Trial Outcomes & Findings for Cardiovascular Outcomes Study of Alogliptin in Patients With Type 2 Diabetes and Acute Coronary Syndrome (NCT NCT00968708)

Last Updated: 2014-05-02

Results Overview

Primary Major Adverse Cardiac Events were defined as a composite of cardiovascular death, nonfatal myocardial infarction and nonfatal stroke; these events were adjudicated by an independent cardiovascular endpoints committee.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

5380 participants

Primary outcome timeframe

From randomization until the adjudication cut-off date of May 31 2013 (maximum time on study was 41 months).

Results posted on

2014-05-02

Participant Flow

Participants took part in the study at 898 investigative sites worldwide from 24 September 2009 to 18 June 2013.

Participants with a diagnosis of type 2 diabetes mellitus and acute coronary syndrome were enrolled equally in 1 of 2 treatment groups, once a day placebo or alogliptin, in addition to receiving standard of care for cardiovascular disease and diabetes.

Participant milestones

Participant milestones
Measure	Placebo Alogliptin placebo matching tablets, orally, once daily. Participants continued to receive standard of care for cardiovascular disease and diabetes according to regional guidelines.	Alogliptin Alogliptin 25 mg, tablets, orally, once daily for participants with normal or mildly impaired renal function as defined by estimated glomerular filtration rate (eGFR) ≥ 60 mL/min). Alogliptin 12.5 mg, tablets, orally, once daily for participants with moderately impaired renal function (eGFR ≥30 and \<60 mL/min). Alogliptin 6.25 mg, tablets, orally, once daily for participants with severely impaired renal function or end stage renal disease (eGFR \<30 mL/min). Participants continued to receive standard of care for cardiovascular disease and diabetes according to regional guidelines.
Overall Study STARTED	2679	2701
Overall Study Treated	2676	2698
Overall Study COMPLETED	2361	2403
Overall Study NOT COMPLETED	318	298

Reasons for withdrawal

Reasons for withdrawal
Measure	Placebo Alogliptin placebo matching tablets, orally, once daily. Participants continued to receive standard of care for cardiovascular disease and diabetes according to regional guidelines.	Alogliptin Alogliptin 25 mg, tablets, orally, once daily for participants with normal or mildly impaired renal function as defined by estimated glomerular filtration rate (eGFR) ≥ 60 mL/min). Alogliptin 12.5 mg, tablets, orally, once daily for participants with moderately impaired renal function (eGFR ≥30 and \<60 mL/min). Alogliptin 6.25 mg, tablets, orally, once daily for participants with severely impaired renal function or end stage renal disease (eGFR \<30 mL/min). Participants continued to receive standard of care for cardiovascular disease and diabetes according to regional guidelines.
Overall Study Adverse Event	169	150
Overall Study Major Protocol Deviation	0	1
Overall Study Lost to Follow-up	19	11
Overall Study Voluntary Withdrawal	104	101
Overall Study Investigator Discretion	0	1
Overall Study Other	26	34

Baseline Characteristics

Cardiovascular Outcomes Study of Alogliptin in Patients With Type 2 Diabetes and Acute Coronary Syndrome

