TOPCAT: Aldosterone Antagonist Therapy for Adults With Heart Failure and Preserved Systolic Function

• Sponsor: HealthCore-NERI (Other)
• Overall Status: Completed
• CT.gov ID: NCT00094302
• Collaborator: National Heart, Lung, and Blood Institute (NHLBI) (NIH)
• Enrollment: 3,445
• Locations: 270
• Arms: 2
• Duration (Months): 82
• Patients Per Site: 12.8
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

The purpose of this study is to evaluate the effectiveness of aldosterone antagonist therapy in reducing cardiovascular mortality, aborted cardiac arrest, and heart failure hospitalization in patients who have heart failure with preserved systolic function.

Condition or Disease	Intervention/Treatment	Phase
Cardiovascular Diseases; Heart Diseases; Heart Failure, Congestive	Drug: Spironolactone; Drug: Placebo	Phase 3

Detailed Description

BACKGROUND:

Heart failure (HF) is a major cause of morbidity and mortality, particularly in older people. Indeed, it is the most common discharge diagnosis in patients older than 65 years. As the United States population ages, heart failure will continue to grow as a public health concern. Therapeutic trials of heart failure have dealt almost exclusively with patients who have systolic dysfunction. However, there is now an emerging awareness that nearly half of the patients with heart failure have preserved systolic function and that the survival of these patients is adversely affected. This study is a randomized clinical trial of a novel therapeutic approach, specifically the use of spironolactone, an aldosterone antagonist, in treating these patients. While this treatment has been shown to be useful in treating heart failure with reduced systolic function, it has not been studied in patients with preserved systolic function.

Patients with heart failure and preserved systolic function have a poor prognosis. The annual mortality rate is intermediate between the prognosis for those without heart failure and for those with heart failure and reduced systolic function. For instance, Family Health Study participants with heart failure and preserved systolic function had a mortality rate of 9% compared to 3% for their age- and gender-matched controls. The mortality rate was 19% in heart failure patients with reduced systolic function heart failure compared to 4% for their matched controls.

As heart failure develops, neurohormones are released that initially improve cardiac output but ultimately contribute to progression of left ventricular dysfunction. The renin-angiotensin-aldosterone system is an important part of this compensatory response. Aldosterone levels may rise to 20 times normal levels in heart failure and aldosterone contributes to the development of myocardial fibrosis. Spironolactone is a potassium-sparing diuretic that acts on the distal tubule, inhibiting sodium and potassium ion exchange. There are several potential beneficial actions, including prevention of cardiac fibrosis. A recent trial evaluated spironolactone in patients with systolic dysfunction heart failure. Spironolactone treatment caused a 30% reduction in mortality compared to placebo (p< 0.001). The improvement resulted from a reduction in all cause mortality. More recently, the Eplerenone Post-Myocardial Infarction (MI) study showed that this aldosterone antagonist significantly reduces mortality despite background treatment with an angiotensin-converting enzyme (ACE) inhibitor and beta-blocker. Advantages of using spironolactone in this study are that it is commercially available, inexpensive, and no longer under patent (therefore this study will not be done by industry). Also, there is a clear physiologic rationale for its use, and the side effect profile is well understood. The study enrolled subjects who had preserved systolic function with heart failure and who met clearly defined eligibility criteria that were selected to make the results widely generalizable to clinical practice.

DESIGN NARRATIVE:

This is a randomized, double-blinded, placebo-controlled trial of aldosterone antagonist therapy (15 mg dose spironolactone or placebo; titrated up to 30 or 45 mg/day) in 3,445 adult patients with heart failure and preserved systolic function. Patients were recruited from August 2006 through January 2012, treated, and will be followed through June 2013. Approximately 270 clinical sites in six countries were subcontracted by the clinical trial coordinating center. Subject visits to a clinical center will occur every four or six months. Data collected include demographic and clinical data, including the results of history and physical exams, laboratory and imaging data, repository specimens for special physiology studies, and genetic studies. Additionally, data regarding quality of life and compliance with assigned treatment will also be collected and assessed.

Study Design

• Study Type: Interventional
• Actual Enrollment: 3445 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Care Provider, Investigator)
• Primary Purpose: Treatment
• Official Title: Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist (TOPCAT)
• Study Start Date: Aug 1, 2006
• Actual Primary Completion Date: Jun 1, 2013
• Actual Study Completion Date: Jun 1, 2013

Arms and Interventions

Arm	Intervention/Treatment
Placebo Comparator: Placebo Placebo of spironolactone	Drug: Placebo; Placebo of spironolactone
Experimental: Spironolactone Spironolactone (an aldosterone antagonist) is supplied as 15 mg tablets. Drug is taken orally by subjects. The initial study drug dose is 15 mg/day (one tablet) and may be titrated up to 30 mg/day (two tablets) or 45 mg/day (three tablets). Subjects are on study drug for the duration of the trial.	Drug: Spironolactone; Spironolactone (an aldosterone antagonist) is supplied as 15 mg tablets. Drug is taken orally by subjects. The initial study drug dose is 15 mg/day (one tablet) and may be titrated up to 30 mg/day (two tablets) or 45 mg/day (three tablets). Subjects are on study drug for the duration of the trial.; Other Names: aldosterone antagonist

Outcome Measures

Primary Outcome Measures

1. Composite Outcome of Cardiovascular Mortality, Aborted Cardiac Arrest, or Hospitalization for the Management of Heart Failure, Whichever Occurred First [Randomization through each subject's last semi-annual visit, up to a maximum of 6 years per subject.]

Secondary Outcome Measures

1. Cardiovascular Mortality [Randomization through each subject's last semi-annual visit, up to a maximum of 6 years per subject.]

2. Aborted Cardiac Arrest [Randomization through each subject's last semi-annual visit, up to a maximum of 6 years per subject.]

   First incidence of aborted cardiac arrest

3. Hospitalization for the Management of Heart Failure [Randomization through each subject's last semi-annual visit, up to a maximum of 6 years per subject.]

   First incidence of a hospitalization for the management of heart failure

4. All-cause Mortality [Randomization through each subject's last semi-annual visit, up to a maximum of 6 years per subject.]

5. Composite Outcome of Cardiovascular Mortality or Cardiovascular-related Hospitalization (i.e., Hospitalization for Myocardial Infarction(MI), Stroke, or the Management of Heart Failure), Whichever Occurred First [Randomization through each subject's last semi-annual visit, up to a maximum of 6 years per subject.]

6. Cardiovascular-related Hospitalization [Randomization through each subject's last semi-annual visit, up to a maximum of 6 years per subject.]

   Hospitalization for MI, stroke or the management of heart failure, whichever occurred first

7. Total Hospitalizations (Including Repeat Hospitalizations) for the Management of Heart Failure [Randomization through each subject's last semi-annual visit, up to a maximum of 6 years per subject.]

8. Composite Outcome of Sudden Death or Aborted Cardiac Arrest, Whichever Occurred First [Randomization through each subject's last semi-annual visit, up to a maximum of 6 years per subject.]

9. New Onset Diabetes Mellitus, Among Subjects Without a History of Diabetes Mellitus at Baseline. [Randomization through each subject's last semi-annual visit, up to a maximum of 6 years per subject.]

   First incidence of new onset diabetes mellitus among subjects without a history of diabetes mellitus at baseline.

10. Development of Atrial Fibrillation, Among Subjects Without a History of Atrial Fibrillation at Baseline. [Randomization through each subject's last semi-annual visit, up to a maximum of 6 years per subject.]

    First incidence of atrial fibrillation among subjects without a history of atrial fibrillation at baseline

11. Myocardial Infarction [Randomization through each subject's last semi-annual visit, up to a maximum of 6 years per subject.]

    First incidence of myocardial infarction

12. Stroke [Randomization through each subject's last semi-annual visit, up to a maximum of 6 years per subject.]

    First incidence of stroke

13. Deterioration of Renal Function [Randomization through each subject's last semi-annual visit, up to a maximum of 6 years per subject.]

    First incidence of a deterioration of renal function. The TOPCAT protocol defines deterioration of renal function as occurring if a subject has a serum creatinine value which is at least double the baseline value for that subject, and is also above the upper limit of normal (assumed to be 1.0 mg/dL for females and 1.2 mg/dL for males.)

14. Composite Outcome of Sudden Death, Aborted Cardiac Arrest, or Hospitalization for the Management of Ventricular Tachycardia, Whichever Occurred First [Randomization through each subject's last semi-annual visit, up to a maximum of 6 years per subject.]

15. Quality of Life, as Measured by the Kansas City Cardiomyopathy Questionnaire. [Randomization through each subject's last semi-annual visit, up to a maximum of 6 years per subject.]

    Average post-baseline quality of life, taking into consideration baseline quality of life, treatment group, the time between the post-baseline measures, and the correlation between repeated measures within an individual. The Kansas City Cardiomyopathy Questionnaire (KCCQ) is a 23-item, self-administered instrument that quantifies physical function, symptoms (frequency, severity and recent change), social function, self-efficacy and knowledge, and quality of life. Scores are transformed to a range of 0-100, in which higher scores reflect better health status. The KCCQ was administered at the following study visits: baseline, month 4, month 12 and annually thereafter.

16. Quality of Life, as Measured by the EuroQOL Visual Analog Scale. [Randomization through each subject's last semi-annual visit, up to a maximum of 6 years per subject.]

    Average post-baseline quality of life, taking into consideration baseline quality of life, treatment group, the time between the post-baseline measures, and the correlation between repeated measures within an individual. The EuroQOL visual analog scale (EQ5D) is a single-item, self-administered instrument that quantifies current health status. Scores can range from 0-100, in which higher scores reflect better health status. The EQ5D was administered at the following study visits: baseline, month 4, month 12 and annually thereafter.

17. Quality of Life, as Measured by McMaster Overall Treatment Evaluation Questionnaire. [Randomization through each subject's last semi-annual visit, up to a maximum of 6 years per subject.]

    Average post-baseline quality of life, taking into consideration baseline quality of life and treatment group. The McMaster Overall Treatment Evaluation questionnaire is a self-administered 3-item instrument that measures a patient's perception of change in their health-related quality of life since the start of therapy. The questionnaire consists of a single question - "Since treatment started, has there been any change in your activity limitation, symptoms and/or feelings related to your heart condition?" Scores can range from -7 to +7, and higher scores reflect better health status. The questionnaire was administered at the following study visits: month 4 and month 12. Valid translations of this questionnaire were only available for subjects enrolled in the United States, Canada and Argentina.

18. Depression Symptoms, as Measured by Patient Health Questionnaire. [Randomization through each subject's last semi-annual visit, up to a maximum of 6 years per subject.]

    Average post-baseline depression, taking into consideration baseline depression, treatment group, the time between the post-baseline measures, and the correlation between repeated measures within an individual. The Patient Health Questionnaire (PHQ) is a 10-item, self-administered instrument for screening, diagnosing, monitoring and measuring the severity of depression. Scores can range from 0-27, in which lower scores reflect better mental health status. The PH-Q was administered at the following study visits: baseline, month 12 and annually thereafter. Valid translations of this questionnaire were only available for subjects enrolled in the United States and Canada.

19. Hospitalization for Any Reason [Randomization through each subject's last semi-annual visit, up to a maximum of 6 years per subject.]

    First incidence of a hospitalization for any reason

20. Potassium [Randomization through each subject's last semi-annual visit, up to a maximum of 6 years per subject.]

    Average post-baseline Potassium, taking into consideration baseline Potassium, treatment group, the time between the post-baseline measures, and the correlation between repeated measures within an individual.

21. Serum Creatinine [Randomization through each subject's last semi-annual visit, up to a maximum of 6 years per subject.]

    Average post-baseline serum creatinine, taking into consideration baseline serum creatinine, treatment group, the time between the post-baseline measures, and the correlation between repeated measures within an individual.

22. Sodium [Randomization through each subject's last semi-annual visit, up to a maximum of 6 years per subject.]

    Average post-baseline Sodium, taking into consideration baseline Sodium, treatment group, the time between the post-baseline measures, and the correlation between repeated measures within an individual.

23. Chloride [Randomization through each subject's last semi-annual visit, up to a maximum of 6 years per subject.]

    Average post-baseline Chloride, taking into consideration baseline Chloride, treatment group, the time between the post-baseline measures, and the correlation between repeated measures within an individual.

24. Estimated Glomerular Filtration Rate (GFR) [Randomization through each subject's last semi-annual visit, up to a maximum of 6 years per subject.]

    Average post-baseline GFR, taking into consideration baseline GFR, treatment group, the time between the post-baseline measures, and the correlation between repeated measures within an individual.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 50 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

INCLUSION CRITERIA:

• Heart failure as defined by at least one of symptom (paroxysmal nocturnal dyspnea; orthopnea; or dyspnea on mild or moderate exertion) at the time of screening and at least one sign (any rales post cough; jugular venous pressure(JVP) greater than or equal to 10cm of water(H2O); lower extremity edema; or chest x-ray demonstrating pleural effusion, pulmonary congestion, or cardiomegaly) within 12 months prior to study entry:

• left ventricular ejection fraction greater than or equal to 45% (per local reading); the ejection fraction must have been obtained within 6 months prior to randomization and after any MI or other event that would affect ejection fraction

• Controlled systolic blood pressure(BP), defined as a target systolic BP less than 140 mm Hg; participants with BP up to and including 160 mm Hg are eligible for enrollment if they are on three or more medications to control BP

• Serum potassium less than 5.0 mmol/L prior to randomization

• At least one hospital admission for which heart failure was a major component of the hospitalization some time within the 12 months prior to study entry OR brain natriuretic peptide (BNP) greater than or equal to 100pg/ml or N-terminal pro-BNP greater than or equal to 360pg/ml within the 60 days prior to study entry

• Women of child-bearing potential must have a negative serum/urine pregnancy test within 72 hours prior to randomization, must not be lactating, and must agree to use an effective method of contraception during the entire course of study participation

• Willing to comply with scheduled visits

• Informed consent form signed by the subject prior to participation in the trial

EXCLUSION CRITERIA:

• Severe systemic illness with an expected life expectancy of less than 3 years

• Chronic pulmonary disease requiring home O2, oral steroid therapy, or hospitalization for exacerbation within 12 months of study entry, or significant chronic pulmonary disease in the opinion of the investigator

• Known infiltrative or hypertrophic obstructive cardiomyopathy or known pericardial constriction

• Primary hemodynamically significant uncorrected valvular heart disease, obstructive or regurgitant, or any valvular disease expected to lead to surgery during the trial

• Atrial fibrillation with a resting heart rate greater than 90 bpm

• MI in the past 90 days

• Coronary artery bypass graft surgery in the past 90 days

• Percutaneous coronary intervention in the past 30 days

• Heart transplant recipient

• Currently implanted left ventricular assist device

• Stroke in past 90 days

• Systolic BP (SBP) greater than 160 mm Hg

• Known orthostatic hypotension

• Gastrointestinal disorder that could interfere with study drug absorption

• Use of any aldosterone antagonist or potassium sparing medication in the last 14 days or any known condition that would require the use of an aldosterone antagonist during study participation;

• Known intolerance to aldosterone antagonists

• Current lithium use

• Current participation (including prior 30 days) in any other therapeutic trial

• Any condition that, in the opinion of the investigator, may prevent the participant from adhering to the trial protocol

• History of hyperkalemia (serum potassium greater than or equal to 5.5mmol/L) in the past 6 months or serum potassium greater than or equal to 5.0mmol/L within the past 2 weeks

• Severe renal dysfunction, defined as an estimated glomerular filtration rate(GFR) less than 30ml/min. Participants with serum creatinine greater than or equal to 2.5mg/dl are also excluded even if their GFR is greater than or equal to 30ml/min

