Apixaban for the Prevention of Stroke in Subjects With Atrial Fibrillation

All suspected efficacy events were adjudicated by the Central Events Committee (CEC). Diagnosis of stroke=the nontraumatic focal neurological deficit lasting at least 24 hours, and includes ischemic stroke, hemorrhagic stroke, ischemic stroke with hemorrhagic conversion, stroke of uncertain type, and retinal ischemic event (embolism, infarction). Diagnosis of SE=clinical history consistent with an acute loss of blood flow to a peripheral artery (or arteries), supported by evidence of embolism from surgical specimens, autopsy, angiography, vascular imaging, or other objective testing.

Time frame: Time to first event in Intended Treatment Period: started on day of randomization, ended at efficacy cut-off date (date target number of primary efficacy events [448] was expected to have occurred; set to 30-Jan-2011, prior to unblinding).

Population: Intention to treat analysis, randomized participants. Participants who did not experience an efficacy endpoint event were censored at the earlier of their death date (when death is not part of the endpoint), last contact date (for subjects who withdrew consent to be followed up or were lost to follow-up) or the efficacy cut-off date (30-Jan-2011).

Rate=Number of adjudicated stroke or SE events per 100 patient years. Diagnosis of stroke=the nontraumatic focal neurological deficit lasting at least 24 hours, and includes ischemic stroke, hemorrhagic stroke, ischemic stroke with hemorrhagic conversion, stroke of uncertain type, and retinal ischemic event (embolism, infarction). Diagnosis of SE=clinical history consistent with an acute loss of blood flow to a peripheral artery (or arteries), supported by evidence of embolism from surgical specimens, autopsy, angiography, vascular imaging, or other objective testing.

Time frame: Intended Treatment Period started on the day of randomization and ended at the efficacy cut-off date (date on which it was expected that the target number of primary efficacy events [448] would have occurred; set to 30-Jan-2011, prior to unblinding).

Population: Intention to treat analysis, randomized participants. Participants who did not experience an efficacy endpoint event were censored at the earlier of their death date (when death is not part of the endpoint), last contact date (for subjects who withdrew consent to be followed up or were lost to follow-up) or the efficacy cut-off date (30-Jan-2011).

All bleeding events include major bleeding, CRNM bleeding (see Outcome Measure 12 Description for definitions), plus events of minor bleeding and fatal bleeding. Minor bleeding: All acute clinically overt bleeding events not meeting the criteria for either major bleeding or clinically relevant non-major bleeding will be classified as minor bleeding. Fatal bleeding is defined as a bleeding event that the Clinical Events Committee determines is the primary cause of death or contributes directly to death.

Time frame: Treatment Period started with first dose of blinded study drug and ended 2 days after the last dose of blinded study drug. Mean duration of exposure to double-blind study drug was 1.7 years in each treatment group.

Population: Treated participants. Participants who did not experience a bleeding endpoint were censored at the earlier of 2 days after discontinuation of study drug, or death date, or last-contact date (for participants who withdrew consent to be followed up or were lost to follow-up) at the end of the study.

ISTH Bleeding Criteria: Major bleeding=a bleeding event that was: clinically overt bleeding accompanied by a decrease in hemoglobin (Hgb) of 2 g/dL or more, and/or a transfusion of 2 or more units of packed red blood cells; bleeding that occurred in at least 1 of the following critical sites: intracranial, intraspinal, intraocular (within the corpus of the eye; a conjunctival bleed is not an intraocular bleed), pericardial, intra-articular, intramuscular with compartment syndrome, and retroperitoneal; bleeding that was fatal.

Time frame: Treatment Period started with first dose of blinded study drug and ended 2 days after the last dose of blinded study drug. Mean duration of exposure to double-blind study drug was 1.7 years in each treatment group.

Population: Treated participants. Participants who did not experience a bleeding endpoint were censored at the earlier of 2 days after discontinuation of study drug, or death date, or last-contact date (for participants who withdrew consent to be followed up or were lost to follow-up) at the end of the study.

