominal p-value is reported. | |
| Method of Estimation | Estimation Parameter | Risk Ratio (RR) |
| Estimated Value | 0.4793 | |
| Confidence Interval |
(2-Sided) 95% 0.3815 to 0.6022 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | Relative Risk and CI was calculated based on CMH test stratified by index event strata. | |
| Title | Incidence of Adjudicated Minor Bleeding During the Treatment Period in Treated Participants |
|---|---|
| Description | 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) |
Outcome Measure Data
| Analysis Population Description |
|---|
| 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. |
| Arm/Group Title | Apixaban | Enoxaparin + Warfarin |
|---|---|---|
| Arm/Group Description | 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: 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 |
| Measure Participants | 2676 | 2689 |
| Number (95% Confidence Interval) [proportion of participants] |
0.1170
0%
|
0.1878
0%
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Apixaban, Enoxaparin + Warfarin |
|---|---|---|
| Comments | Exploratory hypothesis of apixaban therapy being superior to enoxaparin/warfarin therapy for the adjudicated endpoint. | |
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | <0.0001 |
| Comments | Tested at 2-sided alpha=0.05 significance. | |
| Method | Cochran-Mantel-Haenszel | |
| Comments | Nominal p-value is reported. | |
| Method of Estimation | Estimation Parameter | Risk Ratio (RR) |
| Estimated Value | 0.6182 | |
| Confidence Interval |
(2-Sided) 95% 0.5432 to 0.7034 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | Relative Risk and CI was calculated based on CMH test stratified by index event strata. | |
| Title | Incidence of Adjudicated Total Bleeding During the Treatment Period in Treated Participants |
|---|---|
| Description | 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) |
Outcome Measure Data
| Analysis Population Description |
|---|
| 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. |
| Arm/Group Title | Apixaban | Enoxaparin + Warfarin |
|---|---|---|
| Arm/Group Description | 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: 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 |
| Measure Participants | 2676 | 2689 |
| Number (95% Confidence Interval) [proportion of participants] |
0.1502
0%
|
0.2514
0%
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Apixaban, Enoxaparin + Warfarin |
|---|---|---|
| Comments | Exploratory hypothesis of apixaban therapy being superior to enoxaparin/warfarin therapy for the adjudicated endpoint. | |
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | <0.0001 |
| Comments | Tested at 2-sided alpha=0.05 significance. | |
| Method | Cochran-Mantel-Haenszel | |
| Comments | Nominal p-value is reported. | |
| Method of Estimation | Estimation Parameter | Risk Ratio (RR) |
| Estimated Value | 0.5937 | |
| Confidence Interval |
(2-Sided) 95% 0.5318 to 0.6629 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | Relative Risk and CI was calculated based on CMH test stratified by index event strata. | |
| Title | 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 |
|---|---|
| Description | 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 |
Outcome Measure Data
| Analysis Population Description |
|---|
| Total number of participants receiving at least one dose of study drug. Participants were categorized according to the actual treatment received. |
| Arm/Group Title | Apixaban | Enoxaparin + Warfarin |
|---|---|---|
| Arm/Group Description | 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: 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 |
| Measure Participants | 2676 | 2689 |
| AE |
1795
66.7%
|
1923
71.1%
|
| SAE |
417
15.5%
|
410
15.2%
|
| Bleeding AE or SAE |
415
15.4%
|
695
25.7%
|
| Discontinued Due to AE or SAE |
162
6%
|
199
7.4%
|
| Death |
37
1.4%
|
44
1.6%
|
| Title | Number of Treated Participants With Marked Abnormalities in Hematology Laboratory Tests |
|---|---|
| Description | 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) |
Outcome Measure Data
| Analysis Population Description |
|---|
| N=Treated participants who received at least one dose of study drug and had non-missing laboratory measurements. |
| Arm/Group Title | Apixaban | Enoxaparin + Warfarin |
|---|---|---|
| Arm/Group Description | 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: 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 |
| Measure Participants | 2599 | 2593 |
| Erthrocytes Low (N=2599, 2593) |
23
0.9%
|
17
0.6%
|
| Hematocrit Low (N=2588, 2587) |
26
1%
|
20
0.7%
|
| Hemoglobin Low (N=2599, 2593) |
96
3.6%
|
101
3.7%
|
| Platelet Count Low (N=2594, 2589) |
23
0.9%
|
13
0.5%
|
| Leukocytes Low (N=2528, 2519) |
41
1.5%
|
41
1.5%
|
| Leukocytes High (N=2528, 2519) |
26
1%
|
15
0.6%
|
| Absolute Basophils High (N=2594,2589) |
1
0%
|
2
0.1%
|
| Absolute Eosinophils High (N=2594,2589) |
84
3.1%
|
79
2.9%
|
| Absolute Lyphocytes Low (N=2594,2589) |
94
3.5%
|
76