• Known chronic hepatic disease, defined as aspartate aminotransferase(AST) and alanine aminotransferase(ALT) levels greater than 3.0 times the upper limit of normal as read at the local lab.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Alabama at Birmingham	Birmingham	Alabama	United States	35294
2	Cardiovascular Consultants, Ltd.	Glendale	Arizona	United States	85306
3	Carl T. Hayden VA Medical Center	Phoenix	Arizona	United States	85012
4	Central Arkansas Veterans Healthcare System	Little Rock	Arkansas	United States	72205
5	Heart Clinic Arkansas	Little Rock	Arkansas	United States	72205
6	Cynthia Thaik	Burbank	California	United States	91505
7	Fresno VA Medical Center	Fresno	California	United States	93703
8	Clinica Medica San Miguel	Los Angeles	California	United States	90015
9	CAPRI	Los Angeles	California	United States	90048
10	VA Medical Center West Los Angeles	Los Angeles	California	United States	90073
11	Mehrdad Kevin Ariani, MD, Inc.	Northridge	California	United States	91325
12	UC Davis Medical Center	Sacremento	California	United States	95829
13	Central Coast Cardiology	Salinas	California	United States	93901
14	Naval Medical Center San Diego	San Diego	California	United States	92134
15	Olive View - UCLA Medial Center	Sylmar	California	United States	91342
16	University of Colorado Health Sciences Center	Aurora	Colorado	United States	80045
17	Cardio-Vascular Institute	Greeley	Colorado	United States	80631
18	University of Connecticut Health Center	Farmington	Connecticut	United States	06030
19	Howard University Hospital	Washington DC	District of Columbia	United States	20060'
20	Washington Hospital Center	Washington	District of Columbia	United States	20010
21	Washington DC VA Hospital	Washington	District of Columbia	United States	20422
22	Daytona Heart Group	Daytona Beach	Florida	United States	32114
23	M & O Clinical Research, LLC	Ft. Lauderdale	Florida	United States	33316
24	Florida Heart Center	Ft. Pierce	Florida	United States	34950
25	University of Florida	Gainesville	Florida	United States	32610
26	Mayo Clinic Florida	Jacksonville	Florida	United States	32224
27	Brevard Cardiovascular Research Associates, Inc	Rockledge	Florida	United States	37955
28	Tallahassee Research Institute	Tallahassee	Florida	United States	32308
29	Emory University at Grady Health System	Atlanta	Georgia	United States	30303
30	Morehouse School of Medicine	Atlanta	Georgia	United States	30310
31	Northside Cardiology Center	Atlanta	Georgia	United States	30342
32	InnovaMed Alliance	Marietta	Georgia	United States	30060
33	Rush University Medical Center	Chicago	Illinois	United States	60612
34	University of Illinois at Chicago Medical Center	Chicago	Illinois	United States	60612
35	Northwestern University	Chicago	Illinois	United States	60657
36	Cardiovascular Research Foundation	Elk Grove Village	Illinois	United States	60007
37	Heart, Lung and Vascular Institute	Peoria	Illinois	United States	61606
38	HeartCare Midwest	Peoria	Illinois	United States	61614
39	The Care Group, LLC	Indianapolis	Indiana	United States	46260
40	Cardiovascular Research of Northwest Indiana, LLC	Munster	Indiana	United States	46321
41	University of Iowa Hospitals and Clinics	Iowa City	Iowa	United States	52242
42	Baptist Healthcare System, Inc. d/b/a Baptist Hospital East	Louisville	Kentucky	United States	40207
43	Leonard J. Chabert Medical Center	Houma	Louisiana	United States	70363
44	Ochsner Clinic Foundation	New Orleans	Louisiana	United States	70121
45	Northeast Cardiology	Bangor	Maine	United States	04401
46	University of Maryland Medical Center	Baltimore	Maryland	United States	21201
47	Sinai Hospital of Baltimore	Baltimore	Maryland	United States	21215
48	Kaiser Permanente	Largo	Maryland	United States	20774
49	Northwest Hospital	Randallstown	Maryland	United States	21133
50	Delmarva Heart Research Foundation	Salisbury	Maryland	United States	21804
51	Associates in Cardiology, PA	Silver Spring	Maryland	United States	20910
52	Brigham and Women's Hospital	Boston	Massachusetts	United States	02115
53	Boston University Medical Center	Boston	Massachusetts	United States	02118
54	Caritas St. Elizabeth's Medical Center	Boston	Massachusetts	United States	02135
55	Merrimack Valley Cardiology Associates	Chelmsford	Massachusetts	United States	01824
56	Compass Medical East Bridgewater	East Bridgewater	Massachusetts	United States	02333
57	Pentucket Medical Associates	Haverhill	Massachusetts	United States	01830
58	Charles River Medical Associates	Natick	Massachusetts	United States	01760
59	Hawthorn Medical Associates	North Dartmouth	Massachusetts	United States	02747
60	Baystate Medical Center	Springfield	Massachusetts	United States	01199
61	Umass Memorial Medical Center	Worcester	Massachusetts	United States	01655
62	Veterans Affairs Ann Arbor Health Care System	Ann Arbor	Michigan	United States	48105
63	Oakwood Hospital and Medical Center	Dearborn	Michigan	United States	48123
64	Detroit VA Medical Center	Detroit	Michigan	United States	48201
65	Henry Ford Hospital	Detroit	Michigan	United States	48202
66	William Beaumont Health Center	Royal Oak	Michigan	United States	48073
67	Minneapolis VA Medical Center	Minneapolis	Minnesota	United States	55417
68	Heartland Regional Medical Clinic	St. Joseph	Missouri	United States	64506
69	Glacier View Cardiology	Kalispell	Montana	United States	59901
70	Bryan LGH Heart Institute	Lincoln	Nebraska	United States	68506
71	The Creighton Cardiac Center	Omaha	Nebraska	United States	68131
72	Deborah Heart and Lung Center	Browns Mills	New Jersey	United States	08015
73	Cardiovascular Associates of the Delaware Valley	Elmer	New Jersey	United States	08318
74	Cardiovascular Associates of the Delaware Valley	Haddon Heights	New Jersey	United States	08035
75	NJ Heart	Linden	New Jersey	United States	07036
76	St. Joseph's Regional Medical Center	Paterson	New Jersey	United States	07503
77	The Valley Hospital	Ridgewood	New Jersey	United States	07450
78	Electrophysiology Research Foundation	Somerset	New Jersey	United States	08873
79	Community Medical Center	Toms River	New Jersey	United States	08755
80	New Jersey Cardiology Associates	West Orange	New Jersey	United States	07052
81	Bronx-Lebanon Hospital Center	Bronx	New York	United States	10457
82	New York Methodist Hospital	Brooklyn	New York	United States	11215
83	Research Foundation State University of New York at Buffalo	Buffalo	New York	United States	14203
84	Buffalo Heart Group, LLC	Buffalo	New York	United States	14215
85	Jamaica Hospital Medical Center	Jamaica	New York	United States	11418
86	Mid Valley Cardiology	Kingston	New York	United States	12401
87	Winthrop Cardiology Associates	Mineola	New York	United States	11501
88	Soundshore Medical Center of Westchester	New Rochelle	New York	United States	10802
89	NYU School of Medicine	New York	New York	United States	10016
90	St. Lukes Roosevelt	New York	New York	United States	10019
91	Northport VA Medical Center	Northport	New York	United States	11768
92	University of Rochester Medical Center	Rochester	New York	United States	14618
93	Lewin, Fagen, and Lown, MD, PC	Smithtown	New York	United States	11787
94	SUNY Upstate Medical Center	Syracuse	New York	United States	13210
95	Syracuse VA Medical Center	Syracuse	New York	United States	13210
96	Northeast Medical Center	Concord	North Carolina	United States	28025
97	Durham VA Medical Center	Durham	North Carolina	United States	27705
98	Wake Forest University Health Sciences	Winston-Salem	North Carolina	United States	27157
99	The Lindner Clinical Trial Center	Cincinnati	Ohio	United States	45219
100	University of Cincinnati	Cincinnati	Ohio	United States	45267
101	University Hospitals of Cleveland/Case Western Reserve University	Cleveland	Ohio	United States	44106
102	MetroHealth Medical Center	Cleveland	Ohio	United States	44109
103	Ohio State University Hospital East	Columbus	Ohio	United States	43205
104	VAMC Dayton	Dayton	Ohio	United States	45428
105	CCHS Clinical Research Office/Marymount Hospital	Garfield Heights	Ohio	United States	44125
106	CCHS Clinical Research Office/ Hillcrest Hospital	Mayfield Heights	Ohio	United States	44124
107	COR Clinical Research	Oklahoma City	Oklahoma	United States	73103
108	Oklahoma City VA Medical Center	Oklahoma City	Oklahoma	United States	73104
109	Oklahoma Foundation for Cardiovascular Research	Oklahoma City	Oklahoma	United States	73210
110	Oklahoma Heart Institute	Tulsa	Oklahoma	United States	74137
111	St. Charles Health System	Bend	Oregon	United States	97701
112	Providence Heart and Vascular Institute	Portland	Oregon	United States	97213
113	Capital Area Research	Camp Hill	Pennsylvania	United States	17011
114	Geisinger Medical Center	Danville	Pennsylvania	United States	17822
115	Medicor Associates, Inc	Erie	Pennsylvania	United States	16507
116	The Milton S. Hershey Medical Center	Hershey	Pennsylvania	United States	17033
117	Lancaster Heart and Stroke Foundation	Lancaster	Pennsylvania	United States	17603
118	Drexel University College of Medicine	Philadelphia	Pennsylvania	United States	19102
119	University of Pennsylvania	Philadelphia	Pennsylvania	United States	19104
120	Thomas Jefferson University Hospital- Dept. of Family and Community Health	Philadelphia	Pennsylvania	United States	19107
121	Thomas Jefferson University	Philadelphia	Pennsylvania	United States	19107
122	Temple University Hospital	Philadelphia	Pennsylvania	United States	19140
123	Eastwick Primary Care	Philadelphia	Pennsylvania	United States	19153
124	Pittsburgh VA Healthcare System	Pittsburgh	Pennsylvania	United States	15240
125	The Reading Hospital and Medical Center	West Reading	Pennsylvania	United States	19611
126	Memorial Hospital Rhode Island	Pawtucket	Rhode Island	United States	02860
127	VAMC - Charleston, SC	Charleston	South Carolina	United States	29401
128	Black Hills VA Health Care System	Ft. Meade	South Dakota	United States	57741
129	The Stern Cardiovascular Center	Germantown	Tennessee	United States	38138
130	Memphis VA Medical Center	Memphis	Tennessee	United States	38104
131	Memphis Heart Clinic	Memphis	Tennessee	United States	38120
132	University of Tennessee Health Science Center	Memphis	Tennessee	United States	38163
133	Vanderbilt Heart and Vascular Institute	Nashville	Tennessee	United States	37232
134	DCT - APHC, LLC dba Discovery Clinical Trials	Arlington	Texas	United States	76014
135	Dallas VA Medical Center	Dallas	Texas	United States	75216
136	Cardiovascular Research Institute of Dallas	Dallas	Texas	United States	75231
137	U.T. Southwestern Medical Center	Dallas	Texas	United States	75390
138	Michael E. DeBakey VA Medical Cntr.	Houston	Texas	United States	77030
139	The Methodist Hospital Research Institute	Houston	Texas	United States	77030
140	Wilford Hall Medical Center	Lackland	Texas	United States	78236
141	Texas Tech University Health Sciences Center	Odessa	Texas	United States	79763
142	Cardiology Clinic of San Antonio	San Antonio	Texas	United States	78229
143	Tyler Cardiovascular Consultants	Tyler	Texas	United States	75701
144	LDS Hospital	Murray	Utah	United States	84157
145	University of Utah	Salt Lake City	Utah	United States	84132
146	Cardiovascular Associates Ltd.	Chesapeake	Virginia	United States	23320
147	Sentara Cardiovascular Research Institute	Norfolk	Virginia	United States	23507
148	Evergreen Healthcare	Kirkland	Washington	United States	98034
149	Providence St. Peter Hospital	Olympia	Washington	United States	98506
150	Sound Health Research	Port Orchard	Washington	United States	98366
151	University of Washington	Seattle	Washington	United States	98195
152	CAMC Health Education and Research Institute	Charleston	West Virginia	United States	25304
153	William S. Middleton Memorial VA Hospital	Madison	Wisconsin	United States	53705
154	University of Wisconsin-Madison	Madison	Wisconsin	United States	53792
155	Aspirus Heart and Vascular Institute	Wausau	Wisconsin	United States	54401
156	Instituto de Investigaciones Clinicas de Bahia Blanca	Bahia Blanca	Buenos Aires	Argentina	B80001JH
157	Clinica Coronel Suarez	Coronel Suarez	Buenos Aires	Argentina	b7540ghd
158	Hospital Italiano de La Plata	La Plata	Buenos Aires	Argentina	B1900 AXI
159	Instituto de Investigaciones Clinicas de Mar Del Plata	Mar del Plata	Buenos Aires	Argentina	B7600 FZN
160	Instituto de Investigaciones Clinicas de Quilmes	Quilmes	Buenos Aires	Argentina	1878
161	Policlinico Modelo de Cipoletti	Cipolletti	Rio Negro	Argentina	8324
162	IMAI Research	Buenos Aires		Argentina	1425
163	CIPREC	Buenos Aires		Argentina	C1119ACN
164	Instituto Cardiologico Ezpecializado S.R.L	Buenos Aires		Argentina	C1426 ANZ
165	Clinica IMA	Buenos Aires		Argentina	J846
166	Clinica Privada Del Prado	Cordoba		Argentina	X500AAW
167	Instituto de Investigaciones Clinicas de Rosario	Rosario Santa Fe		Argentina	2000
168	Hospital San Bernardo	Salta		Argentina	A4406CLA
169	Centro de Investigaciones Clinicas del Litoral SRL	Santa Fe		Argentina	3000
170	Sanatorio Mayo S.A.	Santa Fe		Argentina
171	Centro Privado de Cardiologia	Tucuman		Argentina	T4000NIL
172	Centro Modelo de Cardiología	Tucuman		Argentina
173	Instituto de Cardiologia SRL	Tucuman		Argentina
174	Hospital Felicio Rocho	Belo Horizonte		Brazil
175	Santa Casa De Belo Horizonte	Belo Horizonte		Brazil
176	HMCP PUC Campinas	Campinas		Brazil
177	Irmandade da Santa Casa de Misericordia de Curitiba	Curitiba Parana		Brazil
178	Hospital das Clinicas da Universidade Federal de Goias	Goias		Brazil
179	Instituto do Coracao de Marilia	Marilia Sao Paulo		Brazil
180	Hospital Sao Vicente de Paulo	Passo Fundo		Brazil
181	PROCAPE	Pernambuco		Brazil
182	Hospital de Clinicas de Porto Alegre	Porto Alegre		Brazil	90035-903
183	Hospital Mae De Deus	Porto Alegre		Brazil
184	Hospital Universitario Pedro Ernesto	Rio de Janeiro		Brazil
185	Santa Casa de Misericordia do Rio de Janeiro	Rio de Janeiro		Brazil
186	Instituto de Molestias Cardiosvaculares	San Paulo		Brazil
187	Instituto de Cardiologia de Santa Catarina	Santa Catarina		Brazil
188	Incor Fmusp	Sao Paulo		Brazil
189	UNIFESP/Hospital Sao Paulo	Sao Paulo		Brazil
190	Instituto do Coracao do Triangulo Mineiro	Uberlandia		Brazil
191	University of Calgary	Calgary	Alberta	Canada	T2N 4N1
192	Fraser Clinical Trials Inc.	New Westminster	British Columbia	Canada	V3L 3W4
193	St. Boniface General Hospital	Winnipeg	Manitoba	Canada	R2H2A6
194	Health Science Centre	St. John's	Newfoundland and Labrador	Canada	AIB 3V6
195	Capital District Health Authority	Halifax	Nova Scotia	Canada	B3H 3A7
196	Dr. Saul Vizel Cardiac Research Office	Cambridge	Ontario	Canada	N1R 7R1
197	Cornwall Clinical Trials	Cornwall	Ontario	Canada	K6H 4M4
198	Hamilton Health Sciences - General Site	Hamilton	Ontario	Canada	L8L 2X2
199	London Health Sciences Center	London	Ontario	Canada	N6A 5A5
200	Ottawa Heart Institute	Ottawa	Ontario	Canada	K1Y 4W7
201	Dr. Gurcharan Syan (PP)	Sudbury	Ontario	Canada	P3C 5K7
202	St. Michael's Hospital	Toronto	Ontario	Canada	M5B 1W8
203	Mount Sinai Hospital	Toronto	Ontario	Canada	M5G1X5
204	CHUS - Hopital Fleurimont	Fleurimont	Quebec	Canada	J1H 5N4
205	Service de la Recherche	Granby	Quebec	Canada	J2G 1T7
206	Cite de la Sante de Laval	Laval	Quebec	Canada	H7M 3L9
207	Clinique Cardiologie Levis	Levis	Quebec	Canada	G6V 4Z5
208	Hopital Du Sacre Coeur de Montreal	Montreal	Quebec	Canada	A4J 1C5
209	Montreal Heart Institute	Montreal	Quebec	Canada	H1T 1C8
210	CHUM - Hotel Dieu	Montreal	Quebec	Canada	H2W 1T8
211	Chum Hotel Dieu	Montreal	Quebec	Canada	H2W IT8
212	Royal Victoria Hospital	Montreal	Quebec	Canada	H3A 1A1
213	Montreal General Hospital	Montreal	Quebec	Canada	H3G IA4
214	Centre de recherche clinique de Quebec	Quebec City	Quebec	Canada	G1J 1Z6
215	Centre Hosp Regional de Lanaudiere	Sainte Charles Borromee	Quebec	Canada	J6E 6J2
216	C.S.S.S.B.	St. George	Quebec	Canada	G5Y 4T8
217	Hopital Laval	Ste-Foy	Quebec	Canada	GIV 4G5
218	CSSS du Sud de Lanaudiere (Hopital Pierre-Le Gardeur)	Terrebonne	Quebec	Canada	J6V 2H2
219	Centre De Sante et De Services Sociaux De Thetford	Thetford-Mines	Quebec	Canada	G6G 2V4
220	Misericordia Hospital - Cardiac Sciences	Edmonton		Canada
221	CDRC Rive-Sud	Longueuil		Canada
222	SMBD Jewish General Hospital	Montreal		Canada
223	Saskatchewan Heart Centre	Saskatoon		Canada
224	Cardiology Clinical Trials - Surrey Memorial Hospital	Surrey		Canada
225	Centre Hospitalier de Trois-Rivieres	Trois Rivieres		Canada
226	L &J Clinic	Kutaisi		Georgia	4600
227	Tbilisi State Medical University Clinic #1	Tbilisi		Georgia	0102
228	Cardio-Reanimation Centre	Tbilisi		Georgia	0141
229	Multiprofile Clinical Hospital of Tbilisi #2	Tbilisi		Georgia	0154
230	Emergency Cardiology Centre	Tbilisi		Georgia	0159
231	National Center of Therapy	Tbilisi		Georgia	0159
232	Diagnostic Services Clinic	Tbilisi		Georgia	0179
233	Clinic of Angiocardiology "ADAPTI"	Tbilisi		Georgia	0186
234	Cardiology Clinic	Tibilisi		Georgia	0144
235	Municipal Healthcare Institution <>	Gatchina	Leningrad Region	Russian Federation	188300
236	Altay State Medical University of federal agency of public health and social progress RF	Barnaul		Russian Federation	656038
237	Municipal Health Care Institution "City Hospital #1"	Barnaul		Russian Federation	656099
238	Kaliningrad Region Hospital	Kaliningrad		Russian Federation	236016
239	Kemerovo Cadiologiy Dispensary, Kemerovo Medical Academy	Kemerovo		Russian Federation	650002
240	Nonstate Healthcare Institution	Kemerovo		Russian Federation	650036
241	State Healthcare Institution "Region Clinical Hospital #1	Krasnodar		Russian Federation	350086
242	National Research Center for Preventitive Medicine	Moscow		Russian Federation	101990
243	Russian State Medical University, Hospital Therapy Department #1	Moscow		Russian Federation	111539
244	State Education High Professional Education Russian State Medical University	Moscow		Russian Federation	115093
245	Federal State Institution "Outpatient clinic #3 of President's Management Department of Russian Fede	Moscow		Russian Federation	129090
246	Research Institute of Physico-Chemical Medicine Center for Atheosclerosis and Laboratory	Moscow		Russian Federation	777020
247	Non State Health Care Institution Central Hospital #6 of Russian Railways JSC	Moscow		Russian Federation
248	Novosibirsk Municipal Clinical Emergency Hosp. # 2	Novosibirsk		Russian Federation	630008
249	Saint-Petersburg State Healthcare Institution "City Alexander's Hospital"	Saint Petersburg		Russian Federation	193312
250	Saint-Petersburg State Institution of Health Protection, "City Hosptial # 15"	Saint Petersburg		Russian Federation	198205
251	Chair of Nephrology and Dialysis of St Petersburg State Medical University	Saint Petersburg		Russian Federation
252	Public Institution of Health City Hospital # 28	Saint-Petersburg		Russian Federation	190000
253	Federal State Health Care Institution	Saint-Petersburg		Russian Federation	194291
254	Medico- Military Academy, Navy Therapy Dept	Saint-Petersburg		Russian Federation	198013
255	Saint-Petersburg State Health Institution "Pokrovskaya City Hospital"	Saint-Petersburg		Russian Federation	199106
256	Federal State Institution	Saratov		Russian Federation	410028
257	State Educational Institution of High Professional Education Saratov State Medical University	Saratov		Russian Federation	410054
258	Almasov research institute of Cardiology	St. Petersberg		Russian Federation	194156
259	State Institution Saint-Petersburg Dzhanelidze Scientific	St. Petersburg		Russian Federation	192242
260	Saint-Petersburg Clinical Hospital of RAMS, policlinic department	St. Petersburg		Russian Federation	194017
261	Saint-Petersburg State Health Care Institution "City Hospital of Saint George the Martyr"	St. Petersburg		Russian Federation	194354
262	Non-state Health Care Institution	St. Petersburg		Russian Federation	195221
263	City Hospital #26	St. Petersburg		Russian Federation	196247
264	City Hospital No 26	St. Petersburg		Russian Federation	196247
265	Chair and Department of Hospital Therapy	St. Petersburg		Russian Federation	197089
266	State Institition Research Institution of Cardiology of Tomsk	Tomsk		Russian Federation	634012
267	State Educational institution of Higher Professional Education "Volgograd State Medical University o	Volgograd		Russian Federation	400001
268	State Health Care Institution "Voronezh Regional Clinical Consultative & Diagnostic Centre"	Voronezh		Russian Federation	396018
269	City Healthcare Institution Clinical Hospital #8	Yaroslavl		Russian Federation	150030
270	Yaroslavl Regional Clinical Hospital	Yaroslavl		Russian Federation	150068

Sponsors and Collaborators

• HealthCore-NERI
• National Heart, Lung, and Blood Institute (NHLBI)

Investigators

• Principal Investigator: Sonja M. McKinlay, PhD, New England Research Institutes, Inc.

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Link to PubMed Identification (ID) #22137068 publication in the American Heart Journal
• Link to PubMed ID #23258572 publication in Circulation: Heart Failure
• Link to PubMed ID #24249049 publication in Circulation: Heart Failure
• Link to PubMed ID #24716680 publication in the New England Journal of Medicine
• Link to PubMed ID #25122186 publication in Circulation: Heart Failure
• Link to PubMed ID #25406305 publication in Circulation

Publications

• Desai AS, Lewis EF, Li R, Solomon SD, Assmann SF, Boineau R, Clausell N, Diaz R, Fleg JL, Gordeev I, McKinlay S, O'Meara E, Shaburishvili T, Pitt B, Pfeffer MA. Rationale and design of the treatment of preserved cardiac function heart failure with an aldosterone antagonist trial: a randomized, controlled study of spironolactone in patients with symptomatic heart failure and preserved ejection fraction. Am Heart J. 2011 Dec;162(6):966-972.e10. doi: 10.1016/j.ahj.2011.09.007. Epub 2011 Nov 8.

• Responsible Party: HealthCore-NERI
• ClinicalTrials.gov Identifier: NCT00094302
• Other Study ID Numbers: 160; HHSN268200425207C
• First Posted: Oct 15, 2004
• Last Update Posted: Mar 2, 2015
• Last Verified: Jan 1, 2014

• Keywords provided by HealthCore-NERI: Heart Failure; Diastolic Heart Failure; Preserved Ejection Fraction
• Additional relevant MeSH terms: Heart Failure; Cardiovascular Diseases; Heart Diseases; Spironolactone; Mineralocorticoid Receptor Antagonists

Study Results

Participant Flow

Recruitment Details	TOPCAT enrolled 3445 patients with heart failure and preserved ejection fraction at 233 academic and community medical centers in 6 countries between August 2006 and January 2012. Trial follow-up ended in June 2013.
Pre-assignment Detail	Trial randomization was stratified by whether patients were enrolled into the study on the basis of having a hospitalization for heart failure within the past year (N=2,464) or having an elevated natriuretic peptide level within 60 days before randomization (N=981). The second criterion was considered only for those who did not meet the first.

Arm/Group Title	Placebo	Spironolactone
Arm/Group Description	Placebo of spironolactone	Spironolactone (an aldosterone antagonist) is supplied as 15 mg tablets. Drug is taken orally by subjects. The initial study drug dose is 15 mg/day (one tablet) and may be titrated up to 30 mg/day (two tablets) or 45 mg/day (three tablets). Subjects are on study drug for the duration of the trial.
Period Title: Overall Study
STARTED	1723	1722
COMPLETED	1306	1316
NOT COMPLETED	417	406

Baseline Characteristics

Arm/Group Title	Placebo	Spironolactone	Total
Arm/Group Description	Placebo of spironolactone	Spironolactone (an aldosterone antagonist) is supplied as 15 mg tablets. Drug is taken orally by subjects. The initial study drug dose is 15 mg/day (one tablet) and may be titrated up to 30 mg/day (two tablets) or 45 mg/day (three tablets). Subjects are on study drug for the duration of the trial.	Total of all reporting groups
Overall Participants	1723	1722	3445
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	649 37.7%	654 38%	1303 37.8%
>=65 years	1074 62.3%	1068 62%	2142 62.2%
Age (years) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [years]	68.7	68.7	68.7
Sex: Female, Male (Count of Participants)
Female	887 51.5%	888 51.6%	1775 51.5%
Male	836 48.5%	834 48.4%	1670 48.5%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	3 0.2%	6 0.3%	9 0.3%
Asian	9 0.5%	10 0.6%	19 0.6%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	149 8.6%	151 8.8%	300 8.7%
White	1537 89.2%	1525 88.6%	3062 88.9%
More than one race	0 0%	2 0.1%	2 0.1%
Unknown or Not Reported	25 1.5%	28 1.6%	53 1.5%
Region of Enrollment (participants) [Number]
United States	579 33.6%	572 33.2%	1151 33.4%
Canada	160 9.3%	166 9.6%	326 9.5%
Argentina	60 3.5%	63 3.7%	123 3.6%
Brazil	82 4.8%	85 4.9%	167 4.8%
Russian Federation	537 31.2%	529 30.7%	1066 30.9%
Georgia	305 17.7%	307 17.8%	612 17.8%
Eligibility Stratum (participants) [Number]
Hospitalization in previous year for heart failure	1232 71.5%	1232 71.5%	2464 71.5%
Elevated natriuretic peptide in previous 60 days	491 28.5%	490 28.5%	981 28.5%

Outcome Measures

1. Primary Outcome

Title	Composite Outcome of Cardiovascular Mortality, Aborted Cardiac Arrest, or Hospitalization for the Management of Heart Failure, Whichever Occurred First
Time Frame	Randomization through each subject's last semi-annual visit, up to a maximum of 6 years per subject.

Outcome Measure Data

Analysis Population Description

All Participants who were randomized were included in the analysis. The analysis was Intention to Treat, meaning all participants were analyzed based on their initial treatment assignment and not on the treatment eventually received.

Arm/Group Title	Placebo	Spironolactone
Arm/Group Description	Placebo of spironolactone	Spironolactone (an aldosterone antagonist) is supplied as 15 mg tablets. Drug is taken orally by subjects. The initial study drug dose is 15 mg/day (one tablet) and may be titrated up to 30 mg/day (two tablets) or 45 mg/day (three tablets). Subjects are on study drug for the duration of the trial.
Measure Participants	1723	1722
Number [Events per 100 person-years]	6.6	5.9

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Spironolactone
	Comments	Composite endpoint was compared by trial arm using logrank test of time to first event from time of randomization. Time to event was the time at which the first observed event component of the composite endpoint was observed. This endpoint was adjudicated by the TOPCAT clinical endpoints committee. There were 320 subjects in the Spironolactone group and 351 subjects in Placebo group with a confirmed event. Subjects who did not experience this endpoint were censored at time of last contact.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.14
	Comments	No covariate adjustment
	Method	Log Rank
	Comments	Two-sided log rand test (0.05 Type 1 error)
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.89
	Confidence Interval	(2-Sided) 95%; 0.77 to 1.04
	Parameter Dispersion	Type: Value:
	Estimation Comments	Spironolactone compared to Placebo

2. Secondary Outcome

Title	Cardiovascular Mortality
Time Frame	Randomization through each subject's last semi-annual visit, up to a maximum of 6 years per subject.

Outcome Measure Data

Analysis Population Description

All Participants who were randomized were included in the analysis. The analysis was Intention to Treat, meaning all participants were analyzed based on their initial treatment assignment and not on the treatment eventually received.