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Placebo n=2679 Participants Alogliptin placebo matching tablets, orally, once daily.	Alogliptin n=2701 Participants Alogliptin 25 mg, tablets, orally, once daily for participants with normal or mildly impaired renal function as defined by estimated glomerular filtration rate (eGFR) ≥ 60 mL/min). Alogliptin 12.5 mg, tablets, orally, once daily for participants with moderately impaired renal function (eGFR ≥30 and \<60 mL/min). Alogliptin 6.25 mg, tablets, orally, once daily for participants with severely impaired renal function or end stage renal disease (eGFR \<30 mL/min).	Total n=5380 Participants Total of all reporting groups
Age, Continuous	60.7 years STANDARD_DEVIATION 9.88 • n=5 Participants	61.0 years STANDARD_DEVIATION 9.96 • n=7 Participants	60.9 years STANDARD_DEVIATION 9.92 • n=5 Participants
Sex: Female, Male Female	856 Participants n=5 Participants	873 Participants n=7 Participants	1729 Participants n=5 Participants
Sex: Female, Male Male	1823 Participants n=5 Participants	1828 Participants n=7 Participants	3651 Participants n=5 Participants
Race/Ethnicity, Customized American Indian or Alaska Native	54 participants n=5 Participants	56 participants n=7 Participants	110 participants n=5 Participants
Race/Ethnicity, Customized Asian	542 participants n=5 Participants	547 participants n=7 Participants	1089 participants n=5 Participants
Race/Ethnicity, Customized Black or African American	115 participants n=5 Participants	101 participants n=7 Participants	216 participants n=5 Participants
Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander	5 participants n=5 Participants	6 participants n=7 Participants	11 participants n=5 Participants
Race/Ethnicity, Customized White	1943 participants n=5 Participants	1966 participants n=7 Participants	3909 participants n=5 Participants
Race/Ethnicity, Customized More than one race	20 participants n=5 Participants	25 participants n=7 Participants	45 participants n=5 Participants
Race/Ethnicity, Customized Hispanic or Latino	764 participants n=5 Participants	773 participants n=7 Participants	1537 participants n=5 Participants
Race/Ethnicity, Customized Non-Hispanic or Latino	1915 participants n=5 Participants	1928 participants n=7 Participants	3843 participants n=5 Participants
Region of Enrollment Argentina	136 participants n=5 Participants	136 participants n=7 Participants	272 participants n=5 Participants
Region of Enrollment Australia	7 participants n=5 Participants	8 participants n=7 Participants	15 participants n=5 Participants
Region of Enrollment Austria	8 participants n=5 Participants	8 participants n=7 Participants	16 participants n=5 Participants
Region of Enrollment Belgium	11 participants n=5 Participants	12 participants n=7 Participants	23 participants n=5 Participants
Region of Enrollment Brazil	179 participants n=5 Participants	181 participants n=7 Participants	360 participants n=5 Participants
Region of Enrollment Bulgaria	41 participants n=5 Participants	41 participants n=7 Participants	82 participants n=5 Participants
Region of Enrollment Canada	54 participants n=5 Participants	55 participants n=7 Participants	109 participants n=5 Participants
Region of Enrollment Chile	51 participants n=5 Participants	55 participants n=7 Participants	106 participants n=5 Participants
Region of Enrollment Colombia	15 participants n=5 Participants	13 participants n=7 Participants	28 participants n=5 Participants
Region of Enrollment Croatia	38 participants n=5 Participants	39 participants n=7 Participants	77 participants n=5 Participants
Region of Enrollment Czech Republic	13 participants n=5 Participants	13 participants n=7 Participants	26 participants n=5 Participants
Region of Enrollment Denmark	3 participants n=5 Participants	3 participants n=7 Participants	6 participants n=5 Participants
Region of Enrollment Egypt	7 participants n=5 Participants	7 participants n=7 Participants	14 participants n=5 Participants
Region of Enrollment Finland	12 participants n=5 Participants	10 participants n=7 Participants	22 participants n=5 Participants
Region of Enrollment France	11 participants n=5 Participants	11 participants n=7 Participants	22 participants n=5 Participants
Region of Enrollment Germany	26 participants n=5 Participants	27 participants n=7 Participants	53 participants n=5 Participants
Region of Enrollment Greece	0 participants n=5 Participants	1 participants n=7 Participants	1 participants n=5 Participants
Region of Enrollment Guatemala	25 participants n=5 Participants	24 participants n=7 Participants	49 participants n=5 Participants
Region of Enrollment Hong Kong	11 participants n=5 Participants	12 participants n=7 Participants	23 participants n=5 Participants
Region of Enrollment Hungary	60 participants n=5 Participants	59 participants n=7 Participants	119 participants n=5 Participants
Region of Enrollment India	165 participants n=5 Participants	165 participants n=7 Participants	330 participants n=5 Participants
Region of Enrollment Israel	100 participants n=5 Participants	101 participants n=7 Participants	201 participants n=5 Participants
Region of Enrollment Italy	25 participants n=5 Participants	25 participants n=7 Participants	50 participants n=5 Participants
Region of Enrollment Japan	105 participants n=5 Participants	104 participants n=7 Participants	209 participants n=5 Participants
