Trial Outcomes & Findings for Edoxaban Treatment Versus Vitamin K Antagonist (VKA) in Patients With Atrial Fibrillation (AF) Undergoing Catheter Ablation (NCT NCT02942576)

Last Updated: 2019-09-23

Results Overview

Stroke (ischemic, hemorrhagic, or undetermined) was defined by Valve Academic Research Consortium-2 (VARC-2) as an acute episode of focal or global neurological dysfunction caused by brain, spinal cord, or retinal vascular injury following hemorrhage or infarction. A stroke event was based on any of the following: duration of neurological dysfunction \>24 hours (h), duration of neurological dysfunction \<24 h in case of imaging-documented new hemorrhage or infarction, and a neurological dysfunction resulting in death. Major bleeding was defined by the International Society on Thrombosis and Hemostasis (ISTH) as fatal bleeding and/or bleeding that is symptomatic and occurs in a critical area or organ and/or extrasurgical site bleeding causing a fall in hemoglobin level of \>2 g/dL or leads to blood transfusion, surgical site bleeding that requires a second intervention, causes hemarthrosis that delays mobilization or wound healing, or causes hemodynamic instability.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

632 participants

Primary outcome timeframe

Day 1 to Day 90

Results posted on

2019-09-23

Participant Flow

A total of 614 participants who met the inclusion and none of the exclusion criteria were randomized; 602 received study drug.

Participants were required to have completed between 21 to 28 days of anticoagulation with study treatment prior to the catheter ablation visit/periprocedural visit (Day 0).

Participant milestones

Participant milestones
Measure	Edoxaban-based Regimen Edoxaban-based regimen for 21 days pre- and 90 days post-ablation period. Edoxaban: Edoxaban 60 mg once-daily or 30 mg once-daily in selected subjects.	VKA-based Regimen VKA-based regimen for 21 days pre- and 90 days post-ablation period (control regimen) VKA-Based Regimen: Dosed at International Normalised Ratio (INR) levels, which is a test of how long it takes for blood to clot. Standard of Care treatment in Canada, Italy, Poland, Hungary, Czech Republic, UK, Taiwan and Korea. VKA-Based Regimen: Dosed at INR levels. Standard of Care treatment in Germany, Belgium, and the Netherlands. VKA-Based Regimen: Dosed at INR levels. Standard of Care treatment in France. VKA-Based Regimen: Dosed at INR levels. Standard of Care treatment in Spain.
Overall Study STARTED	405	197
Overall Study COMPLETED	359	174
Overall Study NOT COMPLETED	46	23

Reasons for withdrawal

Reasons for withdrawal
Measure	Edoxaban-based Regimen Edoxaban-based regimen for 21 days pre- and 90 days post-ablation period. Edoxaban: Edoxaban 60 mg once-daily or 30 mg once-daily in selected subjects.	VKA-based Regimen VKA-based regimen for 21 days pre- and 90 days post-ablation period (control regimen) VKA-Based Regimen: Dosed at International Normalised Ratio (INR) levels, which is a test of how long it takes for blood to clot. Standard of Care treatment in Canada, Italy, Poland, Hungary, Czech Republic, UK, Taiwan and Korea. VKA-Based Regimen: Dosed at INR levels. Standard of Care treatment in Germany, Belgium, and the Netherlands. VKA-Based Regimen: Dosed at INR levels. Standard of Care treatment in France. VKA-Based Regimen: Dosed at INR levels. Standard of Care treatment in Spain.
Overall Study Adverse Event	28	6
Overall Study Withdrawal by Subject	7	5
Overall Study Physician Decision	1	4
Overall Study Other	10	8

Baseline Characteristics

Race and Ethnicity were not collected from any participant.