2.8%
|
| Absolute Lyphocytes High (N=2594,2589) |
4
0.1%
|
3
0.1%
|
| Absolute Monocytes High (N=2594,2589) |
1
0%
|
2
0.1%
|
| Absolute Neutrophils Low (N=2594,2589) |
9
0.3%
|
20
0.7%
|
| Title | Number of Treated Participants With Marked Abnormalities in Electrolyte Laboratory Tests |
|---|---|
| Description | 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) |
Outcome Measure Data
| Analysis Population Description |
|---|
| N=Treated participants who received at least one dose of study drug and had non-missing laboratory measurements. |
| Arm/Group Title | Apixaban | Enoxaparin + Warfarin |
|---|---|---|
| Arm/Group Description | 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: 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 |
| Measure Participants | 2601 | 2596 |
| Bicarbonate Low (N=2600,2593) |
44
1.6%
|
31
1.1%
|
| Bicarbonate High (N=2600,2593) |
17
0.6%
|
11
0.4%
|
| Total Calcium Low (N=2601,2596) |
3
0.1%
|
10
0.4%
|
| Total Calcium High (N=2601,2596) |
12
0.4%
|
11
0.4%
|
| Chloride Low Total Calcium Low (N=2601,2596) |
5
0.2%
|
3
0.1%
|
| Chloride Low Total Calcium High (N=2601,2596) |
0
0%
|
1
0%
|
| Potassium Low (N=2601,2596) |
26
1%
|
22
0.8%
|
| Potassium High (N=2601,2596) |
19
0.7%
|
22
0.8%
|
| Sodium Low (N=2601,2596) |
10
0.4%
|
6
0.2%
|
| Sodium Low (N=2601,2596) |
4
0.1%
|
4
0.1%
|
| Title | Number of Treated Participants With Marked Abnormalities in Kidney and Liver Function Laboratory Tests |
|---|---|
| Description | 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) |
Outcome Measure Data
| Analysis Population Description |
|---|
| N=Treated participants who received at least one dose of study drug and had non-missing laboratory measurements. |
| Arm/Group Title | Apixaban | Enoxaparin + Warfarin |
|---|---|---|
| Arm/Group Description | 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: 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 |
| Measure Participants | 2601 | 2598 |
| BUN High (N=517, 523) |
2
0.1%
|
7
0.3%
|
| Creatinine High (N=2601, 2596) |
47
1.7%
|
37
1.4%
|
| ALT High (N=2601, 2598) |
52
1.9%
|
145
5.4%
|
| ALP High (N=2601, 2598) |
35
1.3%
|
27
1%
|
| AST High (N=2601, 2598) |
40
1.5%
|
40
1.5%
|
| Direct Bilirubin High (N=2601, 2593) |
28
1%
|
21
0.8%
|
| Total Bilirubin High (N=2601, 2597) |
8
0.3%
|
7
0.3%
|
| Title | Number of Treated Participants With Marked Abnormalities in Creatine Kinase, Uric Acid, and Total Protein Laboratory Tests |
|---|---|
| Description | 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) |
Outcome Measure Data
| Analysis Population Description |
|---|
| N=Treated participants who received at least one dose of study drug and had non-missing laboratory measurements. |
| Arm/Group Title | Apixaban | Enoxaparin + Warfarin |
|---|---|---|
| Arm/Group Description | 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: 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 |
| Measure Participants | 2601 | 2596 |
| Creatine Kinase High (N=2601, 2596) |
20
0.7%
|
24
0.9%
|
| Uric Acid High (N=2601, 2596) |
6
0.2%
|
3
0.1%
|
| Total Protein Low (N=2601, 2596) |
15
0.6%
|
16
0.6%
|
| Total Protein High (N=2601, 2596) |
0
0%
|
0
0%
|
| Title | Number of Treated Participants With Marked Abnormalities in Urinalysis Laboratory Tests |
|---|---|
| Description | 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) |
Outcome Measure Data
| Analysis Population Description |
|---|
| N=Treated participants who received at least one dose of study drug and had non-missing laboratory measurements. |
| Arm/Group Title | Apixaban | Enoxaparin + Warfarin |
|---|---|---|
| Arm/Group Description | 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: 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 |
| Measure Participants | 1685 | 1719 |
| Blood in Urine High (N=2289, 2273) |
85
3.2%
|
127
4.7%
|
| Glucose in Urine High (N=2289, 2273) |
46
1.7%
|
31
1.1%
|
| Leukocyte Esterase in Urine High (N=2289, 2273) |
105
3.9%
|
102
3.8%
|
| Protein in Urine High (N=2289, 2273) |
41
1.5%
|
50
1.8%
|
| RBC + WBC in Urine High (N=1685, 1719) |
359
13.3%
|
361
13.4%
|
| RBC in Urine High (N=1293, 1389) |
111
4.1%
|
140
5.2%
|
| WBC in Urine High (N=1354, 1361) |
274
10.2%
|
263
9.7%
|
Adverse Events
| Time Frame | Day 1 up to 24 Weeks + 2 Days or 355 Days (for those participants who discontinued early)/ | |||
|---|---|---|---|---|
| Adverse Event Reporting Description | ||||
| Arm/Group Title | Apixaban | Enoxaparin/Warfarin | ||
| Arm/Group Description | 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: 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 | ||
All Cause Mortality |
||||
| Apixaban | Enoxaparin/Warfarin | |||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | / (NaN) | / (NaN) | ||
Serious Adverse Events |
||||
| Apixaban | Enoxaparin/Warfarin | |||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 417/2676 (15.6%) | 410/2689 (15.2%) | ||
| Blood and lymphatic system disorders | ||||
| ANAEMIA | 6/2676 (0.2%) | 4/2689 (0.1%) | ||
