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This appendix has been provided by the authors to give readers additional information about their work.
Supplement to: Yusuf S, Bosch J, Dagenais G, et al. Cholesterol lowering in intermediate-risk persons without
cardiovascular disease. N Engl J Med. DOI: 10.1056/NEJMoa1600176
SUPPLEMENTARY APPENDIX
This appendix has been provided by the authors to give readers additional information for
the following 3 papers:
1. Lonn E, Bosch J, Lopez-Jaramillo P, et al., for the HOPE-3 Investigators. Blood
pressure lowering in intermediate risk people without vascular disease. NEJM 2016.
2. Yusuf, S., Bosch, J., Dagenais, G., et al. for the HOPE-3 Investigators. Rosuvastatin
in intermediate-risk people without cardiovascular disease. NEJM 2016.
3. Yusuf, S., Lonn, E., Pais, P. et al. for the HOPE-3 Investigators. Blood pressure and
cholesterol lowering in people without cardiovascular disease. NEJM 2016.
Figure S8: Cumulative Incidence of the Secondary Outcome for the Rosuvastatin versus
Placebo Comparison ..................................................................................................... 32
Figure S9: Cumulative Incidence of Co-Primary Outcome 1 in the
Candesartan/HCTZ+Rosuvastatin, Rosuvastatin Alone, Candesartan-HCTZ Alone and
Double Placebo Groups ................................................................................................ 33
Figure S10: Cumulative Incidence of the Secondary Outcome for the
Candesartan/HCTZ+Rosuvastatin, Rosuvastatin Alone, Candesartan-HCTZ Alone and
Double Placebo Groups ................................................................................................ 34
Figure S11A: Secondary Outcome 1 by Tertiles of Baseline Systolic Blood Pressure for
the Candesartan/HCTZ versus Placebo Comparison .................................................... 35
Figure S11B: Secondary Outcome 2 by Tertiles of Baseline Systolic Blood Pressure for
the Candesartan/HCTZ versus Placebo Comparison .................................................... 36
Figure S12: Selected Subgroup Analysis for Co-Primary Outcome 1: Candesartan/HCTZ
versus Placebo Comparison .......................................................................................... 37
Figure S13: Selected Subgroup Analysis for Co-Primary Outcome 2: Candesartan/HCTZ
versus ............................................................................................................................ 38
Figure S14: Selected Subgroup Analysis for Co-Primary Outcome 1: Rosuvastatin versus
Placebo Comparison* ................................................................................................... 39
Figure S15: Selected Subgroup Analysis for Co-Primary Outcome 2: Rosuvastatin versus
Placebo Comparison ..................................................................................................... 40
Figure S16: Selected Subgroup Analysis for Co-Primary Outcome 1:
Candesartan/HCTZ+Rosuvastatin, versus Double Placebo Comparisons.................... 41
Figure S17: Selected Subgroup Analysis for Co-Primary Outcome 2:
Candesartan/HCTZ+Rosuvastatin, versus Double Placebo Comparisons.................... 42
Figure S18: HOPE-3 Results* in the Context Major Vascular Event Reduction versus
LDL Cholesterol in mg/dl Lowering in Randomized Controlled Trials....................... 43
Table S1: The Heart Outcomes Prevention Evaluation (HOPE) - 3 Trial Design........ 44
Table S2: HOPE-3 Eligibility Criteria ......................................................................... 45
Table S3: Adherence to Study Drug and Open Label Use of ARBs, ACE-Is and Thiazides
in the Candesartan/HCTZ and Placebo Groups ............................................................ 46
Table S4: Adherence to Study Drug and Open Label Use of Statins and Other Lipid
Lowering Drugs in the Rosuvastatin and Placebo Groups ........................................... 47
Table S5: Adherence to Study Drug and Open Label Use of ARBs, ACE-Is, Thiazides
and Statins in the Candesartan/HCTZ+Rosuvastatin and the Double Placebo Groups 48
Table S6: Predefined Safety Outcomes in Candesartan/HCTZ and Placebo Groups .. 49
Table S7: Reasons for Hospitalization in the Candesartan/HCTZ and Placebo Groups50
Table S8: Causes of Death in the Candesartan/HCTZ and Placebo Groups* .............. 52
Table S9: Adverse Events Leading to Permanent Study Drug Discontinuations in the
Candesartan/HCTZ and Placebo Groups ...................................................................... 53
Table S10: Adverse Events Leading to Temporary Study Drug Discontinuations in the
Candesartan/HCTZ and Placebo Groups ...................................................................... 54
Table S11: Reported Serious Unexpected Suspected Adverse Reactions (SUSARS) in the
Candesartan/HCTZ and Placebo Groups* .................................................................... 55
Table S12: Causes of Death in the Rosuvastatin and Placebo Groups* ....................... 56
Table S13: Predefined Safety Outcomes in the Rosuvastatin and Placebo Groups .... 57
Table S14: Reasons for Hospitalization in the Rosuvastatin and Placebo Groups ....... 58
Table S15: Adverse Events Leading to Permanent Study Drug Discontinuations in the
Rosuvastatin and Placebo Groups ................................................................................. 60
Table S16: Adverse Events Leading to Temporary Study Drug Discontinuations in the
Rosuvastatin and Placebo Groups ................................................................................. 61
Table S17: Reported Serious Unexpected Suspected Adverse Reactions (SUSARS) in the
Rosuvastatin and Placebo Groups* ............................................................................... 62
Table S18: Causes of Death in the Candesartan/HCTZ+Rosuvastatin, Rosuvastatin Alone,
Candesartan/HCTZ Alone and Double Placebo Broups* ............................................. 63
Table S19: Predefined Safety Outcomes in the Candesartan/HCTZ+Rosuvastatin,
Rosuvastatin Alone, Candesartan/HCTZ Alone and Double Placebo Groups ............. 64
Table S20: Reasons for Hospitalization in the Candesartan/HCTZ+Rosuvastatin,
Rosuvastatin Alone, Candesartan/HCTZ Alone and Double Placebo Groups ............. 65
Table S21A: Adverse Events Leading to Permanent Study Drug Discontinuation of
Candesartan/HCTZ or Candesartan/HCTZ Placebo ONLY in the
Candesartan/HCTZ+Rosuvastatin, Rosuvastatin Alone, Candesartan/HCTZ Alone and
Double Placebo Groups ................................................................................................ 67
Table S21B: Adverse Events Leading to Permanent Study Drug Discontinuation of
Rosuvastatin or Rosuvastatin Placebo ONLY in the Candesartan/HCTZ+Rosuvastatin,
Rosuvastatin Alone, Candesartan/HCTZ Alone and Double Placebo Groups ............. 68
Table S21C: Adverse Events Leading to Permanent Study Drug Discontinuation of Both
Candesartan/HCTZ and Rosuvastatin or Their Placebos in the
Candesartan/HCTZ+Rosuvastatin, Rosuvastatin Alone, Candesartan/HCTZ Alone and
Double Placebo Groups ................................................................................................ 69
Table S22A: Adverse Events Leading to Temporary Study Drug Discontinuation of
Candesartan/HCTZ or Candesartan/HCTZ Placebo ONLY in the
10
11
12
B. Analytical Methods
Quantitative determination of serum analytes was performed on the Beckman Coulter
UniCel DxC600 System using turbimetric methods for Apolipoproteins A1 and B (ApoA1
and ApoB), timed endpoint methods for Cholesterol (CHOL), High Density Lipoprotein
(HDL) and Triglycerides (TG), and a highly sensitive Near Infrared Particle Immunoassay
for C-Reactive Protein (CRP).
Measurements were made at three laboratories; the Core Laboratory at the Population
Health Research Institute in Hamilton, Canada, the Laboratory of Human Genetics, Beijing
Hypertension League in Beijing, China and the Laboratory of the Centre for Chronic
Conditions & Injuries of the Public Health Foundation of India, in Haryana, India. All
laboratories used the same assays/methods standardized at the Core Laboratory in Hamilton,
Canada, which provided also quality control.
13
14
Deaths occurring in patients with documented heart failure with systolic dysfunction who
die suddenly during an admission for worsening heart failure were considered as heart
failure deaths.