Death was defined as all-cause mortality. All unobserved deaths were assumed to be cardiovascular in nature unless a non-cardiovascular cause could be clearly provided. Cardiovascular=deaths due to ischemic and hemorrhagic stroke, SE, myocardial infarction (MI), sudden death, heart failure, other cardiovascular, and unobserved deaths. Non-cardiovascular=all deaths due to a clearly documented non-cardiovascular cause (further classified into the categories: bleeding, study drug toxicity other than bleeding, malignancy, infection, trauma, and pulmonary causes of death).

Time frame: Intended Treatment Period started on the day of randomization and ended at the efficacy cut-off date (date on which it was expected that the target number of primary efficacy events [448] would have occurred; set to 30-Jan-2011, prior to unblinding).

Population: Intention to treat analysis, randomized participants. Participants who did not experience an efficacy endpoint event were censored at the earlier of their death date (when death is not part of the endpoint), last contact date (for subjects who withdrew consent to be followed up or were lost to follow-up) or the efficacy cut-off date (30-Jan-2011).

Major bleeding=bleeding that is clinically overt and that either resulted in a decrease in hemoglobin of 2 g/dL or more over a 24-hour period, led to a transfusion of 2 or more units of packed red blood cells, occurred in a critical site, or led to death. CRNM bleeding=bleeding that is clinically overt, that satisfies none of the additional criteria required for the event to be adjudicated as a major bleeding event, that led to either hospital admission for bleeding, physician-guided medical or surgical treatment for bleeding, or a change in antithrombotic therapy.

Time frame: Treatment Period started with first dose of blinded study drug and ended 2 days after the last dose of blinded study drug. Mean duration of exposure to double-blind study drug was 1.7 years in each treatment group.

Population: Treated participants. Participants who did not experience a bleeding endpoint were censored at the earlier of 2 days after discontinuation of study drug, or death date, or last-contact date (for participants who withdrew consent to be followed up or were lost to follow-up) at the end of the study.

For descriptions of Stroke and SE, see Outcome Measure 1. For description of Major bleeding, see Outcome Measure 3.

Time frame: Intended Treatment Period started on the day of randomization and ended at the efficacy cut-off date (date on which it was expected that the target number of primary efficacy events [448] would have occurred; set to 30-Jan-2011, prior to unblinding).

Population: Intention to treat analysis, randomized participants who were Warfarin/Vitamin K Antagonist (VKA) naïve (a stratification variable, defined as receiving ≤30 consecutive days of prior warfarin/VKA treatment). Participants not experiencing efficacy endpoint event were censored at earlier of death, last contact, or efficacy cut-off date (30-Jan-2011).

All unobserved deaths were assumed to be cardiovascular in nature unless a non-cardiovascular cause could be clearly provided. Cardiovascular=deaths due to ischemic and hemorrhagic stroke, SE, MI, sudden death, heart failure, other cardiovascular, and unobserved deaths. Non-cardiovascular=all deaths due to a clearly documented non-cardiovascular cause (further classified into the categories: bleeding, study drug toxicity other than bleeding, malignancy, infection, trauma, and pulmonary causes of death).

Time frame: Intended Treatment Period started on the day of randomization and ended at the efficacy cut-off date (date on which it was expected that the target number of primary efficacy events [448] would have occurred; set to 30-Jan-2011, prior to unblinding).

Population: Intention to treat analysis, randomized participants. Participants who did not experience an efficacy endpoint event were censored at the earlier of their death date (when death is not part of the endpoint), last contact date (for subjects who withdrew consent to be followed up or were lost to follow-up) or the efficacy cut-off date (30-Jan-2011).

Rate=number of adjudicated major (ISTH) bleed events per 100 patient years. ISTH Bleeding Criteria: Major bleeding=a bleeding event that was: clinically overt bleeding accompanied by a decrease in hemoglobin (Hgb) of 2 g/dL or more and/or a transfusion of 2 or more units of packed red blood cells; bleeding that occurred in at least 1 of the following sites: intracranial, intraspinal, intraocular (within the corpus of the eye; a conjunctival bleed is not an intraocular bleed), pericardial, intra-articular, intramuscular with compartment syndrome, and retroperitoneal; bleeding that was fatal.