| ANAEMIA MEGALOBLASTIC | 1/2676 (0%) | 0/2689 (0%) | ||
| ANAEMIA OF CHRONIC DISEASE | 0/2676 (0%) | 1/2689 (0%) | ||
| DISSEMINATED INTRAVASCULAR COAGULATION | 1/2676 (0%) | 1/2689 (0%) | ||
| HAEMORRHAGIC ANAEMIA | 0/2676 (0%) | 1/2689 (0%) | ||
| HILAR LYMPHADENOPATHY | 1/2676 (0%) | 0/2689 (0%) | ||
| IRON DEFICIENCY ANAEMIA | 1/2676 (0%) | 0/2689 (0%) | ||
| NEUTROPENIA | 1/2676 (0%) | 0/2689 (0%) | ||
| NORMOCHROMIC NORMOCYTIC ANAEMIA | 0/2676 (0%) | 1/2689 (0%) | ||
| SPLENIC INFARCTION | 1/2676 (0%) | 0/2689 (0%) | ||
| THROMBOCYTOPENIA | 3/2676 (0.1%) | 1/2689 (0%) | ||
| Cardiac disorders | ||||
| ACUTE MYOCARDIAL INFARCTION | 5/2676 (0.2%) | 2/2689 (0.1%) | ||
| ANGINA PECTORIS | 3/2676 (0.1%) | 1/2689 (0%) | ||
| ANGINA UNSTABLE | 1/2676 (0%) | 2/2689 (0.1%) | ||
| ATRIAL FIBRILLATION | 6/2676 (0.2%) | 7/2689 (0.3%) | ||
| ATRIAL FLUTTER | 1/2676 (0%) | 0/2689 (0%) | ||
| ATRIAL TACHYCARDIA | 1/2676 (0%) | 0/2689 (0%) | ||
| ATRIAL THROMBOSIS | 0/2676 (0%) | 1/2689 (0%) | ||
| ATRIOVENTRICULAR BLOCK | 0/2676 (0%) | 1/2689 (0%) | ||
| BRADYCARDIA | 1/2676 (0%) | 1/2689 (0%) | ||
| CARDIAC ARREST | 2/2676 (0.1%) | 1/2689 (0%) | ||
| CARDIAC FAILURE | 5/2676 (0.2%) | 8/2689 (0.3%) | ||
| CARDIAC FAILURE ACUTE | 1/2676 (0%) | 0/2689 (0%) | ||
| CARDIAC FAILURE CONGESTIVE | 5/2676 (0.2%) | 2/2689 (0.1%) | ||
| CARDIO-RESPIRATORY ARREST | 1/2676 (0%) | 0/2689 (0%) | ||
| CARDIOGENIC SHOCK | 0/2676 (0%) | 2/2689 (0.1%) | ||
| CARDIOMYOPATHY | 1/2676 (0%) | 0/2689 (0%) | ||
| CARDIOPULMONARY FAILURE | 1/2676 (0%) | 0/2689 (0%) | ||
| CORONARY ARTERY DISEASE | 1/2676 (0%) | 5/2689 (0.2%) | ||
| DILATATION VENTRICULAR | 0/2676 (0%) | 1/2689 (0%) | ||
| INTRACARDIAC THROMBUS | 1/2676 (0%) | 1/2689 (0%) | ||
| MYOCARDIAL INFARCTION | 2/2676 (0.1%) | 3/2689 (0.1%) | ||
| PALPITATIONS | 1/2676 (0%) | 0/2689 (0%) | ||
| PERICARDIAL HAEMORRHAGE | 1/2676 (0%) | 0/2689 (0%) | ||
| PERICARDITIS | 1/2676 (0%) | 0/2689 (0%) | ||
| PRINZMETAL ANGINA | 1/2676 (0%) | 0/2689 (0%) | ||
| RIGHT VENTRICULAR DYSFUNCTION | 0/2676 (0%) | 1/2689 (0%) | ||
| SUPRAVENTRICULAR TACHYCARDIA | 2/2676 (0.1%) | 0/2689 (0%) | ||
| TACHYCARDIA | 0/2676 (0%) | 1/2689 (0%) | ||
| VENTRICULAR EXTRASYSTOLES | 0/2676 (0%) | 1/2689 (0%) | ||
| VENTRICULAR FIBRILLATION | 1/2676 (0%) | 0/2689 (0%) | ||
| VENTRICULAR HYPOKINESIA | 0/2676 (0%) | 1/2689 (0%) | ||
| Congenital, familial and genetic disorders | ||||
| SICKLE CELL ANAEMIA WITH CRISIS | 0/2676 (0%) | 1/2689 (0%) | ||
| Ear and labyrinth disorders | ||||
| INNER EAR DISORDER | 1/2676 (0%) | 0/2689 (0%) | ||
| VERTIGO | 1/2676 (0%) | 0/2689 (0%) | ||
| Eye disorders | ||||
| CONJUNCTIVITIS | 0/2676 (0%) | 1/2689 (0%) | ||
| RETINAL HAEMORRHAGE | 0/2676 (0%) | 1/2689 (0%) | ||
| Gastrointestinal disorders | ||||
| ABDOMINAL DISTENSION | 1/2676 (0%) | 0/2689 (0%) | ||
| ABDOMINAL PAIN | 4/2676 (0.1%) | 2/2689 (0.1%) | ||
| ABDOMINAL PAIN LOWER | 1/2676 (0%) | 0/2689 (0%) | ||
| ABDOMINAL PAIN UPPER | 0/2676 (0%) | 1/2689 (0%) | ||
| ABDOMINAL WALL HAEMATOMA | 1/2676 (0%) | 2/2689 (0.1%) | ||
| ABDOMINAL WALL HAEMORRHAGE | 0/2676 (0%) | 1/2689 (0%) | ||
| ASCITES | 0/2676 (0%) | 1/2689 (0%) | ||
| COLITIS | 1/2676 (0%) | 0/2689 (0%) | ||
| COLONIC POLYP | 1/2676 (0%) | 1/2689 (0%) | ||
| CONSTIPATION | 1/2676 (0%) | 0/2689 (0%) | ||
| DIAPHRAGMATIC HERNIA | 0/2676 (0%) | 1/2689 (0%) | ||
| DIVERTICULUM | 0/2676 (0%) | 1/2689 (0%) | ||
| DUODENAL ULCER HAEMORRHAGE | 0/2676 (0%) | 2/2689 (0.1%) | ||
| DUODENITIS | 0/2676 (0%) | 1/2689 (0%) | ||
| DUODENOGASTRIC REFLUX | 0/2676 (0%) | 1/2689 (0%) | ||
| DYSPEPSIA | 1/2676 (0%) | 1/2689 (0%) | ||
| DYSPHAGIA | 0/2676 (0%) | 1/2689 (0%) | ||
| ENTERITIS | 1/2676 (0%) | 0/2689 (0%) | ||
| FLATULENCE | 0/2676 (0%) | 1/2689 (0%) | ||
| GASTRIC HAEMORRHAGE | 1/2676 (0%) | 0/2689 (0%) | ||
| GASTRIC POLYPS | 0/2676 (0%) | 1/2689 (0%) | ||
| GASTRIC ULCER HAEMORRHAGE | 1/2676 (0%) | 0/2689 (0%) | ||
| GASTRITIS | 0/2676 (0%) | 2/2689 (0.1%) | ||
| GASTRITIS EROSIVE | 0/2676 (0%) | 1/2689 (0%) | ||
| GASTROINTESTINAL HAEMORRHAGE | 8/2676 (0.3%) | 14/2689 (0.5%) | ||
| GASTROINTESTINAL HYPOMOTILITY | 0/2676 (0%) | 1/2689 (0%) | ||
| GASTROINTESTINAL ULCER HAEMORRHAGE | 0/2676 (0%) | 1/2689 (0%) | ||
| GASTROLITHIASIS | 1/2676 (0%) | 0/2689 (0%) | ||
| GINGIVAL BLEEDING | 0/2676 (0%) | 1/2689 (0%) | ||
| HAEMATEMESIS | 1/2676 (0%) | 1/2689 (0%) | ||
| HAEMATOCHEZIA | 2/2676 (0.1%) | 0/2689 (0%) | ||
| HAEMORRHOIDAL HAEMORRHAGE | 0/2676 (0%) | 1/2689 (0%) | ||
| HAEMORRHOIDS | 1/2676 (0%) | 1/2689 (0%) | ||
| ILEUS PARALYTIC | 0/2676 (0%) | 1/2689 (0%) | ||
| INTESTINAL ISCHAEMIA | 1/2676 (0%) | 0/2689 (0%) | ||
| INTESTINAL OBSTRUCTION | 1/2676 (0%) | 2/2689 (0.1%) | ||
| IRRITABLE BOWEL SYNDROME | 1/2676 (0%) | 0/2689 (0%) | ||
| LOWER GASTROINTESTINAL HAEMORRHAGE | 0/2676 (0%) | 2/2689 (0.1%) | ||
| MALLORY-WEISS SYNDROME | 0/2676 (0%) | 1/2689 (0%) | ||
| MELAENA | 1/2676 (0%) | 1/2689 (0%) | ||
| NAUSEA | 0/2676 (0%) | 1/2689 (0%) | ||