Death after invasive cardiovascular intervention
Death occurring within 30 days of cardiovascular surgery or limb amputation, or within 7
days of catheterization, arrhythmia ablation, angioplasty (with or without stent placement),
atherectomy (coronary, cerebral or peripheral artery disease), or other invasive coronary or
peripheral vascular interventions.
Death due to stroke
Death occurring within 30 days of signs/symptoms of stroke or autopsy evidence of a recent
stroke with no evidence of another cause of death.
Other cardiovascular causes of death
Other vascular events, including pulmonary embolism and ruptured abdominal aortic
aneurysm.
Presumed cardiovascular death
Death suspicious of cardiovascular death with supporting clinical evidence that may not
fulfill other criteria (e.g. presentation with chest pain typical for MI, but without ECG
tracing or cardiac biomarker documentation that fulfill MI criteria).
Death from unknown causes
Considered to be a cardiovascular death unless evidence of a non-cardiovascular cause
exists.
MYOCARDIAL INFARCTION
Definite Non-procedural MI
EITHER
Cardiac Ischemic Symptoms lasting > 20 minutes, determined by the site investigator to be
secondary to ischemia
OR
ECG or changes consistent with acute infarction or ischemia MI:
New diagnostic Q waves (Q wave in leads V2 and V3 0.02 sec or QS complex in
leads V2 and V3; Q wave 0.03 sec and 0.1 mV deep or QS complex in leads I,
II, aVL, aVF or V4-V6 in any two leads of a contiguous lead grouping (I and aVL;
V1-V6; II, III, aVF, R wave 0.04 sec in V1 and V2 and R/S 1 with a concordant
positive T wave)) in the absence of conduction abnormalities
15
AND
Elevated cardiac biomarkers (values according to each hospitals laboratory):
A rise and/or fall in cardiac biomarker values (preferably troponin, CKMB, AST, LDH or
myoglobin) with at least one value above the 99th percentile of the upper reference limit.
Probable Non-procedural MI
In cases of missing cardiac biomarkers:
Ischemic symptoms lasting 20 minutes considered to be of cardiac origin and
requiring hospitalization with ECG changes consistent with acute ischemia or with
thrombolysis or coronary revascularization within 12 hours.
In cases of missing information on symptoms and ECG report or tracing:
History of hospitalization for MI with cardiac enzymes showing a typical pattern of
MI as for definite MI. However, the local PI should find out if the participant had
chest pain or if the event occurred in a peri-operative period.
In cases of missing information on cardiac markers, ECG findings and duration of typical
symptoms:
History of hospitalization for MI with a documented finding compatible with recent
MI on follow-up ECG or on imaging (cardiac echocardiography, nuclear scan, MRI)
in a participant without previous MI or in a participant with previous MI having a
new ECG or imaging finding compatible with MI in comparison to a previous ECG
or imaging finding.
Procedural MI: PCI-related MI
An MI after a PCI is defined as:
EITHER
Cardiac ischemic symptoms as above
OR
ECG or imaging changes consistent with MI, as above, or angiographic findings consistent
with a procedural complication,
AND
Increased troponin values greater than 5 X 99th percentile URL in patients with normal
baseline values (less than 99th percentile URL), or a rise of troponin values greater than
20% if baseline values are elevated and are stable or falling.
CABG-related MI
An MI after CABG surgery is defined as:
16
ECG changes consistent with MI, including new pathological Q waves or new LBBB; or
angiographic documented new graft or new native coronary artery occlusion, or imaging
evidence of new loss of viable myocardium or new regional wall motion abnormality,
AND
Increased cardiac biomarker values (greater than 10 X 99th percentile URL) during the first
48 hours following CABG in patients with normal troponin values.
Procedural MI: MI related to other cardiac procedures
For cardiac catheterization same criteria as for Definite Non-procedural MI. For
transcatheter aortic valve implantation or mitral clip procedure same criteria as for as
CABG-related MI.
MI associated with non-cardiac procedures (within 48 to 72 hours of procedure)
Same criteria a as for Definite Non-procedural MI
Unrecognized (silent) MI
MI documented on ECG that may not have been clinically recognized. If the investigator
(based on review of the clinical status and ECGs) feels that this occurred, he/she should
submit information supporting the diagnosis of a clinically unrecognized MI. Such
documents could be an ECG showing new and significant Q-waves not attributed to
intraventricular conduction defect, left ventricular hypertrophy, pre-excitation syndrome,
idioventricular rhythm, or electronic pacer. In addition, confirmation may be achieved by
echocardiographic or other evidence of new regional wall motion or perfusion
abnormalities.
STROKE
Stroke is defined as the presence of an acute focal neurological deficit thought to be of
vascular origin. The duration of the neurological deficit should be > 24 hours if no imaging
is done or when there is no acute stroke on imaging. The duration of symptoms may be less
than 24 hours if a new stroke is documented on CT or MRI.
On the basis of clinical symptoms or signs, and CT or MRI imaging, strokes will be
classified as:
Definite Ischemic Stroke
Stroke with CT or MRI performed within 3 weeks that is either normal or shows infarction
in the clinically concordant area:
Lacunar infarct
Cerebral infarction with:
Consciousness and higher mental functions maintained.
One of the typical lacunar syndromes, such as pure motor stroke, pure
sensory stroke, mixed sensori-motor stroke or ataxic hemiparesis.
CT/MRI performed within 3 weeks that is either normal (for CT only) or
shows a small (< 2 cm) subcortical infarct in the basal ganglia, internal
capsule, brain stem or elsewhere.
17
Cardioembolic infarct
Cerebral infarction with:
Absence of lacunar syndrome and findings symptoms cortical involvement.
No definite evidence of large artery disease in the neck.
Major cardioembolic source present (e.g. atrial fibrillation, MI in the last 6
weeks, cardiomyopathy, endocarditis or prosthetic heart valve).
CT/MRI performed within 3 weeks that is either normal (CT only) or shows a >
2 cm or cortically-based infarct.
Large artery infarct
Absence of lacunar syndrome and symptoms suggesting cortical involvement.
No major cardioembolic source present.
Evidence of large ipsilateral artery disease in the neck (e.g. a bruit or duplex scan
evidence of arterial stenosis of more than 50%).
CT/MRI performed within 3 weeks that is either normal (CT only) or shows a >
2 cm cortically- or subcortically-based infarct but not in the classical lacunar
region.
Unclassified infarct
Cerebral infarction that is not lacunar, cardioembolic or large artery in origin. This category
also includes patients who have more than one potential cause for stroke (e.g. atrial
fibrillation and large artery disease) if it is not possible to determine which mechanism is the
cause of the stroke.
Definite hemorrhagic stroke (Intracerebral hemorrhage)
Definite stroke with CT/MRI evidence of cerebral hemorrhage. (Note: Does not include
hemorrhage secondary to cerebral infarct, post-traumatic intracerebral hemorrhage,
hemorrhage into a tumor and hemorrhage into a vascular malformation.)
Subarachnoid hemorrhage
Typical clinical syndrome of sudden onset headache, with or without focal signs*, and CT
or cerebrospinal fluid evidence of bleeding primarily in the subarachnoid space.
Non traumatic subarachnoid hemorrhage documented by imaging is considered a
hemorrhagic stroke.
Stroke, type uncertain or unknown
Definite stroke that does not meet the above criteria for cerebral infarction or hemorrhage
(CT scan or MRI not done).
HEART FAILURE
A diagnosis is made based on signs and symptoms. Heart Failure symptoms include dyspnea
(at rest or on exertion), orthopnea, paroxysmal nocturnal dyspnea; and signs: rales, edema,
elevated jugular venous pressure includes:
18
19
AND
Ischemic ECG changes as compared to the most recent ECG or during the previous stable
phase:
> 0.5 mm transient ST segment depression in two contiguous limb or precordial
leads
> 1 mm transient ST elevation of two contiguous leads (or ST depression in V1 or
V2)
> 2 mm transient T wave change in two or more contiguous leads
OR
Cardiac Markers (CKMB and/or other enzymes or myoglobin) suggestive of myocardial
injury, > ULN but not sufficient to meet MI criteria.
Probable unstable angina
Defined as ischemic symptoms considered to be of cardiac origin and having required
hospitalization and treated as acute coronary syndrome but when data on cardiac biomarkers
and ECG are missing.