Time frame: Treatment Period started with first dose of blinded study drug and ended 2 days after the last dose of blinded study drug. Mean duration of exposure to double-blind study drug was 1.7 years in each treatment group.

Population: Treated participants. Participants who did not experience a bleeding endpoint were censored at the earlier of 2 days after discontinuation of study drug, or death date, or last-contact date (for participants who withdrew consent to be followed up or were lost to follow-up) at the end of the study.

Rate=number of all bleeding events per 100 patient years. All bleeding events include major bleeding, CRNM bleeding (see Outcome Measure 12 Description for definitions), plus events of minor bleeding and fatal bleeding. Minor bleeding: All acute clinically overt bleeding events not meeting the criteria for either major bleeding or clinically relevant non-major bleeding will be classified as minor bleeding. Fatal bleeding is defined as a bleeding event that the Clinical Events Committee determines is the primary cause of death or contributes directly to death.

Time frame: Treatment Period started with first dose of blinded study drug and ended 2 days after the last dose of blinded study drug. Mean duration of exposure to double-blind study drug was 1.7 years in each treatment group.

Population: Treated participants. Participants who did not experience a bleeding endpoint were censored at the earlier of 2 days after discontinuation of study drug, or death date, or last-contact date (for participants who withdrew consent to be followed up or were lost to follow-up) at the end of the study.

Time frame: Intended Treatment Period started on the day of randomization and ended at the efficacy cut-off date (date on which it was expected that the target number of primary efficacy events [448] would have occurred; set to 30-Jan-2011, prior to unblinding).

Population: Intention to treat analysis, randomized participants. Participants who did not experience an efficacy endpoint event were censored at the earlier of their death date, last contact date, or the efficacy cut-off date (30-Jan-2011).

Rate=number of major or CRNM bleed events per 100 patient years. Major=clinically overt and either 1) resulted in a decrease in hemoglobin of 2 g/dL or more, or 2) led to a transfusion of 2 or more units of packed red blood cells, or 3) occurred in a critical site, or 4) led to death. CRNM bleeding=clinically overt, but satisfied no additional criteria required to be adjudicated as a major bleeding event, and led to either 1) hospital admission for bleeding or 2) physician guided medical or surgical treatment for bleeding or 3) a change in antithrombotic therapy.

Time frame: Treatment Period started with first dose of blinded study drug and ended 2 days after the last dose of blinded study drug. Mean duration of exposure to double-blind study drug was 1.7 years in each treatment group.

Population: Treated participants. Participants who did not experience a bleeding endpoint were censored at the earlier of 2 days after discontinuation of study drug, or death date, or last-contact date (for participants who withdrew consent to be followed up or were lost to follow-up) at the end of the study.

Diagnosis for an acute or evolving MI=elevation of creatine kinase-MB isoenzyme (CK-MB) or Troponin T or I ≥ 2 × the upper limit of normal (ULN), or if no CK-MB or troponin values are available, a total CK ≥ 2×ULN, or new, significant (≥0.04 s) Q waves in ≥2 contiguous leads. For descriptions of Stroke and SE, see Outcome Measure 1.

Time frame: Intended Treatment Period started on the day of randomization and ended at the efficacy cut-off date (date on which it was expected that the target number of primary efficacy events [448] would have occurred; set to 30-Jan-2011, prior to unblinding).

Population: Intention to treat analysis, randomized participants. Participants who did not experience an efficacy endpoint event were censored at the earlier of their death date (when death is not part of the endpoint), last contact date, or the efficacy cut-off date (30-Jan-2011). n=number of participants experiencing stated event.

Diagnosis for an acute or evolving MI=elevation of CK-MB or Troponin T or I ≥ 2 × the ULN, or if no CK-MB or troponin values are available, a total CK ≥ 2×ULN, or new, significant (≥0.04 s) Q waves in ≥2 contiguous leads. For descriptions of Stroke and SE, see Outcome Measure 1. For description of ACD, see Outcome Measure 5.

Time frame: Intended Treatment Period started on the day of randomization and ended at the efficacy cut-off date (date on which it was expected that the target number of primary efficacy events [448] would have occurred; set to 30-Jan-2011, prior to unblinding).