| NEUTROPENIC COLITIS | 0/2676 (0%) | 1/2689 (0%) | ||
| OESOPHAGITIS | 0/2676 (0%) | 1/2689 (0%) | ||
| PANCREATITIS | 1/2676 (0%) | 0/2689 (0%) | ||
| PANCREATITIS ACUTE | 1/2676 (0%) | 0/2689 (0%) | ||
| PANCREATITIS RELAPSING | 0/2676 (0%) | 1/2689 (0%) | ||
| PERITONEAL CYST | 0/2676 (0%) | 1/2689 (0%) | ||
| RECTAL HAEMORRHAGE | 2/2676 (0.1%) | 3/2689 (0.1%) | ||
| RETROPERITONEAL HAEMORRHAGE | 0/2676 (0%) | 1/2689 (0%) | ||
| SMALL INTESTINAL OBSTRUCTION | 1/2676 (0%) | 0/2689 (0%) | ||
| TONGUE OEDEMA | 1/2676 (0%) | 0/2689 (0%) | ||
| UMBILICAL HERNIA | 1/2676 (0%) | 0/2689 (0%) | ||
| UMBILICAL HERNIA, OBSTRUCTIVE | 1/2676 (0%) | 0/2689 (0%) | ||
| UPPER GASTROINTESTINAL HAEMORRHAGE | 0/2676 (0%) | 1/2689 (0%) | ||
| VOMITING | 0/2676 (0%) | 1/2689 (0%) | ||
| General disorders | ||||
| ASTHENIA | 1/2676 (0%) | 2/2689 (0.1%) | ||
| AXILLARY PAIN | 1/2676 (0%) | 0/2689 (0%) | ||
| CHEST PAIN | 3/2676 (0.1%) | 4/2689 (0.1%) | ||
| DEATH | 4/2676 (0.1%) | 2/2689 (0.1%) | ||
| DEVICE OCCLUSION | 1/2676 (0%) | 0/2689 (0%) | ||
| HERNIA OBSTRUCTIVE | 1/2676 (0%) | 0/2689 (0%) | ||
| MULTI-ORGAN DISORDER | 1/2676 (0%) | 0/2689 (0%) | ||
| MULTI-ORGAN FAILURE | 3/2676 (0.1%) | 1/2689 (0%) | ||
| NON-CARDIAC CHEST PAIN | 9/2676 (0.3%) | 6/2689 (0.2%) | ||
| OEDEMA PERIPHERAL | 3/2676 (0.1%) | 3/2689 (0.1%) | ||
| PELVIC MASS | 0/2676 (0%) | 1/2689 (0%) | ||
| PYREXIA | 4/2676 (0.1%) | 1/2689 (0%) | ||
| SYSTEMIC INFLAMMATORY RESPONSE SYNDROME | 1/2676 (0%) | 0/2689 (0%) | ||
| Hepatobiliary disorders | ||||
| CHOLECYSTITIS | 2/2676 (0.1%) | 3/2689 (0.1%) | ||
| CHOLECYSTITIS ACUTE | 2/2676 (0.1%) | 0/2689 (0%) | ||
| CHOLELITHIASIS | 2/2676 (0.1%) | 2/2689 (0.1%) | ||
| CHOLESTASIS | 0/2676 (0%) | 1/2689 (0%) | ||
| DRUG-INDUCED LIVER INJURY | 0/2676 (0%) | 1/2689 (0%) | ||
| HEPATIC CYST | 1/2676 (0%) | 0/2689 (0%) | ||
| HEPATIC FAILURE | 0/2676 (0%) | 2/2689 (0.1%) | ||
| HEPATIC FUNCTION ABNORMAL | 1/2676 (0%) | 0/2689 (0%) | ||
| HEPATITIS | 0/2676 (0%) | 1/2689 (0%) | ||
| JAUNDICE CHOLESTATIC | 1/2676 (0%) | 0/2689 (0%) | ||
| Immune system disorders | ||||
| ALLERGY TO ARTHROPOD BITE | 0/2676 (0%) | 1/2689 (0%) | ||
| AUTOIMMUNE DISORDER | 0/2676 (0%) | 1/2689 (0%) | ||
| BEHCET'S SYNDROME | 1/2676 (0%) | 0/2689 (0%) | ||
| DRUG HYPERSENSITIVITY | 0/2676 (0%) | 1/2689 (0%) | ||
| HYPERSENSITIVITY | 2/2676 (0.1%) | 0/2689 (0%) | ||
| Infections and infestations | ||||
| ABDOMINAL ABSCESS | 1/2676 (0%) | 0/2689 (0%) | ||
| ABDOMINAL WALL ABSCESS | 0/2676 (0%) | 1/2689 (0%) | ||
| ABSCESS INTESTINAL | 0/2676 (0%) | 1/2689 (0%) | ||
| ABSCESS LIMB | 1/2676 (0%) | 0/2689 (0%) | ||
| APPENDICITIS | 1/2676 (0%) | 0/2689 (0%) | ||
| ARTHRITIS BACTERIAL | 0/2676 (0%) | 1/2689 (0%) | ||
| BACTERAEMIA | 1/2676 (0%) | 0/2689 (0%) | ||
| BRONCHITIS | 4/2676 (0.1%) | 2/2689 (0.1%) | ||
| BRONCHITIS BACTERIAL | 1/2676 (0%) | 0/2689 (0%) | ||
| BRONCHOPNEUMONIA | 1/2676 (0%) | 3/2689 (0.1%) | ||
| CARDIAC VALVE VEGETATION | 1/2676 (0%) | 0/2689 (0%) | ||
| CELLULITIS | 6/2676 (0.2%) | 3/2689 (0.1%) | ||
| CELLULITIS ORBITAL | 1/2676 (0%) | 0/2689 (0%) | ||
| CLOSTRIDIAL INFECTION | 1/2676 (0%) | 0/2689 (0%) | ||
| CYSTITIS | 1/2676 (0%) | 0/2689 (0%) | ||
| CYTOMEGALOVIRUS COLITIS | 1/2676 (0%) | 0/2689 (0%) | ||
| DEVICE RELATED INFECTION | 0/2676 (0%) | 1/2689 (0%) | ||
| DIVERTICULITIS | 1/2676 (0%) | 2/2689 (0.1%) | ||
| ENTEROCOLITIS INFECTIOUS | 0/2676 (0%) | 1/2689 (0%) | ||
| ERYSIPELAS | 3/2676 (0.1%) | 2/2689 (0.1%) | ||
| GASTROENTERITIS | 2/2676 (0.1%) | 3/2689 (0.1%) | ||
| GENITAL HERPES | 1/2676 (0%) | 0/2689 (0%) | ||
| GROIN ABSCESS | 0/2676 (0%) | 1/2689 (0%) | ||
| HELICOBACTER GASTRITIS | 1/2676 (0%) | 0/2689 (0%) | ||
| HERPES ZOSTER | 1/2676 (0%) | 0/2689 (0%) | ||
| INFECTED SKIN ULCER | 1/2676 (0%) | 1/2689 (0%) | ||
| INFECTION | 1/2676 (0%) | 0/2689 (0%) | ||
| LOCALISED INFECTION | 1/2676 (0%) | 0/2689 (0%) | ||
| LUNG ABSCESS | 1/2676 (0%) | 0/2689 (0%) | ||
| LUNG INFECTION | 1/2676 (0%) | 0/2689 (0%) | ||
| MASTOIDITIS | 1/2676 (0%) | 0/2689 (0%) | ||
| MYCOBACTERIAL INFECTION | 1/2676 (0%) | 0/2689 (0%) | ||
| MYELITIS | 1/2676 (0%) | 0/2689 (0%) | ||
| OROPHARYNGEAL CANDIDIASIS | 1/2676 (0%) | 0/2689 (0%) | ||
| OSTEOMYELITIS | 2/2676 (0.1%) | 1/2689 (0%) | ||
| PERINEAL ABSCESS | 0/2676 (0%) | 1/2689 (0%) | ||
| PERITONITIS | 1/2676 (0%) | 0/2689 (0%) | ||
| PNEUMOCYSTIS JIROVECI PNEUMONIA | 0/2676 (0%) | 1/2689 (0%) | ||
| PNEUMONIA | 16/2676 (0.6%) | 12/2689 (0.4%) | ||
| PULMONARY TUBERCULOSIS | 0/2676 (0%) | 1/2689 (0%) | ||
| PURULENT PERICARDITIS | 0/2676 (0%) | 1/2689 (0%) | ||
| PYELONEPHRITIS | 1/2676 (0%) | 2/2689 (0.1%) | ||
| RESPIRATORY TRACT INFECTION | 2/2676 (0.1%) | 1/2689 (0%) | ||
| SEPSIS | 5/2676 (0.2%) | 5/2689 (0.2%) | ||
| SEPTIC SHOCK | 3/2676 (0.1%) | 1/2689 (0%) | ||
| STAPHYLOCOCCAL INFECTION | 0/2676 (0%) | 1/2689 (0%) | ||
| STAPHYLOCOCCAL SEPSIS | 1/2676 (0%) | 0/2689 (0%) | ||
| TONSILLITIS | 0/2676 (0%) | 1/2689 (0%) | ||
| TUBERCULOSIS | 1/2676 (0%) | 0/2689 (0%) | ||
| TULARAEMIA | 1/2676 (0%) | 0/2689 (0%) | ||