ARTERIAL REVASCULARIZATION
1. Percutaneous coronary intervention (with or without stenting)
2. Coronary artery bypass graft surgery
3. Carotid endarterectomy or carotid bypass
4. Other arterial angioplasty (with or without stenting).
5. Other arterial surgery: This includes aortic (thoracic or abdominal) aneurysm
repair including stent for aortic aneurysm, aortobifemoral bypass, femoropopliteal
bypass, femoral-tibial bypass and cerebral aneurysm.
NON-CARDIOVASCULAR DEATH
Defined as any death for which clear evidence of a non-cardiovascular cause exists.
Cancer death
Death due to cancer or as a consequence of cancer related treatment complications. These
were classified by the following sites:
Gastrointestinal malignancy (including pancreatic and liver cancer)
Lung malignancy
Breast malignancy
Prostate malignancy
Brain malignancy
Skin malignancy
Hematologic malignancy (e.g. leukemia or lymphoma, multiple myeloma)
Genito-urinary malignancy
Bone/connective tissue (e.g. sarcoma)
Unknown primary site
Other malignancy (specify)
20
21
22
AEs were classified by MEDRA coding, by groupings according to organ class and by
special events of interest as defined by the Principal Investigators and the DSMB based on
the profile of the study drugs used and the study population evaluated.
C. Suspected Unexpected Serious Adverse Reports (SUSAR)
Investigators were instructed to complete a suspected unexpected serious adverse reaction
(SUSARs) form for those events they deemed to be serious (i.e. resulting in death,
hospitalization or persistent or significant disability, is life-threatening or considered
medically important), were not predefined cardiovascular outcomes, were unexpected (in
terms of drug labeling and the subjects history) and were unexpected in terms of study
medication and were thought to be causally associated with either of the study medications.
Investigators were encouraged to submit SUSAR forms even when they were not certain the
event met the HOPE-3 SUSAR criteria. These events were then adjudicated centrally and
sent to regulators when pre-specified criteria were met.
23
24
HCTZ=hydrochlorothiazide
Vital status was ascertained at the end of follow-up in 12,587 (99.1%) participants, 6,289 in
the Candesartan/HCTZ group and 6,298 in the Placebo group.
* The most common side effects resulting in run-in failure were hypotension, N=283 (1.9%)
and abnormal laboratory values, N=252 (1.7%). Note that participants could have more than
one side effect.
25
Vital status was ascertained at the end of follow up in 12,587 (99.1%) participants,
6,306 in the Rosuvastatin group and 6,281 in the Placebo group.
* The most common side effects resulting in run-in failure were hypotension, N=283
(1.9%) and abnormal laboratory values, N=252 (1.7%). Note that participants could
have more than one side effect.
26
Figure S3: CONSORT Diagram for the Double Active versus Double
Placebo Comparison
14, 682 Participants screened for eligibility
3,180 assigned
Cand/HCTZ Active
Rosuvastatin Active
3,181 assigned
Rosuvastatin Active
Cand/HCTZ Placebo
3,176 assigned
Cand/HCTZ Active
Rosuvastatin Placebo
3,180 Included in
analysis
3,181 Included in
analysis
3,168 assigned
Double Placebo
3,176 Included in
analysis
3,168 Included in
analysis
Vital status was ascertained at the end of follow up in 12,587 (99.1%) participants,
3,149 in the Double Active group, 3,157 in the Rosuvastatin Active/ Candesartan/HCTZ
Placebo group, 3140 in the Candesartan/HCTZ Active/ Rosuvastatin Placebo group and
3,141 in the Double Placebo group
* The most common side effects resulting in run-in failure were hypotension, N=283
(1.9%) and abnormal laboratory values, N=252 (1.7%). Note that participants could
have more than one side effect.
27
75
80
Placebo
Candesartan/HCTZ
70
85
Figure S4: Diastolic Blood Pressure Over the Course of the Trial in the
Candesartan/HCTZ and Placebo Groups
Cand/HCTZ
Placebo
6356
6347
5907
5879
5667
5623
5446
5442
Years
5213
5185
3862
3822
1437
1424
350
334
28
CV Death, MI,Stroke
1.0
0.10
HR (95% CI) = 0.93 (0.79-1.10)
0.08
0.8
P-value: 0.40
0.06
0.6
Placebo
0.04
Candesartan/HCTZ
0.02
0.4
0.0
0
0.2
0.0
0
No. at Risk
Candesartan/HCTZ
Placebo
6005
6004
5008
5008
2099
2096
530
501
Years
6356
6349
6282
6278
6216
6217
6127
6126
29
1.0
0.10
0.8
0.6
0.08
0.06
P-value: 0.26
Placebo
0.04
Candesartan/HCTZ
0.02
0.4
0.0
0
0.2
0.0
0
No. at Risk
Candesartan/HCTZ 6356
Placebo
6349
5948
5940
4952
4944
2068
2062
522
484
Years
6266
6259
6189
6184
6086
6073
30
CV Death,MI,Stroke
1.0
0.10
0.08
0.8
0.06
Placebo
0.6
0.04
Rosuvastatin
0.02
0.4
P-value: 0.0019
0.0
0
0.2
0.0
0
3019
2987
2524
2488
1056
1041
265
244
Years
No. at Risk
Rosuvastatin
Placebo
3168
3185
3137
3140
3112
3097
3079
3054
31
0.10
0.08
0.8
0.06
Placebo
0.6
0.04
Rosuvastatin
0.02
0.4
P-value: 0.0006
0.0
0
0.2
0.0
0
5982
5906
4993
4903
2092
2038
519
487
Years
No. at Risk
Rosuvastatin
Placebo
6361
6344
6281
6244
6215
6158
6103
6056
32
CV Death,MI,Stroke
1.0
0.10
0.08
0.8
Combination
Rosuvastatin
Candesartan/HCTZ
Double Placebo
0.06
0.6
0.04
0.02
0.4
0.0
0
0.2
0.0
No. at Risk
Combination
Rosuvastatin
Candesartan/HCTZ
Double Placebo
3180
3181
3176
3168
3151
3145
3131
3133
3125
3116
3091
3101
3077
3076
3050
3050
3014
3025
2991
2979
2526
2520
2482
2488
1068
1054
1031
1042
276
255
254
246
Years
Cumulative hazard curves are shown for those receiving rosuvastatin + BP lowering,
rosuvastatin alone, BP lowering alone, and double placebo. The hazard ratios (HR), 95%
confidence intervals (CI), and P values are presented for the comparison between dual active
therapy (rosuvastatin + BP lowering) and dual placebo.
Rosuvastatin refers to the Rosuvastatin Active/ Candesartan/HCTZ Placebo group
Candesartan/HCTZ refers to the Candesartan/HCTZ Active/ Rosuvastatin Placebo group
33
1.0
0.10
0.8
0.08
Combination
Rosuvastatin
Candesartan/HCTZ
Double Placebo
0.06
0.6
0.04
0.02
0.4
0.0
0
0.2
0.0
No. at Risk
Combination
Rosuvastatin
Candesartan/HCTZ
Double Placebo
3180
3181
3176
3168
3144
3137
3122
3122
3112
3103
3077
3081
3054
3049
3032
3024
2987
2995
2961
2945
2500
2493
2452
2451
1053
1039
1015
1023
272
247
250
237
Years
Cumulative hazard curves are shown for those receiving rosuvastatin + BP lowering,
rosuvastatin alone, BP lowering alone, and double placebo. The hazard ratios (HR), 95%
confidence intervals (CI), and P values are presented for the comparison between dual
active therapy (rosuvastatin + BP lowering) and dual placebo.