Arm/Group Title	Placebo	Spironolactone
Arm/Group Description	Placebo of spironolactone	Spironolactone (an aldosterone antagonist) is supplied as 15 mg tablets. Drug is taken orally by subjects. The initial study drug dose is 15 mg/day (one tablet) and may be titrated up to 30 mg/day (two tablets) or 45 mg/day (three tablets). Subjects are on study drug for the duration of the trial.
Measure Participants	1723	1722
Number [Events per 100 person-years]	3.1	2.8

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Spironolactone
	Comments	This endpoint was compared by trial arm (spironolactone vs. placebo) using a logrank test of time to event from the time of randomization. Subjects who did not experience this endpoint were censored at the time of their last contact. This endpoint was adjudicated by the TOPCAT clinical endpoints committee. There were 336 subjects (160 in the Spironolactone group and 176 in the Placebo group) with a confirmed event.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.35
	Comments	No covariate adjustment
	Method	Log Rank
	Comments	Two-sided log rand test (0.05 Type 1 error)
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.90
	Confidence Interval	(2-Sided) 95%; 0.73 to 1.12
	Parameter Dispersion	Type: Value:
	Estimation Comments	Spironolactone compared to Placebo

3. Secondary Outcome

Title	Aborted Cardiac Arrest
Description	First incidence of aborted cardiac arrest
Time Frame	Randomization through each subject's last semi-annual visit, up to a maximum of 6 years per subject.

Outcome Measure Data

Analysis Population Description

All Participants who were randomized were included in the analysis. The analysis was Intention to Treat, meaning all participants were analyzed based on their initial treatment assignment and not on the treatment eventually received.

Arm/Group Title	Placebo	Spironolactone
Arm/Group Description	Placebo of spironolactone	Spironolactone (an aldosterone antagonist) is supplied as 15 mg tablets. Drug is taken orally by subjects. The initial study drug dose is 15 mg/day (one tablet) and may be titrated up to 30 mg/day (two tablets) or 45 mg/day (three tablets). Subjects are on study drug for the duration of the trial.
Measure Participants	1723	1722
Number [Events per 100 person-years]	0.09	0.05

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Spironolactone
	Comments	This endpoint was compared by trial arm (spironolactone vs. placebo) using a logrank test of time to first event from the time of randomization. Subjects who did not experience this endpoint were censored at the time of their last contact. This endpoint was adjudicated by the TOPCAT clinical endpoints committee. There were 8 subjects (3 in the Spironolactone group and 5 in the Placebo group) with a confirmed event.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.48
	Comments	No covariate adjustment
	Method	Log Rank
	Comments	Two-sided log rand test (0.05 Type 1 error)
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.60
	Confidence Interval	(2-Sided) 95%; 0.14 to 2.50
	Parameter Dispersion	Type: Value:
	Estimation Comments	Spironolactone compared to Placebo

4. Secondary Outcome

Title	Hospitalization for the Management of Heart Failure
Description	First incidence of a hospitalization for the management of heart failure
Time Frame	Randomization through each subject's last semi-annual visit, up to a maximum of 6 years per subject.

Outcome Measure Data

Analysis Population Description

All Participants who were randomized were included in the analysis. The analysis was Intention to Treat, meaning all participants were analyzed based on their initial treatment assignment and not on the treatment eventually received.

Arm/Group Title	Placebo	Spironolactone
Arm/Group Description	Placebo of spironolactone	Spironolactone (an aldosterone antagonist) is supplied as 15 mg tablets. Drug is taken orally by subjects. The initial study drug dose is 15 mg/day (one tablet) and may be titrated up to 30 mg/day (two tablets) or 45 mg/day (three tablets). Subjects are on study drug for the duration of the trial.
Measure Participants	1723	1722
Number [Events per 100 person-years]	4.6	3.8

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Spironolactone
	Comments	This endpoint was compared by trial arm (spironolactone vs. placebo) using a logrank test of time to first event from the time of randomization. Subjects who did not experience this endpoint were censored at the time of their last contact. This endpoint was adjudicated by the TOPCAT clinical endpoints committee. There were 451 subjects (206 in the Spironolactone group and 245 in the Placebo group) who have been confirmed to have experienced the event
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.04
	Comments	No covariate adjustment
	Method	Log Rank
	Comments	Two-sided log rand test (0.05 Type 1 error)
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.83
	Confidence Interval	(2-Sided) 95%; 0.69 to 0.99
	Parameter Dispersion	Type: Value:
	Estimation Comments	Spironolactone compared to Placebo

5. Secondary Outcome

Title	All-cause Mortality
Time Frame	Randomization through each subject's last semi-annual visit, up to a maximum of 6 years per subject.

Outcome Measure Data

Analysis Population Description

All Participants who were randomized were included in the analysis. The analysis was Intention to Treat, meaning all participants were analyzed based on their initial treatment assignment and not on the treatment eventually received.

Arm/Group Title	Placebo	Spironolactone
Arm/Group Description	Placebo of spironolactone	Spironolactone (an aldosterone antagonist) is supplied as 15 mg tablets. Drug is taken orally by subjects. The initial study drug dose is 15 mg/day (one tablet) and may be titrated up to 30 mg/day (two tablets) or 45 mg/day (three tablets). Subjects are on study drug for the duration of the trial.
Measure Participants	1723	1722
Number [Events per 100 person-years]	4.6	4.2

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Spironolactone
	Comments	Endpoint compared by trial arm using logrank test of time to event from randomization. Subjects who did not experience endpoint were censored at time of last contact. Attempts were made to determine vital status as of each subject's last potential visit, based on randomization, even if the subject ended study participation before then. This outcome was adjudicated. There were 252 events over 6,022 patient-years in Spironolactone arm and 274 events over 5,981 patient-years in Placebo arm.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.29
	Comments	No covariate adjustment
	Method	Log Rank
	Comments	Two-sided log rand test (0.05 Type 1 error)
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.91
	Confidence Interval	(2-Sided) 95%; 0.77 to 1.08
	Parameter Dispersion	Type: Value:
	Estimation Comments	Spironolactone compared to Placebo

6. Secondary Outcome

Title	Composite Outcome of Cardiovascular Mortality or Cardiovascular-related Hospitalization (i.e., Hospitalization for Myocardial Infarction(MI), Stroke, or the Management of Heart Failure), Whichever Occurred First
Time Frame	Randomization through each subject's last semi-annual visit, up to a maximum of 6 years per subject.

Outcome Measure Data

Analysis Population Description

All Participants who were randomized were included in the analysis. The analysis was Intention to Treat, meaning all participants were analyzed based on their initial treatment assignment and not on the treatment eventually received.

Arm/Group Title	Placebo	Spironolactone
Arm/Group Description	Placebo of spironolactone	Spironolactone (an aldosterone antagonist) is supplied as 15 mg tablets. Drug is taken orally by subjects. The initial study drug dose is 15 mg/day (one tablet) and may be titrated up to 30 mg/day (two tablets) or 45 mg/day (three tablets). Subjects are on study drug for the duration of the trial.
Measure Participants	1723	1722
Number [Events per 100 person-years]	7.8	7.2

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Spironolactone
	Comments	Composite endpoint was compared by trial arm using logrank test of time to first event from time of randomization. Time to event was the time at which the first observed event component of the composite endpoint was observed. Component endpoints were adjudicated by the TOPCAT clinical endpoints committee. There were 382 subjects in Spironolactone group and 404 subjects in Placebo group with a confirmed event. Subjects who did not experience this endpoint were censored at time of last contact.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.28
	Comments	No covariate adjustment
	Method	Log Rank
	Comments	Two-sided log rank test (0.05 Type 1 error)
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.93
	Confidence Interval	(2-Sided) 95%; 0.80 to 1.06
	Parameter Dispersion	Type: Value:
	Estimation Comments	Spironolactone compared to Placebo

7. Secondary Outcome

Title	Cardiovascular-related Hospitalization
Description	Hospitalization for MI, stroke or the management of heart failure, whichever occurred first
Time Frame	Randomization through each subject's last semi-annual visit, up to a maximum of 6 years per subject.

Outcome Measure Data

Analysis Population Description

All Participants who were randomized were included in the analysis. The analysis was Intention to Treat, meaning all participants were analyzed based on their initial treatment assignment and not on the treatment eventually received.

Arm/Group Title	Placebo	Spironolactone
Arm/Group Description	Placebo of spironolactone	Spironolactone (an aldosterone antagonist) is supplied as 15 mg tablets. Drug is taken orally by subjects. The initial study drug dose is 15 mg/day (one tablet) and may be titrated up to 30 mg/day (two tablets) or 45 mg/day (three tablets). Subjects are on study drug for the duration of the trial.
Measure Participants	1723	1722
Number [Events per 100 person-years]	6.2	5.5

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Spironolactone
	Comments	Endpoint was compared by trial arm using logrank test of time to first event from time of randomization. Time to event was the time at which the first observed event component of the composite endpoint was observed. Component endpoints were adjudicated by the TOPCAT clinical endpoints committee. There were 291 subjects in Spironolactone group and 320 subjects in Placebo group with a confirmed event. Subjects who did not experience this endpoint were censored at time of last contact.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.15
	Comments	No covariate adjustment
	Method	Log Rank
	Comments	Two-sided log rank test (0.05 Type 1 error)
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.89
	Confidence Interval	(2-Sided) 95%; 0.76 to 1.04
	Parameter Dispersion	Type: Value:
	Estimation Comments	Spironolactone compared to Placebo

8. Secondary Outcome

Title	Total Hospitalizations (Including Repeat Hospitalizations) for the Management of Heart Failure
Time Frame	Randomization through each subject's last semi-annual visit, up to a maximum of 6 years per subject.

Outcome Measure Data

Analysis Population Description

All Participants who were randomized were included in the analysis. The analysis was Intention to Treat, meaning all participants were analyzed based on their initial treatment assignment and not on the treatment eventually received.

Arm/Group Title	Placebo	Spironolactone
Arm/Group Description	Placebo of spironolactone	Spironolactone (an aldosterone antagonist) is supplied as 15 mg tablets. Drug is taken orally by subjects. The initial study drug dose is 15 mg/day (one tablet) and may be titrated up to 30 mg/day (two tablets) or 45 mg/day (three tablets). Subjects are on study drug for the duration of the trial.
Measure Participants	1723	1722
Number [Events per 100 person-years]	8.3	6.8

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Spironolactone
	Comments	There were a total of 869 confirmed heart failure hospitalizations (394 in the Spironolactone group and 475 in the Placebo group) during the 11,471 person-years collected over the course of the TOPCAT trial (5,755 person-years in the Spironolactone group and 5,716 person-years in the Placebo group). The incidence rate of heart failure hospitalizations for each treatment group was compared using a negative binomial regression with a p-value threshold of 0.05 for statistical significance.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.03
	Comments	No covariate adjustment
	Method	Negative binomial regression
	Comments
Method of Estimation	Estimation Parameter	incidence rate ratio
	Estimated Value	0.75
	Confidence Interval	(2-Sided) 95%; 0.58 to 0.97
	Parameter Dispersion	Type: Value:
	Estimation Comments	Spironolactone compared to Placebo

9. Secondary Outcome

Title	Composite Outcome of Sudden Death or Aborted Cardiac Arrest, Whichever Occurred First
Time Frame	Randomization through each subject's last semi-annual visit, up to a maximum of 6 years per subject.

Outcome Measure Data

Analysis Population Description

All Participants who were randomized were included in the analysis. The analysis was Intention to Treat, meaning all participants were analyzed based on their initial treatment assignment and not on the treatment eventually received.

Arm/Group Title	Placebo	Spironolactone
Arm/Group Description	Placebo of spironolactone	Spironolactone (an aldosterone antagonist) is supplied as 15 mg tablets. Drug is taken orally by subjects. The initial study drug dose is 15 mg/day (one tablet) and may be titrated up to 30 mg/day (two tablets) or 45 mg/day (three tablets). Subjects are on study drug for the duration of the trial.
Measure Participants	1723	1722
Number [Events per 100 person-years]	1.1	1.0

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Spironolactone
	Comments	Composite endpoint was compared by trial arm using logrank test of time to first event from time of randomization. Time to event was the time at which the first observed event component of the composite endpoint was observed. Component endpoints were adjudicated by the TOPCAT clinical endpoints committee. There were 58 subjects in the Spironolactone group and 60 subjects in Placebo group with a confirmed event. Subjects who did not experience this endpoint were censored at time of last contact.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.82
	Comments	No covariate adjustment
	Method	Log Rank
	Comments	Two-sided log rank test (0.05 Type 1 error)
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.96
	Confidence Interval	(2-Sided) 95%; 0.67 to 1.38
	Parameter Dispersion	Type: Value:
	Estimation Comments	Spironolactone compared to Placebo

10. Secondary Outcome

Title	New Onset Diabetes Mellitus, Among Subjects Without a History of Diabetes Mellitus at Baseline.
Description	First incidence of new onset diabetes mellitus among subjects without a history of diabetes mellitus at baseline.
Time Frame	Randomization through each subject's last semi-annual visit, up to a maximum of 6 years per subject.

Outcome Measure Data

Analysis Population Description

All Participants who were randomized and did not have a history of diabetes mellitus at baseline were included in the analysis. The analysis was Intention to Treat, meaning all participants were analyzed based on their initial treatment assignment and not on the treatment eventually received.

Arm/Group Title	Placebo	Spironolactone
Arm/Group Description	Placebo of spironolactone	Spironolactone (an aldosterone antagonist) is supplied as 15 mg tablets. Drug is taken orally by subjects. The initial study drug dose is 15 mg/day (one tablet) and may be titrated up to 30 mg/day (two tablets) or 45 mg/day (three tablets). Subjects are on study drug for the duration of the trial.
Measure Participants	1167	1156
Number [Events per 100 person-years]	0.7	0.7

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Spironolactone
	Comments	This endpoint was compared by trial arm (spironolactone vs. placebo) using a logrank test of time to first event from the time of randomization. Subjects who did not experience this endpoint were censored at the time of their last contact. This endpoint was adjudicated by the TOPCAT clinical endpoints committee. There were 56 subjects (29 in the Spironolactone group and 27 in the Placebo group) with confirmed events.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.76
	Comments	No covariate adjustment
	Method	Log Rank
	Comments	Two-sided log rank test (0.05 Type 1 error)
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.08
	Confidence Interval	(2-Sided) 95%; 0.64 to 1.83
	Parameter Dispersion	Type: Value:
	Estimation Comments	Spironolactone compared to Placebo

11. Secondary Outcome

Title	Development of Atrial Fibrillation, Among Subjects Without a History of Atrial Fibrillation at Baseline.
Description	First incidence of atrial fibrillation among subjects without a history of atrial fibrillation at baseline
Time Frame	Randomization through each subject's last semi-annual visit, up to a maximum of 6 years per subject.

Outcome Measure Data

Analysis Population Description

All Participants who were randomized and did not have a history of atrial fibrillation at baseline were included in the analysis. The analysis was Intention to Treat, meaning all participants were analyzed based on their initial treatment assignment and not on the treatment eventually received.

Arm/Group Title	Placebo	Spironolactone
Arm/Group Description	Placebo of spironolactone	Spironolactone (an aldosterone antagonist) is supplied as 15 mg tablets. Drug is taken orally by subjects. The initial study drug dose is 15 mg/day (one tablet) and may be titrated up to 30 mg/day (two tablets) or 45 mg/day (three tablets). Subjects are on study drug for the duration of the trial.
Measure Participants	1117	1111
Number [Events per 100 person-years]	1.4	1.4

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Spironolactone
	Comments	This endpoint was compared by trial arm (spironolactone vs. placebo) using a logrank test of time to first event from the time of randomization. Subjects who did not experience this endpoint were censored at the time of their last contact. This endpoint was adjudicated by the TOPCAT clinical endpoints committee. There were 103 subjects (52 in the Spironolactone group and 51 in the Placebo group) with confirmed events.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.94
	Comments	No covariate adjustment
	Method	Log Rank
	Comments	Two-sided log rank test (0.05 Type 1 error)
Method of Estimation	Estimation Parameter	Hazard Ratio, log
	Estimated Value	1.02
	Confidence Interval	(2-Sided) 95%; 0.69 to 1.50
	Parameter Dispersion	Type: Value:
	Estimation Comments	Spironolactone compared to Placebo

12. Secondary Outcome

Title	Myocardial Infarction
Description	First incidence of myocardial infarction
Time Frame	Randomization through each subject's last semi-annual visit, up to a maximum of 6 years per subject.

Outcome Measure Data

Analysis Population Description

All Participants who were randomized were included in the analysis. The analysis was Intention to Treat, meaning all participants were analyzed based on their initial treatment assignment and not on the treatment eventually received.

Arm/Group Title	Placebo	Spironolactone
Arm/Group Description	Placebo of spironolactone	Spironolactone (an aldosterone antagonist) is supplied as 15 mg tablets. Drug is taken orally by subjects. The initial study drug dose is 15 mg/day (one tablet) and may be titrated up to 30 mg/day (two tablets) or 45 mg/day (three tablets). Subjects are on study drug for the duration of the trial.
Measure Participants	1723	1722
Number [Events per 100 person-years]	1.1	1.2

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Spironolactone
	Comments	This endpoint was compared by trial arm (spironolactone vs. placebo) using a logrank test of time to first event from the time of randomization. Subjects who did not experience this endpoint were censored at the time of their last contact. This endpoint was adjudicated by the TOPCAT clinical endpoints committee. There were 129 subjects (65 in the Spironolactone group and 64 in the Placebo group) with confirmed events.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.98
	Comments	No covariate adjustment
	Method	Log Rank
	Comments	Two-sided log rand test (0.05 Type 1 error)
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.00
	Confidence Interval	(2-Sided) 95%; 0.71 to 1.42
	Parameter Dispersion	Type: Value:
	Estimation Comments	Spironolactone compared to Placebo

13. Secondary Outcome

Title	Stroke
Description	First incidence of stroke
Time Frame	Randomization through each subject's last semi-annual visit, up to a maximum of 6 years per subject.

Outcome Measure Data

Analysis Population Description

All Participants who were randomized were included in the analysis. The analysis was Intention to Treat, meaning all participants were analyzed based on their initial treatment assignment and not on the treatment eventually received.

Arm/Group Title	Placebo	Spironolactone
Arm/Group Description	Placebo of spironolactone	Spironolactone (an aldosterone antagonist) is supplied as 15 mg tablets. Drug is taken orally by subjects. The initial study drug dose is 15 mg/day (one tablet) and may be titrated up to 30 mg/day (two tablets) or 45 mg/day (three tablets). Subjects are on study drug for the duration of the trial.
Measure Participants	1723	1722
Number [Events per 100 person-years]	1.1	1.0

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Spironolactone
	Comments	This endpoint was compared by trial arm (spironolactone vs. placebo) using a logrank test of time to first event from the time of randomization. Subjects who did not experience this endpoint were censored at the time of their last contact. This endpoint was adjudicated by the TOPCAT clinical endpoints committee. There were 117 subjects (57 in the Spironolactone group and 60 in the Placebo group) with confirmed events.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.73
	Comments	No covariate adjustment
	Method	Log Rank
	Comments	Two-sided log rand test (0.05 Type 1 error)
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.94
	Confidence Interval	(2-Sided) 95%; 0.65 to 1.35
	Parameter Dispersion	Type: Value:
	Estimation Comments	Spironolactone compared to Placebo

14. Secondary Outcome

Title	Deterioration of Renal Function
Description	First incidence of a deterioration of renal function. The TOPCAT protocol defines deterioration of renal function as occurring if a subject has a serum creatinine value which is at least double the baseline value for that subject, and is also above the upper limit of normal (assumed to be 1.0 mg/dL for females and 1.2 mg/dL for males.)
Time Frame	Randomization through each subject's last semi-annual visit, up to a maximum of 6 years per subject.

Outcome Measure Data

Analysis Population Description

All Participants who were randomized were included in the analysis. The analysis was Intention to Treat, meaning all participants were analyzed based on their initial treatment assignment and not on the treatment eventually received.

Arm/Group Title	Placebo	Spironolactone
Arm/Group Description	Placebo of spironolactone	Spironolactone (an aldosterone antagonist) is supplied as 15 mg tablets. Drug is taken orally by subjects. The initial study drug dose is 15 mg/day (one tablet) and may be titrated up to 30 mg/day (two tablets) or 45 mg/day (three tablets). Subjects are on study drug for the duration of the trial.
Measure Participants	1723	1722
Number [Events per 100 person-years]	2.2	3.2

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Spironolactone
	Comments	This endpoint was compared by trial arm (spironolactone vs. placebo) using a logrank test of time to first event from the time of randomization. Subjects who did not experience this endpoint were censored at the time of their last contact. There were 295 subjects (175 in the Spironolactone group and 120 in the Placebo group) experiencing this endpoint. This endpoint did not undergo adjudication by the TOPCAT clinical endpoints committee.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.01
	Comments	No covariate adjustment
	Method	Log Rank
	Comments	Two-sided log rand test (0.05 Type 1 error)
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.49
	Confidence Interval	(2-Sided) 95%; 1.18 to 1.87
	Parameter Dispersion	Type: Value:
	Estimation Comments	Spironolactone compared to Placebo

15. Secondary Outcome

Title	Composite Outcome of Sudden Death, Aborted Cardiac Arrest, or Hospitalization for the Management of Ventricular Tachycardia, Whichever Occurred First
Time Frame	Randomization through each subject's last semi-annual visit, up to a maximum of 6 years per subject.

Outcome Measure Data

Analysis Population Description

All Participants who were randomized were included in the analysis. The analysis was Intention to Treat, meaning all participants were analyzed based on their initial treatment assignment and not on the treatment eventually received.

Arm/Group Title	Placebo	Spironolactone
Arm/Group Description	Placebo of spironolactone	Spironolactone (an aldosterone antagonist) is supplied as 15 mg tablets. Drug is taken orally by subjects. The initial study drug dose is 15 mg/day (one tablet) and may be titrated up to 30 mg/day (two tablets) or 45 mg/day (three tablets). Subjects are on study drug for the duration of the trial.
Measure Participants	1723	1722
Number [Events per 100 person-years]	1.1	1.0

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Spironolactone
	Comments	Composite endpoint was compared by trial arm using logrank test of time to first event from time of randomization. Time to event was the time at which the first observed event component of the composite endpoint was observed. Component endpoints were adjudicated by the TOPCAT clinical endpoints committee. There were 58 subjects in the Spironolactone group and 61 subjects in Placebo group with a confirmed event. Subjects who did not experience this endpoint were censored at time of last contact.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.75
	Comments	No covariate adjustment
	Method	Log Rank
	Comments	Two-sided log rank test (0.05 Type 1 error)
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.94
	Confidence Interval	(2-Sided) 95%; 0.66 to 1.35
	Parameter Dispersion	Type: Value:
	Estimation Comments	Spironolactone compared to Placebo

16. Secondary Outcome

Title	Quality of Life, as Measured by the Kansas City Cardiomyopathy Questionnaire.
Description	Average post-baseline quality of life, taking into consideration baseline quality of life, treatment group, the time between the post-baseline measures, and the correlation between repeated measures within an individual. The Kansas City Cardiomyopathy Questionnaire (KCCQ) is a 23-item, self-administered instrument that quantifies physical function, symptoms (frequency, severity and recent change), social function, self-efficacy and knowledge, and quality of life. Scores are transformed to a range of 0-100, in which higher scores reflect better health status. The KCCQ was administered at the following study visits: baseline, month 4, month 12 and annually thereafter.
Time Frame	Randomization through each subject's last semi-annual visit, up to a maximum of 6 years per subject.