Region of Enrollment Kuwait	2 participants n=5 Participants	3 participants n=7 Participants	5 participants n=5 Participants
Region of Enrollment Latvia	6 participants n=5 Participants	6 participants n=7 Participants	12 participants n=5 Participants
Region of Enrollment Lithuania	16 participants n=5 Participants	20 participants n=7 Participants	36 participants n=5 Participants
Region of Enrollment Malaysia	39 participants n=5 Participants	42 participants n=7 Participants	81 participants n=5 Participants
Region of Enrollment Mexico	192 participants n=5 Participants	191 participants n=7 Participants	383 participants n=5 Participants
Region of Enrollment New Zealand	13 participants n=5 Participants	13 participants n=7 Participants	26 participants n=5 Participants
Region of Enrollment Peru	79 participants n=5 Participants	81 participants n=7 Participants	160 participants n=5 Participants
Region of Enrollment Philippines	52 participants n=5 Participants	50 participants n=7 Participants	102 participants n=5 Participants
Region of Enrollment Poland	121 participants n=5 Participants	118 participants n=7 Participants	239 participants n=5 Participants
Region of Enrollment Portugal	13 participants n=5 Participants	16 participants n=7 Participants	29 participants n=5 Participants
Region of Enrollment Puerto Rico	16 participants n=5 Participants	19 participants n=7 Participants	35 participants n=5 Participants
Region of Enrollment Korea, Republic Of	61 participants n=5 Participants	62 participants n=7 Participants	123 participants n=5 Participants
Region of Enrollment Romania	40 participants n=5 Participants	38 participants n=7 Participants	78 participants n=5 Participants
Region of Enrollment Russian Federation	153 participants n=5 Participants	151 participants n=7 Participants	304 participants n=5 Participants
Region of Enrollment Serbia	35 participants n=5 Participants	35 participants n=7 Participants	70 participants n=5 Participants
Region of Enrollment Slovakia	46 participants n=5 Participants	49 participants n=7 Participants	95 participants n=5 Participants
Region of Enrollment South Africa	39 participants n=5 Participants	41 participants n=7 Participants	80 participants n=5 Participants
Region of Enrollment Spain	21 participants n=5 Participants	22 participants n=7 Participants	43 participants n=5 Participants
Region of Enrollment Sweden	16 participants n=5 Participants	16 participants n=7 Participants	32 participants n=5 Participants
Region of Enrollment Taiwan, Province Of China	14 participants n=5 Participants	13 participants n=7 Participants	27 participants n=5 Participants
Region of Enrollment Thailand	57 participants n=5 Participants	58 participants n=7 Participants	115 participants n=5 Participants
Region of Enrollment Ukraine	138 participants n=5 Participants	138 participants n=7 Participants	276 participants n=5 Participants
Region of Enrollment United Arab Emirates	3 participants n=5 Participants	3 participants n=7 Participants	6 participants n=5 Participants
Region of Enrollment United Kingdom	32 participants n=5 Participants	34 participants n=7 Participants	66 participants n=5 Participants
Region of Enrollment United States	372 participants n=5 Participants	372 participants n=7 Participants	744 participants n=5 Participants
Body Mass Index	29.53 kg/m^2 STANDARD_DEVIATION 5.758 • n=5 Participants	29.42 kg/m^2 STANDARD_DEVIATION 5.422 • n=7 Participants	29.48 kg/m^2 STANDARD_DEVIATION 5.591 • n=5 Participants
Duration of Type 2 Diabetes Mellitus	9.18 years STANDARD_DEVIATION 8.121 • n=5 Participants	9.13 years STANDARD_DEVIATION 8.198 • n=7 Participants	9.16 years STANDARD_DEVIATION 8.159 • n=5 Participants
Smoking History Never smoked	1144 participants n=5 Participants	1158 participants n=7 Participants	2302 participants n=5 Participants
Smoking History Current smoker	383 participants n=5 Participants	351 participants n=7 Participants	734 participants n=5 Participants
Smoking History Ex-smoker	1152 participants n=5 Participants	1192 participants n=7 Participants	2344 participants n=5 Participants
Estimated Glomerular Filtration Rate (eGFR)	71.01 mL/min/1.73 m^2 STANDARD_DEVIATION 21.541 • n=5 Participants	70.86 mL/min/1.73 m^2 STANDARD_DEVIATION 21.297 • n=7 Participants	70.93 mL/min/1.73 m^2 STANDARD_DEVIATION 21.417 • n=5 Participants
Renal Impairment Category Normal Renal Function	440 participants n=5 Participants	399 participants n=7 Participants	839 participants n=5 Participants
Renal Impairment Category Mild Renal Impairment	1446 participants n=5 Participants	1530 participants n=7 Participants	2976 participants n=5 Participants
Renal Impairment Category Moderate Renal Impairment	714 participants n=5 Participants	694 participants n=7 Participants	1408 participants n=5 Participants
Renal Impairment Category Severe Renal Impairment/End-Stage Renal Disease	79 participants n=5 Participants	78 participants n=7 Participants	157 participants n=5 Participants
Index Acute Coronary Syndrome (ACS) Event Type Myocardial Infarction	2068 participants n=5 Participants	2084 participants n=7 Participants	4152 participants n=5 Participants
Index Acute Coronary Syndrome (ACS) Event Type Unstable Angina	605 participants n=5 Participants	609 participants n=7 Participants	1214 participants n=5 Participants
Time From Index ACS Event to Randomization	48.0 days STANDARD_DEVIATION 21.95 • n=5 Participants	47.6 days STANDARD_DEVIATION 22.04 • n=7 Participants	47.8 days STANDARD_DEVIATION 22.00 • n=5 Participants