Rosuvastatin refers to the Rosuvastatin Active/ Candesartan/HCTZ Placebo group
Candesartan/HCTZ refers to the Candesartan/HCTZ Active/ Rosuvastatin Placebo group
34
Figure S11A: Secondary Outcome 1 by Tertiles of Baseline Systolic Blood Pressure for the Candesartan/HCTZ versus
Placebo Comparison
Candesartan
/HCTZ
Placebo
P Trend
Overall
6.0/3.0
335/6356 (5.3)
364/6349 (5.7)
0.92 (0.79-1.06)
131.5 (Mean=122.2)
6.1/3.1
97/2080 (4.7)
83/2122 (3.9)
1.20 (0.89-1.60)
131.6-143.5 (Mean=137.6)
5.6/2.7
109/2120 (5.1)
109/2141 (5.1)
1.01 (0.77-1.31)
>143.5 (Mean=154.1)
5.8/3.0
129/2156 (6.0)
172/2084 (8.3)
0.72 (0.57-0.90)
SBP-mmHg
0.005
0.5
1.0
2.0
Candesartan/HCTZ Placebo
Better
Better
35
Figure S11B: Secondary Outcome 2 by Tertiles of Baseline Systolic Blood Pressure for the Candesartan/HCTZ versus
Placebo Comparison
Stroke
Overall
BP
(mmHg)
Placebo
Candesartan
/HCTZ
no. of events / total no.(%)
6.0/3.0
75/6356 (1.2)
94/6349 (1.5)
P Trend
0.80 (0.59-1.08)
SBP-mmHg
0.217
11/2080 (0.5)
15/2122 (0.7)
0.75 (0.35-1.64)
32/2120 (1.5)
26/2141 (1.2)
1.24 (0.74-2.08)
32/2156 (1.5)
53/2084 (2.5)
0.58 (0.37-0.90)
0.5
1.0
2.0
Candesartan/HCTZ Placebo
Better
Better
36
Figure S12: Selected Subgroup Analysis for Co-Primary Outcome 1: Candesartan/HCTZ versus Placebo Comparison
Candesartan/HCTZ Placebo
BP
(mmHg)
no. of events / total no.
P Interaction
Overall
6.0/3.0
260/6356
279/6349
0.93 (0.79-1.10)
Rosuvastatin Active
Rosuvastatin Placebo
5.8/2.8
6.1/3.1
113/3180
147/3176
122/3181
157/3168
0.92 (0.72-1.19)
0.93 (0.75-1.17)
0.951
6.0/3.2
6.0/2.8
85/3053
175/3303
81/3006
198/3342
1.03 (0.76-1.39)
0.90 (0.73-1.10)
0.464
Female
Male
5.1/2.4
6.8/3.5
95/2910
165/3446
115/2964
164/3385
0.83 (0.63-1.09)
0.99 (0.80-1.23)
0.322
DBP-mmHg
78 (Mean=71.8)
78.1-86 (Mean=82.2)
>86 (Mean=92.1)
5.5/2.7
5.7/2.8
6.6/3.2
84/2135
78/2157
98/2064
96/2181
98/2146
85/2020
0.89 (0.66-1.19)
0.78 (0.58-1.06)
1.13 (0.85-1.51)
0.245
5.5/2.8
6.1/2.7
6.3/3.4
78/2344
67/1901
115/2111
66/2391
100/1938
113/2020
1.21 (0.87-1.67)
0.68 (0.50-0.93)
0.97 (0.75-1.26)
0.479
LDL-Cmg/dl
112.3 (Mean=89.1)
112.4-141.7 (Mean=126.8)
>141.7 (Mean=166.7)
6.0/2.9
6.7/3.3
6.3/3.5
85/1928
76/1888
80/1891
83/1834
90/1891
91/1966
0.98 (0.73-1.33)
0.84 (0.62-1.14)
0.91 (0.67-1.23)
0.731
8.7/4.5
7.2/3.7
2.2/1.1
6.0/2.5
10.8/5.7
5.4/2.5
44/1284
67/1739
56/1844
53/932
19/342
14/116
50/1262
84/1757
66/1847
42/922
21/354
13/109
0.87 (0.58-1.30)
0.80 (0.58-1.10)
0.85 (0.59-1.21)
1.27 (0.85-1.90)
0.92 (0.50-1.72)
1.02 (0.48-2.18)
0.483
Ethnicity*
European descent
Latin American
Chinese
South Asian
Other Asian
Black African
0.5
1.0
2.0
Candesartan/HCTZ Placebo
Better
Better
P for interaction provided for all subgroups except DBP, Risk Score and LDL-C, in which P for trend is provided
* 197 participants of Other ethnicity
BP blood pressure; yrs years; DBP diastolic blood pressure; LDL-C low density lipoprotein cholesterol
37
Figure S13: Selected Subgroup Analysis for Co-Primary Outcome 2: Candesartan/HCTZ versus
BP
Candesartan/HCTZ Placebo
(mmHg)
no. of events / total no.
P Interaction
Overall
6.0/3.0
312/6356
328/6349
0.95 (0.81-1.11)
Rosuvastatin Active
Rosuvastatin Placebo
5.8/2.8
6.1/3.1
136/3180
176/3176
141/3181
187/3168
0.96 (0.76-1.22)
0.94 (0.76-1.15)
0.873
Age 65 yrs(Mean=60.4)
Age >65 yrs (Mean=70.6)
6.0/3.2
6.0/2.8
106/3053
206/3303
101/3006
227/3342
1.03 (0.78-1.35)
0.92 (0.76-1.11)
0.507
Female
Male
5.1/2.4
6.8/3.5
109/2910
203/3446
129/2964
199/3385
0.85 (0.66-1.10)
1.01 (0.83-1.22)
0.310
DBP-mmHg
78 (Mean=71.8)
78.1-86 (Mean=82.2)
>86 (Mean=92.1)
5.5/2.7
5.7/2.8
6.6/3.2
102/2135
99/2157
111/2064
113/2181
115/2146
100/2020
0.92 (0.70-1.20)
0.85 (0.65-1.11)
1.09 (0.83-1.43)
0.372
5.5/2.8
6.1/2.7
6.3/3.4
95/2344
82/1901
135/2111
86/2391
112/1938
130/2020
1.12 (0.84-1.51)
0.75 (0.56-1.00)
0.99 (0.78-1.26)
0.660
LDL-Cmg/dl
112.3 (Mean=89.1)
112.4-141.7 (Mean=126.8)
>141.7 (Mean=166.7)
6.0/2.9
6.7/3.3
6.3/3.5
96/1928
94/1888
99/1891
95/1834
106/1891
107/1966
0.97 (0.73-1.29)
0.88 (0.67-1.17)
0.96 (0.73-1.26)
0.965
8.7/4.5
7.2/3.7
2.2/1.1
6.0/2.5
10.8/5.7
5.4/2.5
54/1284
88/1739
70/1844
58/932
20/342
15/116
69/1262
100/1757
73/1847
45/922
24/354
13/109
0.77 (0.54-1.09)
0.88 (0.66-1.17)
0.96 (0.69-1.33)
1.29 (0.88-1.91)
0.85 (0.47-1.54)
1.10 (0.52-2.31)
0.494
Ethnicity*
European Descent
Latin American
Chinese
South Asian
Other Asian
Black African
0.5
1.0
2.0
Candesartan/HCTZ Placebo
Better
Better
P for interaction provided for all subgroups except DBP, Risk Score and LDL-C, in which P for trend is provided
* 197 participants of Other ethnicity
BP blood pressure; yrs years; DBP diastolic blood pressure; LDL-C low density lipoprotein cholesterol
38
Figure S14: Selected Subgroup Analysis for Co-Primary Outcome 1: Rosuvastatin versus Placebo
Comparison*
Rosuvastatin
Placebo
P Interaction*
235/6361
304/6344
0.76 (0.64-0.91)
Candesartan Active
Candesartan Placebo
113/3180
122/3181
147/3176
157/3168
0.76 (0.59-0.97)
0.77 (0.61-0.97)
0.949
70/1888
71/1865
85/1952
98/1874
95/1914
86/1905
0.70 (0.52-0.96)
0.76 (0.56-1.03)
0.96 (0.71-1.29)
0.159
57/2341
76/1904
102/2116
87/2394
91/1935
126/2015
0.66 (0.47-0.92)
0.85 (0.63-1.15)
0.77 (0.59-0.99)
0.567
112/2871
115/2905
136/2902
146/2853
0.82 (0.64-1.06)
0.77 (0.60-0.98)
0.694
53/2113
75/2129
107/2119
79/2089
93/2132
132/2121
0.64 (0.46-0.91)
0.80 (0.59-1.09)
0.81 (0.63-1.05)
0.347
80/3192
155/3168
101/3162
203/3182
0.78 (0.59-1.05)
0.75 (0.61-0.93)
0.828
Male
Female
139/3410
96/2951
190/3421
114/2923
0.72 (0.58-0.90)
0.83 (0.64-1.09)
0.427