| URINARY TRACT INFECTION | 8/2676 (0.3%) | 3/2689 (0.1%) | ||
| UROSEPSIS | 4/2676 (0.1%) | 0/2689 (0%) | ||
| VIRAL INFECTION | 0/2676 (0%) | 1/2689 (0%) | ||
| VULVAL ABSCESS | 0/2676 (0%) | 1/2689 (0%) | ||
| Injury, poisoning and procedural complications | ||||
| ACCIDENTAL OVERDOSE | 2/2676 (0.1%) | 1/2689 (0%) | ||
| ANKLE FRACTURE | 0/2676 (0%) | 2/2689 (0.1%) | ||
| CERVICAL VERTEBRAL FRACTURE | 0/2676 (0%) | 1/2689 (0%) | ||
| CONTUSION | 2/2676 (0.1%) | 0/2689 (0%) | ||
| DRUG ADMINISTRATION ERROR | 1/2676 (0%) | 0/2689 (0%) | ||
| EXCORIATION | 0/2676 (0%) | 1/2689 (0%) | ||
| EXTRADURAL HAEMATOMA | 1/2676 (0%) | 0/2689 (0%) | ||
| FACE INJURY | 1/2676 (0%) | 0/2689 (0%) | ||
| FACIAL BONES FRACTURE | 0/2676 (0%) | 1/2689 (0%) | ||
| FALL | 1/2676 (0%) | 0/2689 (0%) | ||
| FEMUR FRACTURE | 0/2676 (0%) | 2/2689 (0.1%) | ||
| HEAD INJURY | 0/2676 (0%) | 1/2689 (0%) | ||
| HIP FRACTURE | 0/2676 (0%) | 1/2689 (0%) | ||
| HUMERUS FRACTURE | 1/2676 (0%) | 1/2689 (0%) | ||
| INCORRECT DOSE ADMINISTERED | 1/2676 (0%) | 0/2689 (0%) | ||
| JOINT DISLOCATION | 0/2676 (0%) | 1/2689 (0%) | ||
| LOWER LIMB FRACTURE | 1/2676 (0%) | 0/2689 (0%) | ||
| LUMBAR VERTEBRAL FRACTURE | 0/2676 (0%) | 1/2689 (0%) | ||
| MENISCUS LESION | 0/2676 (0%) | 1/2689 (0%) | ||
| OVERDOSE | 15/2676 (0.6%) | 11/2689 (0.4%) | ||
| PELVIC FRACTURE | 0/2676 (0%) | 1/2689 (0%) | ||
| PERIPHERAL ARTERIAL REOCCLUSION | 1/2676 (0%) | 0/2689 (0%) | ||
| POST PROCEDURAL HAEMORRHAGE | 2/2676 (0.1%) | 0/2689 (0%) | ||
| RADIUS FRACTURE | 0/2676 (0%) | 1/2689 (0%) | ||
| RENAL HAEMATOMA | 1/2676 (0%) | 0/2689 (0%) | ||
| SPINAL COLUMN INJURY | 0/2676 (0%) | 1/2689 (0%) | ||
| SPINAL COMPRESSION FRACTURE | 2/2676 (0.1%) | 0/2689 (0%) | ||
| SUBCUTANEOUS HAEMATOMA | 0/2676 (0%) | 2/2689 (0.1%) | ||
| SUBDURAL HAEMORRHAGE | 1/2676 (0%) | 0/2689 (0%) | ||
| TOXICITY TO VARIOUS AGENTS | 0/2676 (0%) | 1/2689 (0%) | ||
| TRAUMATIC HAEMATOMA | 0/2676 (0%) | 1/2689 (0%) | ||
| UPPER LIMB FRACTURE | 0/2676 (0%) | 1/2689 (0%) | ||
| VASCULAR PSEUDOANEURYSM | 2/2676 (0.1%) | 0/2689 (0%) | ||
| WRIST FRACTURE | 0/2676 (0%) | 1/2689 (0%) | ||
| Investigations | ||||
| ALANINE AMINOTRANSFERASE INCREASED | 1/2676 (0%) | 0/2689 (0%) | ||
| COAGULATION TIME PROLONGED | 1/2676 (0%) | 0/2689 (0%) | ||
| GAMMA-GLUTAMYLTRANSFERASE INCREASED | 0/2676 (0%) | 1/2689 (0%) | ||
| HEPATIC ENZYME INCREASED | 1/2676 (0%) | 1/2689 (0%) | ||
| INTERNATIONAL NORMALISED RATIO INCREASED | 3/2676 (0.1%) | 7/2689 (0.3%) | ||
| LIVER FUNCTION TEST ABNORMAL | 1/2676 (0%) | 0/2689 (0%) | ||
| Metabolism and nutrition disorders | ||||
| DEHYDRATION | 0/2676 (0%) | 3/2689 (0.1%) | ||
| DIABETES MELLITUS | 1/2676 (0%) | 0/2689 (0%) | ||
| FAILURE TO THRIVE | 0/2676 (0%) | 1/2689 (0%) | ||
| GOUT | 1/2676 (0%) | 0/2689 (0%) | ||
| HYPERGLYCAEMIA | 0/2676 (0%) | 2/2689 (0.1%) | ||
| HYPERKALAEMIA | 1/2676 (0%) | 0/2689 (0%) | ||
| HYPOKALAEMIA | 1/2676 (0%) | 0/2689 (0%) | ||
| HYPONATRAEMIA | 4/2676 (0.1%) | 0/2689 (0%) | ||
| Musculoskeletal and connective tissue disorders | ||||
| ARTHRALGIA | 1/2676 (0%) | 3/2689 (0.1%) | ||
| BACK PAIN | 0/2676 (0%) | 1/2689 (0%) | ||
| COSTOCHONDRITIS | 1/2676 (0%) | 1/2689 (0%) | ||
| FRACTURE MALUNION | 0/2676 (0%) | 1/2689 (0%) | ||
| GOUTY ARTHRITIS | 1/2676 (0%) | 0/2689 (0%) | ||
| GROIN PAIN | 1/2676 (0%) | 0/2689 (0%) | ||
| INTERVERTEBRAL DISC PROTRUSION | 0/2676 (0%) | 1/2689 (0%) | ||
| JOINT EFFUSION | 0/2676 (0%) | 1/2689 (0%) | ||
| LIGAMENT DISORDER | 0/2676 (0%) | 1/2689 (0%) | ||
| LIMB DISCOMFORT | 0/2676 (0%) | 1/2689 (0%) | ||
| MUSCLE HAEMORRHAGE | 1/2676 (0%) | 2/2689 (0.1%) | ||
| MUSCULOSKELETAL CHEST PAIN | 6/2676 (0.2%) | 1/2689 (0%) | ||
| MUSCULOSKELETAL PAIN | 0/2676 (0%) | 2/2689 (0.1%) | ||
| MYALGIA | 1/2676 (0%) | 0/2689 (0%) | ||
| OSTEOARTHRITIS | 1/2676 (0%) | 0/2689 (0%) | ||
| PAIN IN EXTREMITY | 5/2676 (0.2%) | 2/2689 (0.1%) | ||
| PATHOLOGICAL FRACTURE | 2/2676 (0.1%) | 0/2689 (0%) | ||
| POLYMYALGIA RHEUMATICA | 0/2676 (0%) | 1/2689 (0%) | ||
| PSEUDARTHROSIS | 0/2676 (0%) | 1/2689 (0%) | ||
| ROTATOR CUFF SYNDROME | 1/2676 (0%) | 0/2689 (0%) | ||
| SPINAL OSTEOARTHRITIS | 1/2676 (0%) | 0/2689 (0%) | ||
| SYNOVIAL CYST | 0/2676 (0%) | 1/2689 (0%) | ||
| SYSTEMIC LUPUS ERYTHEMATOSUS | 0/2676 (0%) | 1/2689 (0%) | ||
| Neoplasms benign, malignant and unspecified (incl cysts and polyps) | ||||
| ADENOCARCINOMA | 2/2676 (0.1%) | 1/2689 (0%) | ||
| BASAL CELL CARCINOMA | 1/2676 (0%) | 3/2689 (0.1%) | ||
| BENIGN OVARIAN TUMOUR | 1/2676 (0%) | 0/2689 (0%) | ||
| BILE DUCT CANCER | 3/2676 (0.1%) | 0/2689 (0%) | ||
| BLADDER CANCER | 2/2676 (0.1%) | 0/2689 (0%) | ||
| BLADDER PAPILLOMA | 1/2676 (0%) | 0/2689 (0%) | ||
| BLADDER TRANSITIONAL CELL CARCINOMA | 0/2676 (0%) | 1/2689 (0%) | ||
| BONE NEOPLASM | 0/2676 (0%) | 1/2689 (0%) | ||
| BRAIN CANCER METASTATIC | 1/2676 (0%) | 0/2689 (0%) | ||
| BREAST CANCER | 3/2676 (0.1%) | 2/2689 (0.1%) | ||
| BREAST CANCER RECURRENT | 0/2676 (0%) | 1/2689 (0%) | ||