Population: Intention to treat analysis, randomized participants. Participants who didn't experience an efficacy endpoint event were censored at the earlier of their death date (when death is not part of the endpoint), last contact date, or the efficacy cut-off date (30-Jan-2011). n= number of participants experiencing stated combination of events.

AE: all SAEs or AEs with onset from first dose through 2 days (AEs) or 30 days (SAEs) after the last dose of blinded study drug (BSD). SAE: all SAEs with onset from first dose through 30 days after the last dose of BSD. Bleeding AE: all serious or non-serious bleeding-related AEs with onset from first dose through 2 days after the last dose of BSD. Discontinuations due to AE: all SAEs or AEs with onset from first dose of BSD and with action taken=drug discontinued. Deaths: all deaths occurring from first dose through 30 days after the last dose of BSD.

Time frame: Treatment Period started with first dose of blinded study drug and ended 2 days after the last dose of blinded study drug. Mean duration of exposure to double-blind study drug was 1.7 years in each treatment group.

Population: Treated participants. Participants who did not experience a bleeding endpoint were censored at the earlier of 2 days after discontinuation of study drug, or death date, or last-contact date (for participants who withdrew consent to be followed up or were lost to follow-up) at the end of the study.

Net-Clinical Benefit = Composite of stroke, systemic embolism and ISTH major bleeding.

Time frame: Treatment Period started with first dose of blinded study drug and ended 2 days after the last dose of blinded study drug. Mean duration of exposure to double-blind study drug was 1.7 years in each treatment group.

Population: Treated participants. Participants who did not experience a bleeding endpoint were censored at the earlier of 2 days after discontinuation of study drug, or death date, or last-contact date (for participants who withdrew consent to be followed up or were lost to follow-up) at the end of the study.

Rate=number of adjudicated GUSTO bleeding events per 100 patient years. GUSTO Bleeding Criteria: GUSTO severe (or life-threatening) bleeding: either intracranial hemorrhage or bleeding that causes hemodynamic compromise and requires intervention. GUSTO moderate bleeding: bleeding that requires blood transfusion but does not result in hemodynamic compromise.

Time frame: Treatment Period started with first dose of blinded study drug and ended 2 days after the last dose of blinded study drug. Mean duration of exposure to double-blind study drug was 1.7 years in each treatment group.

Population: Treated participants. Participants who did not experience a bleeding endpoint were censored at the earlier of 2 days after discontinuation of study drug, or death date, or last-contact date (for participants who withdrew consent to be followed up or were lost to follow-up) at the end of the study. n=number of participants experiencing events.

Rate=number of adjudicated TIMI bleeding events per 100 patient years. TIMI Bleeding Criteria: Major bleeding=Intracranial bleeding and/or clinically overt bleeding associated with ≥5 gm/dL fall in Hgb or 15% fall in hematocrit (Hct) from baseline, accounting for transfusions. Minor bleeding=Clinically overt bleeding associated with ≥3 gm/dL fall in Hgb or a ≥10% fall in Hct from baseline, accounting for transfusions.

Time frame: Treatment Period started with first dose of blinded study drug and ended 2 days after the last dose of blinded study drug. Mean duration of exposure to double-blind study drug was 1.7 years in each treatment group.

Population: Treated participants. Participants who did not experience a bleeding endpoint were censored at the earlier of 2 days after discontinuation of study drug, or death date, or last-contact date (for participants who withdrew consent to be followed up or were lost to follow-up) at the end of the study. n=number of participants experiencing events.

Rate=number of events of net-clinical benefit per 100 patient years. Net-Clinical Benefit = Composite of stroke, systemic embolism and ISTH major bleeding

Time frame: Treatment Period started with first dose of blinded study drug and ended 2 days after the last dose of blinded study drug. Mean duration of exposure to double-blind study drug was 1.7 years in each treatment group.

Population: Treated participants. Participants who did not experience a bleeding endpoint were censored at the earlier of 2 days after discontinuation of study drug, or death date, or last-contact date (for participants who withdrew consent to be followed up or were lost to follow-up) at the end of the study.