36/1286
53 /1854
61/1268
69/1744
16/209
58/1260
69/1837
74/1282
82/1752
21/213
0.60 (0.40-0.92)
0.76 (0.53-1.08)
0.83 (0.59-1.16)
0.84 (0.61-1.15)
0.75 (0.39-1.43)
0.777
Ethnicity
European Descent
Chinese
Other Asian
Latin American
Other
0.5
Rosuvastatin Better
1.0
2.0
Placebo Better
P for interaction provided for all subgroups except DBP, Risk Score and LDL-C, in which P for trend is provided
* 197 participants of Other ethnicity
BP blood pressure; yrs years; DBP diastolic blood pressure; LDL-C low density lipoprotein cholesterol
39
Figure S15: Selected Subgroup Analysis for Co-Primary Outcome 2: Rosuvastatin versus Placebo
Comparison
Rosuvastatin
Placebo
P Interaction*
277/6361
363/6344
0.75 (0.64-0.88)
Candesartan Active
Candesartan Placebo
136/3180
141/3181
176/3176
187/3168
0.76 (0.61-0.95)
0.74 (0.60-0.93)
0.876
79/1888
85/1865
101/1952
112/1874
115/1914
105/1905
0.69 (0.52-0.92)
0.75 (0.57-1.00)
0.93 (0.71-1.22)
0.145
72/2341
86/1904
119/2116
109/2394
108/1935
146/2015
0.66 (0.49-0.89)
0.81 (0.61-1.07)
0.77 (0.60-0.98)
0.486
128/2871
140/2905
163/2902
174/2853
0.79 (0.62-0.99)
0.78 (0.63-0.98)
0.992
66/2113
87/2129
124/2119
98/2089
110/2132
155/2121
0.65 (0.47-0.88)
0.79 (0.60-1.05)
0.80 (0.63-1.01)
0.335
98/3192
179/3168
125/3162
238/3182
0.78 (0.60-1.01)
0.74 (0.61-0.90)
0.779
Male
Female
169/3410
108/2951
233/3421
130/2923
0.72 (0.59-0.87)
0.82 (0.64-1.06)
0.404
48/1286
61/1854
66/1268
85/1744
17/209
75/1260
82/1837
81/1282
103/1752
22/213
0.62 (0.43-0.89)
0.73 (0.52-1.02)
0.82 (0.59-1.13)
0.82 (0.61-1.09)
0.76 (0.40-1.42)
0.790
Ethnicity
European Descent
Chinese
Other Asian
Latin American
Other
0.5
Rosuvastatin Better
1.0
2.0
Placebo Better
* P for interaction provided for all subgroups except LDL, Risk Score and SBP, in which P for trend is provided
LDL low density lipoprotein cholesterol in mg/dl; CRP high sensitivity C-reactive protein; SBP systolic blood pressure; yr years
40
Double
Placebo
P Interaction*
6.2
25.2
113/3180
157/3168
0.71 (0.56-0.90)
5.9
5.7
6.4
23.8
24.5
26.4
24/1059
44/1050
45/1071
33/1068
50/1062
74/1036
0.71 (0.42-1.21)
0.89 (0.59-1.33)
0.59 (0.40-0.85)
0.386
6.1
6.9
6.6
20.2
24.8
32.5
36/992
34/917
40/950
49/938
53/943
46/964
0.69 (0.45-1.06)
0.65 (0.42-1.00)
0.87 (0.57-1.33)
0.444
5.9
5.8
6.4
26.5
29.5
17.6
31/1158
29/942
53/1080
40/1208
53/976
64/984
0.79 (0.50-1.27)
0.56 (0.36-0.88)
0.75 (0.52-1.08)
0.980
5.7
6.6
23.9
26.5
37/1604
76/1576
46/1567
111/1601
0.78 (0.51-1.21)
0.68 (0.51-0.92)
0.614
Male
Female
7.2
5.0
26.7
23.3
67/1715
46/1465
92/1690
65/1478
0.71 (0.52-0.97)
0.70 (0.48-1.03)
0.980
Ethnicity
European descent
Chinese
Other Asian
Latin American
Other
8.9
2.4
7.3
6.9
9.0
49.5
14.5
0.4
25.1
39.7
16/651
23/922
31/634
32/864
11/109
30/627
36/915
33/642
47/877
11/107
0.51 (0.28-0.93)
0.63 (0.37-1.06)
0.95 (0.58-1.55)
0.68 (0.43-1.06)
0.97 (0.42-2.23)
0.514
0.5
1.0
* P for interaction provided for all subgroups except SBP, LDL, and Risk Score in which P for trend is provided
SBP systolic blood pressure; LDL-C low density lipoprotein cholesterol; yr - years
2.0
41
P Interaction*
6.2
25.2
136/3180
187/3168
0.72 (0.57-0.89)
5.9
5.7
6.4
23.8
24.5
26.4
31/1059
51/1050
54/1071
39/1068
62/1062
86/1036
0.78 (0.49-1.25)
0.83 (0.57-1.20)
0.60 (0.43-0.84)
0.298
6.1
6.9
6.6
20.2
24.8
32.5
41/992
43/917
49/950
57/938
64/943
55/964
0.67 (0.45-1.00)
0.68 (0.46-1.00)
0.89 (0.61-1.31)
0.319
5.9
5.8
6.4
26.5
29.5
17.6
39/1158
34/942
63/1080
53/1208
60/976
74/984
0.75 (0.50-1.14)
0.58 (0.38-0.89)
0.77 (0.55-1.08)
0.821
5.7
6.6
23.9
26.5
46/1604
90/1576
57/1567
130/1601
0.79 (0.53-1.16)
0.69 (0.53-0.90)
0.591
Male
Female
7.2
5.0
26.7
23.3
85/1715
51/1465
115/1690
72/1478
0.72 (0.54-0.95)
0.71 (0.49-1.01)
0.936
Ethnicity
European descent
Chinese
Other Asian
Latin American
Other
8.9
2.4
7.3
6.9
9.0
49.5
14.5
0.4
25.1
39.7
20/651
30/922
34/634
41/864
11/109
41/627
42/915
37/642
56/877
11/107
0.46 (0.27-0.79)
0.70 (0.44-1.12)
0.93 (0.58-1.48)
0.73 (0.49-1.09)
0.96 (0.42-2.22)
0.374
0.5
1.0
2.0
* P for interaction provided for all subgroups except SBP, LDL, and Risk Score in which P for trend is provided
SBP systolic blood pressure; LDL-C low density lipoprotein cholesterol in mg/dl; yr - years
42
Figure S18: HOPE-3 Results* in the Context Major Vascular Event Reduction versus LDL
Cholesterol in mg/dl Lowering in Randomized Controlled Trials
HOPE-3
*Co-Primary Outcome 2
HOPE-3 results plotted on the graphs created by CTT Collaboration based on individual patient data (Lancet 2005;
366:1267-78. Lancet 2010; 376: 1670-81).
43
Table S1: The Heart Outcomes Prevention Evaluation (HOPE) - 3 Trial Design
(N=12,705)
Candesartan/HCTZ
Active
Placebo
Rosuvastatin
Active
Placebo
Candesartan/HCTZ
Margins
Rosuvastatin Active/
Candesartan/HCTZ
Active
n=3,180
Rosuvastatin Active/
Candesartan/HCTZ
Placebo
n=3,181
Rosuvastatin Placebo/
Candesartan/HCTZ
Active
n=3,176
Candesartan/HCTZ
Active
n=6,356
Rosuvastatin Placebo/
Candesartan/HCTZ
Placebo
n=3,168
Candesartan/HCTZ
Placebo
n=6,349
Rosuvastatin
Margins
Rosuvastatin
Active
n=6,361
Rosuvastatin
Placebo
n=6,344
HCTZ=hydrochlorothiazide
44
Subjects with persistently elevated BP and who are considered by the recruiting /local physician to require antihypertensive therapy can be entered in
the trial after BP control is attained with lifestyle interventions or with non-study drugs such as beta-blockers, calcium channel blockers or alpha
blockers. Subjects on lipid lowering therapy other than a statin or a fibrate can also be considered for the trial.