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Edoxaban-based Regimen n=405 Participants Edoxaban-based regimen for 21 days pre- and 90 days post-ablation period. Edoxaban: Edoxaban 60 mg once-daily or 30 mg once-daily in selected subjects.	VKA-based Regimen n=197 Participants VKA-based regimen for 21 days pre- and 90 days post-ablation period (control regimen) VKA-Based Regimen: Dosed at International Normalised Ratio (INR) levels, which is a test of how long it takes for blood to clot. Standard of Care treatment in Canada, Italy, Poland, Hungary, Czech Republic, United Kingdon (UK), Taiwan and Korea. VKA-Based Regimen: Dosed at INR levels. Standard of Care treatment in Germany, Belgium, and the Netherlands. VKA-Based Regimen: Dosed at INR levels. Standard of Care treatment in France. VKA-Based Regimen: Dosed at INR levels. Standard of Care treatment in Spain.	Total n=602 Participants Total of all reporting groups
Age, Categorical <=18 years	0 Participants n=405 Participants	0 Participants n=197 Participants	0 Participants n=602 Participants
Age, Categorical Between 18 and 65 years	262 Participants n=405 Participants	130 Participants n=197 Participants	392 Participants n=602 Participants
Age, Categorical >=65 years	143 Participants n=405 Participants	67 Participants n=197 Participants	210 Participants n=602 Participants
Age, Continuous	59.5 years STANDARD_DEVIATION 10.2 • n=405 Participants	59.6 years STANDARD_DEVIATION 10.0 • n=197 Participants	59.5 years STANDARD_DEVIATION 10.1 • n=602 Participants
Sex: Female, Male Female	118 Participants n=405 Participants	51 Participants n=197 Participants	169 Participants n=602 Participants
Sex: Female, Male Male	287 Participants n=405 Participants	146 Participants n=197 Participants	433 Participants n=602 Participants
Race and Ethnicity Not Collected	—	—	0 Participants Race and Ethnicity were not collected from any participant.
Region of Enrollment Canada	35 participants n=405 Participants	18 participants n=197 Participants	53 participants n=602 Participants
Region of Enrollment South Korea	28 participants n=405 Participants	11 participants n=197 Participants	39 participants n=602 Participants
Region of Enrollment Belgium	5 participants n=405 Participants	4 participants n=197 Participants	9 participants n=602 Participants
Region of Enrollment Hungary	52 participants n=405 Participants	23 participants n=197 Participants	75 participants n=602 Participants
Region of Enrollment Czechia	74 participants n=405 Participants	35 participants n=197 Participants	109 participants n=602 Participants
Region of Enrollment Taiwan	25 participants n=405 Participants	14 participants n=197 Participants	39 participants n=602 Participants
Region of Enrollment Poland	54 participants n=405 Participants	24 participants n=197 Participants	78 participants n=602 Participants
Region of Enrollment Italy	42 participants n=405 Participants	21 participants n=197 Participants	63 participants n=602 Participants
Region of Enrollment United Kingdom	40 participants n=405 Participants	20 participants n=197 Participants	60 participants n=602 Participants
Region of Enrollment Germany	28 participants n=405 Participants	16 participants n=197 Participants	44 participants n=602 Participants
Region of Enrollment Spain	22 participants n=405 Participants	11 participants n=197 Participants	33 participants n=602 Participants

PRIMARY outcome

Timeframe: Day 1 to Day 90

Population: The composite of all-cause death, stroke (VARC-2), and major bleeding (ISTH) was assessed in the Per Protocol (PP) Analysis Set.

Outcome measures

Outcome measures
Measure	Edoxaban-based Regimen n=316 Participants Edoxaban-based regimen for 21 days pre- and 90 days post-ablation period. Edoxaban: Edoxaban 60 mg once-daily or 30 mg once-daily in selected subjects.	VKA-based Regimen n=101 Participants VKA-based regimen for 21 days pre- and 90 days post-ablation period (control regimen) VKA-Based Regimen: Dosed at International Normalised Ratio (INR) levels, which is a test of how long it takes for blood to clot. Standard of Care treatment in Canada, Italy, Poland, Hungary, Czech Republic, UK, Taiwan and Korea. VKA-Based Regimen: Dosed at INR levels. Standard of Care treatment in Germany, Belgium, and the Netherlands. VKA-Based Regimen: Dosed at INR levels. Standard of Care treatment in France. VKA-Based Regimen: Dosed at INR levels. Standard of Care treatment in Spain.
Number of Participants Who Experienced the Composite of All-cause Death, Stroke (VARC-2), and Major Bleeding (ISTH) in the Edoxaban Group Compared With Vitamin K Antagonist (VKA) Group in Participants Undergoing Catheter Ablation (Adjudicated Data)	1 Participants	2 Participants