| BRONCHIAL CARCINOMA | 2/2676 (0.1%) | 0/2689 (0%) | ||
| CERVIX CARCINOMA | 0/2676 (0%) | 1/2689 (0%) | ||
| CERVIX NEOPLASM | 0/2676 (0%) | 1/2689 (0%) | ||
| CHOLESTEATOMA | 0/2676 (0%) | 1/2689 (0%) | ||
| COLON CANCER | 2/2676 (0.1%) | 2/2689 (0.1%) | ||
| COLON CANCER METASTATIC | 2/2676 (0.1%) | 3/2689 (0.1%) | ||
| COLON NEOPLASM | 0/2676 (0%) | 1/2689 (0%) | ||
| COLORECTAL CANCER | 1/2676 (0%) | 1/2689 (0%) | ||
| ENDOCRINE NEOPLASM MALIGNANT | 1/2676 (0%) | 0/2689 (0%) | ||
| ESSENTIAL THROMBOCYTHAEMIA | 0/2676 (0%) | 1/2689 (0%) | ||
| GALLBLADDER CANCER | 1/2676 (0%) | 0/2689 (0%) | ||
| GASTRIC CANCER | 1/2676 (0%) | 0/2689 (0%) | ||
| GASTRIC CANCER RECURRENT | 0/2676 (0%) | 1/2689 (0%) | ||
| GASTROINTESTINAL CANCER METASTATIC | 0/2676 (0%) | 1/2689 (0%) | ||
| GASTROINTESTINAL CARCINOMA | 1/2676 (0%) | 0/2689 (0%) | ||
| GASTROINTESTINAL STROMAL TUMOUR | 1/2676 (0%) | 0/2689 (0%) | ||
| GASTROINTESTINAL TRACT ADENOMA | 1/2676 (0%) | 0/2689 (0%) | ||
| GLIOBLASTOMA MULTIFORME | 1/2676 (0%) | 0/2689 (0%) | ||
| HEPATIC CANCER METASTATIC | 1/2676 (0%) | 0/2689 (0%) | ||
| INTESTINAL ADENOCARCINOMA | 0/2676 (0%) | 1/2689 (0%) | ||
| LEIOMYOMA | 1/2676 (0%) | 0/2689 (0%) | ||
| LUNG ADENOCARCINOMA | 1/2676 (0%) | 0/2689 (0%) | ||
| LUNG CANCER METASTATIC | 0/2676 (0%) | 2/2689 (0.1%) | ||
| LUNG NEOPLASM MALIGNANT | 2/2676 (0.1%) | 6/2689 (0.2%) | ||
| LUNG SQUAMOUS CELL CARCINOMA STAGE UNSPECIFIED | 0/2676 (0%) | 1/2689 (0%) | ||
| LYMPHOMA | 1/2676 (0%) | 0/2689 (0%) | ||
| MALIGNANT NEOPLASM PROGRESSION | 1/2676 (0%) | 2/2689 (0.1%) | ||
| MALIGNANT PERITONEAL NEOPLASM | 1/2676 (0%) | 0/2689 (0%) | ||
| METASTASES TO ABDOMINAL CAVITY | 0/2676 (0%) | 1/2689 (0%) | ||
| METASTASES TO BONE | 1/2676 (0%) | 0/2689 (0%) | ||
| METASTASES TO CENTRAL NERVOUS SYSTEM | 0/2676 (0%) | 1/2689 (0%) | ||
| METASTASES TO LIVER | 1/2676 (0%) | 0/2689 (0%) | ||
| METASTASES TO LUNG | 2/2676 (0.1%) | 0/2689 (0%) | ||
| METASTASES TO PERITONEUM | 0/2676 (0%) | 1/2689 (0%) | ||
| METASTASIS | 1/2676 (0%) | 0/2689 (0%) | ||
| METASTATIC CARCINOMA OF THE BLADDER | 0/2676 (0%) | 1/2689 (0%) | ||
| METASTATIC NEOPLASM | 2/2676 (0.1%) | 3/2689 (0.1%) | ||
| METASTATIC RENAL CELL CARCINOMA | 1/2676 (0%) | 0/2689 (0%) | ||
| MYELODYSPLASTIC SYNDROME | 1/2676 (0%) | 0/2689 (0%) | ||
| NEOPLASM | 1/2676 (0%) | 0/2689 (0%) | ||
| NEOPLASM MALIGNANT | 2/2676 (0.1%) | 1/2689 (0%) | ||
| NEUROENDOCRINE TUMOUR | 0/2676 (0%) | 1/2689 (0%) | ||
| NON-HODGKIN'S LYMPHOMA | 0/2676 (0%) | 1/2689 (0%) | ||
| OESOPHAGEAL CANCER METASTATIC | 0/2676 (0%) | 1/2689 (0%) | ||
| ONCOCYTOMA | 0/2676 (0%) | 1/2689 (0%) | ||
| OVARIAN CANCER | 1/2676 (0%) | 1/2689 (0%) | ||
| OVARIAN CANCER METASTATIC | 0/2676 (0%) | 1/2689 (0%) | ||
| PANCREATIC CARCINOMA | 1/2676 (0%) | 4/2689 (0.1%) | ||
| PANCREATIC CARCINOMA METASTATIC | 0/2676 (0%) | 3/2689 (0.1%) | ||
| PANCREATIC CARCINOMA RECURRENT | 0/2676 (0%) | 1/2689 (0%) | ||
| PANCREATIC CARCINOMA STAGE IV | 0/2676 (0%) | 1/2689 (0%) | ||
| PANCREATIC NEUROENDOCRINE TUMOUR | 0/2676 (0%) | 1/2689 (0%) | ||
| PARAPROTEINAEMIA | 0/2676 (0%) | 1/2689 (0%) | ||
| PELVIC NEOPLASM | 1/2676 (0%) | 1/2689 (0%) | ||
| POLYCYTHAEMIA VERA | 0/2676 (0%) | 1/2689 (0%) | ||
| PROSTATE CANCER | 3/2676 (0.1%) | 3/2689 (0.1%) | ||
| PROSTATE CANCER RECURRENT | 0/2676 (0%) | 1/2689 (0%) | ||
| RECTAL CANCER | 0/2676 (0%) | 1/2689 (0%) | ||
| RECTOSIGMOID CANCER | 1/2676 (0%) | 0/2689 (0%) | ||
| RENAL CANCER | 0/2676 (0%) | 2/2689 (0.1%) | ||
| RENAL CELL CARCINOMA | 2/2676 (0.1%) | 1/2689 (0%) | ||
| SALIVARY GLAND CANCER | 0/2676 (0%) | 1/2689 (0%) | ||
| SMALL CELL LUNG CANCER METASTATIC | 0/2676 (0%) | 1/2689 (0%) | ||
| SQUAMOUS CELL CARCINOMA | 2/2676 (0.1%) | 2/2689 (0.1%) | ||
| TESTIS CANCER | 1/2676 (0%) | 0/2689 (0%) | ||
| THYROID CANCER METASTATIC | 1/2676 (0%) | 0/2689 (0%) | ||
| THYROID NEOPLASM | 1/2676 (0%) | 0/2689 (0%) | ||
| TONGUE NEOPLASM MALIGNANT STAGE UNSPECIFIED | 1/2676 (0%) | 0/2689 (0%) | ||
| TRANSITIONAL CELL CARCINOMA | 2/2676 (0.1%) | 0/2689 (0%) | ||
| TUMOUR ULCERATION | 0/2676 (0%) | 1/2689 (0%) | ||
| UTERINE CANCER | 1/2676 (0%) | 0/2689 (0%) | ||
| UTERINE LEIOMYOMA | 0/2676 (0%) | 1/2689 (0%) | ||
| Nervous system disorders | ||||
| CAROTID ARTERY STENOSIS | 0/2676 (0%) | 1/2689 (0%) | ||
| CEREBRAL HAEMORRHAGE | 2/2676 (0.1%) | 1/2689 (0%) | ||
| CEREBRAL INFARCTION | 2/2676 (0.1%) | 0/2689 (0%) | ||
| CEREBROVASCULAR ACCIDENT | 2/2676 (0.1%) | 2/2689 (0.1%) | ||
| CERVICOBRACHIAL SYNDROME | 0/2676 (0%) | 1/2689 (0%) | ||
| COMA | 1/2676 (0%) | 0/2689 (0%) | ||
| COMPLEX REGIONAL PAIN SYNDROME | 0/2676 (0%) | 1/2689 (0%) | ||
| CONVULSION | 1/2676 (0%) | 2/2689 (0.1%) | ||
| ENCEPHALOPATHY | 0/2676 (0%) | 1/2689 (0%) | ||
| GRAND MAL CONVULSION | 1/2676 (0%) | 0/2689 (0%) | ||
| HAEMORRHAGE INTRACRANIAL | 0/2676 (0%) | 1/2689 (0%) | ||
| HAEMORRHAGIC STROKE | 2/2676 (0.1%) | 1/2689 (0%) | ||
| HEADACHE | 0/2676 (0%) | 2/2689 (0.1%) | ||
| ISCHAEMIC STROKE | 5/2676 (0.2%) | 5/2689 (0.2%) | ||