45
Table S3: Adherence to Study Drug and Open Label Use of ARBs, ACE-Is and Thiazides in the
Candesartan/HCTZ and Placebo Groups
A. Candesartan
Candesartan/HCTZ
On Open Label
On Study Drug
Visit
1 year
2 years
3 years
4 years
5 years
End
Eligible
Cand/HCTZ
N (%)
ARB
N (%)
ACE-I
N (%)
Thiazide
N (%)
6314
6267
6205
6101
4854
5990
5567(88.2)
5374(85.8)
5189(83.6)
4967(81.4)
3639(75.0)
4599(76.8)
14(0.2)
28(0.4)
45(0.7)
52(0.9)
60(1.2)
93(1.6)
24(0.4)
41(0.7)
48(0.8)
59(1.0)
66(1.4)
100 (1.7)
1(0)
10(0.2)
15(0.2)
30(0.5)
30(0.6)
47(0.8)
Other BP Lowering
Drug(s)*
N (%)
1011(16.5)
1068(18.2)
B. Placebo
Placebo
Visit
Eligible
6306
6262
6188
6089
4818
5985
On Study Drug
Cand/HCTZ
Placebo
N (%)
5545(87.9)
5359(85.6)
5161(83.4)
4953(81.3)
3588 (74.5)
4530(75.7)
On Open Label
ARB
N (%)
ACE-I
N (%)
Thiazide
N (%)
30(0.5)
66(1.1)
76(1.2)
106(1.7)
104(2.2)
146(2.4)
48(0.8)
67(1.1)
82(1.3)
102(1.7)
110(2.3)
137(2.3)
9(0.1)
27(0.4)
45(0.7)
57(0.9)
57(1.2)
79 (1.3)
Other BP Lowering
Drug(s)*
N (%)
1514(24.7)
1688(28.8)
46
Table S4: Adherence to Study Drug and Open Label Use of Statins and Other Lipid Lowering Drugs
in the Rosuvastatin and Placebo Groups
A. Rosuvastatin
On Drug
Visit
1 year
2 years
3 years
4 years
5 years
End
Eligible
Rosuvastatin
N (%)
6327
6286
6223
6118
4870
6014
5565 (88.0)
5384 (85.7)
5196 (83.5)
4961 (81.1)
3678 (75.5)
4649 (77.3)
Rosuvastatin
On Open Label
Other Lipid Lowering
Statin
Drugs
N (%)
N (%)
35 (0.6)
17 (0.3)
62 (1.0)
17 (0.3)
103 (1.7)
20 (0.3)
124 (2.0)
31 (0.5)
120 (2.5)
33 (0.7)
163 (2.7)
32 (0.5)
B. Placebo
Placebo
Visit
1 year
2 years
3 years
4 years
5 years
End
Eligible
6293
6243
6170
6072
4802
5961
On Drug
Rosuvastatin
Placebo
N (%)
5528 (87.8)
5312 (85.1)
5121 (83.0)
4879 (80.4)
3515 (73.2)
4457 (74.8)
Statin
N (%)
76 (1.2)
152 (2.4)
203 (3.3)
265 (4.4)
270 (5.6)
370 (6.2)
On Open Label
Other Lipid Lowering
Drugs
N (%)
20 (0.3)
45 (0.7)
64 (1.0)
87 (1.4)
70 (1.5)
76 (1.3)
47
Table S5: Adherence to Study Drug and Open Label Use of ARBs, ACE-Is, Thiazides and Statins in
the Candesartan/HCTZ+Rosuvastatin and the Double Placebo Groups
A. Candesartan/HCTZ + Rosuvastatin (Double Active)
On Open Label
N (%)
On Study Drug
N (%)
Visit
1 year
2 years
3 years
4 years
5 years
End
Eligible
3164
3144
3114
3056
2438
3008
Both
Candesartan/HCTZ
and Rosuvastatin
2728 (86.2)
2627 (83.6)
2519 (80.9)
2400 (78.5)
1762 (72.3)
2245 (74.6)
Only
Candesartan/HCTZ
Only
Rosuvastatin
ARB
ACE-I
Thiazide
Other BP*
Statin
47 (1.5)
44 (1.4)
50 (1.6)
51 (1.7)
39 (1.6)
45 (1.5)
53 (1.7)
49 (1.6)
58 (1.9)
59 (1.9)
69 (2.8)
87 (2.9)
8 (0.3)
10 (0.3)
23 (0.7)
25 (0.8)
30 (1.2)
42 (1.4)
11 (0.3)
21 (0.7)
22 (0.7)
31 (1.0)
38 (1.6)
47 (1.6)
1 (0)
2 (0.1)
9 (0.3)
14 (0.5)
14 (0.6)
23 (0.8)
489 (15.9)
518 (17.6)
16 (0.5)
31 (1.0)
50 (1.6)
61 (2.0)
62 (2.5)
77 (2.6)
B. Double Placebo
On Open Label
N (%)
On Study Drug
N (%)
Visit
1 year
2 years
3 years
4 years
5 years
End
Eligible
3143
3120
3079
3027
2386
2979
Both
Candesartan/HCTZ
and Rosuvastatin
Placebo
2700 (85.9)
2598 (83.3)
2489 (80.8)
2367 (78.2)
1666 (69.8)
2140 (71.8)
Only
Candesartan/HCTZ
Placbeo
Only
Rosuvastatin
Placebo
ARB
ACE-I
Thiazide
Other BP*
Statin
53 (1.7)
60 (1.9)
72 (2.3)
102 (3.4)
99 (4.1)
103 (3.5)
47 (1.5)
36 (1.2)
44 (1.4)
40 (1.3)
52 (2.2)
48 (1.6)
20 (0.6)
38 (1.2)
42 (1.4)
62 (2.0)
58 (2.4)
78 (2.6)
24 (0.8)
38 (1.2)
38 (1.2)
48 (1.6)
62 (2.6)
79 (2.7)
4 (0.1)
13 (0.4)
21 (0.7)
32 (1.1)
33 (1.4)
42 (1.4)
744 (24.4)
836 (28.7)
38 (1.2)
87 (2.8)
105 (3.4)
147 (4.9)
150 (6.3)
196 (6.6)
*measured only at baseline two years and end of study; beta blockers or calcium channel blockers were used by 448 (14.6) at 2
years and 478 (16.2) at study end
measured only at baseline two years and end of study; beta blockers or calcium channel blockers were used by 705 (23.1) at
2 years and 794 (27.2) at study end
48
Cancer
Myopathy
Rhabdomyolysis
Hospitalizations Cardiovascular
Hospitalizations Non-cardiovascular
Total Hospitalizations
Candesartan/HCTZ
N=6,356
N (%)
277 (4.4)
1 (0)
0
319 (5.0)
899 (14.1)
1112 (17.5)
Placebo
N=6,349
N (%)
276 (4.3)
1 (0)
1 (0)
331 (5.2)
861 (13.6)
1079 (17.0)
P value
1.0
1.0
0.50
0.63
0.34
0.47
49
Table S7: Reasons for Hospitalization in the Candesartan/HCTZ and Placebo Groups
Total Hospitalizations
Cardiovascular Hospitalizations
Myocardial infarction
Stroke
Transient ischemic attack
Congestive heart failure
Unstable/new/worsening angina
Cardiac arrest
Supraventricular arrhythmia
Sustained ventricular tachycardia/arrhythmia
Pulmonary embolism
Coronary angiography
CABG
Percutaneous Coronary Intervention