Outcome Measure Data

Analysis Population Description

All Participants who were randomized were included in the analysis. The analysis was Intention to Treat, meaning all participants were analyzed based on their initial treatment assignment and not on the treatment eventually received.

Arm/Group Title	Placebo	Spironolactone
Arm/Group Description	Placebo of spironolactone	Spironolactone (an aldosterone antagonist) is supplied as 15 mg tablets. Drug is taken orally by subjects. The initial study drug dose is 15 mg/day (one tablet) and may be titrated up to 30 mg/day (two tablets) or 45 mg/day (three tablets). Subjects are on study drug for the duration of the trial.
Measure Participants	1723	1722
Least Squares Mean (Standard Error) [units on a scale]	63.1 (0.3)	64.4 (0.3)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Spironolactone
	Comments	A generalized linear model was fit, with the post-baseline quality of life scores as the dependent variable, and the baseline quality of life score, treatment group, month of visit, and the interaction between treatment group and month of visit as predictor variables. This tests whether the slope of the post-baseline quality of life parameter differs by treatment group, taking into account that measurements in the same subject over time may be correlated.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.27
	Comments
	Method	Regression, Linear
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Spironolactone
	Comments	Since the p-value for the preceding test (Statistical Analysis 1) was not significant at the 0.05 level, another generalized linear model was fit, omitting the interaction between treatment group and month of visit. This tests whether the value of the post-baseline quality of life parameter differs by treatment group, taking into account that measurements in the same subject over time may be correlated.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.01
	Comments
	Method	Regression, Linear
	Comments

17. Secondary Outcome

Title	Quality of Life, as Measured by the EuroQOL Visual Analog Scale.
Description	Average post-baseline quality of life, taking into consideration baseline quality of life, treatment group, the time between the post-baseline measures, and the correlation between repeated measures within an individual. The EuroQOL visual analog scale (EQ5D) is a single-item, self-administered instrument that quantifies current health status. Scores can range from 0-100, in which higher scores reflect better health status. The EQ5D was administered at the following study visits: baseline, month 4, month 12 and annually thereafter.
Time Frame	Randomization through each subject's last semi-annual visit, up to a maximum of 6 years per subject.

Outcome Measure Data

Analysis Population Description

All Participants who were randomized were included in the analysis. The analysis was Intention to Treat, meaning all participants were analyzed based on their initial treatment assignment and not on the treatment eventually received.

Arm/Group Title	Placebo	Spironolactone
Arm/Group Description	Placebo of spironolactone	Spironolactone (an aldosterone antagonist) is supplied as 15 mg tablets. Drug is taken orally by subjects. The initial study drug dose is 15 mg/day (one tablet) and may be titrated up to 30 mg/day (two tablets) or 45 mg/day (three tablets). Subjects are on study drug for the duration of the trial.
Measure Participants	1723	1722
Least Squares Mean (Standard Error) [units on a scale]	65.9 (0.3)	66.4 (0.3)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Spironolactone
	Comments	A generalized linear model was fit, with the post-baseline quality of life scores as the dependent variable, and the baseline quality of life score, treatment group, month of visit, and the interaction between treatment group and month of visit as predictor variables. This tests whether the slope of the post-baseline quality of life parameter differs by treatment group, taking into account that measurements in the same subject over time may be correlated.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.87
	Comments
	Method	Regression, Linear
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Spironolactone
	Comments	Since the p-value for the preceding test (Statistical Analysis 1) was not significant at the 0.05 level, another generalized linear model was fit, omitting the interaction between treatment group and month of visit. This tests whether the value of the post-baseline quality of life parameter differs by treatment group, taking into account that measurements in the same subject over time may be correlated.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.16
	Comments
	Method	Regression, Linear
	Comments

18. Secondary Outcome

Title	Quality of Life, as Measured by McMaster Overall Treatment Evaluation Questionnaire.
Description	Average post-baseline quality of life, taking into consideration baseline quality of life and treatment group. The McMaster Overall Treatment Evaluation questionnaire is a self-administered 3-item instrument that measures a patient's perception of change in their health-related quality of life since the start of therapy. The questionnaire consists of a single question - "Since treatment started, has there been any change in your activity limitation, symptoms and/or feelings related to your heart condition?" Scores can range from -7 to +7, and higher scores reflect better health status. The questionnaire was administered at the following study visits: month 4 and month 12. Valid translations of this questionnaire were only available for subjects enrolled in the United States, Canada and Argentina.
Time Frame	Randomization through each subject's last semi-annual visit, up to a maximum of 6 years per subject.

Outcome Measure Data

Analysis Population Description

All Participants from United States, Canada and Argentina who were randomized were included in the analysis. The analysis was Intention to Treat, meaning all participants were analyzed based on their initial treatment assignment and not on the treatment eventually received.

Arm/Group Title	Placebo	Spironolactone
Arm/Group Description	Placebo of spironolactone	Spironolactone (an aldosterone antagonist) is supplied as 15 mg tablets. Drug is taken orally by subjects. The initial study drug dose is 15 mg/day (one tablet) and may be titrated up to 30 mg/day (two tablets) or 45 mg/day (three tablets). Subjects are on study drug for the duration of the trial.
Measure Participants	799	801
Least Squares Mean (Standard Error) [units on a scale]	1.2 (0.1)	1.2 (0.1)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Spironolactone
	Comments	A generalized linear model was fit, with the post-baseline quality of life scores as the dependent variable, and the baseline quality of life score and treatment group as predictor variables. This tests whether the value of the post-baseline quality of life parameter differs by treatment group.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.99
	Comments
	Method	Regression, Linear
	Comments

19. Secondary Outcome

Title	Depression Symptoms, as Measured by Patient Health Questionnaire.
Description	Average post-baseline depression, taking into consideration baseline depression, treatment group, the time between the post-baseline measures, and the correlation between repeated measures within an individual. The Patient Health Questionnaire (PHQ) is a 10-item, self-administered instrument for screening, diagnosing, monitoring and measuring the severity of depression. Scores can range from 0-27, in which lower scores reflect better mental health status. The PH-Q was administered at the following study visits: baseline, month 12 and annually thereafter. Valid translations of this questionnaire were only available for subjects enrolled in the United States and Canada.
Time Frame	Randomization through each subject's last semi-annual visit, up to a maximum of 6 years per subject.

Outcome Measure Data

Analysis Population Description

All Participants from the United States and Canada who were randomized were included in the analysis. The analysis was Intention to Treat, meaning all participants were analyzed based on their initial treatment assignment and not on the treatment eventually received.

Arm/Group Title	Placebo	Spironolactone
Arm/Group Description	Placebo of spironolactone	Spironolactone (an aldosterone antagonist) is supplied as 15 mg tablets. Drug is taken orally by subjects. The initial study drug dose is 15 mg/day (one tablet) and may be titrated up to 30 mg/day (two tablets) or 45 mg/day (three tablets). Subjects are on study drug for the duration of the trial.
Measure Participants	739	738
Least Squares Mean (Standard Error) [units on a scale]	5.6 (0.1)	5.1 (0.2)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Spironolactone
	Comments	A generalized linear model was fit, with the post-baseline quality of life scores as the dependent variable, and the baseline quality of life score, treatment group, month of visit, and the interaction between treatment group and month of visit as predictor variables. This tests whether the slope of the post-baseline quality of life parameter differs by treatment group, taking into account that measurements in the same subject over time may be correlated.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.39
	Comments
	Method	Regression, Linear
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Spironolactone
	Comments	Since the p-value for the preceding test (Statistical Analysis 1) was not significant at the 0.05 level, another generalized linear model was fit, omitting the interaction between treatment group and month of visit. This tests whether the value of the post-baseline quality of life parameter differs by treatment group, taking into account that measurements in the same subject over time may be correlated.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.01
	Comments
	Method	Regression, Linear
	Comments

20. Secondary Outcome

Title	Hospitalization for Any Reason
Description	First incidence of a hospitalization for any reason
Time Frame	Randomization through each subject's last semi-annual visit, up to a maximum of 6 years per subject.

Outcome Measure Data

Analysis Population Description

All Participants who were randomized were included in the analysis. The analysis was Intention to Treat, meaning all participants were analyzed based on their initial treatment assignment and not on the treatment eventually received.

Arm/Group Title	Placebo	Spironolactone
Arm/Group Description	Placebo of spironolactone	Spironolactone (an aldosterone antagonist) is supplied as 15 mg tablets. Drug is taken orally by subjects. The initial study drug dose is 15 mg/day (one tablet) and may be titrated up to 30 mg/day (two tablets) or 45 mg/day (three tablets). Subjects are on study drug for the duration of the trial.
Measure Participants	1723	1722
Number [Events per 100 person-years]	20.0	18.8

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Spironolactone
	Comments	This endpoint was compared by trial arm (spironolactone vs. placebo) using a logrank test of time to first event from the time of randomization. Subjects who did not experience this endpoint were censored at the time of their last contact. There were a total of 1558 subjects (766 subjects in the Spironolactone group and 792 subjects in the Placebo) who were hospitalized for any cause while on study. This endpoint was not adjudicated by the TOPCAT clinical endpoints committee.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.25
	Comments	No covariate adjustment
	Method	Log Rank
	Comments	Two-sided log rand test (0.05 Type 1 error)
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.94
	Confidence Interval	(2-Sided) 95%; 0.85 to 1.04
	Parameter Dispersion	Type: Value:
	Estimation Comments	Spironolactone compared to Placebo

21. Secondary Outcome

Title	Potassium
Description	Average post-baseline Potassium, taking into consideration baseline Potassium, treatment group, the time between the post-baseline measures, and the correlation between repeated measures within an individual.
Time Frame	Randomization through each subject's last semi-annual visit, up to a maximum of 6 years per subject.

Outcome Measure Data

Analysis Population Description

All Participants who were randomized were included in the analysis. The analysis was Intention to Treat, meaning all participants were analyzed based on their initial treatment assignment and not on the treatment eventually received.

Arm/Group Title	Placebo	Spironolactone
Arm/Group Description	Placebo of spironolactone	Spironolactone (an aldosterone antagonist) is supplied as 15 mg tablets. Drug is taken orally by subjects. The initial study drug dose is 15 mg/day (one tablet) and may be titrated up to 30 mg/day (two tablets) or 45 mg/day (three tablets). Subjects are on study drug for the duration of the trial.
Measure Participants	1723	1722
Least Squares Mean (Standard Error) [mEq/L]	4.32 (0.01)	4.49 (0.01)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Spironolactone
	Comments	A generalized linear model was fit, with the post-baseline laboratory value as the dependent variable, and the baseline laboratory value, treatment group, month of visit, and the interaction between treatment group and month of visit as predictor variables. This tests whether the slope of the post-baseline laboratory parameter differs by treatment group, taking into account that measurements in the same subject over time may be correlated.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.27
	Comments
	Method	Regression, Linear
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Spironolactone
	Comments	Since the p-value for the preceding test (Statistical Analysis 1) was not significant at the 0.05 level, another generalized linear model was fit, omitting the interaction between treatment group and month of visit. This tests whether the value of the post-baseline laboratory parameter differs by treatment group, taking into account that measurements in the same subject over time may be correlated.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.01
	Comments
	Method	Regression, Linear
	Comments

22. Secondary Outcome

Title	Serum Creatinine
Description	Average post-baseline serum creatinine, taking into consideration baseline serum creatinine, treatment group, the time between the post-baseline measures, and the correlation between repeated measures within an individual.
Time Frame	Randomization through each subject's last semi-annual visit, up to a maximum of 6 years per subject.

Outcome Measure Data

Analysis Population Description

All Participants who were randomized were included in the analysis. The analysis was Intention to Treat, meaning all participants were analyzed based on their initial treatment assignment and not on the treatment eventually received.

Arm/Group Title	Placebo	Spironolactone
Arm/Group Description	Placebo of spironolactone	Spironolactone (an aldosterone antagonist) is supplied as 15 mg tablets. Drug is taken orally by subjects. The initial study drug dose is 15 mg/day (one tablet) and may be titrated up to 30 mg/day (two tablets) or 45 mg/day (three tablets). Subjects are on study drug for the duration of the trial.
Measure Participants	1723	1722
Least Squares Mean (Standard Error) [mg/dL]	1.11 (0.005)	1.17 (0.01)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Spironolactone
	Comments	A generalized linear model was fit, with the post-baseline laboratory value as the dependent variable, and the baseline laboratory value, treatment group, month of visit, and the interaction between treatment group and month of visit as predictor variables. This tests whether the slope of the post-baseline laboratory parameter differs by treatment group, taking into account that measurements in the same subject over time may be correlated.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.53
	Comments
	Method	Regression, Linear
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Spironolactone
	Comments	Since the p-value for the preceding test (Statistical Analysis 1) was not significant at the 0.05 level, another generalized linear model was fit, omitting the interaction between treatment group and month of visit. This tests whether the value of the post-baseline laboratory parameter differs by treatment group, taking into account that measurements in the same subject over time may be correlated.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.01
	Comments
	Method	Regression, Linear
	Comments

23. Secondary Outcome

Title	Sodium
Description	Average post-baseline Sodium, taking into consideration baseline Sodium, treatment group, the time between the post-baseline measures, and the correlation between repeated measures within an individual.
Time Frame	Randomization through each subject's last semi-annual visit, up to a maximum of 6 years per subject.

Outcome Measure Data

Analysis Population Description

All Participants who were randomized were included in the analysis. The analysis was Intention to Treat, meaning all participants were analyzed based on their initial treatment assignment and not on the treatment eventually received.

Arm/Group Title	Placebo	Spironolactone
Arm/Group Description	Placebo of spironolactone	Spironolactone (an aldosterone antagonist) is supplied as 15 mg tablets. Drug is taken orally by subjects. The initial study drug dose is 15 mg/day (one tablet) and may be titrated up to 30 mg/day (two tablets) or 45 mg/day (three tablets). Subjects are on study drug for the duration of the trial.
Measure Participants	1723	1722
Least Squares Mean (Standard Error) [mEq/L]	140.95 (0.06)	140.33 (0.06)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Spironolactone
	Comments	A generalized linear model was fit, with the post-baseline laboratory value as the dependent variable, and the baseline laboratory value, treatment group, month of visit, and the interaction between treatment group and month of visit as predictor variables. This tests whether the slope of the post-baseline laboratory parameter differs by treatment group, taking into account that measurements in the same subject over time may be correlated.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.11
	Comments
	Method	Regression, Linear
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Spironolactone
	Comments	Since the p-value for the preceding test (Statistical Analysis 1) was not significant at the 0.05 level, another generalized linear model was fit, omitting the interaction between treatment group and month of visit. This tests whether the value of the post-baseline laboratory parameter differs by treatment group, taking into account that measurements in the same subject over time may be correlated.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.01
	Comments
	Method	Regression, Linear
	Comments

24. Secondary Outcome

Title	Chloride
Description	Average post-baseline Chloride, taking into consideration baseline Chloride, treatment group, the time between the post-baseline measures, and the correlation between repeated measures within an individual.
Time Frame	Randomization through each subject's last semi-annual visit, up to a maximum of 6 years per subject.

Outcome Measure Data

Analysis Population Description

All Participants who were randomized were included in the analysis. The analysis was Intention to Treat, meaning all participants were analyzed based on their initial treatment assignment and not on the treatment eventually received.

Arm/Group Title	Placebo	Spironolactone
Arm/Group Description	Placebo of spironolactone	Spironolactone (an aldosterone antagonist) is supplied as 15 mg tablets. Drug is taken orally by subjects. The initial study drug dose is 15 mg/day (one tablet) and may be titrated up to 30 mg/day (two tablets) or 45 mg/day (three tablets). Subjects are on study drug for the duration of the trial.
Measure Participants	1723	1722
Least Squares Mean (Standard Error) [mEq/L]	102.33 (0.08)	102.26 (0.08)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Spironolactone
	Comments	A generalized linear model was fit, with the post-baseline laboratory value as the dependent variable, and the baseline laboratory value, treatment group, month of visit, and the interaction between treatment group and month of visit as predictor variables. This tests whether the slope of the post-baseline laboratory parameter differs by treatment group, taking into account that measurements in the same subject over time may be correlated.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.59
	Comments
	Method	Regression, Linear
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Spironolactone
	Comments	Since the p-value for the preceding test (Statistical Analysis 1) was not significant at the 0.05 level, another generalized linear model was fit, omitting the interaction between treatment group and month of visit. This tests whether the value of the post-baseline laboratory parameter differs by treatment group, taking into account that measurements in the same subject over time may be correlated.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.54
	Comments
	Method	Regression, Linear
	Comments

25. Secondary Outcome

Title	Estimated Glomerular Filtration Rate (GFR)
Description	Average post-baseline GFR, taking into consideration baseline GFR, treatment group, the time between the post-baseline measures, and the correlation between repeated measures within an individual.
Time Frame	Randomization through each subject's last semi-annual visit, up to a maximum of 6 years per subject.

Outcome Measure Data

Analysis Population Description

All Participants who were randomized were included in the analysis. The analysis was Intention to Treat, meaning all participants were analyzed based on their initial treatment assignment and not on the treatment eventually received.

Arm/Group Title	Placebo	Spironolactone
Arm/Group Description	Placebo of spironolactone	Spironolactone (an aldosterone antagonist) is supplied as 15 mg tablets. Drug is taken orally by subjects. The initial study drug dose is 15 mg/day (one tablet) and may be titrated up to 30 mg/day (two tablets) or 45 mg/day (three tablets). Subjects are on study drug for the duration of the trial.
Measure Participants	1723	1722
Least Squares Mean (Standard Error) [mL/min/1.73m2]	67.50 (0.29)	65.20 (0.90)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Spironolactone
	Comments	A generalized linear model was fit, with the post-baseline laboratory value as the dependent variable, and the baseline laboratory value, treatment group, month of visit, and the interaction between treatment group and month of visit as predictor variables. This tests whether the slope of the post-baseline laboratory parameter differs by treatment group, taking into account that measurements in the same subject over time may be correlated.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.98
	Comments
	Method	Regression, Linear
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Spironolactone
	Comments	Since the p-value for the preceding test (Statistical Analysis 1) was not significant at the 0.05 level, another generalized linear model was fit, omitting the interaction between treatment group and month of visit. This tests whether the value of the post-baseline laboratory parameter differs by treatment group, taking into account that measurements in the same subject over time may be correlated.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.02
	Comments
	Method	Regression, Linear
	Comments