| LACUNAR INFARCTION | 1/2676 (0%) | 0/2689 (0%) | ||
| MIGRAINE | 1/2676 (0%) | 0/2689 (0%) | ||
| MULTIPLE SCLEROSIS | 2/2676 (0.1%) | 0/2689 (0%) | ||
| NERVOUS SYSTEM DISORDER | 1/2676 (0%) | 1/2689 (0%) | ||
| NEURALGIA | 1/2676 (0%) | 0/2689 (0%) | ||
| NEURITIS | 1/2676 (0%) | 0/2689 (0%) | ||
| NEUROPATHY PERIPHERAL | 2/2676 (0.1%) | 0/2689 (0%) | ||
| PARAESTHESIA | 1/2676 (0%) | 0/2689 (0%) | ||
| PARAPLEGIA | 1/2676 (0%) | 0/2689 (0%) | ||
| PERONEAL NERVE PALSY | 1/2676 (0%) | 0/2689 (0%) | ||
| POLYNEUROPATHY | 1/2676 (0%) | 0/2689 (0%) | ||
| PRESYNCOPE | 0/2676 (0%) | 1/2689 (0%) | ||
| SCIATICA | 2/2676 (0.1%) | 3/2689 (0.1%) | ||
| SPINAL CORD COMPRESSION | 1/2676 (0%) | 0/2689 (0%) | ||
| SUBARACHNOID HAEMORRHAGE | 0/2676 (0%) | 2/2689 (0.1%) | ||
| SYNCOPE | 3/2676 (0.1%) | 3/2689 (0.1%) | ||
| THALAMIC INFARCTION | 1/2676 (0%) | 0/2689 (0%) | ||
| TOXIC ENCEPHALOPATHY | 1/2676 (0%) | 0/2689 (0%) | ||
| TRANSIENT ISCHAEMIC ATTACK | 2/2676 (0.1%) | 3/2689 (0.1%) | ||
| Pregnancy, puerperium and perinatal conditions | ||||
| ABORTION SPONTANEOUS | 1/2676 (0%) | 0/2689 (0%) | ||
| PREGNANCY | 5/2676 (0.2%) | 2/2689 (0.1%) | ||
| Psychiatric disorders | ||||
| ADJUSTMENT DISORDER | 0/2676 (0%) | 1/2689 (0%) | ||
| ALCOHOL ABUSE | 0/2676 (0%) | 1/2689 (0%) | ||
| ALCOHOLISM | 0/2676 (0%) | 1/2689 (0%) | ||
| ANXIETY | 3/2676 (0.1%) | 2/2689 (0.1%) | ||
| APATHY | 1/2676 (0%) | 0/2689 (0%) | ||
| BIPOLAR DISORDER | 1/2676 (0%) | 0/2689 (0%) | ||
| CONFUSIONAL STATE | 1/2676 (0%) | 1/2689 (0%) | ||
| DEPRESSION | 2/2676 (0.1%) | 3/2689 (0.1%) | ||
| DEPRESSION SUICIDAL | 1/2676 (0%) | 0/2689 (0%) | ||
| MENTAL DISORDER | 1/2676 (0%) | 0/2689 (0%) | ||
| PANIC ATTACK | 0/2676 (0%) | 2/2689 (0.1%) | ||
| SUICIDAL IDEATION | 1/2676 (0%) | 0/2689 (0%) | ||
| TIC | 1/2676 (0%) | 0/2689 (0%) | ||
| Renal and urinary disorders | ||||
| GLOMERULONEPHRITIS CHRONIC | 0/2676 (0%) | 1/2689 (0%) | ||
| GLOMERULONEPHRITIS MEMBRANOPROLIFERATIVE | 0/2676 (0%) | 1/2689 (0%) | ||
| HAEMATURIA | 5/2676 (0.2%) | 13/2689 (0.5%) | ||
| HAEMORRHAGE URINARY TRACT | 0/2676 (0%) | 1/2689 (0%) | ||
| HYDRONEPHROSIS | 0/2676 (0%) | 2/2689 (0.1%) | ||
| NEPHROLITHIASIS | 3/2676 (0.1%) | 1/2689 (0%) | ||
| OLIGURIA | 1/2676 (0%) | 0/2689 (0%) | ||
| RENAL COLIC | 0/2676 (0%) | 1/2689 (0%) | ||
| RENAL CYST HAEMORRHAGE | 0/2676 (0%) | 1/2689 (0%) | ||
| RENAL FAILURE | 3/2676 (0.1%) | 2/2689 (0.1%) | ||
| RENAL FAILURE ACUTE | 3/2676 (0.1%) | 3/2689 (0.1%) | ||
| RENAL FAILURE CHRONIC | 1/2676 (0%) | 0/2689 (0%) | ||
| RENAL IMPAIRMENT | 1/2676 (0%) | 0/2689 (0%) | ||
| URINARY BLADDER HAEMORRHAGE | 0/2676 (0%) | 1/2689 (0%) | ||
| URINARY RETENTION | 1/2676 (0%) | 0/2689 (0%) | ||
| URINARY TRACT OBSTRUCTION | 0/2676 (0%) | 1/2689 (0%) | ||
| Reproductive system and breast disorders | ||||
| ENDOMETRIAL HYPERTROPHY | 0/2676 (0%) | 1/2689 (0%) | ||
| MENORRHAGIA | 1/2676 (0%) | 0/2689 (0%) | ||
| METRORRHAGIA | 2/2676 (0.1%) | 1/2689 (0%) | ||
| OVARIAN CYST | 0/2676 (0%) | 1/2689 (0%) | ||
| UTERINE HAEMORRHAGE | 2/2676 (0.1%) | 2/2689 (0.1%) | ||
| UTERINE POLYP | 1/2676 (0%) | 0/2689 (0%) | ||
| VAGINAL HAEMORRHAGE | 1/2676 (0%) | 1/2689 (0%) | ||
| Respiratory, thoracic and mediastinal disorders | ||||
| ACUTE RESPIRATORY FAILURE | 2/2676 (0.1%) | 0/2689 (0%) | ||
| ADENOIDAL HYPERTROPHY | 0/2676 (0%) | 1/2689 (0%) | ||
| ALLERGIC GRANULOMATOUS ANGIITIS | 0/2676 (0%) | 1/2689 (0%) | ||
| ASTHMA | 6/2676 (0.2%) | 0/2689 (0%) | ||
| ASTHMATIC CRISIS | 1/2676 (0%) | 0/2689 (0%) | ||
| ATELECTASIS | 1/2676 (0%) | 0/2689 (0%) | ||
| BRONCHOSTENOSIS | 1/2676 (0%) | 0/2689 (0%) | ||
| CHRONIC OBSTRUCTIVE PULMONARY DISEASE | 9/2676 (0.3%) | 6/2689 (0.2%) | ||
| DYSPNOEA | 9/2676 (0.3%) | 5/2689 (0.2%) | ||
| EPISTAXIS | 1/2676 (0%) | 2/2689 (0.1%) | ||
| HAEMOPTYSIS | 1/2676 (0%) | 1/2689 (0%) | ||
| INTERSTITIAL LUNG DISEASE | 1/2676 (0%) | 1/2689 (0%) | ||
| LUNG CONSOLIDATION | 1/2676 (0%) | 0/2689 (0%) | ||
| PLEURAL EFFUSION | 3/2676 (0.1%) | 7/2689 (0.3%) | ||
| PLEURISY | 0/2676 (0%) | 1/2689 (0%) | ||
| PLEURITIC PAIN | 5/2676 (0.2%) | 2/2689 (0.1%) | ||
| PNEUMONIA ASPIRATION | 1/2676 (0%) | 0/2689 (0%) | ||
| PNEUMONITIS | 0/2676 (0%) | 1/2689 (0%) | ||
| PNEUMOTHORAX | 0/2676 (0%) | 3/2689 (0.1%) | ||
| PULMONARY ALVEOLAR HAEMORRHAGE | 1/2676 (0%) | 0/2689 (0%) | ||
| PULMONARY AMYLOIDOSIS | 0/2676 (0%) | 1/2689 (0%) | ||
| PULMONARY ARTERIAL HYPERTENSION | 1/2676 (0%) | 0/2689 (0%) | ||
| PULMONARY EMBOLISM | 24/2676 (0.9%) | 38/2689 (1.4%) | ||
| PULMONARY HYPERTENSION | 1/2676 (0%) | 1/2689 (0%) | ||
| PULMONARY INFARCTION | 0/2676 (0%) | 3/2689 (0.1%) | ||
| PULMONARY MASS | 1/2676 (0%) | 0/2689 (0%) | ||
| PULMONARY OEDEMA | 0/2676 (0%) | 1/2689 (0%) | ||
| RESPIRATORY DISTRESS | 1/2676 (0%) | 0/2689 (0%) | ||
| RESPIRATORY FAILURE | 2/2676 (0.1%) | 0/2689 (0%) | ||
| SLEEP APNOEA SYNDROME | 0/2676 (0%) | 1/2689 (0%) | ||
| Skin and subcutaneous tissue disorders | ||||
| CAPILLARITIS | 1/2676 (0%) | 0/2689 (0%) | ||
| CUTANEOUS VASCULITIS | 1/2676 (0%) | 0/2689 (0%) | ||