PRIMARY outcome

Timeframe: Day 1 to Day 90

Population: Major bleeding was assessed in the modified Intent-to-Treat (mITT) Analysis Set.

Major bleeding was defined by the International Society on Thrombosis and Hemostasis (ISTH) as fatal bleeding and/or bleeding that is symptomatic and occurs in a critical area or organ and/or extrasurgical site bleeding causing a fall in hemoglobin level of \>2 g/dL or leads to blood transfusion, surgical site bleeding that requires a second intervention, causes hemarthrosis that delays mobilization or wound healing, or causes hemodynamic instability.

Outcome measures

Outcome measures
Measure	Edoxaban-based Regimen n=405 Participants Edoxaban-based regimen for 21 days pre- and 90 days post-ablation period. Edoxaban: Edoxaban 60 mg once-daily or 30 mg once-daily in selected subjects.	VKA-based Regimen n=197 Participants VKA-based regimen for 21 days pre- and 90 days post-ablation period (control regimen) VKA-Based Regimen: Dosed at International Normalised Ratio (INR) levels, which is a test of how long it takes for blood to clot. Standard of Care treatment in Canada, Italy, Poland, Hungary, Czech Republic, UK, Taiwan and Korea. VKA-Based Regimen: Dosed at INR levels. Standard of Care treatment in Germany, Belgium, and the Netherlands. VKA-Based Regimen: Dosed at INR levels. Standard of Care treatment in France. VKA-Based Regimen: Dosed at INR levels. Standard of Care treatment in Spain.
Number of Participants Who Experienced Major Bleeding (International Society on Thrombosis and Hemostasis [ISTH]) in the Edoxaban Group Compared With VKA Group Among Participants Undergoing Catheter Ablation (Adjudicated Data)	10 Participants	3 Participants

SECONDARY outcome

Timeframe: Day 1 to Day 90

Population: The composite of all-cause death, stroke (alternative), and major bleeding (ISTH) was assessed in the PP Analysis Set.

An alternative definition characterized stroke (ischemic, hemorrhagic, or undetermined) as an abrupt onset, over minutes to hours, of a focal neurological deficit in the distribution of a single brain artery that was not due to an identifiable nonvascular cause (ie, brain tumor or trauma), and that either lasted at least 24 hours or resulted in death within 24 hours of onset. Major bleeding was defined by the International Society on Thrombosis and Hemostasis (ISTH) as fatal bleeding and/or bleeding that is symptomatic and occurs in a critical area or organ and/or extrasurgical site bleeding causing a fall in hemoglobin level of \>2 g/dL or leads to blood transfusion, surgical site bleeding that requires a second intervention, causes hemarthrosis that delays mobilization or wound healing, or causes hemodynamic instability.

Outcome measures

Outcome measures
Measure	Edoxaban-based Regimen n=316 Participants Edoxaban-based regimen for 21 days pre- and 90 days post-ablation period. Edoxaban: Edoxaban 60 mg once-daily or 30 mg once-daily in selected subjects.	VKA-based Regimen n=101 Participants VKA-based regimen for 21 days pre- and 90 days post-ablation period (control regimen) VKA-Based Regimen: Dosed at International Normalised Ratio (INR) levels, which is a test of how long it takes for blood to clot. Standard of Care treatment in Canada, Italy, Poland, Hungary, Czech Republic, UK, Taiwan and Korea. VKA-Based Regimen: Dosed at INR levels. Standard of Care treatment in Germany, Belgium, and the Netherlands. VKA-Based Regimen: Dosed at INR levels. Standard of Care treatment in France. VKA-Based Regimen: Dosed at INR levels. Standard of Care treatment in Spain.
Number of Participants Who Experienced the Composite of All-cause Death, Stroke (Alternative), and Major Bleeding (ISTH) in the Edoxaban Group Compared With VKA Group Among Participants Undergoing Catheter Ablation (Adjudicated Data)	1 Participants	2 Participants