PRIMARY outcome

Timeframe: From randomization until the adjudication cut-off date of May 31 2013 (maximum time on study was 41 months).

Population: Full analysis set (all randomized participants)

Outcome measures

Outcome measures
Measure	Placebo n=2679 Participants Alogliptin placebo matching tablets, orally, once daily.	Alogliptin n=2701 Participants Alogliptin 25 mg, tablets, orally, once daily for participants with normal or mildly impaired renal function as defined by estimated glomerular filtration rate (eGFR) ≥ 60 mL/min). Alogliptin 12.5 mg, tablets, orally, once daily for participants with moderately impaired renal function (eGFR ≥30 and \<60 mL/min). Alogliptin 6.25 mg, tablets, orally, once daily for participants with severely impaired renal function or end stage renal disease (eGFR \<30 mL/min).
Percentage of Participants With Primary Major Adverse Cardiac Events (MACE)	11.8 percentage of participants	11.3 percentage of participants

SECONDARY outcome

Timeframe: From randomization until the adjudication cut-of date of May 31 2013 (maximum time on study was 41 months).

Population: Full analysis set

Secondary MACE composite consisted of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or urgent revascularization due to unstable angina; these events were adjudicated by an independent cardiovascular endpoint committee.

Outcome measures

Outcome measures
Measure	Placebo n=2679 Participants Alogliptin placebo matching tablets, orally, once daily.	Alogliptin n=2701 Participants Alogliptin 25 mg, tablets, orally, once daily for participants with normal or mildly impaired renal function as defined by estimated glomerular filtration rate (eGFR) ≥ 60 mL/min). Alogliptin 12.5 mg, tablets, orally, once daily for participants with moderately impaired renal function (eGFR ≥30 and \<60 mL/min). Alogliptin 6.25 mg, tablets, orally, once daily for participants with severely impaired renal function or end stage renal disease (eGFR \<30 mL/min).
Percentage of Participants With Secondary Major Adverse Cardiac Events (MACE)	13.4 percentage of participants	12.7 percentage of participants

Adverse Events

Placebo

Serious events: 952 serious events

Other events: 1493 other events

Deaths: 0 deaths

Alogliptin

Serious events: 907 serious events

Other events: 1523 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Additional Information