Peripheral angioplasty/stent/abdominal aortic
aneurysm/other vascular surgery
Carotid angioplasty/stent/surgery
Limb amputation due to vascular insufficiency
Valve surgery
Other cardiovascular
Non-cardiovascular hospitalizations
Eye complications
Laser treatment/vitrectomy
Limb/foot infections
Other diabetic issues
Cancer
Injury
Fractures
Renal transplant
Renal dialysis
Hematologic
Sepsis
Candesartan/HCTZ
N=6,356
N (%)
1112 (17.5)
319 (5.0)
47 (0.7)
78 (1.2)
13 (0.2)
24 (0.4)
41 (0.6)
6 (0.1)
37 (0.6)
6 (0.1)
9 (0.1)
53 (0.8)
18 (0.3)
40 (0.6)
Placebo
N=6,349
N (%)
1079 (17.0)
331 (5.2)
63 (1.0)
90 (1.4)
13 (0.2)
22 (0.3)
44 (0.7)
13 (0.2)
37 (0.6)
8 (0.1)
10 (0.2)
67 (1.1)
19 (0.3)
52 (0.8)
6 (0.1)
4 (0.1)
0.75
3 (0)
2 (0)
9 (0.1)
76 (1.2)
899 (14.1)
1 (0)
1 (0)
4 (0.1)
10 (0.2)
160 (2.5)
28 (0.4)
73 (1.1)
0
2 (0)
7 (0.1)
27 (0.4)
1 (0)
0
9 (0.1)
67 (1.1)
861 (13.6)
4 (0.1)
2 (0)
3 (0)
5 (0.1)
172 (2.7)
32 (0.5)
75 (1.2)
0
4 (0.1)
12 (0.2)
18 (0.3)
0.62
0.5
1.0
0.50
0.34
0.22
0.62
1.0
0.30
0.51
0.61
0.87
P value
0.47
0.63
0.13
0.35
1.0
0.88
0.75
0.11
1.0
0.61
0.82
0.20
0.87
0.21
0.45
0.26
0.23
50
Psychiatric
Genito-urinary
Gastrointestinal
Other non-cardiovascular
Candesartan/HCTZ
N=6,356
N (%)
3 (0)
80 (1.3)
116 (1.8)
579 (9.1)
Placebo
N=6,349
N (%)
5 (0.1)
88 (1.4)
113 (1.8)
545 (8.6)
P value
0.51
0.54
0.89
0.30
51
Total death
Cardiovascular death
Non cardiovascular death
Cancer
Pulmonary
Gastrointestinal
Hepatobiliary
Sepsis
Infection
Accidental/Trauma
Suicide
Drug overdose
Renal
Other
Candesartan/HCTZ
N=6,356
N (%)
342 (5.4)
155 (2.4)
187 (2.9)
110 (1.7)
20 (0.3)
12 (0.2)
1 (0)
4 (0.1)
11 (0.2)
16 (0.3)
1 (0)
0
3 (0)
9 (0.1)
Placebo
N=6,349
N (%)
349 (5.5)
170 (2.7)
179 (2.8)
112 (1.8)
17 (0.3)
4 (0.1)
0
6 (0.1)
18 (0.3)
12 (0.2)
2 (0)
0
1 (0)
7 (0.1)
* Note this is not a prespecified safety outcome; total mortality is a predefined adjudicated efficacy outcome. We provide a
listing of causes of death with details on the causes of non-cardiovascular death to further describe the safety in out trial.
52
Table S9: Adverse Events Leading to Permanent Study Drug Discontinuations in the
Candesartan/HCTZ and Placebo Groups
Candesartan/HCTZ
N=6,356
N (%)
1552 (24.4)
1072 (16.9)
217 (3.4)
7 (0.1)
32 (0.5)
0
28 (0.4)
2 (0)
1 (0)
39 (0.6)
1 (0)
0
3 (0)
25 (0.4)
13 (0.2)
23 (0.4)
56 (0.9)
1 (0)
Placebo
N=6,349
N (%)
1598 (25.2)
1128 (17.8)
130 (2.0)
4 (0.1)
20 (0.3)
0
33 (0.5)
2 (0)
1 (0)
30 (0.5)
1 (0)
0
7 (0.1)
26 (0.4)
8 (0.1)
28 (0.4)
53 (0.8)
3 (0)
P value
0.33
0.18
<0.0001
0.55
0.13
0.52
1.00
1.00
0.33
1.00
0.23
0.89
0.38
0.49
0.85
0.37
53
Table S10: Adverse Events Leading to Temporary Study Drug Discontinuations in the
Candesartan/HCTZ and Placebo Groups
Candesartan/HCTZ
N=6,356
N (%)
1654 (26.0)
494 (7.8)
171 (2.7)
5 (0.1)
10 (0.2)
0
54 (0.8)
0
0
23 (0.4)
2 (0)
0
1 (0)
8 (0.1)
1 (0)
2 (0)
6 (0.1)
7 (0.1)
Placebo
N=6,349
N (%)
1551 (24.4)
483 (7.6)
82 (1.3)
1 (0)
6 (0.1)
0
63 (1.0)
1 (0)
1 (0)
22 (0.3)
2 (0)
0
2 (0)
8 (0.1)
0
5 (0.1)
11 (0.2)
5 (0.1)
P value
0.04
0.74
<0.0001
0.22
0.45
0.41
0.50
0.50
1.0
1.0
0.63
1.0
1.0
0.29
0.24
0.77
54
Table S11: Reported Serious Unexpected Suspected Adverse Reactions (SUSARS) in the
Candesartan/HCTZ and Placebo Groups*
Candesartan/HCTZ
N=6,356
N (%)
93 (1.5)
3 (0)
1 (0)
5 (0.1)
2 (0)
9 (0.1)
1 (0)
0
1 (0)
2 (0)
11 (0.2)
11 (0.2)
1 (0)
0
8 (0.1)
9 (0.1)
3 (0)
5 (0.1)
5 (0.1)
14 (0.2)
4 (0.1)
3 (0)
6 (0.1)
2 (0)
5 (0.1)
4 (0.1)
4 (0.1)
1 (0)
Placebo
N=6,349
N (%)
90 (1.4)
3 (0)
2 (0)
3 (0)
0
13 (0.2)
0
1 (0)
0
1 (0)
0
15 (0.2)
7 (0.1)
1 (0)
14 (0.2)
7 (0.1)
1 (0)
3 (0)
4 (0.1)
7 (0.1)
8 (0.1)
3 (0)
4 (0.1)
1 (0)
2 (0)
1 (0)
5 (0.1)
2 (0)
P value
0.88
1.0
0.62
0.73
0.5
0.40
1.0
0.50
1.0
1.0
0
0.44
0.04
0.50
0.21
0.80
0.62
0.73
1.0
0.19
0.27
1.0
0.75
1.0
0.45
0.37
0.75
0.62
* none were confirmed on central adjudication as meeting the criteria for SUSARs
55
Total death
Cardiovascular death
Non cardiovascular death
Cancer
Pulmonary
Gastrointestinal
Hepatobiliary
Sepsis
Infection
Accidental/Trauma
Suicide
Drug overdose
Renal
Other
Rosuvastatin
N=6,361
N (%)
334 (5.3)
154 (2.4)
180 (2.8)
108 (1.7)
20 (0.3)
8 (0.1)
1 (0)
5 (0.1)
17 (0.3)
12 (0.2)
2 (0)
0
0
7 (0.1)
Placebo
N=6,344
N (%)
357 (5.6)
171 (2.7)
186 (2.9)
114 (1.8)
17 (0.3)
8 (0.1)
0
5 (0.1)
12 (0.2)
16 (0.3)
1 (0)
0
4 (0.1)
9 (0.1)
* Note this is not a safety outcome; total mortality is a predefined adjudicated efficacy outcome. We provide a listing of
causes of death with details on the causes of non-cardiovascular death to further describe the safety in out trial.