| DERMATITIS ALLERGIC | 0/2676 (0%) | 1/2689 (0%) | ||
| DIABETIC FOOT | 1/2676 (0%) | 0/2689 (0%) | ||
| DRUG ERUPTION | 1/2676 (0%) | 0/2689 (0%) | ||
| ECCHYMOSIS | 0/2676 (0%) | 1/2689 (0%) | ||
| ECZEMA | 0/2676 (0%) | 2/2689 (0.1%) | ||
| HAEMORRHAGE SUBCUTANEOUS | 0/2676 (0%) | 1/2689 (0%) | ||
| PURPURA | 1/2676 (0%) | 0/2689 (0%) | ||
| RASH | 1/2676 (0%) | 1/2689 (0%) | ||
| SKIN LESION | 0/2676 (0%) | 2/2689 (0.1%) | ||
| SKIN NECROSIS | 0/2676 (0%) | 1/2689 (0%) | ||
| SKIN ULCER | 1/2676 (0%) | 0/2689 (0%) | ||
| STASIS DERMATITIS | 1/2676 (0%) | 0/2689 (0%) | ||
| URTICARIA | 0/2676 (0%) | 1/2689 (0%) | ||
| Social circumstances | ||||
| PREGNANCY OF PARTNER | 1/2676 (0%) | 0/2689 (0%) | ||
| Vascular disorders | ||||
| ANGIODYSPLASIA | 0/2676 (0%) | 1/2689 (0%) | ||
| AORTIC ANEURYSM | 0/2676 (0%) | 1/2689 (0%) | ||
| AORTIC RUPTURE | 0/2676 (0%) | 1/2689 (0%) | ||
| ARTERIAL THROMBOSIS | 1/2676 (0%) | 0/2689 (0%) | ||
| ARTERIOSCLEROSIS | 0/2676 (0%) | 2/2689 (0.1%) | ||
| DEEP VEIN THROMBOSIS | 20/2676 (0.7%) | 33/2689 (1.2%) | ||
| EMBOLISM VENOUS | 2/2676 (0.1%) | 0/2689 (0%) | ||
| FEMORAL ARTERY ANEURYSM | 0/2676 (0%) | 1/2689 (0%) | ||
| HAEMATOMA | 1/2676 (0%) | 4/2689 (0.1%) | ||
| HYPERTENSION | 1/2676 (0%) | 1/2689 (0%) | ||
| HYPERTENSIVE CRISIS | 2/2676 (0.1%) | 0/2689 (0%) | ||
| HYPOTENSION | 0/2676 (0%) | 1/2689 (0%) | ||
| INTRA-ABDOMINAL HAEMATOMA | 0/2676 (0%) | 1/2689 (0%) | ||
| JUGULAR VEIN THROMBOSIS | 0/2676 (0%) | 1/2689 (0%) | ||
| ORTHOSTATIC HYPOTENSION | 1/2676 (0%) | 0/2689 (0%) | ||
| PERIPHERAL ARTERIAL OCCLUSIVE DISEASE | 1/2676 (0%) | 0/2689 (0%) | ||
| PERIPHERAL ARTERY ANEURYSM | 1/2676 (0%) | 0/2689 (0%) | ||
| PERIPHERAL ARTERY STENOSIS | 0/2676 (0%) | 1/2689 (0%) | ||
| PERIPHERAL ISCHAEMIA | 2/2676 (0.1%) | 1/2689 (0%) | ||
| PERIPHERAL VASCULAR DISORDER | 0/2676 (0%) | 1/2689 (0%) | ||
| SHOCK HAEMORRHAGIC | 1/2676 (0%) | 1/2689 (0%) | ||
| TEMPORAL ARTERITIS | 1/2676 (0%) | 0/2689 (0%) | ||
| THROMBOPHLEBITIS | 0/2676 (0%) | 3/2689 (0.1%) | ||
| THROMBOPHLEBITIS SUPERFICIAL | 1/2676 (0%) | 0/2689 (0%) | ||
| THROMBOSIS | 0/2676 (0%) | 2/2689 (0.1%) | ||
| VENA CAVA THROMBOSIS | 0/2676 (0%) | 1/2689 (0%) | ||
| VENOUS STENOSIS | 1/2676 (0%) | 0/2689 (0%) | ||
| VENOUS THROMBOSIS | 6/2676 (0.2%) | 0/2689 (0%) | ||
| VENOUS THROMBOSIS LIMB | 1/2676 (0%) | 0/2689 (0%) | ||
Other (Not Including Serious) Adverse Events |
||||
| Apixaban | Enoxaparin/Warfarin | |||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 1014/2676 (37.9%) | 1207/2689 (44.9%) | ||
| Gastrointestinal disorders | ||||
| CONSTIPATION | 73/2676 (2.7%) | 87/2689 (3.2%) | ||
| DIARRHOEA | 100/2676 (3.7%) | 106/2689 (3.9%) | ||
| NAUSEA | 81/2676 (3%) | 106/2689 (3.9%) | ||
| VOMITING | 50/2676 (1.9%) | 69/2689 (2.6%) | ||
| General disorders | ||||
| FATIGUE | 58/2676 (2.2%) | 50/2689 (1.9%) | ||
| OEDEMA PERIPHERAL | 93/2676 (3.5%) | 111/2689 (4.1%) | ||
| PYREXIA | 54/2676 (2%) | 56/2689 (2.1%) | ||
| Infections and infestations | ||||
| BRONCHITIS | 51/2676 (1.9%) | 56/2689 (2.1%) | ||
| NASOPHARYNGITIS | 104/2676 (3.9%) | 98/2689 (3.6%) | ||
| URINARY TRACT INFECTION | 92/2676 (3.4%) | 82/2689 (3%) | ||
| Injury, poisoning and procedural complications | ||||
| CONTUSION | 48/2676 (1.8%) | 97/2689 (3.6%) | ||
| Investigations | ||||
| ALANINE AMINOTRANSFERASE INCREASED | 30/2676 (1.1%) | 105/2689 (3.9%) | ||
| BLOOD CREATINE PHOSPHOKINASE INCREASED | 33/2676 (1.2%) | 78/2689 (2.9%) | ||
| GAMMA-GLUTAMYLTRANSFERASE INCREASED | 38/2676 (1.4%) | 56/2689 (2.1%) | ||
| Metabolism and nutrition disorders | ||||
| HYPERCHOLESTEROLAEMIA | 28/2676 (1%) | 55/2689 (2%) | ||
| Musculoskeletal and connective tissue disorders | ||||
| ARTHRALGIA | 74/2676 (2.8%) | 84/2689 (3.1%) | ||
| BACK PAIN | 80/2676 (3%) | 87/2689 (3.2%) | ||
| PAIN IN EXTREMITY | 119/2676 (4.4%) | 130/2689 (4.8%) | ||
| Nervous system disorders | ||||
| DIZZINESS | 66/2676 (2.5%) | 69/2689 (2.6%) | ||
| HEADACHE | 169/2676 (6.3%) | 167/2689 (6.2%) | ||
| Renal and urinary disorders | ||||
| HAEMATURIA | 41/2676 (1.5%) | 91/2689 (3.4%) | ||
| Respiratory, thoracic and mediastinal disorders | ||||
| COUGH | 61/2676 (2.3%) | 58/2689 (2.2%) | ||
| DYSPNOEA | 64/2676 (2.4%) | 73/2689 (2.7%) | ||
| EPISTAXIS | 77/2676 (2.9%) | 144/2689 (5.4%) | ||
| Vascular disorders | ||||
| HAEMATOMA | 34/2676 (1.3%) | 72/2689 (2.7%) | ||
| HYPERTENSION | 70/2676 (2.6%) | 68/2689 (2.5%) | ||
Limitations/Caveats
[Not Specified]
More Information
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
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.
Results Point of Contact
| Name/Title | Bristol-Myers Squibb Study Director |
|---|---|
| Organization | Bristol-Myers Squibb |
| Phone | |
| Clinical.Trials@bms.com |
Responsible Party:
Bristol-Myers Squibb
ClinicalTrials.gov Identifier:
NCT00643201
Other Study ID Numbers:
- CV185-056
- EUDRACT: 2007-007867-25
First Posted:
Mar 26, 2008
Last Update Posted:
Apr 21, 2014
Last Verified:
Apr 1, 2014