Adverse Events

Time Frame	Reported Adverse Events (AEs) include any untoward medical occurrence which occurred after a subject gave informed consent and no later than 30 days after a subject permanently discontinued the study medication, for a maximum of 6 years per subject.
Adverse Event Reporting Description	If a subject experiences more than 1 of a given AE within a system organ class (SOC), the subject was counted only once for that AE.
Arm/Group Title	Placebo		Spironolactone
Arm/Group Description	Placebo of spironolactone		Spironolactone (an aldosterone antagonist) is supplied as 15 mg tablets. Drug is taken orally by subjects. The initial study drug dose is 15 mg/day (one tablet) and may be titrated up to 30 mg/day (two tablets) or 45 mg/day (three tablets). Subjects are on study drug for the duration of the trial.
All Cause Mortality
	Placebo		Spironolactone
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Placebo		Spironolactone
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	855/1723 (49.6%)		835/1722 (48.5%)
Blood and lymphatic system disorders
ANEMIA	23/1723 (1.3%)	26	15/1722 (0.9%)	18
AZOTEMIA	0/1723 (0%)	0	1/1722 (0.1%)	1
BRAIN HEMORRHAGE	1/1723 (0.1%)	1	0/1722 (0%)	0
COUMADIN TOXICITY	0/1723 (0%)	0	1/1722 (0.1%)	2
DISSEMINATED INTRAVASCULAR COAGULATION	0/1723 (0%)	0	1/1722 (0.1%)	1
DRUG TOXOCITY	0/1723 (0%)	0	1/1722 (0.1%)	1
ELEVATED INR	1/1723 (0.1%)	1	2/1722 (0.1%)	2
ELEVATED PT	0/1723 (0%)	0	1/1722 (0.1%)	1
EPISTAXIS	1/1723 (0.1%)	1	1/1722 (0.1%)	1
HEMATOMA	3/1723 (0.2%)	3	0/1722 (0%)	0
HYPOXEMIA	0/1723 (0%)	0	1/1722 (0.1%)	1
INTRACRANIAL BLEED	0/1723 (0%)	0	1/1722 (0.1%)	1
LEUKEMIA	1/1723 (0.1%)	1	0/1722 (0%)	0
LEUKOCYTOSIS	0/1723 (0%)	0	1/1722 (0.1%)	1
PANCYTOPENIA	2/1723 (0.1%)	2	0/1722 (0%)	0
SUPRATHERAPEUTIC INR	0/1723 (0%)	0	1/1722 (0.1%)	1
Cardiac disorders
ABDOMINAL AORTIC ANEURYSM	1/1723 (0.1%)	1	0/1722 (0%)	0
ABNORMAL LAB VALUE	0/1723 (0%)	0	1/1722 (0.1%)	1
ACUTE CORONARY SYNDROME	9/1723 (0.5%)	9	11/1722 (0.6%)	11
AMYLOIDOSIS	0/1723 (0%)	0	1/1722 (0.1%)	1
ANEURYSM	0/1723 (0%)	0	1/1722 (0.1%)	1
ANGIOGRAPHY	0/1723 (0%)	0	1/1722 (0.1%)	1
ANGIOPLASTY	0/1723 (0%)	0	2/1722 (0.1%)	2
AORTIC ANEURYSM	1/1723 (0.1%)	1	1/1722 (0.1%)	1
AORTIC REGURGITATION	0/1723 (0%)	0	1/1722 (0.1%)	1
AORTIC STENOSIS	2/1723 (0.1%)	2	5/1722 (0.3%)	5
ARRHYTHMIA	6/1723 (0.3%)	6	6/1722 (0.3%)	6
ARTERIAL STENOSIS	1/1723 (0.1%)	2	2/1722 (0.1%)	2
ATHEROSCLEROSIS	3/1723 (0.2%)	3	1/1722 (0.1%)	1
ATRIAL FIBRILLATION	58/1723 (3.4%)	69	73/1722 (4.2%)	92
ATRIAL FLUTTER	6/1723 (0.3%)	10	8/1722 (0.5%)	10
AV BLOCK	2/1723 (0.1%)	2	3/1722 (0.2%)	3
AV REPLACEMENT	1/1723 (0.1%)	1	1/1722 (0.1%)	1
AV STENOSIS	1/1723 (0.1%)	1	1/1722 (0.1%)	1
BACK PAIN	1/1723 (0.1%)	1	0/1722 (0%)	0
BINODAL DISEASE	0/1723 (0%)	0	1/1722 (0.1%)	1
BRADYCARDIA	10/1723 (0.6%)	11	9/1722 (0.5%)	9
CABG	0/1723 (0%)	0	2/1722 (0.1%)	2
CARDIAC ARREST	12/1723 (0.7%)	12	10/1722 (0.6%)	10
CARDIAC ARRYTHMIA	1/1723 (0.1%)	1	0/1722 (0%)	0
CARDIAC CATHETERIZATION	1/1723 (0.1%)	1	1/1722 (0.1%)	1
CARDIAC TAMPONADE	1/1723 (0.1%)	1	0/1722 (0%)	0
CARDIO RENAL SYNDROME	1/1723 (0.1%)	1	0/1722 (0%)	0
CARDIOGENIC SHOCK	4/1723 (0.2%)	5	3/1722 (0.2%)	3
CARDIOMYOPATHY	3/1723 (0.2%)	4	2/1722 (0.1%)	2
CARDIOPULMONARY ARREST	2/1723 (0.1%)	2	5/1722 (0.3%)	5
CARDIOSCLEROSIS	1/1723 (0.1%)	1	1/1722 (0.1%)	1
CAROTID STENOSIS	1/1723 (0.1%)	1	1/1722 (0.1%)	1
CHEST PAIN	144/1723 (8.4%)	186	143/1722 (8.3%)	203
CHRONIC OBSTRUCTIVE PULMONARY DISEASE	1/1723 (0.1%)	1	1/1722 (0.1%)	3
CONGESTIVE HEART FAILURE	0/1723 (0%)	0	2/1722 (0.1%)	3
CORONARY ARTERY BYPASS GRAFT	2/1723 (0.1%)	2	1/1722 (0.1%)	1
CORONARY ARTERY DISEASE	17/1723 (1%)	18	15/1722 (0.9%)	15
CORONARY ARTERY STENT	0/1723 (0%)	0	1/1722 (0.1%)	1
CORONARY REVASCULARIZATION	0/1723 (0%)	0	1/1722 (0.1%)	1
CORONARY VASOSPASM	0/1723 (0%)	0	1/1722 (0.1%)	1
DEATH	3/1723 (0.2%)	3	4/1722 (0.2%)	4
DESTABILIZATION OF BLOOD PRESSURE	0/1723 (0%)	0	1/1722 (0.1%)	1
DEVICE CHANGE	6/1723 (0.3%)	6	5/1722 (0.3%)	5
DEVICE IMPLANT	1/1723 (0.1%)	1	0/1722 (0%)	0
DEVICE MALFUNCTION	3/1723 (0.2%)	3	0/1722 (0%)	0
DIARRHEA	1/1723 (0.1%)	1	0/1722 (0%)	0
DYSPNEA	11/1723 (0.6%)	12	11/1722 (0.6%)	13
EDEMA	1/1723 (0.1%)	1	0/1722 (0%)	0
ELEVATED CARDIAC ENZYMES	3/1723 (0.2%)	3	2/1722 (0.1%)	2
ENDOCARDITIS	0/1723 (0%)	0	3/1722 (0.2%)	3
ENTERITIS	1/1723 (0.1%)	1	0/1722 (0%)	0
EROSION OF PACEMAKER POCKET	0/1723 (0%)	0	1/1722 (0.1%)	1
EXTRASYSTOLE	2/1723 (0.1%)	2	0/1722 (0%)	0
FAILURE TO THRIVE	0/1723 (0%)	0	1/1722 (0.1%)	1
HEART	0/1723 (0%)	0	1/1722 (0.1%)	1
HEART BLOCK	1/1723 (0.1%)	1	0/1722 (0%)	0
HEART FAILURE	294/1723 (17.1%)	532	256/1722 (14.9%)	465
HEARTBURN	2/1723 (0.1%)	2	0/1722 (0%)	0
HEAT	0/1723 (0%)	0	1/1722 (0.1%)	1
HERNIA	1/1723 (0.1%)	1	0/1722 (0%)	0
HOSPITALIZATION	0/1723 (0%)	0	2/1722 (0.1%)	2
HYPERKALEMIA	0/1723 (0%)	0	1/1722 (0.1%)	1
HYPERTENSION	21/1723 (1.2%)	24	27/1722 (1.6%)	32
HYPERVOLEMIA	3/1723 (0.2%)	3	1/1722 (0.1%)	1
HYPOTENSION	18/1723 (1%)	18	17/1722 (1%)	18
HYPOVOLEMIA	1/1723 (0.1%)	1	0/1722 (0%)	0
ICD MALFUNCTION	1/1723 (0.1%)	1	2/1722 (0.1%)	2
IN-STENT RESTENOSIS	1/1723 (0.1%)	2	0/1722 (0%)	0
KIDNEY DISEASE	5/1723 (0.3%)	6	4/1722 (0.2%)	4
LOWER EXTREMITY EDEMA	1/1723 (0.1%)	1	1/1722 (0.1%)	1
LOWER EXTREMITY ISCHEMIA	0/1723 (0%)	0	1/1722 (0.1%)	1
MEDICAL EXAM	2/1723 (0.1%)	2	1/1722 (0.1%)	1
MEDICATION ADJUSTMENT	1/1723 (0.1%)	1	0/1722 (0%)	0
MITRAL REGURGITATION	0/1723 (0%)	0	1/1722 (0.1%)	2
MITRAL VALVE REPLACEMENT	1/1723 (0.1%)	1	0/1722 (0%)	0
MYOCARDIAL INFARCTION	67/1723 (3.9%)	79	66/1722 (3.8%)	83
MYOCARDIAL INFECTION	1/1723 (0.1%)	1	1/1722 (0.1%)	1
OEDEMA	1/1723 (0.1%)	1	0/1722 (0%)	0
ORTHOPNEA	0/1723 (0%)	0	1/1722 (0.1%)	1
PACEMAKER IMPLANT	0/1723 (0%)	0	1/1722 (0.1%)	1
PALPITATIONS	2/1723 (0.1%)	2	1/1722 (0.1%)	1
PERCUTANEOUS CORONARY INTERVENTION	1/1723 (0.1%)	1	0/1722 (0%)	0
PERICARDITIS	0/1723 (0%)	0	2/1722 (0.1%)	2
PROPHYLACTIC THERAPY	1/1723 (0.1%)	1	0/1722 (0%)	0
PULMONARY EDEMA	3/1723 (0.2%)	4	3/1722 (0.2%)	5
PULMONARY EMBOLISM	1/1723 (0.1%)	1	0/1722 (0%)	0
RADIOFREQUENCY ABLATION	1/1723 (0.1%)	1	1/1722 (0.1%)	1
RESPIRATORY FAILURE	1/1723 (0.1%)	1	2/1722 (0.1%)	2
SECONDARY TO ANTIARRHYTHMIC MEDICATION	0/1723 (0%)	0	1/1722 (0.1%)	1
SHORTNESS OF BREATH	1/1723 (0.1%)	1	2/1722 (0.1%)	2
SHOT	0/1723 (0%)	0	1/1722 (0.1%)	1
SICK SINUS SYNDROME	1/1723 (0.1%)	2	2/1722 (0.1%)	2
SINUS NODE DISEASE	0/1723 (0%)	0	1/1722 (0.1%)	1
STENT GRAFT	0/1723 (0%)	0	1/1722 (0.1%)	1
STROKE	2/1723 (0.1%)	2	3/1722 (0.2%)	3
SURGICAL PROCEDURE	1/1723 (0.1%)	1	0/1722 (0%)	0
SYNCOPE	1/1723 (0.1%)	1	1/1722 (0.1%)	1
TACHYCARDIA	7/1723 (0.4%)	7	5/1722 (0.3%)	5
THROMBOEMBOLISM	1/1723 (0.1%)	1	0/1722 (0%)	0
TRANSIENT ISCHEMIC ATTACK	1/1723 (0.1%)	2	2/1722 (0.1%)	2
TRICUSPID REGURGITATION	0/1723 (0%)	0	1/1722 (0.1%)	1
VALVE REPLACEMENT	1/1723 (0.1%)	1	0/1722 (0%)	0
VENTRICULAR FIBRILLATION	0/1723 (0%)	0	3/1722 (0.2%)	3
WORSENING HF	1/1723 (0.1%)	1	1/1722 (0.1%)	2
Congenital, familial and genetic disorders
HEART FAILURE	1/1723 (0.1%)	1	0/1722 (0%)	0
Ear and labyrinth disorders
ACUTE MENIERE'S DISEASE	1/1723 (0.1%)	1	0/1722 (0%)	0
LABYRINTHITIS	1/1723 (0.1%)	1	0/1722 (0%)	0
VERTIGO	2/1723 (0.1%)	2	1/1722 (0.1%)	1
Endocrine disorders
ADRENAL INSUFFIENCY	1/1723 (0.1%)	1	0/1722 (0%)	0
DIABETES	6/1723 (0.3%)	6	14/1722 (0.8%)	17
GYNECOMASTIA	0/1723 (0%)	0	1/1722 (0.1%)	1
HEART FAILURE	0/1723 (0%)	0	1/1722 (0.1%)	1
HYPERGLYCEMIA	2/1723 (0.1%)	4	9/1722 (0.5%)	10
HYPERTHYROIDISM	1/1723 (0.1%)	1	1/1722 (0.1%)	1
HYPOGLYCEMIA	4/1723 (0.2%)	4	7/1722 (0.4%)	8
HYPONATREMIA	0/1723 (0%)	0	1/1722 (0.1%)	1
HYPOTENSION	1/1723 (0.1%)	1	0/1722 (0%)	0
NEUROPATHY	0/1723 (0%)	0	1/1722 (0.1%)	2
PANCREATIC CANCER	1/1723 (0.1%)	1	0/1722 (0%)	0
PANCREATITIS	3/1723 (0.2%)	3	2/1722 (0.1%)	3
SHINGLES	1/1723 (0.1%)	1	0/1722 (0%)	0
SYNCOPE	1/1723 (0.1%)	1	0/1722 (0%)	0
Eye disorders
BLEEDING IN EYE	0/1723 (0%)	0	1/1722 (0.1%)	3
BLURRED VISION	1/1723 (0.1%)	1	0/1722 (0%)	0
CATARACTS	5/1723 (0.3%)	7	5/1722 (0.3%)	7
CENTRAL CHORIORETINAL DYSTROPHY	1/1723 (0.1%)	1	1/1722 (0.1%)	1
CHORIORRETINOPATHY	0/1723 (0%)	0	1/1722 (0.1%)	1
DRY EYES	1/1723 (0.1%)	1	0/1722 (0%)	0
EYE SURGERY	1/1723 (0.1%)	1	1/1722 (0.1%)	2
OPTIC ATROPHY	0/1723 (0%)	0	1/1722 (0.1%)	2
RETINAL ANGIOPATHY	0/1723 (0%)	0	1/1722 (0.1%)	1
RETINAL DETACHMENT	0/1723 (0%)	0	1/1722 (0.1%)	1
RETINOPATHY	0/1723 (0%)	0	1/1722 (0.1%)	1
VISION CHANGES	0/1723 (0%)	0	1/1722 (0.1%)	1
Gastrointestinal disorders
ABDOMINAL PAIN	7/1723 (0.4%)	7	10/1722 (0.6%)	10
ABDOMINAL VISCUS PERFORATION	0/1723 (0%)	0	1/1722 (0.1%)	1
ACID REFLUX	0/1723 (0%)	0	1/1722 (0.1%)	1
ANEMIA	2/1723 (0.1%)	3	2/1722 (0.1%)	2
APPENDICEAL ABCESS	1/1723 (0.1%)	1	0/1722 (0%)	0
APPENDICITIS	5/1723 (0.3%)	5	1/1722 (0.1%)	1
ARTERIAL THROMBOSIS	1/1723 (0.1%)	1	0/1722 (0%)	0
ASCITES	0/1723 (0%)	0	1/1722 (0.1%)	1
BARIATRIC SURGERY	1/1723 (0.1%)	1	0/1722 (0%)	0
BI BLEED	0/1723 (0%)	0	1/1722 (0.1%)	1
BLOOD IN STOOL	0/1723 (0%)	0	2/1722 (0.1%)	2
BOWEL OBSTRUCTION	5/1723 (0.3%)	7	7/1722 (0.4%)	7
BOWEL PERFORATION	0/1723 (0%)	0	1/1722 (0.1%)	1
CHEST PAIN	0/1723 (0%)	0	1/1722 (0.1%)	1
COLITIS	6/1723 (0.3%)	6	3/1722 (0.2%)	3
COLON CANCER	0/1723 (0%)	0	2/1722 (0.1%)	2
CONSTIPATION	1/1723 (0.1%)	1	2/1722 (0.1%)	2
CROHNS DISEASE	1/1723 (0.1%)	1	0/1722 (0%)	0
DECREASED APPETITE	1/1723 (0.1%)	1	0/1722 (0%)	0
DEHYDRATION	1/1723 (0.1%)	1	0/1722 (0%)	0
DIARRHEA	7/1723 (0.4%)	8	5/1722 (0.3%)	6
DILATED ESOPHAGUS	0/1723 (0%)	0	1/1722 (0.1%)	1
DIVERTICULITIS	3/1723 (0.2%)	3	2/1722 (0.1%)	2
DIVERTICULOSIS	0/1723 (0%)	0	2/1722 (0.1%)	3
DYSPHAGIA	3/1723 (0.2%)	3	0/1722 (0%)	0
ELECTIVE BAND PROCEDURE	1/1723 (0.1%)	1	0/1722 (0%)	0
ENDOSCOPIC RETROGRADE CHOLANGIO-PANCREATOGRAPHY	1/1723 (0.1%)	1	0/1722 (0%)	0
ENTEROCOLITIS	1/1723 (0.1%)	1	0/1722 (0%)	0
EPIGASTRIC PAIN	0/1723 (0%)	0	1/1722 (0.1%)	1
EQUIPMENT MALFUNCTION	0/1723 (0%)	0	1/1722 (0.1%)	1
ESOPHAGITIS	1/1723 (0.1%)	1	0/1722 (0%)	0
FECAL IMPACTION	1/1723 (0.1%)	1	0/1722 (0%)	0
FISTULA	0/1723 (0%)	0	1/1722 (0.1%)	1
GASTRECTOMY	1/1723 (0.1%)	1	0/1722 (0%)	0
GASTRIC BYPASS SURGERY	1/1723 (0.1%)	1	2/1722 (0.1%)	2
GASTRIC REFLUX	1/1723 (0.1%)	1	0/1722 (0%)	0
GASTRITIS	1/1723 (0.1%)	1	3/1722 (0.2%)	3
GASTROENTERITIS	3/1723 (0.2%)	3	7/1722 (0.4%)	7
GASTROPARESIS	1/1723 (0.1%)	1	0/1722 (0%)	0
GATRITIS	0/1723 (0%)	0	1/1722 (0.1%)	1
GERD	0/1723 (0%)	0	1/1722 (0.1%)	1
GI BLEED	22/1723 (1.3%)	30	25/1722 (1.5%)	26
GI DISTRESS	2/1723 (0.1%)	2	1/1722 (0.1%)	1
HEMATOCHEZIA	2/1723 (0.1%)	2	0/1722 (0%)	0
HEMORRHAGE	2/1723 (0.1%)	2	3/1722 (0.2%)	3
HEMORRHOIDS	1/1723 (0.1%)	1	0/1722 (0%)	0
HERNIA	3/1723 (0.2%)	3	1/1722 (0.1%)	1
HIATAL HERNIA	1/1723 (0.1%)	1	0/1722 (0%)	0
ILEITIS	0/1723 (0%)	0	1/1722 (0.1%)	1
ILEUS	1/1723 (0.1%)	1	1/1722 (0.1%)	1
INTESTINAL PERFORATION	1/1723 (0.1%)	1	0/1722 (0%)	0
MALLORY-WEISS SYNDROME	0/1723 (0%)	0	1/1722 (0.1%)	1
MEGACOLON	1/1723 (0.1%)	1	0/1722 (0%)	0
MESENTERIC ISCHEMIA	2/1723 (0.1%)	2	0/1722 (0%)	0
NAUSEA	5/1723 (0.3%)	5	1/1722 (0.1%)	1
OPISTHORCHOSIS	0/1723 (0%)	0	1/1722 (0.1%)	1
PANCREATITIS	1/1723 (0.1%)	1	2/1722 (0.1%)	2
PERITONITIS	2/1723 (0.1%)	2	1/1722 (0.1%)	1
POLYP REMOVAL	1/1723 (0.1%)	1	0/1722 (0%)	0
POLYPS	2/1723 (0.1%)	2	0/1722 (0%)	0
PROCTITIS	0/1723 (0%)	0	1/1722 (0.1%)	1
RECTAL PROLAPSE SURGERY	0/1723 (0%)	0	1/1722 (0.1%)	1
RECTOVESICAL FISTULA	1/1723 (0.1%)	1	0/1722 (0%)	0
REMOVAL OF ADHESIONS	1/1723 (0.1%)	1	0/1722 (0%)	0
RUPTURED ESOPHAGUS	0/1723 (0%)	0	1/1722 (0.1%)	1
SMALL BOWEL OBSTRUCTION	0/1723 (0%)	0	1/1722 (0.1%)	1
ULCER	2/1723 (0.1%)	2	1/1722 (0.1%)	1
VOMITING	2/1723 (0.1%)	2	2/1722 (0.1%)	2
WEAKNESS	0/1723 (0%)	0	1/1722 (0.1%)	1
General disorders
ALCOHOL WITHDRAWAL	0/1723 (0%)	0	1/1722 (0.1%)	1
ASCITES	0/1723 (0%)	0	1/1722 (0.1%)	1
DEATH	83/1723 (4.8%)	84	71/1722 (4.1%)	71
DEHYDRATION	8/1723 (0.5%)	8	7/1722 (0.4%)	7
DIZZINESS	3/1723 (0.2%)	3	5/1722 (0.3%)	5
ELECTROLYTE IMBALANCE	0/1723 (0%)	0	1/1722 (0.1%)	1
FAILURE TO THRIVE	6/1723 (0.3%)	6	0/1722 (0%)	0
FATIGUE	1/1723 (0.1%)	1	2/1722 (0.1%)	2
FEVER	1/1723 (0.1%)	1	2/1722 (0.1%)	2
GENERAL HEALTH DECLINE	0/1723 (0%)	0	3/1722 (0.2%)	3
HYPERCALCEMIA	0/1723 (0%)	0	2/1722 (0.1%)	2
HYPERTENSION	0/1723 (0%)	0	1/1722 (0.1%)	1
HYPERVOLEMIA	1/1723 (0.1%)	1	1/1722 (0.1%)	1
HYPONATREMIA	0/1723 (0%)	0	1/1722 (0.1%)	1
KIDNEY DISEASE	0/1723 (0%)	0	1/1722 (0.1%)	1
MULTIPLE INFIRMITIES OF AGING	0/1723 (0%)	0	1/1722 (0.1%)	1
MULTIPLE ORGAN FAILURE	3/1723 (0.2%)	4	3/1722 (0.2%)	3
SEPSIS	0/1723 (0%)	0	1/1722 (0.1%)	1
SYNCOPE	1/1723 (0.1%)	1	0/1722 (0%)	0