Medical Director

Takeda

Phone: 800-778-2860

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee The first study related publication will be a multi-center publication submitted within 24 months after conclusion or termination of a study at all sites. After such multi site publication, all proposed site publications and presentations will be submitted to sponsor for review 60 days in advance of publication. Site will remove Sponsor confidential information unrelated to study results. Sponsor can delay a proposed publication for another 60 days to preserve intellectual property.
Publication restrictions are in place

Restriction type: OTHER

Serious adverse events
Measure	Placebo n=2679 participants at risk Alogliptin placebo matching tablets, orally, once daily.	Alogliptin n=2701 participants at risk Alogliptin 25 mg, tablets, orally, once daily for participants with normal or mildly impaired renal function as defined by estimated glomerular filtration rate (eGFR) ≥ 60 mL/min). Alogliptin 12.5 mg, tablets, orally, once daily for participants with moderately impaired renal function (eGFR ≥30 and \<60 mL/min). Alogliptin 6.25 mg, tablets, orally, once daily for participants with severely impaired renal function or end stage renal disease (eGFR \<30 mL/min).
Infections and infestations Bronchopneumonia	0.11% 3/2679 • From randomization until the adjudication cut-off date of May 31 2013 (maximum time on study was 41 months). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.04% 1/2701 • From randomization until the adjudication cut-off date of May 31 2013 (maximum time on study was 41 months). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Cardiac disorders Angina unstable	5.3% 142/2679 • From randomization until the adjudication cut-off date of May 31 2013 (maximum time on study was 41 months). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	4.3% 117/2701 • From randomization until the adjudication cut-off date of May 31 2013 (maximum time on study was 41 months). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Cardiac disorders Acute myocardial infarction	3.9% 104/2679 • From randomization until the adjudication cut-off date of May 31 2013 (maximum time on study was 41 months). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	4.6% 125/2701 • From randomization until the adjudication cut-off date of May 31 2013 (maximum time on study was 41 months). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Cardiac disorders Angina pectoris	3.1% 83/2679 • From randomization until the adjudication cut-off date of May 31 2013 (maximum time on study was 41 months). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	3.2% 86/2701 • From randomization until the adjudication cut-off date of May 31 2013 (maximum time on study was 41 months). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Cardiac disorders Myocardial infarction	2.0% 54/2679 • From randomization until the adjudication cut-off date of May 31 2013 (maximum time on study was 41 months). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	2.4% 66/2701 • From randomization until the adjudication cut-off date of May 31 2013 (maximum time on study was 41 months). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Cardiac disorders Cardiac failure congestive	2.0% 53/2679 • From randomization until the adjudication cut-off date of May 31 2013 (maximum time on study was 41 months). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	2.3% 63/2701 • From randomization until the adjudication cut-off date of May 31 2013 (maximum time on study was 41 months). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Cardiac disorders Cardiac failure	2.1% 56/2679 • From randomization until the adjudication cut-off date of May 31 2013 (maximum time on study was 41 months). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	1.7% 45/2701 • From randomization until the adjudication cut-off date of May 31 2013 (maximum time on study was 41 months). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Cardiac disorders Coronary artery disease	1.3% 34/2679 • From randomization until the adjudication cut-off date of May 31 2013 (maximum time on study was 41 months). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	1.3% 35/2701 • From randomization until the adjudication cut-off date of May 31 2013 (maximum time on study was 41 months). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Cardiac disorders Acute coronary syndrome	1.1% 29/2679 • From randomization until the adjudication cut-off date of May 31 2013 (maximum time on study was 41 months). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	1.00% 27/2701 • From randomization until the adjudication cut-off date of May 31 2013 (maximum time on study was 41 months). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Cardiac disorders Myocardial ischaemia	0.71% 19/2679 • From randomization until the adjudication cut-off date of May 31 2013 (maximum time on study was 41 months). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.74% 20/2701 • From randomization until the adjudication cut-off date of May 31 2013 (maximum time on study was 41 months). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Cardiac disorders Atrial fibrillation	0.82% 22/2679 • From randomization until the adjudication cut-off date of May 31 2013 (maximum time on study was 41 months). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.56% 15/2701 • From randomization until the adjudication cut-off date of May 31 2013 (maximum time on study was 41 months). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Cardiac disorders Coronary artery stenosis	0.63% 17/2679 • From randomization until the adjudication cut-off date of May 31 2013 (maximum time on study was 41 months). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.74% 20/2701 • From randomization until the adjudication cut-off date of May 31 2013 (maximum time on study was 41 months). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Cardiac disorders Cardiac arrest	0.41% 11/2679 • From randomization until the adjudication cut-off date of May 31 2013 (maximum time on study was 41 months). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.52% 14/2701 • From randomization until the adjudication cut-off date of May 31 2013 (maximum time on study was 41 months). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Cardiac disorders Cardiogenic shock	0.19% 5/2679 • From randomization until the adjudication cut-off date of May 31 2013 (maximum time on study was 41 months). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.52% 14/2701 • From randomization until the adjudication cut-off date of May 31 2013 (maximum time on study was 41 months). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Cardiac disorders Cardio-respiratory arrest	0.34% 9/2679 • From randomization until the adjudication cut-off date of May 31 2013 (maximum time on study was 41 months). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.22% 6/2701 • From randomization until the adjudication cut-off date of May 31 2013 (maximum time on study was 41 months). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Cardiac disorders Ventricular tachycardia	0.37% 10/2679 • From randomization until the adjudication cut-off date of May 31 2013 (maximum time on study was 41 months). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.19% 5/2701 • From randomization until the adjudication cut-off date of May 31 2013 (maximum time on study was 41 months). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Cardiac disorders Cardiac failure acute	0.30% 8/2679 • From randomization until the adjudication cut-off date of May 31 2013 (maximum time on study was 41 months). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.22% 6/2701 • From randomization until the adjudication cut-off date of May 31 2013 (maximum time on study was 41 months). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Cardiac disorders Cardiac failure chronic	0.26% 7/2679 • From randomization until the adjudication cut-off date of May 31 2013 (maximum time on study was 41 months). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.26% 7/2701 • From randomization until the adjudication cut-off date of May 31 2013 (maximum time on study was 41 months). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Cardiac disorders Ischaemic cardiomyopathy	0.15% 4/2679 • From randomization until the adjudication cut-off date of May 31 2013 (maximum time on study was 41 months). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.33% 9/2701 • From randomization until the adjudication cut-off date of May 31 2013 (maximum time on study was 41 months). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Cardiac disorders Supraventricular tachycardia	0.15% 4/2679 • From randomization until the adjudication cut-off date of May 31 2013 (maximum time on study was 41 months). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.26% 7/2701 • From randomization until the adjudication cut-off date of May 31 2013 (maximum time on study was 41 months). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Cardiac disorders Ventricular fibrillation	0.22% 6/2679 • From randomization until the adjudication cut-off date of May 31 2013 (maximum time on study was 41 months). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.19% 5/2701 • From randomization until the adjudication cut-off date of May 31 2013 (maximum time on study was 41 months). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Cardiac disorders Atrial flutter	0.15% 4/2679 • From randomization until the adjudication cut-off date of May 31 2013 (maximum time on study was 41 months). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.11% 3/2701 • From randomization until the adjudication cut-off date of May 31 2013 (maximum time on study was 41 months). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Cardiac disorders Bradycardia	0.15% 4/2679 • From randomization until the adjudication cut-off date of May 31 2013 (maximum time on study was 41 months). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.11% 3/2701 • From randomization until the adjudication cut-off date of May 31 2013 (maximum time on study was 41 months). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Cardiac disorders Arrhythmia	0.15% 4/2679 • From randomization until the adjudication cut-off date of May 31 2013 (maximum time on study was 41 months). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.07% 2/2701 • From randomization until the adjudication cut-off date of May 31 2013 (maximum time on study was 41 months). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Cardiac disorders Atrioventricular block complete	0.00% 0/2679 • From randomization until the adjudication cut-off date of May 31 2013 (maximum time on study was 41 months). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.22% 6/2701 • From randomization until the adjudication cut-off date of May 31 2013 (maximum time on study was 41 months). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Cardiac disorders Cardiomyopathy	0.04% 1/2679 • From randomization until the adjudication cut-off date of May 31 2013 (maximum time on study was 41 months). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.15% 4/2701 • From randomization until the adjudication cut-off date of May 31 2013 (maximum time on study was 41 months). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Cardiac disorders Left ventricular failure	0.07% 2/2679 • From randomization until the adjudication cut-off date of May 31 2013 (maximum time on study was 41 months). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.11% 3/2701 • From randomization until the adjudication cut-off date of May 31 2013 (maximum time on study was 41 months). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Cardiac disorders Cardiopulmonary failure	0.04% 1/2679 • From randomization until the adjudication cut-off date of May 31 2013 (maximum time on study was 41 months). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.11% 3/2701 • From randomization until the adjudication cut-off date of May 31 2013 (maximum time on study was 41 months). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Cardiac disorders Mitral valve incompetence	0.07% 2/2679 • From randomization until the adjudication cut-off date of May 31 2013 (maximum time on study was 41 months). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.04% 1/2701 • From randomization until the adjudication cut-off date of May 31 2013 (maximum time on study was 41 months). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Cardiac disorders Silent myocardial infarction	0.07% 2/2679 • From randomization until the adjudication cut-off date of May 31 2013 (maximum time on study was 41 months). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.04% 1/2701 • From randomization until the adjudication cut-off date of May 31 2013 (maximum time on study was 41 months). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Cardiac disorders Tachycardia	0.11% 3/2679 • From randomization until the adjudication cut-off date of May 31 2013 (maximum time on study was 41 months). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/2701 • From randomization until the adjudication cut-off date of May 31 2013 (maximum time on study was 41 months). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Cardiac disorders Acute left ventricular failure	0.00% 0/2679 • From randomization until the adjudication cut-off date of May 31 2013 (maximum time on study was 41 months). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.07% 2/2701 • From randomization until the adjudication cut-off date of May 31 2013 (maximum time on study was 41 months). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Cardiac disorders Arteriosclerosis coronary artery	0.04% 1/2679 • From randomization until the adjudication cut-off date of May 31 2013 (maximum time on study was 41 months). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.04% 1/2701 • From randomization until the adjudication cut-off date of May 31 2013 (maximum time on study was 41 months). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Cardiac disorders Atrial tachycardia	0.07% 2/2679 • From randomization until the adjudication cut-off date of May 31 2013 (maximum time on study was 41 months). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/2701 • From randomization until the adjudication cut-off date of May 31 2013 (maximum time on study was 41 months). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Cardiac disorders Cardiac discomfort	0.07% 2/2679 • From randomization until the adjudication cut-off date of May 31 2013 (maximum time on study was 41 months). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/2701 • From randomization until the adjudication cut-off date of May 31 2013 (maximum time on study was 41 months). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Cardiac disorders Cardiorenal syndrome	0.04% 1/2679 • From randomization until the adjudication cut-off date of May 31 2013 (maximum time on study was 41 months). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.04% 1/2701 • From randomization until the adjudication cut-off date of May 31 2013 (maximum time on study was 41 months). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Cardiac disorders Coronary artery insufficiency	0.00% 0/2679 • From randomization until the adjudication cut-off date of May 31 2013 (maximum time on study was 41 months). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.07% 2/2701 • From randomization until the adjudication cut-off date of May 31 2013 (maximum time on study was 41 months). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Cardiac disorders Left ventricular dysfunction	0.04% 1/2679 • From randomization until the adjudication cut-off date of May 31 2013 (maximum time on study was 41 months). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.04% 1/2701 • From randomization until the adjudication cut-off date of May 31 2013 (maximum time on study was 41 months). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Cardiac disorders Postinfarction angina	0.07% 2/2679 • From randomization until the adjudication cut-off date of May 31 2013 (maximum time on study was 41 months). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.00% 0/2701 • From randomization until the adjudication cut-off date of May 31 2013 (maximum time on study was 41 months). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Cardiac disorders Right ventricular failure	0.04% 1/2679 • From randomization until the adjudication cut-off date of May 31 2013 (maximum time on study was 41 months). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.	0.04% 1/2701 • From randomization until the adjudication cut-off date of May 31 2013 (maximum time on study was 41 months). At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.