SECONDARY outcome

Timeframe: Day 1 to Day 90

Population: The composite of stroke (VARC-2), systemic embolic events (SEE), and cardiovascular (CV) mortality was assessed in the PP Analysis Set.

Stroke (ischemic, hemorrhagic, or undetermined) was defined by Valve Academic Research Consortium-2 (VARC-2) as an acute episode of focal or global neurological dysfunction caused by brain, spinal cord, or retinal vascular injury following hemorrhage or infarction. A stroke event was based on any of the following: duration of neurological dysfunction \>24 hours (h), duration of neurological dysfunction \<24 h in case of imaging-documented new hemorrhage or infarction, and a neurological dysfunction resulting in death. SEE was defined as an arterial embolism resulting in clinical ischemia, excluding the central nervous system, coronary, and pulmonary arterial circulation. CV mortality was defined as cardiac or vascular death according to Academic Research Consortium.

Outcome measures

Outcome measures
Measure	Edoxaban-based Regimen n=316 Participants Edoxaban-based regimen for 21 days pre- and 90 days post-ablation period. Edoxaban: Edoxaban 60 mg once-daily or 30 mg once-daily in selected subjects.	VKA-based Regimen n=101 Participants VKA-based regimen for 21 days pre- and 90 days post-ablation period (control regimen) VKA-Based Regimen: Dosed at International Normalised Ratio (INR) levels, which is a test of how long it takes for blood to clot. Standard of Care treatment in Canada, Italy, Poland, Hungary, Czech Republic, UK, Taiwan and Korea. VKA-Based Regimen: Dosed at INR levels. Standard of Care treatment in Germany, Belgium, and the Netherlands. VKA-Based Regimen: Dosed at INR levels. Standard of Care treatment in France. VKA-Based Regimen: Dosed at INR levels. Standard of Care treatment in Spain.
Number of Participants Who Experienced the Composite of Stroke (VARC-2), Systemic Embolic Events (SEE), and Cardiovascular (CV) Mortality in the Edoxaban Group Compared With VKA Group Among Participants Undergoing Catheter Ablation (Adjudicated Data)	1 Participants	0 Participants

Adverse Events

Edoxaban-based Regimen

Serious events: 40 serious events

Other events: 210 other events

Deaths: 0 deaths

VKA-based Regimen

Serious events: 15 serious events

Other events: 99 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Additional Information