WEAKNESS	2/1723 (0.1%)	2	7/1722 (0.4%)	7
Hepatobiliary disorders
ABDOMINAL PAIN	0/1723 (0%)	0	1/1722 (0.1%)	1
ASCITES	0/1723 (0%)	0	1/1722 (0.1%)	1
BILIARY COLIC	1/1723 (0.1%)	1	0/1722 (0%)	0
CARDIAC CIRRHOSIS	1/1723 (0.1%)	1	0/1722 (0%)	0
CHOLANGITIS	1/1723 (0.1%)	1	1/1722 (0.1%)	1
CHOLE	1/1723 (0.1%)	1	0/1722 (0%)	0
CHOLECYSTECTOMY	1/1723 (0.1%)	1	0/1722 (0%)	0
CHOLECYSTITIS	10/1723 (0.6%)	11	7/1722 (0.4%)	7
CHOLESTASIS	0/1723 (0%)	0	1/1722 (0.1%)	1
CHOLESTATIC SYNDROME	0/1723 (0%)	0	1/1722 (0.1%)	1
CIRRHOSIS	1/1723 (0.1%)	2	1/1722 (0.1%)	1
ELEVATED LIVER ENZYMES	1/1723 (0.1%)	1	0/1722 (0%)	0
ENCEPHALOPATHY	3/1723 (0.2%)	3	1/1722 (0.1%)	3
EXACERBATION OF THE CHRONIC CALCULOUS CHOLECYSTITIS	0/1723 (0%)	0	1/1722 (0.1%)	1
GALLSTONES	10/1723 (0.6%)	11	6/1722 (0.3%)	6
HEPATIC ENCEPHALOPATHY	1/1723 (0.1%)	1	0/1722 (0%)	0
HEPATOMEGALY	0/1723 (0%)	0	1/1722 (0.1%)	1
JAUNDICE	1/1723 (0.1%)	1	0/1722 (0%)	0
LIVER CANCER	1/1723 (0.1%)	1	0/1722 (0%)	0
LIVER LACERATION	0/1723 (0%)	0	1/1722 (0.1%)	1
NON-CALCULOUS CHOLECYSTITIS	1/1723 (0.1%)	1	0/1722 (0%)	0
OBTURATIVE SUPPURATIVE GANGRENOUSE CALCULOUS CHOLECYSTITIS	0/1723 (0%)	0	1/1722 (0.1%)	1
PANCREATITIS	1/1723 (0.1%)	1	7/1722 (0.4%)	9
Immune system disorders
ALLERGY	1/1723 (0.1%)	1	0/1722 (0%)	0
AMYLOIDOSIS	1/1723 (0.1%)	1	0/1722 (0%)	0
GUILLIAN BARRE SYNDROME	1/1723 (0.1%)	2	0/1722 (0%)	0
SICCA SYNDROME	1/1723 (0.1%)	1	0/1722 (0%)	0
Infections and infestations
BACTERIAL INFECTION	0/1723 (0%)	0	2/1722 (0.1%)	2
C-DIFF INFECTION	3/1723 (0.2%)	3	2/1722 (0.1%)	2
CELLULITIS	14/1723 (0.8%)	14	13/1722 (0.8%)	14
DENTAL ABSCESS	1/1723 (0.1%)	1	0/1722 (0%)	0
ENCEPHALITIS	0/1723 (0%)	0	1/1722 (0.1%)	1
GANGRENE	2/1723 (0.1%)	2	1/1722 (0.1%)	1
HEART FAILURE	0/1723 (0%)	0	1/1722 (0.1%)	1
HERNIA	1/1723 (0.1%)	1	0/1722 (0%)	0
INFECTION	3/1723 (0.2%)	3	3/1722 (0.2%)	4
INFLUENZA	1/1723 (0.1%)	1	1/1722 (0.1%)	1
MRSA INFECTION	3/1723 (0.2%)	3	1/1722 (0.1%)	1
OPISTHORCHOSIS	0/1723 (0%)	0	1/1722 (0.1%)	1
OSTEOMYELITIS	0/1723 (0%)	0	1/1722 (0.1%)	1
PERITONITIS	0/1723 (0%)	0	1/1722 (0.1%)	1
PNEUMONIA	0/1723 (0%)	0	2/1722 (0.1%)	2
PYELONEPHRITIS	0/1723 (0%)	0	1/1722 (0.1%)	1
SALMONELLOSIS	1/1723 (0.1%)	1	0/1722 (0%)	0
SEPSIS	15/1723 (0.9%)	15	16/1722 (0.9%)	16
SEPTIC SHOCK	5/1723 (0.3%)	5	3/1722 (0.2%)	3
SKIN CANCER	1/1723 (0.1%)	1	0/1722 (0%)	0
SKIN LESION	0/1723 (0%)	0	1/1722 (0.1%)	1
SUBUNGUAL AND THECAL WHITLOW PANARICIUM OF THE LEFT HAND	1/1723 (0.1%)	1	0/1722 (0%)	0
TOOTH ABSCESS	1/1723 (0.1%)	1	0/1722 (0%)	0
TOOTHACHE	0/1723 (0%)	0	1/1722 (0.1%)	1
UPPER RESPIRATORY INFECTION	1/1723 (0.1%)	1	1/1722 (0.1%)	2
URINARY TRACT INFECTION	1/1723 (0.1%)	1	0/1722 (0%)	0
WOUND INFECTION	2/1723 (0.1%)	2	3/1722 (0.2%)	3
Injury, poisoning and procedural complications
ABSCESS	0/1723 (0%)	0	1/1722 (0.1%)	1
BRAIN HEMORRHAGE	1/1723 (0.1%)	1	1/1722 (0.1%)	1
CHOLECYSTECTOMY	1/1723 (0.1%)	1	0/1722 (0%)	0
CHOPPED WOUND OF LEFT HAND	1/1723 (0.1%)	1	0/1722 (0%)	0
DEATH	1/1723 (0.1%)	1	0/1722 (0%)	0
DENATURED ALCOHOL POISONING	1/1723 (0.1%)	1	0/1722 (0%)	0
DRUG OVERDOSE	0/1723 (0%)	0	1/1722 (0.1%)	1
FALL	1/1723 (0.1%)	1	0/1722 (0%)	0
FISTULA	2/1723 (0.1%)	2	0/1722 (0%)	0
FOOT INJURY	0/1723 (0%)	0	1/1722 (0.1%)	1
FRACTURE	3/1723 (0.2%)	3	1/1722 (0.1%)	1
HEAD INJURY	3/1723 (0.2%)	3	0/1722 (0%)	0
HEMORRHAGE	1/1723 (0.1%)	1	0/1722 (0%)	0
INFECTION	0/1723 (0%)	0	2/1722 (0.1%)	2
LEG INJURY	1/1723 (0.1%)	1	0/1722 (0%)	0
MOTOR VEHICLE ACCIDENT	1/1723 (0.1%)	1	1/1722 (0.1%)	1
SKIN LACERATION	0/1723 (0%)	0	1/1722 (0.1%)	1
STERNUM DIASTASIS	0/1723 (0%)	0	1/1722 (0.1%)	1
SYNCOPE	1/1723 (0.1%)	1	0/1722 (0%)	0
TRAUMA	1/1723 (0.1%)	1	0/1722 (0%)	0
WARFARIN ALLERGIC REACTION	0/1723 (0%)	0	1/1722 (0.1%)	1
WARFARIN OVERDOSE	1/1723 (0.1%)	1	0/1722 (0%)	0
Investigations
CHEST PAIN	1/1723 (0.1%)	1	0/1722 (0%)	0
MEDICAL EXAM	23/1723 (1.3%)	33	22/1722 (1.3%)	34
Metabolism and nutrition disorders
ABNORMAL ELECTROLYTE	1/1723 (0.1%)	1	0/1722 (0%)	0
DEHYDRATION	1/1723 (0.1%)	1	0/1722 (0%)	0
ELECTROLYTE IMBALANCE	1/1723 (0.1%)	1	0/1722 (0%)	0
HYPERNATREMIA	1/1723 (0.1%)	1	0/1722 (0%)	0
HYPONATREMIA	2/1723 (0.1%)	2	0/1722 (0%)	0
KIDNEY DISEASE	0/1723 (0%)	0	1/1722 (0.1%)	1
MALNUTRITION	1/1723 (0.1%)	1	1/1722 (0.1%)	1
WEIGHT GAIN	1/1723 (0.1%)	1	0/1722 (0%)	0
Musculoskeletal and connective tissue disorders
ABDOMINAL PAIN	0/1723 (0%)	0	1/1722 (0.1%)	1
ARM INJURY	0/1723 (0%)	0	2/1722 (0.1%)	2
ARTHRALGIA	1/1723 (0.1%)	2	0/1722 (0%)	0
ARTHRITIS	3/1723 (0.2%)	3	3/1722 (0.2%)	3
BACK INJURY	2/1723 (0.1%)	2	2/1722 (0.1%)	2
BACK PAIN	3/1723 (0.2%)	3	10/1722 (0.6%)	12
BLISTERS	0/1723 (0%)	0	1/1722 (0.1%)	1
BODY PAIN	0/1723 (0%)	0	1/1722 (0.1%)	1
BRUISE	0/1723 (0%)	0	1/1722 (0.1%)	1
BUTTOCK PAIN	0/1723 (0%)	0	1/1722 (0.1%)	1
CHEST PAIN	5/1723 (0.3%)	5	6/1722 (0.3%)	8
DISCITIS	0/1723 (0%)	0	1/1722 (0.1%)	3
DORSOPATHY	2/1723 (0.1%)	2	0/1722 (0%)	0
EDEMA	1/1723 (0.1%)	1	1/1722 (0.1%)	1
FALL	1/1723 (0.1%)	1	7/1722 (0.4%)	7
FOOT PAIN	1/1723 (0.1%)	1	1/1722 (0.1%)	1
FRACTURE	39/1723 (2.3%)	41	31/1722 (1.8%)	34
GOUT	6/1723 (0.3%)	11	6/1722 (0.3%)	6
GROIN PAIN	0/1723 (0%)	0	1/1722 (0.1%)	1
HAND PAIN	1/1723 (0.1%)	1	0/1722 (0%)	0
HEART FAILURE	1/1723 (0.1%)	1	1/1722 (0.1%)	1
HEEL PAIN	1/1723 (0.1%)	1	0/1722 (0%)	0
HEMATOMA	1/1723 (0.1%)	1	0/1722 (0%)	0
HERNIA	3/1723 (0.2%)	3	8/1722 (0.5%)	10
HERNIATED DISC	0/1723 (0%)	0	1/1722 (0.1%)	2
HIP PAIN	1/1723 (0.1%)	1	0/1722 (0%)	0
HIP REPLACEMENT	2/1723 (0.1%)	2	1/1722 (0.1%)	1
KNEE INJURY	2/1723 (0.1%)	2	2/1722 (0.1%)	2
KNEE PAIN	3/1723 (0.2%)	3	2/1722 (0.1%)	2
LEG PAIN	1/1723 (0.1%)	2	2/1722 (0.1%)	2
LEUKEMIA	1/1723 (0.1%)	1	0/1722 (0%)	0
MYOPATHY	0/1723 (0%)	0	1/1722 (0.1%)	1
OSTEOARTHRITIS	7/1723 (0.4%)	7	10/1722 (0.6%)	12
OSTEOCHONDROSIS	1/1723 (0.1%)	1	3/1722 (0.2%)	3
OSTEOMYELITIS	1/1723 (0.1%)	1	5/1722 (0.3%)	5
POLYMYALGIA	1/1723 (0.1%)	1	0/1722 (0%)	0
RECTUS HEMATOMA	0/1723 (0%)	0	1/1722 (0.1%)	1
RHABDOMYOLYSIS	3/1723 (0.2%)	3	0/1722 (0%)	0
SCLERODERMA	1/1723 (0.1%)	1	0/1722 (0%)	0
SCLEROTIC METASTASIS	0/1723 (0%)	0	1/1722 (0.1%)	1
SHOULDER INJURY	0/1723 (0%)	0	2/1722 (0.1%)	3
SHOULDER PAIN	1/1723 (0.1%)	1	2/1722 (0.1%)	2
SHOULDER SURGERY	2/1723 (0.1%)	2	0/1722 (0%)	0
SKIN LACERATION	1/1723 (0.1%)	1	0/1722 (0%)	0
SKULL FRACTURE	0/1723 (0%)	0	1/1722 (0.1%)	1
SPINAL STENOSIS	1/1723 (0.1%)	1	1/1722 (0.1%)	1
SPINAL SURGERY	1/1723 (0.1%)	1	0/1722 (0%)	0
TOE AMPUTATION	0/1723 (0%)	0	1/1722 (0.1%)	1
ULCER	1/1723 (0.1%)	1	1/1722 (0.1%)	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
ABNORMAL VAGINAL BLEEDING	1/1723 (0.1%)	1	0/1722 (0%)	0
ANAL CANCER	1/1723 (0.1%)	1	0/1722 (0%)	0
BILE DUCT CANCER	0/1723 (0%)	0	1/1722 (0.1%)	1
BLADDER CANCER	1/1723 (0.1%)	1	0/1722 (0%)	0
BOWEL CANCER	1/1723 (0.1%)	2	5/1722 (0.3%)	6
BRAIN CANCER	1/1723 (0.1%)	1	0/1722 (0%)	0
BRAIN TUMOR	2/1723 (0.1%)	2	0/1722 (0%)	0
BREAST CANCER	6/1723 (0.3%)	6	3/1722 (0.2%)	4
BREAST TUMOR	1/1723 (0.1%)	1	0/1722 (0%)	0
CANCER	1/1723 (0.1%)	1	0/1722 (0%)	0
CHOLANGIOCARCINOMA	0/1723 (0%)	0	1/1722 (0.1%)	2
COLON CANCER	4/1723 (0.2%)	5	3/1722 (0.2%)	3
ESOPHAGEAL CANCER	1/1723 (0.1%)	1	2/1722 (0.1%)	2
EYE LESION	0/1723 (0%)	0	1/1722 (0.1%)	1
INCREASE THIGH MASS	0/1723 (0%)	0	1/1722 (0.1%)	1
INTESTINAL CANCER	0/1723 (0%)	0	2/1722 (0.1%)	2
LARYNGEAL CANCER	1/1723 (0.1%)	1	0/1722 (0%)	0
LESION	1/1723 (0.1%)	1	1/1722 (0.1%)	1
LEUKEMIA	0/1723 (0%)	0	2/1722 (0.1%)	2
LIVER CANCER	3/1723 (0.2%)	3	1/1722 (0.1%)	2
LUNG CANCER	3/1723 (0.2%)	4	9/1722 (0.5%)	9
LYMPHOMA	4/1723 (0.2%)	11	0/1722 (0%)	0
NECK CANCER	0/1723 (0%)	0	1/1722 (0.1%)	1
PANCREATIC CANCER	2/1723 (0.1%)	2	4/1722 (0.2%)	4
PANCREATIC MASS	1/1723 (0.1%)	1	0/1722 (0%)	0
PAROTID GLAND CANCER	1/1723 (0.1%)	1	0/1722 (0%)	0
PLEURAL EFFUSION	1/1723 (0.1%)	1	0/1722 (0%)	0
POLYPS	4/1723 (0.2%)	5	0/1722 (0%)	0
PROSTATE CANCER	4/1723 (0.2%)	4	3/1722 (0.2%)	3
RECTAL CANCER	0/1723 (0%)	0	1/1722 (0.1%)	1
RENAL CANCER	2/1723 (0.1%)	2	1/1722 (0.1%)	1
RENAL MASS	1/1723 (0.1%)	1	0/1722 (0%)	0
SINUS CANCER	0/1723 (0%)	0	1/1722 (0.1%)	1
SKIN CANCER	2/1723 (0.1%)	2	5/1722 (0.3%)	5
STOMACH CANCER	2/1723 (0.1%)	2	2/1722 (0.1%)	2
THROAT CANCER	2/1723 (0.1%)	2	0/1722 (0%)	0
THYROIDECTOMY	1/1723 (0.1%)	1	0/1722 (0%)	0
UTERINE CANCER	1/1723 (0.1%)	1	2/1722 (0.1%)	2
UTERINE TUMOR	0/1723 (0%)	0	1/1722 (0.1%)	1
Nervous system disorders
ALTERED MENTAL STATUS	9/1723 (0.5%)	9	8/1722 (0.5%)	8
ALZHEIMER'S DISEASE	0/1723 (0%)	0	2/1722 (0.1%)	2
AMYOTROPHIC LATERAL SCLEROSIS	1/1723 (0.1%)	1	0/1722 (0%)	0
ANXIETY	2/1723 (0.1%)	2	0/1722 (0%)	0
ATAXIA	2/1723 (0.1%)	2	0/1722 (0%)	0
BELLS PALSY	1/1723 (0.1%)	1	0/1722 (0%)	0
BRAIN CANCER	1/1723 (0.1%)	1	1/1722 (0.1%)	1
BRAIN HEMORRHAGE	3/1723 (0.2%)	4	1/1722 (0.1%)	1
CONFUSION	4/1723 (0.2%)	4	1/1722 (0.1%)	1
DEATH	0/1723 (0%)	0	1/1722 (0.1%)	1
DEMENTIA	1/1723 (0.1%)	1	0/1722 (0%)	0
DIZZINESS	0/1723 (0%)	0	3/1722 (0.2%)	3
DYSARTHRIA	1/1723 (0.1%)	1	1/1722 (0.1%)	1
DYSPHAGIA	0/1723 (0%)	0	1/1722 (0.1%)	1
ENCEPHALOPATHY	5/1723 (0.3%)	6	8/1722 (0.5%)	8
FALL	1/1723 (0.1%)	1	1/1722 (0.1%)	1
HEAD INJURY	0/1723 (0%)	0	1/1722 (0.1%)	1
HEADACHE	1/1723 (0.1%)	1	5/1722 (0.3%)	5
HEARING LOSS	0/1723 (0%)	0	1/1722 (0.1%)	1
HEMATOMA	3/1723 (0.2%)	3	1/1722 (0.1%)	1
HEMORRHAGE	1/1723 (0.1%)	1	0/1722 (0%)	0
MENINGITIS	1/1723 (0.1%)	1	0/1722 (0%)	0
MYASTHENIA GRAVIS	0/1723 (0%)	0	1/1722 (0.1%)	1
MYELOPATHY	0/1723 (0%)	0	1/1722 (0.1%)	1
MYOCARDIAL INFARCTION	1/1723 (0.1%)	1	0/1722 (0%)	0
MYOCLONIA	0/1723 (0%)	0	1/1722 (0.1%)	1
NEURONITIS	0/1723 (0%)	0	1/1722 (0.1%)	1
NEUROPATHY	3/1723 (0.2%)	3	0/1722 (0%)	0
PARASTHESIA	2/1723 (0.1%)	2	1/1722 (0.1%)	1
PARKINSON'S DISEASE	1/1723 (0.1%)	1	0/1722 (0%)	0
SCIATICA	1/1723 (0.1%)	1	0/1722 (0%)	0
SEIZURE	4/1723 (0.2%)	5	1/1722 (0.1%)	1
SEPTIC SHOCK	1/1723 (0.1%)	1	0/1722 (0%)	0
SPINAL STENOSIS	2/1723 (0.1%)	2	1/1722 (0.1%)	1
STROKE	57/1723 (3.3%)	65	71/1722 (4.1%)	80
SYNCOPE	28/1723 (1.6%)	30	21/1722 (1.2%)	24
TRANSIENT ISCHEMIC ATTACK	7/1723 (0.4%)	8	8/1722 (0.5%)	9
TREMOR	1/1723 (0.1%)	1	3/1722 (0.2%)	3
VERTEBROBASILAR INSUFFICIENCY	0/1723 (0%)	0	1/1722 (0.1%)	1
VERTIGO	1/1723 (0.1%)	1	1/1722 (0.1%)	1
WEAKNESS	3/1723 (0.2%)	3	1/1722 (0.1%)	1
Psychiatric disorders
BIPOLAR DISORDER	0/1723 (0%)	0	1/1722 (0.1%)	1
DEPRESSION	1/1723 (0.1%)	1	3/1722 (0.2%)	5
PSYCHOSIS	1/1723 (0.1%)	1	0/1722 (0%)	0
Renal and urinary disorders
ARTERIAL STENOSIS	0/1723 (0%)	0	1/1722 (0.1%)	1
ATRIAL FIBRILLATION	1/1723 (0.1%)	1	0/1722 (0%)	0
BLADDER OBSTRUCTION	2/1723 (0.1%)	2	0/1722 (0%)	0
CHEST PAIN	0/1723 (0%)	0	1/1722 (0.1%)	1
CHOLECYSTITIS	2/1723 (0.1%)	2	0/1722 (0%)	0
CHRONIC OBSTRUCTIVE PULMONARY DISEASE	1/1723 (0.1%)	1	0/1722 (0%)	0
DYSPNEA	0/1723 (0%)	0	1/1722 (0.1%)	1
ELEVATED CREATININE	1/1723 (0.1%)	1	5/1722 (0.3%)	5
HEART FAILURE	1/1723 (0.1%)	1	1/1722 (0.1%)	1
HEMATURIA	4/1723 (0.2%)	4	5/1722 (0.3%)	5
HYDRONEPHROSIS	0/1723 (0%)	0	1/1722 (0.1%)	1
HYPERKALEMIA	5/1723 (0.3%)	5	20/1722 (1.2%)	21
HYPOKALEMIA	4/1723 (0.2%)	5	0/1722 (0%)	0
HYPONATREMIA	1/1723 (0.1%)	1	2/1722 (0.1%)	2
HYPOVOLEMIA	0/1723 (0%)	0	2/1722 (0.1%)	2
INCREASING NITRONGENATED SCORIAS	0/1723 (0%)	0	1/1722 (0.1%)	1
KIDNEY DISEASE	51/1723 (3%)	68	63/1722 (3.7%)	79
KIDNEY FAILURE	0/1723 (0%)	0	1/1722 (0.1%)	1
KIDNEY INFECTION	1/1723 (0.1%)	1	0/1722 (0%)	0
KIDNEY STONE	2/1723 (0.1%)	2	3/1722 (0.2%)	3
METABOLIC ACIDOSIS	1/1723 (0.1%)	1	0/1722 (0%)	0
OBSTRUCTIVE UROPATHY	0/1723 (0%)	0	1/1722 (0.1%)	1
OVERACTIVE BLADDER	1/1723 (0.1%)	1	0/1722 (0%)	0
PNEUMONIA	1/1723 (0.1%)	1	0/1722 (0%)	0
PROSTATITIS	0/1723 (0%)	0	1/1722 (0.1%)	1
PYELOCYSTITIS	0/1723 (0%)	0	2/1722 (0.1%)	2
PYELONEPHRITIS	1/1723 (0.1%)	1	2/1722 (0.1%)	2
RENAL FAILURE	1/1723 (0.1%)	1	1/1722 (0.1%)	1
RESPIRATORY INSUFFICIENCY	1/1723 (0.1%)	1	0/1722 (0%)	0
SCLERODERMA	0/1723 (0%)	0	1/1722 (0.1%)	1
SEPSIS	1/1723 (0.1%)	1	0/1722 (0%)	0
URETER STONE	1/1723 (0.1%)	1	0/1722 (0%)	0
URETHRITIS	0/1723 (0%)	0	1/1722 (0.1%)	1
URINARY INCONTINENCE	0/1723 (0%)	0	1/1722 (0.1%)	1
URINARY RETENTION	3/1723 (0.2%)	3	2/1722 (0.1%)	2
URINARY TRACT INFECTION	16/1723 (0.9%)	22	18/1722 (1%)	18
URINARY TRACT STONES	1/1723 (0.1%)	1	2/1722 (0.1%)	2
Reproductive system and breast disorders
EPIDIDYMITIS	0/1723 (0%)	0	3/1722 (0.2%)	4
ERECTILE DYSFUNCTION	0/1723 (0%)	0	1/1722 (0.1%)	1
EROSION OF THE VAGINAL EPITHELIUM	1/1723 (0.1%)	1	0/1722 (0%)	0
GYNECOMASTIA	0/1723 (0%)	0	1/1722 (0.1%)	2
HYPERPLASIA	0/1723 (0%)	0	1/1722 (0.1%)	1
HYSTERECTOMY	0/1723 (0%)	0	1/1722 (0.1%)	1
MYOMA	1/1723 (0.1%)	1	0/1722 (0%)	0
PATHOLOGY OF ENDOMETRIUM	1/1723 (0.1%)	1	0/1722 (0%)	0