Daiichi Sankyo

Contact for Clinical Trial Information

Phone: 1-908-992-6400

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Measure	Edoxaban-based Regimen n=405 participants at risk Edoxaban-based regimen for 21 days pre- and 90 days post-ablation period. Edoxaban: Edoxaban 60 mg once-daily or 30 mg once-daily in selected subjects.	VKA-based Regimen n=197 participants at risk VKA-based regimen for 21 days pre- and 90 days post-ablation period (control regimen) VKA-Based Regimen: Dosed at International Normalised Ratio (INR) levels, which is a test of how long it takes for blood to clot. Standard of Care treatment in Canada, Italy, Poland, Hungary, Czech Republic, UK, Taiwan and Korea. VKA-Based Regimen: Dosed at INR levels. Standard of Care treatment in Germany, Belgium, and the Netherlands. VKA-Based Regimen: Dosed at INR levels. Standard of Care treatment in France. VKA-Based Regimen: Dosed at INR levels. Standard of Care treatment in Spain.
Infections and infestations Pneumonia	0.49% 2/405 • Adverse event data were collected from the first dose of the study drug to 30 days after last dose of study drug. Adverse events that emerge (or worsen) from the first dose of the study drug to the last dose of the study drug.	0.51% 1/197 • Adverse event data were collected from the first dose of the study drug to 30 days after last dose of study drug. Adverse events that emerge (or worsen) from the first dose of the study drug to the last dose of the study drug.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Colon adenoma	0.25% 1/405 • Adverse event data were collected from the first dose of the study drug to 30 days after last dose of study drug. Adverse events that emerge (or worsen) from the first dose of the study drug to the last dose of the study drug.	0.00% 0/197 • Adverse event data were collected from the first dose of the study drug to 30 days after last dose of study drug. Adverse events that emerge (or worsen) from the first dose of the study drug to the last dose of the study drug.
Blood and lymphatic system disorders Anemia	0.25% 1/405 • Adverse event data were collected from the first dose of the study drug to 30 days after last dose of study drug. Adverse events that emerge (or worsen) from the first dose of the study drug to the last dose of the study drug.	0.00% 0/197 • Adverse event data were collected from the first dose of the study drug to 30 days after last dose of study drug. Adverse events that emerge (or worsen) from the first dose of the study drug to the last dose of the study drug.
Blood and lymphatic system disorders Leukopenia	0.25% 1/405 • Adverse event data were collected from the first dose of the study drug to 30 days after last dose of study drug. Adverse events that emerge (or worsen) from the first dose of the study drug to the last dose of the study drug.	0.00% 0/197 • Adverse event data were collected from the first dose of the study drug to 30 days after last dose of study drug. Adverse events that emerge (or worsen) from the first dose of the study drug to the last dose of the study drug.
Blood and lymphatic system disorders Normochromic normocytic anemia	0.25% 1/405 • Adverse event data were collected from the first dose of the study drug to 30 days after last dose of study drug. Adverse events that emerge (or worsen) from the first dose of the study drug to the last dose of the study drug.	0.00% 0/197 • Adverse event data were collected from the first dose of the study drug to 30 days after last dose of study drug. Adverse events that emerge (or worsen) from the first dose of the study drug to the last dose of the study drug.
Blood and lymphatic system disorders Thrombocytopenia	0.25% 1/405 • Adverse event data were collected from the first dose of the study drug to 30 days after last dose of study drug. Adverse events that emerge (or worsen) from the first dose of the study drug to the last dose of the study drug.	0.00% 0/197 • Adverse event data were collected from the first dose of the study drug to 30 days after last dose of study drug. Adverse events that emerge (or worsen) from the first dose of the study drug to the last dose of the study drug.
Endocrine disorders Hyperthyroidism	0.00% 0/405 • Adverse event data were collected from the first dose of the study drug to 30 days after last dose of study drug. Adverse events that emerge (or worsen) from the first dose of the study drug to the last dose of the study drug.	0.51% 1/197 • Adverse event data were collected from the first dose of the study drug to 30 days after last dose of study drug. Adverse events that emerge (or worsen) from the first dose of the study drug to the last dose of the study drug.
Nervous system disorders Headache	0.25% 1/405 • Adverse event data were collected from the first dose of the study drug to 30 days after last dose of study drug. Adverse events that emerge (or worsen) from the first dose of the study drug to the last dose of the study drug.	0.00% 0/197 • Adverse event data were collected from the first dose of the study drug to 30 days after last dose of study drug. Adverse events that emerge (or worsen) from the first dose of the study drug to the last dose of the study drug.