PENILE BLEEDING	0/1723 (0%)	0	1/1722 (0.1%)	1
POLYPS	1/1723 (0.1%)	1	0/1722 (0%)	0
POST-MENOPAUSAL BLEEDING	1/1723 (0.1%)	1	0/1722 (0%)	0
PROSTATE CANCER	0/1723 (0%)	0	1/1722 (0.1%)	1
PROSTATIC HYPERPLASIA	5/1723 (0.3%)	5	2/1722 (0.1%)	2
PROSTATITIS	1/1723 (0.1%)	1	0/1722 (0%)	0
UTERINE PROLAPSE	0/1723 (0%)	0	1/1722 (0.1%)	1
VAGINITIS	1/1723 (0.1%)	1	0/1722 (0%)	0
Respiratory, thoracic and mediastinal disorders
ABDOMINAL PAIN	0/1723 (0%)	0	1/1722 (0.1%)	1
ABNORMAL VAGINAL BLEEDING	0/1723 (0%)	0	1/1722 (0.1%)	1
ACUTE RESPIRATORY DISTRESS	0/1723 (0%)	0	2/1722 (0.1%)	2
ALVEOLITIS	1/1723 (0.1%)	1	0/1722 (0%)	0
ASTHMA	5/1723 (0.3%)	7	5/1722 (0.3%)	6
ATRIAL FIBRILLATION	0/1723 (0%)	0	1/1722 (0.1%)	1
BRONCHIECTASIS	1/1723 (0.1%)	1	0/1722 (0%)	0
BRONCHITIS	15/1723 (0.9%)	15	11/1722 (0.6%)	12
CHRONIC OBSTRUCTIVE PULMONARY DISEASE	21/1723 (1.2%)	24	23/1722 (1.3%)	32
COUGH	1/1723 (0.1%)	1	1/1722 (0.1%)	1
DYSPNEA	2/1723 (0.1%)	2	3/1722 (0.2%)	3
EPISTAXIS	1/1723 (0.1%)	1	0/1722 (0%)	0
HEART FAILURE	3/1723 (0.2%)	3	2/1722 (0.1%)	2
HEMOPTYSIS	2/1723 (0.1%)	2	1/1722 (0.1%)	1
HYPERCAPNIA	1/1723 (0.1%)	1	0/1722 (0%)	0
HYPERTENSION	1/1723 (0.1%)	1	0/1722 (0%)	0
HYPOVENTILATION	1/1723 (0.1%)	1	0/1722 (0%)	0
HYPOXIA	4/1723 (0.2%)	4	2/1722 (0.1%)	2
KIDNEY DISEASE	2/1723 (0.1%)	2	0/1722 (0%)	0
LARYNGEAL EDEMA	0/1723 (0%)	0	1/1722 (0.1%)	1
LUNG CONTUSION	0/1723 (0%)	0	1/1722 (0.1%)	1
PLEURAL EFFUSION	5/1723 (0.3%)	5	9/1722 (0.5%)	12
PLEURISY	1/1723 (0.1%)	1	0/1722 (0%)	0
PNEUMONIA	75/1723 (4.4%)	83	76/1722 (4.4%)	87
PULMONARY CONGESTION	0/1723 (0%)	0	1/1722 (0.1%)	1
PULMONARY EDEMA	8/1723 (0.5%)	12	10/1722 (0.6%)	11
PULMONARY EMBOLISM	9/1723 (0.5%)	9	8/1722 (0.5%)	8
PULMONARY EMBOLUS	2/1723 (0.1%)	2	0/1722 (0%)	0
PULMONARY FIBROSIS	1/1723 (0.1%)	1	1/1722 (0.1%)	1
PULMONARY OVERLOAD	1/1723 (0.1%)	4	1/1722 (0.1%)	1
RESPIRATORY ARREST	1/1723 (0.1%)	1	0/1722 (0%)	0
RESPIRATORY CONGESTION	1/1723 (0.1%)	1	0/1722 (0%)	0
RESPIRATORY DISTRESS	3/1723 (0.2%)	3	1/1722 (0.1%)	1
RESPIRATORY FAILURE	11/1723 (0.6%)	13	10/1722 (0.6%)	10
RESPIRATORY INSUFFICIENCY	3/1723 (0.2%)	3	0/1722 (0%)	0
RESPIRATORY TRACT INFECTION	2/1723 (0.1%)	2	1/1722 (0.1%)	1
SHORTNESS OF BREATH	17/1723 (1%)	19	22/1722 (1.3%)	26
SINUSITIS	0/1723 (0%)	0	1/1722 (0.1%)	1
THROMBOEMBOLISM	3/1723 (0.2%)	5	1/1722 (0.1%)	1
TOXIC ALLERGIC ALVEOLITIS	0/1723 (0%)	0	1/1722 (0.1%)	1
TOXIC PNEUMONITIS	1/1723 (0.1%)	1	0/1722 (0%)	0
UPPER RESPIRATORY INFECTION	3/1723 (0.2%)	3	4/1722 (0.2%)	4
Skin and subcutaneous tissue disorders
ABSCESS	1/1723 (0.1%)	1	0/1722 (0%)	0
ACTINIC KERATOSIS	1/1723 (0.1%)	1	0/1722 (0%)	0
ANGIOEDEMA	0/1723 (0%)	0	1/1722 (0.1%)	1
ARM INJURY	0/1723 (0%)	0	1/1722 (0.1%)	1
CELLULITIS	21/1723 (1.2%)	25	14/1722 (0.8%)	17
HYPEREMIA	1/1723 (0.1%)	1	0/1722 (0%)	0
PURPURA	0/1723 (0%)	0	1/1722 (0.1%)	2
SKIN DISEASE	1/1723 (0.1%)	1	0/1722 (0%)	0
ULCER	2/1723 (0.1%)	2	2/1722 (0.1%)	2
URTICARIA	1/1723 (0.1%)	1	1/1722 (0.1%)	1
XERODERMA	1/1723 (0.1%)	1	0/1722 (0%)	0
Surgical and medical procedures
ABSCESS	0/1723 (0%)	0	1/1722 (0.1%)	1
APPENDECTOMY	0/1723 (0%)	0	2/1722 (0.1%)	2
ARTHROPLASTY	0/1723 (0%)	0	1/1722 (0.1%)	1
BREAST REDUCTION	1/1723 (0.1%)	1	0/1722 (0%)	0
CABG	0/1723 (0%)	0	2/1722 (0.1%)	2
CAROTID STENT	1/1723 (0.1%)	1	0/1722 (0%)	0
CHOLECYSTECTOMY	0/1723 (0%)	0	2/1722 (0.1%)	2
CORONAROGRAPHY	0/1723 (0%)	0	1/1722 (0.1%)	1
CORONARY ANGIOGRAPHY	0/1723 (0%)	0	1/1722 (0.1%)	1
CORRECTION THERAPY	1/1723 (0.1%)	1	0/1722 (0%)	0
EMBOLECTOMY	1/1723 (0.1%)	1	0/1722 (0%)	0
ENDARTERECTOMY	1/1723 (0.1%)	1	1/1722 (0.1%)	1
FASCIOTOMY	1/1723 (0.1%)	2	0/1722 (0%)	0
GASTRIC BYPASS SURGERY	0/1723 (0%)	0	1/1722 (0.1%)	1
HEART SURGERY	1/1723 (0.1%)	1	0/1722 (0%)	0
HEPARIN BRIDGING	1/1723 (0.1%)	1	0/1722 (0%)	0
HERNIA	1/1723 (0.1%)	1	0/1722 (0%)	0
HIP REPLACEMENT	1/1723 (0.1%)	1	0/1722 (0%)	0
ICD IMPLANTATION	1/1723 (0.1%)	1	0/1722 (0%)	0
KNEE ARTHROPLASTY	0/1723 (0%)	0	1/1722 (0.1%)	1
KNEE SURGERY	4/1723 (0.2%)	4	3/1722 (0.2%)	3
LEG AMPUTATION	0/1723 (0%)	0	1/1722 (0.1%)	1
NEPHRECTOMY	0/1723 (0%)	0	1/1722 (0.1%)	1
PRE-CANCEROUS TUMOR SURGERY, LEFT TEMPORAL LEVEL.	0/1723 (0%)	0	1/1722 (0.1%)	1
PREVENTIVE TREATMENT	1/1723 (0.1%)	1	0/1722 (0%)	0
PROSTATE SURGERY	2/1723 (0.1%)	2	1/1722 (0.1%)	1
RADIATION	0/1723 (0%)	0	1/1722 (0.1%)	1
RADIOFREQUENCY ABLATION	0/1723 (0%)	0	2/1722 (0.1%)	2
RESECTION OF CUBITAL	1/1723 (0.1%)	1	0/1722 (0%)	0
SPINAL STENOSIS	1/1723 (0.1%)	1	1/1722 (0.1%)	1
STENT RESTENOSIS	1/1723 (0.1%)	1	0/1722 (0%)	0
STROKE	1/1723 (0.1%)	1	0/1722 (0%)	0
TEE	1/1723 (0.1%)	1	0/1722 (0%)	0
TOE AMPUTATION	0/1723 (0%)	0	1/1722 (0.1%)	1
TRANSURETHRAL PROSTATIC RESECTION	1/1723 (0.1%)	1	0/1722 (0%)	0
TUMOR REMOVAL	1/1723 (0.1%)	1	1/1722 (0.1%)	1
VALVE REPLACEMENT	0/1723 (0%)	0	2/1722 (0.1%)	2
Vascular disorders
ABDOMINAL AORTIC ANEURYSM	2/1723 (0.1%)	2	2/1722 (0.1%)	2
ANEURYSM	3/1723 (0.2%)	3	0/1722 (0%)	0
AORTIC ANEURYSM	0/1723 (0%)	0	1/1722 (0.1%)	1
ARM INJURY	1/1723 (0.1%)	1	0/1722 (0%)	0
ARTERIAL OCCLUSIVE DISEASE	0/1723 (0%)	0	2/1722 (0.1%)	2
ARTERIAL THROMBOSIS	1/1723 (0.1%)	1	0/1722 (0%)	0
ATHEROSCLEROSIS	2/1723 (0.1%)	2	1/1722 (0.1%)	1
CAROTID STENOSIS	1/1723 (0.1%)	1	0/1722 (0%)	0
COLD EXTREMITIES	0/1723 (0%)	0	1/1722 (0.1%)	1
DEEP VEIN THROMBOSIS	6/1723 (0.3%)	7	4/1722 (0.2%)	5
EPISTAXIS	1/1723 (0.1%)	1	2/1722 (0.1%)	3
FEMORAL EMBOLUS	1/1723 (0.1%)	1	0/1722 (0%)	0
FOOT ULCER	1/1723 (0.1%)	1	0/1722 (0%)	0
GANGRENE	1/1723 (0.1%)	1	4/1722 (0.2%)	4
HEMATOMA	0/1723 (0%)	0	1/1722 (0.1%)	1
HEMORRHAGE	0/1723 (0%)	0	1/1722 (0.1%)	1
KNEE AMPUTATION	0/1723 (0%)	0	1/1722 (0.1%)	1
LEG CLAUDICATION	1/1723 (0.1%)	1	0/1722 (0%)	0
LEG ULCERS	1/1723 (0.1%)	1	0/1722 (0%)	0
LIMB ISCHEMIA	1/1723 (0.1%)	1	1/1722 (0.1%)	1
LYMPHANGITIS	1/1723 (0.1%)	1	0/1722 (0%)	0
PERIPHERAL ARTERIAL DISEASE	6/1723 (0.3%)	11	1/1722 (0.1%)	1
PERIPHERAL VASCULAR DISEASE	0/1723 (0%)	0	1/1722 (0.1%)	1
PHLEBOTHROMBOSIS	1/1723 (0.1%)	1	0/1722 (0%)	0
SCLERODERMA	1/1723 (0.1%)	2	0/1722 (0%)	0
THROMBOEMBOLISM	1/1723 (0.1%)	1	1/1722 (0.1%)	1
THROMBOSIS	2/1723 (0.1%)	3	1/1722 (0.1%)	3
ULCER	0/1723 (0%)	0	1/1722 (0.1%)	1
VARICOSE VEINS	1/1723 (0.1%)	1	0/1722 (0%)	0
VENOUS INSUFFICIENCY	0/1723 (0%)	0	2/1722 (0.1%)	2
VENOUS STASIS	1/1723 (0.1%)	1	0/1722 (0%)	0
VOLUME OVERLOAD	0/1723 (0%)	0	1/1722 (0.1%)	1
Other (Not Including Serious) Adverse Events
	Placebo		Spironolactone
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1086/1723 (63%)		1152/1722 (66.9%)
Blood and lymphatic system disorders
ANEMIA	44/1723 (2.6%)	48	41/1722 (2.4%)	45
BLEEDING	2/1723 (0.1%)	2	0/1722 (0%)	0
BRUISE	0/1723 (0%)	0	2/1722 (0.1%)	2
ELEVATED INR	2/1723 (0.1%)	3	4/1722 (0.2%)	4
ERYTHROCYTOSIS	2/1723 (0.1%)	2	0/1722 (0%)	0
HEMATOMA	1/1723 (0.1%)	1	3/1722 (0.2%)	3
HEMATURIA	2/1723 (0.1%)	3	0/1722 (0%)	0
IRON DEFICIENCY	2/1723 (0.1%)	2	0/1722 (0%)	0
IRON OVERLOAD	2/1723 (0.1%)	2	0/1722 (0%)	0
LEUKOCYTOSIS	5/1723 (0.3%)	5	2/1722 (0.1%)	2
LOW HEMOGLOBIN	2/1723 (0.1%)	2	2/1722 (0.1%)	2
SUPRATHERAPEUTIC INR	3/1723 (0.2%)	3	1/1722 (0.1%)	2
THROMBOCYTOPENIA	0/1723 (0%)	0	2/1722 (0.1%)	3
Cardiac disorders
ABDOMINAL PAIN	0/1723 (0%)	0	2/1722 (0.1%)	2
ANEMIA	2/1723 (0.1%)	2	0/1722 (0%)	0
ANEURYSM	3/1723 (0.2%)	3	0/1722 (0%)	0
ANGINA	2/1723 (0.1%)	2	0/1722 (0%)	0
ARRHYTHMIA	16/1723 (0.9%)	18	10/1722 (0.6%)	13
ARTERIAL STENOSIS	2/1723 (0.1%)	2	1/1722 (0.1%)	1
ATHEROSCLEROSIS	2/1723 (0.1%)	2	3/1722 (0.2%)	4
ATRIAL FIBRILLATION	85/1723 (4.9%)	123	74/1722 (4.3%)	97
ATRIAL FLUTTER	5/1723 (0.3%)	6	7/1722 (0.4%)	9
AV BLOCK	0/1723 (0%)	0	2/1722 (0.1%)	2
BRADYCARDIA	8/1723 (0.5%)	8	20/1722 (1.2%)	22
BUNDLE BRANCH BLOCK	0/1723 (0%)	0	2/1722 (0.1%)	2
CARDIOVERSION	4/1723 (0.2%)	5	2/1722 (0.1%)	2
CHEST PAIN	102/1723 (5.9%)	130	80/1722 (4.6%)	102
CORONARY ARTERY DISEASE	3/1723 (0.2%)	3	0/1722 (0%)	0
DESTABILIZATION OF BLOOD PRESSURE	2/1723 (0.1%)	2	0/1722 (0%)	0
DEVICE CHANGE	3/1723 (0.2%)	3	4/1722 (0.2%)	4
DIZZINESS	3/1723 (0.2%)	3	2/1722 (0.1%)	2
DYSLIPIDEMIA	2/1723 (0.1%)	2	1/1722 (0.1%)	1
DYSPNEA	37/1723 (2.1%)	44	31/1722 (1.8%)	32
EDEMA	3/1723 (0.2%)	3	4/1722 (0.2%)	4
ELEVATED BNP	2/1723 (0.1%)	2	0/1722 (0%)	0
ELEVATED CARDIAC ENZYMES	5/1723 (0.3%)	5	9/1722 (0.5%)	9
EXTRASYSTOLE	7/1723 (0.4%)	7	7/1722 (0.4%)	8
FATIGUE	2/1723 (0.1%)	2	1/1722 (0.1%)	1
HEADACHE	2/1723 (0.1%)	2	2/1722 (0.1%)	2
HEART FAILURE	135/1723 (7.8%)	174	121/1722 (7%)	150
HEART VALVE CALCIFICATION	3/1723 (0.2%)	3	0/1722 (0%)	0
HEARTBURN	1/1723 (0.1%)	1	2/1722 (0.1%)	2
HYPERKALEMIA	0/1723 (0%)	0	2/1722 (0.1%)	2
HYPERTENSIC CRISIS	4/1723 (0.2%)	4	0/1722 (0%)	0
HYPERTENSION	145/1723 (8.4%)	265	113/1722 (6.6%)	219
HYPERVOLEMIA	6/1723 (0.3%)	9	7/1722 (0.4%)	14
HYPOTENSION	52/1723 (3%)	59	71/1722 (4.1%)	90
LEG EDEMA	3/1723 (0.2%)	3	0/1722 (0%)	0
LIMB EDEMA	2/1723 (0.1%)	2	2/1722 (0.1%)	2
LOWER EXTREMITY EDEMA	40/1723 (2.3%)	44	36/1722 (2.1%)	41
MYOCARDIAL INFARCTION	2/1723 (0.1%)	2	2/1722 (0.1%)	2
ORTHOPNEA	2/1723 (0.1%)	2	0/1722 (0%)	0
PALPITATIONS	26/1723 (1.5%)	29	25/1722 (1.5%)	26
PERICARDITIS	1/1723 (0.1%)	1	2/1722 (0.1%)	2
PERIPHERAL EDEMA	4/1723 (0.2%)	4	1/1722 (0.1%)	1
SHORTNESS OF BREATH	2/1723 (0.1%)	4	3/1722 (0.2%)	4
SICK SINUS SYNDROME	1/1723 (0.1%)	1	4/1722 (0.2%)	4
TACHYCARDIA	20/1723 (1.2%)	29	22/1722 (1.3%)	25
WEAKNESS	2/1723 (0.1%)	2	0/1722 (0%)	0
Ear and labyrinth disorders
EAR ACHE	2/1723 (0.1%)	2	2/1722 (0.1%)	2
EAR INFECTION	7/1723 (0.4%)	7	6/1722 (0.3%)	6
EAR PAIN	0/1723 (0%)	0	3/1722 (0.2%)	3
HEARING LOSS	8/1723 (0.5%)	9	4/1722 (0.2%)	4
LABYRINTHITIS	0/1723 (0%)	0	3/1722 (0.2%)	3
OTITIS	0/1723 (0%)	0	2/1722 (0.1%)	2
TINNITUS	2/1723 (0.1%)	2	5/1722 (0.3%)	5
VERTIGO	16/1723 (0.9%)	20	11/1722 (0.6%)	11
Endocrine disorders
DIABETES	37/1723 (2.1%)	40	38/1722 (2.2%)	42
GOITER	2/1723 (0.1%)	2	7/1722 (0.4%)	7
GYNECOMASTIA	0/1723 (0%)	0	6/1722 (0.3%)	6
HOT FLASHES	2/1723 (0.1%)	2	1/1722 (0.1%)	1
HYPERGLYCEMIA	26/1723 (1.5%)	29	21/1722 (1.2%)	25
HYPERKALEMIA	2/1723 (0.1%)	2	1/1722 (0.1%)	1
HYPERTHYROIDISM	2/1723 (0.1%)	2	3/1722 (0.2%)	3
HYPOGLYCEMIA	19/1723 (1.1%)	27	9/1722 (0.5%)	9
HYPOTHYROIDISM	8/1723 (0.5%)	8	15/1722 (0.9%)	15
INCREASED OF TSH	2/1723 (0.1%)	2	1/1722 (0.1%)	1
THYROID NODULE	2/1723 (0.1%)	2	1/1722 (0.1%)	1
Eye disorders
BLEEDING IN EYE	1/1723 (0.1%)	1	7/1722 (0.4%)	8
BLURRED VISION	9/1723 (0.5%)	9	5/1722 (0.3%)	5
CATARACTS	17/1723 (1%)	21	18/1722 (1%)	21
CONJUCTIVITIS	5/1723 (0.3%)	5	8/1722 (0.5%)	8
DRY EYES	1/1723 (0.1%)	1	2/1722 (0.1%)	2
EYE PAIN	2/1723 (0.1%)	3	3/1722 (0.2%)	4
EYELID CYSTS	0/1723 (0%)	0	2/1722 (0.1%)	2
GLAUCOMA	2/1723 (0.1%)	2	3/1722 (0.2%)	3
MACULAR DEGENERATION	2/1723 (0.1%)	2	2/1722 (0.1%)	2
RETINOPATHY	0/1723 (0%)	0	2/1722 (0.1%)	2
VISION CHANGES	2/1723 (0.1%)	2	2/1722 (0.1%)	2
VISION LOSS	3/1723 (0.2%)	3	5/1722 (0.3%)	5
Gastrointestinal disorders
ABDOMINAL PAIN	28/1723 (1.6%)	31	31/1722 (1.8%)	34
BLOOD IN STOOL	3/1723 (0.2%)	3	0/1722 (0%)	0
COLITIS	3/1723 (0.2%)	3	4/1722 (0.2%)	4
CONSTIPATION	25/1723 (1.5%)	26	28/1722 (1.6%)	31
DECREASED APPETITE	8/1723 (0.5%)	8	10/1722 (0.6%)	10
DEHYDRATION	2/1723 (0.1%)	2	0/1722 (0%)	0
DIARRHEA	74/1723 (4.3%)	83	79/1722 (4.6%)	88
DIVERTICULITIS	3/1723 (0.2%)	3	2/1722 (0.1%)	2
DUODENITIS	1/1723 (0.1%)	1	2/1722 (0.1%)	2
DYSPEPSIA	4/1723 (0.2%)	5	2/1722 (0.1%)	2
DYSPHAGIA	4/1723 (0.2%)	4	4/1722 (0.2%)	4
EPIGASTRIC PAIN	3/1723 (0.2%)	3	1/1722 (0.1%)	1
ESOPHAGITIS	3/1723 (0.2%)	3	0/1722 (0%)	0
FLATULENCE	2/1723 (0.1%)	2	2/1722 (0.1%)	2
GASTRIC REFLUX	7/1723 (0.4%)	7	3/1722 (0.2%)	3
GASTRITIS	58/1723 (3.4%)	59	52/1722 (3%)	59
GASTROENTERITIS	14/1723 (0.8%)	14	6/1722 (0.3%)	6
GI BLEED	8/1723 (0.5%)	8	11/1722 (0.6%)	11
GI DISTRESS	6/1723 (0.3%)	6	7/1722 (0.4%)	7
HEARTBURN	7/1723 (0.4%)	7	7/1722 (0.4%)	7
HEMATEMESIS	1/1723 (0.1%)	1	2/1722 (0.1%)	2
HEMORRHOIDS	1/1723 (0.1%)	1	3/1722 (0.2%)	3
LACTOSE INTOLERANCE	2/1723 (0.1%)	2	0/1722 (0%)	0
NAUSEA	34/1723 (2%)	37	54/1722 (3.1%)	57
PARAGEUSIA	2/1723 (0.1%)	3	2/1722 (0.1%)	2
POLYPS	2/1723 (0.1%)	2	2/1722 (0.1%)	2
SORE THROAT	0/1723 (0%)	0	2/1722 (0.1%)	2
STOMACH ULCER	2/1723 (0.1%)	2	1/1722 (0.1%)	1
ULCER	4/1723 (0.2%)	4	8/1722 (0.5%)	8
URETHRITIS	0/1723 (0%)	0	2/1722 (0.1%)	2
VOMITING	20/1723 (1.2%)	20	20/1722 (1.2%)	21
WEAKNESS	2/1723 (0.1%)	2	0/1722 (0%)	0
XEROSTOMIA	7/1723 (0.4%)	7	6/1722 (0.3%)	6
General disorders
ABNORMAL BMP	5/1723 (0.3%)	9	1/1722 (0.1%)	1
ARM INJURY	2/1723 (0.1%)	2	0/1722 (0%)	0
CHILLS	0/1723 (0%)	0	2/1722 (0.1%)	3
COLD SYMPTOMS	3/1723 (0.2%)	3	0/1722 (0%)	0
DEHYDRATION	4/1723 (0.2%)	4	13/1722 (0.8%)	13
DIAPHORESIS	2/1723 (0.1%)	2	0/1722 (0%)	0