Nervous system disorders Paresthesia	0.25% 1/405 • Adverse event data were collected from the first dose of the study drug to 30 days after last dose of study drug. Adverse events that emerge (or worsen) from the first dose of the study drug to the last dose of the study drug.	0.00% 0/197 • Adverse event data were collected from the first dose of the study drug to 30 days after last dose of study drug. Adverse events that emerge (or worsen) from the first dose of the study drug to the last dose of the study drug.
Nervous system disorders Syncope	0.25% 1/405 • Adverse event data were collected from the first dose of the study drug to 30 days after last dose of study drug. Adverse events that emerge (or worsen) from the first dose of the study drug to the last dose of the study drug.	0.00% 0/197 • Adverse event data were collected from the first dose of the study drug to 30 days after last dose of study drug. Adverse events that emerge (or worsen) from the first dose of the study drug to the last dose of the study drug.
Cardiac disorders Atrial fibrillation	3.7% 15/405 • Adverse event data were collected from the first dose of the study drug to 30 days after last dose of study drug. Adverse events that emerge (or worsen) from the first dose of the study drug to the last dose of the study drug.	3.0% 6/197 • Adverse event data were collected from the first dose of the study drug to 30 days after last dose of study drug. Adverse events that emerge (or worsen) from the first dose of the study drug to the last dose of the study drug.
Cardiac disorders Atrial flutter	0.74% 3/405 • Adverse event data were collected from the first dose of the study drug to 30 days after last dose of study drug. Adverse events that emerge (or worsen) from the first dose of the study drug to the last dose of the study drug.	0.00% 0/197 • Adverse event data were collected from the first dose of the study drug to 30 days after last dose of study drug. Adverse events that emerge (or worsen) from the first dose of the study drug to the last dose of the study drug.
Cardiac disorders Atrial tachycardia	0.00% 0/405 • Adverse event data were collected from the first dose of the study drug to 30 days after last dose of study drug. Adverse events that emerge (or worsen) from the first dose of the study drug to the last dose of the study drug.	1.0% 2/197 • Adverse event data were collected from the first dose of the study drug to 30 days after last dose of study drug. Adverse events that emerge (or worsen) from the first dose of the study drug to the last dose of the study drug.
Cardiac disorders Atrial thrombosis	0.25% 1/405 • Adverse event data were collected from the first dose of the study drug to 30 days after last dose of study drug. Adverse events that emerge (or worsen) from the first dose of the study drug to the last dose of the study drug.	0.51% 1/197 • Adverse event data were collected from the first dose of the study drug to 30 days after last dose of study drug. Adverse events that emerge (or worsen) from the first dose of the study drug to the last dose of the study drug.
Cardiac disorders Left ventricular dysfunction	0.49% 2/405 • Adverse event data were collected from the first dose of the study drug to 30 days after last dose of study drug. Adverse events that emerge (or worsen) from the first dose of the study drug to the last dose of the study drug.	0.00% 0/197 • Adverse event data were collected from the first dose of the study drug to 30 days after last dose of study drug. Adverse events that emerge (or worsen) from the first dose of the study drug to the last dose of the study drug.
Cardiac disorders Atrioventricular block complete	0.00% 0/405 • Adverse event data were collected from the first dose of the study drug to 30 days after last dose of study drug. Adverse events that emerge (or worsen) from the first dose of the study drug to the last dose of the study drug.	0.51% 1/197 • Adverse event data were collected from the first dose of the study drug to 30 days after last dose of study drug. Adverse events that emerge (or worsen) from the first dose of the study drug to the last dose of the study drug.
Cardiac disorders Cardiac arrest	0.25% 1/405 • Adverse event data were collected from the first dose of the study drug to 30 days after last dose of study drug. Adverse events that emerge (or worsen) from the first dose of the study drug to the last dose of the study drug.	0.00% 0/197 • Adverse event data were collected from the first dose of the study drug to 30 days after last dose of study drug. Adverse events that emerge (or worsen) from the first dose of the study drug to the last dose of the study drug.
Cardiac disorders Cardiac failure	0.00% 0/405 • Adverse event data were collected from the first dose of the study drug to 30 days after last dose of study drug. Adverse events that emerge (or worsen) from the first dose of the study drug to the last dose of the study drug.	0.51% 1/197 • Adverse event data were collected from the first dose of the study drug to 30 days after last dose of study drug. Adverse events that emerge (or worsen) from the first dose of the study drug to the last dose of the study drug.
Cardiac disorders Intracardiac thrombus	0.25% 1/405 • Adverse event data were collected from the first dose of the study drug to 30 days after last dose of study drug. Adverse events that emerge (or worsen) from the first dose of the study drug to the last dose of the study drug.	0.00% 0/197 • Adverse event data were collected from the first dose of the study drug to 30 days after last dose of study drug. Adverse events that emerge (or worsen) from the first dose of the study drug to the last dose of the study drug.
Cardiac disorders Pericarditis	0.25% 1/405 • Adverse event data were collected from the first dose of the study drug to 30 days after last dose of study drug. Adverse events that emerge (or worsen) from the first dose of the study drug to the last dose of the study drug.	0.00% 0/197 • Adverse event data were collected from the first dose of the study drug to 30 days after last dose of study drug. Adverse events that emerge (or worsen) from the first dose of the study drug to the last dose of the study drug.
Cardiac disorders Sinus bradycardia	0.25% 1/405 • Adverse event data were collected from the first dose of the study drug to 30 days after last dose of study drug. Adverse events that emerge (or worsen) from the first dose of the study drug to the last dose of the study drug.	0.00% 0/197 • Adverse event data were collected from the first dose of the study drug to 30 days after last dose of study drug. Adverse events that emerge (or worsen) from the first dose of the study drug to the last dose of the study drug.
Vascular disorders Arteriovenous fistula	0.49% 2/405 • Adverse event data were collected from the first dose of the study drug to 30 days after last dose of study drug. Adverse events that emerge (or worsen) from the first dose of the study drug to the last dose of the study drug.	0.00% 0/197 • Adverse event data were collected from the first dose of the study drug to 30 days after last dose of study drug. Adverse events that emerge (or worsen) from the first dose of the study drug to the last dose of the study drug.
Vascular disorders Hypotension	0.25% 1/405 • Adverse event data were collected from the first dose of the study drug to 30 days after last dose of study drug. Adverse events that emerge (or worsen) from the first dose of the study drug to the last dose of the study drug.	0.00% 0/197 • Adverse event data were collected from the first dose of the study drug to 30 days after last dose of study drug. Adverse events that emerge (or worsen) from the first dose of the study drug to the last dose of the study drug.
Vascular disorders Peripheral artery stenosis	0.00% 0/405 • Adverse event data were collected from the first dose of the study drug to 30 days after last dose of study drug. Adverse events that emerge (or worsen) from the first dose of the study drug to the last dose of the study drug.	0.51% 1/197 • Adverse event data were collected from the first dose of the study drug to 30 days after last dose of study drug. Adverse events that emerge (or worsen) from the first dose of the study drug to the last dose of the study drug.
Respiratory, thoracic and mediastinal disorders Pulmonary edema	0.00% 0/405 • Adverse event data were collected from the first dose of the study drug to 30 days after last dose of study drug. Adverse events that emerge (or worsen) from the first dose of the study drug to the last dose of the study drug.	0.51% 1/197 • Adverse event data were collected from the first dose of the study drug to 30 days after last dose of study drug. Adverse events that emerge (or worsen) from the first dose of the study drug to the last dose of the study drug.
Gastrointestinal disorders Duodenal perforation	0.00% 0/405 • Adverse event data were collected from the first dose of the study drug to 30 days after last dose of study drug. Adverse events that emerge (or worsen) from the first dose of the study drug to the last dose of the study drug.	0.51% 1/197 • Adverse event data were collected from the first dose of the study drug to 30 days after last dose of study drug. Adverse events that emerge (or worsen) from the first dose of the study drug to the last dose of the study drug.
Gastrointestinal disorders Gastritis	0.25% 1/405 • Adverse event data were collected from the first dose of the study drug to 30 days after last dose of study drug. Adverse events that emerge (or worsen) from the first dose of the study drug to the last dose of the study drug.	0.00% 0/197 • Adverse event data were collected from the first dose of the study drug to 30 days after last dose of study drug. Adverse events that emerge (or worsen) from the first dose of the study drug to the last dose of the study drug.