DIZZINESS	35/1723 (2%)	44	34/1722 (2%)	35
DYSLIPIDEMIA	16/1723 (0.9%)	18	13/1722 (0.8%)	13
FATIGUE	17/1723 (1%)	18	7/1722 (0.4%)	7
FEVER	8/1723 (0.5%)	8	3/1722 (0.2%)	3
FLU LIKE SYMPTOMS	2/1723 (0.1%)	2	1/1722 (0.1%)	1
FLUID RETENTION	0/1723 (0%)	0	2/1722 (0.1%)	2
HYPERCALCEMIA	0/1723 (0%)	0	2/1722 (0.1%)	2
INFLUENZA	6/1723 (0.3%)	6	2/1722 (0.1%)	2
SWEATING	2/1723 (0.1%)	2	3/1722 (0.2%)	3
WEAKNESS	35/1723 (2%)	37	45/1722 (2.6%)	53
WEIGHT LOSS	1/1723 (0.1%)	1	2/1722 (0.1%)	2
Hepatobiliary disorders
ABDOMINAL PAIN	1/1723 (0.1%)	1	2/1722 (0.1%)	2
CHOLECYSTITIS	4/1723 (0.2%)	4	5/1722 (0.3%)	5
ELEVATED BILIRUBIN	0/1723 (0%)	0	2/1722 (0.1%)	2
ELEVATED LIVER ENZYMES	4/1723 (0.2%)	4	5/1722 (0.3%)	6
FATTY HEPATOSIS	2/1723 (0.1%)	2	1/1722 (0.1%)	1
GALLSTONES	5/1723 (0.3%)	5	7/1722 (0.4%)	10
Immune system disorders
ALLERGY	11/1723 (0.6%)	12	11/1722 (0.6%)	12
HAIR LOSS	1/1723 (0.1%)	1	3/1722 (0.2%)	3
HAY FEVER	1/1723 (0.1%)	1	2/1722 (0.1%)	2
SEASONAL ALLERGIES	0/1723 (0%)	0	2/1722 (0.1%)	2
Infections and infestations
C-DIFF INFECTION	5/1723 (0.3%)	5	0/1722 (0%)	0
CELLULITIS	11/1723 (0.6%)	11	2/1722 (0.1%)	2
DENTAL ABSCESS	2/1723 (0.1%)	2	1/1722 (0.1%)	1
EAR INFECTION	3/1723 (0.2%)	3	1/1722 (0.1%)	1
FEVER	2/1723 (0.1%)	2	5/1722 (0.3%)	5
HERPES SIMPLEX	1/1723 (0.1%)	1	2/1722 (0.1%)	2
HYPERTHERMIA	0/1723 (0%)	0	2/1722 (0.1%)	2
INFECTION	5/1723 (0.3%)	5	8/1722 (0.5%)	8
INFLUENZA	71/1723 (4.1%)	82	70/1722 (4.1%)	80
ONYCHOMYCOSIS	1/1723 (0.1%)	1	2/1722 (0.1%)	2
SEPSIS	3/1723 (0.2%)	3	0/1722 (0%)	0
SEXUALLY TRANSMITTED DISEASE	2/1723 (0.1%)	2	0/1722 (0%)	0
SHINGLES	7/1723 (0.4%)	7	10/1722 (0.6%)	10
SINUSITIS	4/1723 (0.2%)	4	3/1722 (0.2%)	3
THRUSH	3/1723 (0.2%)	3	1/1722 (0.1%)	1
TONSILLITIS	0/1723 (0%)	0	2/1722 (0.1%)	2
TOOTH ABSCESS	2/1723 (0.1%)	2	2/1722 (0.1%)	2
UPPER RESPIRATORY INFECTION	7/1723 (0.4%)	7	4/1722 (0.2%)	6
WOUND INFECTION	2/1723 (0.1%)	2	1/1722 (0.1%)	1
Injury, poisoning and procedural complications
CONCUSSION	0/1723 (0%)	0	2/1722 (0.1%)	2
FALL	4/1723 (0.2%)	5	3/1722 (0.2%)	3
FRACTURE	3/1723 (0.2%)	3	3/1722 (0.2%)	3
SHOULDER INJURY	0/1723 (0%)	0	2/1722 (0.1%)	2
SKIN LACERATION	2/1723 (0.1%)	2	0/1722 (0%)	0
Metabolism and nutrition disorders
DECREASED APPETITE	2/1723 (0.1%)	2	1/1722 (0.1%)	1
DYSLIPIDEMIA	3/1723 (0.2%)	3	0/1722 (0%)	0
HYPERKALEMIA	3/1723 (0.2%)	4	5/1722 (0.3%)	6
HYPOKALEMIA	2/1723 (0.1%)	2	0/1722 (0%)	0
HYPONATREMIA	1/1723 (0.1%)	1	3/1722 (0.2%)	3
ULCER	2/1723 (0.1%)	2	0/1722 (0%)	0
VITAMIN D DEFICIENCY	1/1723 (0.1%)	1	3/1722 (0.2%)	3
WEIGHT GAIN	16/1723 (0.9%)	17	15/1722 (0.9%)	17
WEIGHT LOSS	8/1723 (0.5%)	9	5/1722 (0.3%)	7
Musculoskeletal and connective tissue disorders
ABDOMINAL PAIN	3/1723 (0.2%)	4	6/1722 (0.3%)	6
ABSCESS	2/1723 (0.1%)	2	0/1722 (0%)	0
ANKLE INJURY	3/1723 (0.2%)	3	4/1722 (0.2%)	4
ARM INJURY	14/1723 (0.8%)	15	10/1722 (0.6%)	10
ARTHRALGIA	4/1723 (0.2%)	5	8/1722 (0.5%)	14
ARTHRITIS	11/1723 (0.6%)	12	10/1722 (0.6%)	10
ASTHENIA	1/1723 (0.1%)	1	3/1722 (0.2%)	3
ATAXIA	1/1723 (0.1%)	1	2/1722 (0.1%)	2
BACK INJURY	2/1723 (0.1%)	2	1/1722 (0.1%)	1
BACK PAIN	64/1723 (3.7%)	74	67/1722 (3.9%)	76
BODY ACHES	4/1723 (0.2%)	4	0/1722 (0%)	0
BODY PAIN	9/1723 (0.5%)	11	9/1722 (0.5%)	9
BRUISE	5/1723 (0.3%)	7	1/1722 (0.1%)	1
BURSITIS	8/1723 (0.5%)	8	2/1722 (0.1%)	2
BUTTOCK PAIN	0/1723 (0%)	0	4/1722 (0.2%)	4
CARPEL TUNNEL RELEASE	2/1723 (0.1%)	2	0/1722 (0%)	0
CARPEL TUNNEL SYNDROME	2/1723 (0.1%)	2	0/1722 (0%)	0
CHEST PAIN	8/1723 (0.5%)	8	11/1722 (0.6%)	12
DERMATITIS	2/1723 (0.1%)	2	1/1722 (0.1%)	1
DORSOPATHY	3/1723 (0.2%)	3	1/1722 (0.1%)	1
EDEMA	3/1723 (0.2%)	3	2/1722 (0.1%)	2
FALL	12/1723 (0.7%)	12	15/1722 (0.9%)	17
FOOT INJURY	1/1723 (0.1%)	1	2/1722 (0.1%)	3
FOOT PAIN	6/1723 (0.3%)	8	7/1722 (0.4%)	7
FRACTURE	33/1723 (1.9%)	34	28/1722 (1.6%)	30
GONITIS	1/1723 (0.1%)	1	3/1722 (0.2%)	4
GOUT	36/1723 (2.1%)	48	34/1722 (2%)	38
HAND INJURY	0/1723 (0%)	0	3/1722 (0.2%)	3
HAND PAIN	2/1723 (0.1%)	2	3/1722 (0.2%)	4
HEAD INJURY	2/1723 (0.1%)	2	0/1722 (0%)	0
HERNIA	13/1723 (0.8%)	14	6/1722 (0.3%)	6
HIP PAIN	10/1723 (0.6%)	10	17/1722 (1%)	20
INGROWN TOENAIL	1/1723 (0.1%)	1	2/1722 (0.1%)	2
KNEE INJURY	3/1723 (0.2%)	3	4/1722 (0.2%)	4
KNEE PAIN	12/1723 (0.7%)	12	20/1722 (1.2%)	22
LEG INJURY	2/1723 (0.1%)	2	2/1722 (0.1%)	2
LEG PAIN	30/1723 (1.7%)	31	29/1722 (1.7%)	30
LOWER EXTREMITY EDEMA	1/1723 (0.1%)	1	2/1722 (0.1%)	2
MOUTH PAIN	2/1723 (0.1%)	2	0/1722 (0%)	0
MUSCLE INJURY	2/1723 (0.1%)	2	0/1722 (0%)	0
MUSCLE PAIN	6/1723 (0.3%)	6	6/1722 (0.3%)	6
MUSCLE SPASM	3/1723 (0.2%)	3	3/1722 (0.2%)	3
NECK PAIN	5/1723 (0.3%)	5	7/1722 (0.4%)	7
OSTEOARTHRITIS	14/1723 (0.8%)	14	26/1722 (1.5%)	27
OSTEOCHONDROSIS	10/1723 (0.6%)	10	14/1722 (0.8%)	15
OSTEOPOROSIS	4/1723 (0.2%)	4	2/1722 (0.1%)	2
PRURITIS	2/1723 (0.1%)	2	2/1722 (0.1%)	2
RIB PAIN	3/1723 (0.2%)	3	3/1722 (0.2%)	3
SCIATICA	2/1723 (0.1%)	2	0/1722 (0%)	0
SHOULDER INJURY	2/1723 (0.1%)	2	4/1722 (0.2%)	4
SHOULDER PAIN	14/1723 (0.8%)	14	9/1722 (0.5%)	10
SKIN LACERATION	4/1723 (0.2%)	4	1/1722 (0.1%)	1
SPINAL STENOSIS	0/1723 (0%)	0	2/1722 (0.1%)	2
STENOSING TENOSYNOVITIS	4/1723 (0.2%)	4	2/1722 (0.1%)	2
TENDONITIS	0/1723 (0%)	0	3/1722 (0.2%)	3
TMJ DISORDER	0/1723 (0%)	0	2/1722 (0.1%)	2
TOOTHACHE	12/1723 (0.7%)	13	8/1722 (0.5%)	9
ULCER	5/1723 (0.3%)	6	3/1722 (0.2%)	3
WEAKNESS	2/1723 (0.1%)	2	5/1722 (0.3%)	5
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
BLADDER CANCER	3/1723 (0.2%)	3	1/1722 (0.1%)	1
BLADDER TUMOR	2/1723 (0.1%)	2	0/1722 (0%)	0
BREAST CANCER	3/1723 (0.2%)	3	1/1722 (0.1%)	1
CYST	14/1723 (0.8%)	14	18/1722 (1%)	19
LIPOMA	2/1723 (0.1%)	2	2/1722 (0.1%)	3
LUNG CANCER	0/1723 (0%)	0	2/1722 (0.1%)	2
POLYPS	6/1723 (0.3%)	6	9/1722 (0.5%)	9
PROSTATE CANCER	1/1723 (0.1%)	1	3/1722 (0.2%)	4
SKIN CANCER	17/1723 (1%)	22	14/1722 (0.8%)	15
THYROID NODULE	0/1723 (0%)	0	2/1722 (0.1%)	2
TONGUE LESION	2/1723 (0.1%)	2	0/1722 (0%)	0
Nervous system disorders
ALTERED MENTAL STATUS	9/1723 (0.5%)	9	12/1722 (0.7%)	12
ANXIETY	3/1723 (0.2%)	3	1/1722 (0.1%)	1
ATAXIA	2/1723 (0.1%)	2	5/1722 (0.3%)	5
ATHEROSCLEROSIS	1/1723 (0.1%)	1	2/1722 (0.1%)	2
CARPEL TUNNEL SYNDROME	3/1723 (0.2%)	5	1/1722 (0.1%)	1
CONFUSION	9/1723 (0.5%)	10	5/1722 (0.3%)	5
DEMENTIA	2/1723 (0.1%)	2	2/1722 (0.1%)	2
DIZZINESS	54/1723 (3.1%)	70	64/1722 (3.7%)	75
DROWSINESS	2/1723 (0.1%)	2	3/1722 (0.2%)	3
ENCEPHALOPATHY	8/1723 (0.5%)	8	6/1722 (0.3%)	6
FALL	4/1723 (0.2%)	7	2/1722 (0.1%)	3
HEADACHE	90/1723 (5.2%)	113	84/1722 (4.9%)	98
INSOMNIA	39/1723 (2.3%)	55	29/1722 (1.7%)	46
MEMORY LOSS	2/1723 (0.1%)	2	7/1722 (0.4%)	9
NEURALGIA	1/1723 (0.1%)	1	2/1722 (0.1%)	2
NEUROPATHY	7/1723 (0.4%)	7	4/1722 (0.2%)	4
PARASTHESIA	20/1723 (1.2%)	24	23/1722 (1.3%)	26
PARKINSON'S DISEASE	1/1723 (0.1%)	1	2/1722 (0.1%)	2
RADICULITIS	7/1723 (0.4%)	8	8/1722 (0.5%)	8
RESTLESS LEG SYNDROME	2/1723 (0.1%)	2	1/1722 (0.1%)	1
SCIATICA	1/1723 (0.1%)	1	7/1722 (0.4%)	7
SEIZURE	4/1723 (0.2%)	4	3/1722 (0.2%)	3
SLEEP DISTURBANCE	1/1723 (0.1%)	1	2/1722 (0.1%)	2
STROKE	10/1723 (0.6%)	11	8/1722 (0.5%)	11
SYNCOPE	24/1723 (1.4%)	27	28/1722 (1.6%)	28
TRANSIENT ISCHEMIC ATTACK	11/1723 (0.6%)	14	3/1722 (0.2%)	3
TREMOR	5/1723 (0.3%)	5	5/1722 (0.3%)	5
VERTIGO	2/1723 (0.1%)	2	1/1722 (0.1%)	1
WEAKNESS	2/1723 (0.1%)	2	2/1722 (0.1%)	2
Psychiatric disorders
ANXIETY	3/1723 (0.2%)	3	4/1722 (0.2%)	4
DEPRESSION	16/1723 (0.9%)	16	20/1722 (1.2%)	20
EMOTIONAL LABILITY	2/1723 (0.1%)	2	4/1722 (0.2%)	4
NEUROSIS	13/1723 (0.8%)	21	6/1722 (0.3%)	8
Renal and urinary disorders
CYST	2/1723 (0.1%)	2	0/1722 (0%)	0
CYSTOSCOPY	2/1723 (0.1%)	2	0/1722 (0%)	0
DIABETES	0/1723 (0%)	0	2/1722 (0.1%)	2
DYSURIA	7/1723 (0.4%)	7	6/1722 (0.3%)	6
ELEVATED BUN	3/1723 (0.2%)	3	4/1722 (0.2%)	4
ELEVATED CREATININE	47/1723 (2.7%)	50	60/1722 (3.5%)	77
ELEVATED LIVER ENZYMES	2/1723 (0.1%)	2	1/1722 (0.1%)	2
HEMATURIA	10/1723 (0.6%)	10	11/1722 (0.6%)	11
HYPERCALCEMIA	2/1723 (0.1%)	2	0/1722 (0%)	0
HYPERKALEMIA	96/1723 (5.6%)	109	226/1722 (13.1%)	273
HYPERURICEMIA	1/1723 (0.1%)	1	4/1722 (0.2%)	5
HYPOKALEMIA	29/1723 (1.7%)	38	13/1722 (0.8%)	17
HYPONATREMIA	0/1723 (0%)	0	10/1722 (0.6%)	12
KIDNEY DISEASE	68/1723 (3.9%)	76	135/1722 (7.8%)	182
KIDNEY STONE	8/1723 (0.5%)	10	5/1722 (0.3%)	6
NOCTURIA	2/1723 (0.1%)	2	0/1722 (0%)	0
OLIGURIA	2/1723 (0.1%)	2	0/1722 (0%)	0
POLYURIA	4/1723 (0.2%)	4	4/1722 (0.2%)	4
PROTEINURIA	2/1723 (0.1%)	2	4/1722 (0.2%)	4
PYELONEPHRITIS	8/1723 (0.5%)	8	9/1722 (0.5%)	9
RENAL FAILURE	2/1723 (0.1%)	2	0/1722 (0%)	0
URETHRITIS	0/1723 (0%)	0	2/1722 (0.1%)	2
URINARY HESITANCY	2/1723 (0.1%)	2	0/1722 (0%)	0
URINARY INCONTINENCE	5/1723 (0.3%)	6	7/1722 (0.4%)	7
URINARY RETENTION	5/1723 (0.3%)	5	10/1722 (0.6%)	10
URINARY TRACT INFECTION	68/1723 (3.9%)	84	60/1722 (3.5%)	74
URINARY TRACT STONES	1/1723 (0.1%)	1	2/1722 (0.1%)	2
URINARY URGENCY	2/1723 (0.1%)	2	0/1722 (0%)	0
Reproductive system and breast disorders
ABNORMAL VAGINAL BLEEDING	2/1723 (0.1%)	2	3/1722 (0.2%)	3
BREAST PAIN	5/1723 (0.3%)	5	18/1722 (1%)	18
BREAST TENDERNESS	0/1723 (0%)	0	2/1722 (0.1%)	2
ELEVATED PSA	0/1723 (0%)	0	2/1722 (0.1%)	2
ERECTILE DYSFUNCTION	4/1723 (0.2%)	4	3/1722 (0.2%)	3
GYNECOMASTIA	7/1723 (0.4%)	8	44/1722 (2.6%)	45
PROSTATIC HYPERPLASIA	6/1723 (0.3%)	6	6/1722 (0.3%)	6
Respiratory, thoracic and mediastinal disorders
ACUTE RESPIRATORY DISEASE	15/1723 (0.9%)	17	9/1722 (0.5%)	9
ASTHMA	7/1723 (0.4%)	9	9/1722 (0.5%)	9
BRONCHITIS	64/1723 (3.7%)	69	63/1722 (3.7%)	75
BRONCHOSPASM	6/1723 (0.3%)	8	2/1722 (0.1%)	2
CHEST CONGESTION	4/1723 (0.2%)	4	3/1722 (0.2%)	3
CHRONIC OBSTRUCTIVE PULMONARY DISEASE	14/1723 (0.8%)	15	10/1722 (0.6%)	12
COUGH	44/1723 (2.6%)	53	44/1722 (2.6%)	47
DYSPNEA	2/1723 (0.1%)	2	3/1722 (0.2%)	3
HEMOPTYSIS	4/1723 (0.2%)	4	5/1722 (0.3%)	6
HOARSENESS	0/1723 (0%)	0	2/1722 (0.1%)	2
HYPERTENSION	3/1723 (0.2%)	3	0/1722 (0%)	0
HYPOXIA	1/1723 (0.1%)	1	2/1722 (0.1%)	2
INFLUENZA	1/1723 (0.1%)	1	2/1722 (0.1%)	2
LUNG MASS	1/1723 (0.1%)	1	2/1722 (0.1%)	2
NASAL CONGESTION	4/1723 (0.2%)	4	4/1722 (0.2%)	4
PHARYNGITIS	5/1723 (0.3%)	5	3/1722 (0.2%)	3
PLEURAL EFFUSION	2/1723 (0.1%)	2	6/1722 (0.3%)	7
PNEUMONIA	31/1723 (1.8%)	32	44/1722 (2.6%)	49
PULMONARY CONGESTION	0/1723 (0%)	0	3/1722 (0.2%)	3
PULMONARY EDEMA	3/1723 (0.2%)	3	2/1722 (0.1%)	2
PULMONARY EMBOLISM	3/1723 (0.2%)	3	4/1722 (0.2%)	5
PULMONARY FIBROSIS	2/1723 (0.1%)	2	0/1722 (0%)	0
PULMONARY OVERLOAD	3/1723 (0.2%)	3	3/1722 (0.2%)	4
RESPIRATORY FAILURE	0/1723 (0%)	0	2/1722 (0.1%)	2
RESPIRATORY TRACT INFECTION	7/1723 (0.4%)	7	5/1722 (0.3%)	5
RHINITIS	7/1723 (0.4%)	7	10/1722 (0.6%)	12
SHORTNESS OF BREATH	34/1723 (2%)	40	27/1722 (1.6%)	30
SINUSITIS	19/1723 (1.1%)	21	14/1722 (0.8%)	17
SLEEP APNEA	13/1723 (0.8%)	13	9/1722 (0.5%)	9
SORE THROAT	0/1723 (0%)	0	3/1722 (0.2%)	3
UPPER RESPIRATORY INFECTION	78/1723 (4.5%)	90	86/1722 (5%)	98
WHEEZING	2/1723 (0.1%)	2	0/1722 (0%)	0
Skin and subcutaneous tissue disorders
ACTINIC KERATOSIS	1/1723 (0.1%)	1	2/1722 (0.1%)	2
BRUISE	9/1723 (0.5%)	9	11/1722 (0.6%)	12
CELLULITIS	20/1723 (1.2%)	20	18/1722 (1%)	22
DERMATITIS	27/1723 (1.6%)	29	25/1722 (1.5%)	26
HEMATOMA	3/1723 (0.2%)	3	1/1722 (0.1%)	3
HYPEREMIA	2/1723 (0.1%)	2	2/1722 (0.1%)	2
PRURITIS	8/1723 (0.5%)	9	14/1722 (0.8%)	14
PSORIASIS	2/1723 (0.1%)	2	1/1722 (0.1%)	1
PURITIS	3/1723 (0.2%)	5	1/1722 (0.1%)	1
RASH	2/1723 (0.1%)	2	0/1722 (0%)	0
SKIN LACERATION	1/1723 (0.1%)	1	6/1722 (0.3%)	6
SKIN LESION	4/1723 (0.2%)	4	3/1722 (0.2%)	3
SKIN WOUND	2/1723 (0.1%)	2	0/1722 (0%)	0
ULCER	6/1723 (0.3%)	7	4/1722 (0.2%)	4
URTICARIA	2/1723 (0.1%)	2	8/1722 (0.5%)	9
Surgical and medical procedures
ANGIOGRAPHY	2/1723 (0.1%)	2	0/1722 (0%)	0
CANCER REMOVAL	0/1723 (0%)	0	2/1722 (0.1%)	2
CHEMOTHERAPY	2/1723 (0.1%)	3	0/1722 (0%)	0
COLONOSCOPY	2/1723 (0.1%)	2	0/1722 (0%)	0
HERNIA	2/1723 (0.1%)	2	0/1722 (0%)	0
TOOTH EXTRACTION	0/1723 (0%)	0	3/1722 (0.2%)	3
Vascular disorders
ANGIOPATHY	2/1723 (0.1%)	2	0/1722 (0%)	0
ATHEROSCLEROSIS	0/1723 (0%)	0	4/1722 (0.2%)	4
CLAUDICATION	2/1723 (0.1%)	2	1/1722 (0.1%)	1
COLD EXTREMITIES	4/1723 (0.2%)	4	1/1722 (0.1%)	1
DEEP VEIN THROMBOSIS	4/1723 (0.2%)	4	2/1722 (0.1%)	2
EPISTAXIS	21/1723 (1.2%)	21	19/1722 (1.1%)	27
HEMORRHOIDS	0/1723 (0%)	0	2/1722 (0.1%)	2
LEG CLAUDICATION	2/1723 (0.1%)	2	1/1722 (0.1%)	1
LOWER EXTREMITY EDEMA	3/1723 (0.2%)	3	3/1722 (0.2%)	3
PERIPHERAL ARTERIAL DISEASE	0/1723 (0%)	0	3/1722 (0.2%)	3
THROMBOPHLEBITIS	6/1723 (0.3%)	6	2/1722 (0.1%)	2
ULCER	3/1723 (0.2%)	4	2/1722 (0.1%)	3
VARICOSE VEINS	5/1723 (0.3%)	5	8/1722 (0.5%)	10
VENOUS INSUFFICIENCY	3/1723 (0.2%)	4	10/1722 (0.6%)	12

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.