Gastrointestinal disorders Pancreatitis	0.25% 1/405 • Adverse event data were collected from the first dose of the study drug to 30 days after last dose of study drug. Adverse events that emerge (or worsen) from the first dose of the study drug to the last dose of the study drug.	0.00% 0/197 • Adverse event data were collected from the first dose of the study drug to 30 days after last dose of study drug. Adverse events that emerge (or worsen) from the first dose of the study drug to the last dose of the study drug.
Gastrointestinal disorders Retroperitoneal mass	0.25% 1/405 • Adverse event data were collected from the first dose of the study drug to 30 days after last dose of study drug. Adverse events that emerge (or worsen) from the first dose of the study drug to the last dose of the study drug.	0.00% 0/197 • Adverse event data were collected from the first dose of the study drug to 30 days after last dose of study drug. Adverse events that emerge (or worsen) from the first dose of the study drug to the last dose of the study drug.
Renal and urinary disorders Hydronephrosis	0.25% 1/405 • Adverse event data were collected from the first dose of the study drug to 30 days after last dose of study drug. Adverse events that emerge (or worsen) from the first dose of the study drug to the last dose of the study drug.	0.00% 0/197 • Adverse event data were collected from the first dose of the study drug to 30 days after last dose of study drug. Adverse events that emerge (or worsen) from the first dose of the study drug to the last dose of the study drug.
Renal and urinary disorders Urethral obstruction	0.25% 1/405 • Adverse event data were collected from the first dose of the study drug to 30 days after last dose of study drug. Adverse events that emerge (or worsen) from the first dose of the study drug to the last dose of the study drug.	0.00% 0/197 • Adverse event data were collected from the first dose of the study drug to 30 days after last dose of study drug. Adverse events that emerge (or worsen) from the first dose of the study drug to the last dose of the study drug.
General disorders Non-cardiac chest pain	0.25% 1/405 • Adverse event data were collected from the first dose of the study drug to 30 days after last dose of study drug. Adverse events that emerge (or worsen) from the first dose of the study drug to the last dose of the study drug.	0.00% 0/197 • Adverse event data were collected from the first dose of the study drug to 30 days after last dose of study drug. Adverse events that emerge (or worsen) from the first dose of the study drug to the last dose of the study drug.
Investigations Alanine aminotransferase increased	0.25% 1/405 • Adverse event data were collected from the first dose of the study drug to 30 days after last dose of study drug. Adverse events that emerge (or worsen) from the first dose of the study drug to the last dose of the study drug.	0.00% 0/197 • Adverse event data were collected from the first dose of the study drug to 30 days after last dose of study drug. Adverse events that emerge (or worsen) from the first dose of the study drug to the last dose of the study drug.
Injury, poisoning and procedural complications Foot fracture	0.25% 1/405 • Adverse event data were collected from the first dose of the study drug to 30 days after last dose of study drug. Adverse events that emerge (or worsen) from the first dose of the study drug to the last dose of the study drug.	0.00% 0/197 • Adverse event data were collected from the first dose of the study drug to 30 days after last dose of study drug. Adverse events that emerge (or worsen) from the first dose of the study drug to the last dose of the study drug.
Injury, poisoning and procedural complications Post procedural complication	0.25% 1/405 • Adverse event data were collected from the first dose of the study drug to 30 days after last dose of study drug. Adverse events that emerge (or worsen) from the first dose of the study drug to the last dose of the study drug.	0.00% 0/197 • Adverse event data were collected from the first dose of the study drug to 30 days after last dose of study drug. Adverse events that emerge (or worsen) from the first dose of the study drug to the last dose of the study drug.
Hepatobiliary disorders Cholecystitis	0.00% 0/405 • Adverse event data were collected from the first dose of the study drug to 30 days after last dose of study drug. Adverse events that emerge (or worsen) from the first dose of the study drug to the last dose of the study drug.	0.51% 1/197 • Adverse event data were collected from the first dose of the study drug to 30 days after last dose of study drug. Adverse events that emerge (or worsen) from the first dose of the study drug to the last dose of the study drug.