56
Table S13: Predefined Safety Outcomes in the Rosuvastatin and Placebo Groups
Cancer
Myopathy
Rhabdomyolysis
Hospitalizations Cardiovascular
Hospitalizations Non-cardiovascular
Total Hospitalizations
Rosuvastatin
N=6,361
N (%)
267 (4.2)
1 (0)
1 (0)
281 (4.4)
881 (13.9)
1066 (16.8)
Placebo
N=6,344
N (%)
286 (4.5)
1 (0)
0
369 (5.8)
879 (13.9)
1125 (17.7)
P value
0.41
1.0
1.0
0.0004
1.0
0.15
57
Table S14: Reasons for Hospitalization in the Rosuvastatin and Placebo Groups
Total Hospitalizations
Cardiovascular Hospitalizations
Myocardial infarction
Stroke
Transient ischemic attack
Congestive heart failure
Unstable/new/worsening angina
Cardiac arrest
Supraventricular arrhythmia
Sustained ventricular tachycardia/arrhythmia
Pulmonary embolism
Coronary angiography
CABG
Percutaneous Coronary Intervention
Peripheral angioplasty/stent/abdominal aortic
aneurysm/other vascular surgery
Carotid angioplasty/stent/surgery
Limb amputation due to vascular insufficiency
Valve surgery
Other cardiovascular
Non-cardiovascular hospitalizations
Eye complications
Laser treatment/vitrectomy
Limb/foot infections
Other diabetic issues
Cancer
Injury
Fractures
Renal transplant
Renal dialysis
Hematologic
Sepsis
Rosuvastatin
N=6,361
N (%)
1066 (16.8)
281 (4.4)
46 (0.7)
68 (1.1)
14 (0.2)
19 (0.3)
38 (0.6)
7 (0.1)
32 (0.5)
6 (0.1)
8 (0.1)
54 (0.8)
13 (0.2)
34 (0.5)
Placebo
N=6,344
N (%)
1125 (17.7)
369 (5.8)
64 (1.0)
100 (1.6)
12 (0.2)
27 (0.4)
47 (0.7)
12 (0.2)
42 (0.7)
8 (0.1)
11 (0.2)
66 (1.0)
24 (0.4)
58 (0.9)
6 (0.1)
4 (0.1)
0.75
2 (0)
1 (0)
9 (0.1)
65 (1.0)
881 (13.9)
5 (0.1)
3 (0)
6 (0.1)
8 (0.1)
165 (2.6)
30 (0.5)
69 (1.1)
0
2 (0)
13 (0.2)
24 (0.4)
2 (0)
1 (0)
9 (0.1)
78 (1.2)
879 (13.9)
0 (0)
0 (0)
1 (0)
7 (0.1)
167 (2.6)
30 (0.5)
79 (1.2)
0 (0)
4 (0.1)
6 (0.1)
21 (0.3)
1.0
1.0
1.0
0.28
1.0
0.06
0.25
0.12
1.0
0.91
1.0
0.41
P value
0.15
0.0004
0.09
0.01
0.84
0.24
0.33
0.26
0.25
0.61
0.50
0.27
0.07
0.01
0.45
0.17
0.77
58
Psychiatric
Genito-urinary
Gastrointestinal
Other non-cardiovascular
Rosuvastatin
N=6,361
N (%)
2 (0)
81 (1.3)
116 (1.8)
567 (8.9)
Placebo
N=6,344
N (%)
6 (0.1)
87 (1.4)
113 (1.8)
557 (8.8)
P value
0.18
0.64
0.89
0.80
59
Table S15: Adverse Events Leading to Permanent Study Drug Discontinuations in the Rosuvastatin
and Placebo Groups
Rosuvastatin
N=6,361
N (%)
1510 (23.7)
1104 (17.4)
80 (1.3)
2 (0)
16 (0.3)
0
44 (0.7)
2 (0)
1 (0)
83 (1.3)
2 (0)
2 (0.1)
16 (0.3)
25 (0.4)
10 (0.2)
123 (1.9)
50 (0.8)
3 (0)
Placebo
N=6,344
N (%)
1664 (26.2)
1088 (17.2)
90 (1.4)
5 (0.1)
11 (0.2)
0
41 (0.6)
0
1 (0)
76 (1.2)
0
1 (0)
9 (0.1)
29 (0.5)
19 (0.3)
284 (4.5)
57 (0.9)
1 (0)
P value
0.001
0.76
0.44
0.29
0.44
0.83
0.50
1.0
0.63
0.50
1.0
0.23
0.59
0.10
<0.0001
0.50
0.62
60
Table S16: Adverse Events Leading to Temporary Study Drug Discontinuations in the Rosuvastatin
and Placebo Groups
Rosuvastatin
N=6,361
N (%)
1643 (25.8)
517 (8.1)
88 (1.4)
1 (0)
8 (0.1)
0
79 (1.2)
0
1 (0)
84 (1.3)
4 (0.1)
0
9 (0.1)
17 (0.3)
3 (0)
26 (0.4)
5 (0.1)
8 (0.1)
Placebo
N=6,344
N (%)
1633 (25.7)
480 (7.6)
77 (1.2)
3 (0)
3 (0)
0
51 (0.8)
0
1 (0)
41 (0.6)
1 (0)
0
5 (0.1)
18 (0.3)
2 (0)
70 (1.1)
8 (0.1)
8 (0.1)
P value
0.92
0.25
0.43
0.37
0.23
0.02
1.0
0.0001
0.37
0.42
0.87
1.0
<0.0001
0.42
1.0
61
Table S17: Reported Serious Unexpected Suspected Adverse Reactions (SUSARS) in the Rosuvastatin
and Placebo Groups*
Rosuvastatin
N=6,361
N (%)
91 (1.4)
3 (0)
1 (0)
5 (0.1)
2 (0)
9 (0.1)
0
0
0
3 (0)
6 (0.1)
14 (0.2)
4 (0.1)
1 (0)
12 (0.2)
8 (0.1)
2 (0)
4 (0.1)
6 (0.1)
12 (0.2)
5 (0.1)
1 (0)
4 (0.1)
2 (0)
3 (0)
4 (0.1)
5 (0.1)
0
Placebo
N=6,344
N (%)
92 (1.5)
3 (0)
2 (0)
3 (0)
0
13 (0.2)
1 (0)
1 (0)
1 (0)
0
5 (0.1)
12 (0.2)
4 (0.1)
0
10 (0.2)
8 (0.1)
2 (0)
4 (0.1)
3 (0)
9 (0.1)
7 (0.1)
5 (0.1)
6 (0.1)
1 (0)
4 (0.1)
1 (0)
4 (0.1)
3 (0)
P value
0.94
1.0
0.62
0.73
0.50
0.40
0.50
0.50
0.50
0.25
1.0
0.84
1.0
1.0
0.83
1.0
1.0
1.0
0.51
0.66
0.58
0.12
0.55
1.0
0.73
0.37
1.0
0.12
62
Total death
Cardiovascular death
Non cardiovascular death
Cancer
Pulmonary
Gastrointestinal
Hepatobiliary
Sepsis
Infection
Accidental/Trauma
Suicide
Drug overdose
Renal
Other
Candesartan/HCTZ+
Rosuvastatin
N=3,180
N (%)
163 (5.1)
75 (2.4)
88 (2.8)
55 (1.7)
10 (0.3)
6 (0.2)
1 (0)
2 (0.1)
5 (0.2)
7 (0.2)
1 (0)
0
0
1 (0)
Rosuvastatin
Alone
N=3,181
N (%)
171 (5.4)
79 (2.5)
92 (2.9)
53 (1.7)
10 (0.3)
2 (0.1)
0
3 (0.1)
12 (0.4)
5 (0.2)
1 (0)
0
0
6 (0.2)
Candesartan/HCTZ
Alone
N=3,176
N (%)
179 (5.6)
80 (2.5)
99 (3.1)
55 (1.7)
10 (0.3)
6 (0.2)
0
2 (0.1)
6 (0.2)
9 (0.3)
0
0
3 (0.1)
8 (0.3)
Double
Placebo
N=3,168
N (%)
178 (5.6)
91 (2.9)
87 (2.7)
59 (1.9)
7 (0.2)
2 (0.1)
0
3 (0.1)
6 (0.2)
7 (0.2)
1 (0)
0
1 (0)
1 (0)
* Note this is not a safety outcome; total mortality is a predefined adjudicated efficacy outcome. We provide a listing of
causes of death with details on the causes of non-cardiovascular death to further describe the safety in out trial.
Rosuvastatin Alone group refers to the Rosuvastatin Active/ Candesartan/HCTZ Placebo group
Candesartan/HCTZ Alone group refers to the Candesartan/HCTZ Active/ Rosuvastatin Placebo group
63
Cancer
Myopathy
Rhabdomyolysis
Hospitalizations Cardiovascular
Hospitalizations Non-cardiovascular
Total Hospitalizations
Candesartan/HCTZ
+Rosuvastatin
N=3,180
N (%)
135 (4.2)
1 (0)
0
141 (4.4)
463 (14.6)
560 (17.6)
Rosuvastatin
Alone
N=3,181
N (%)
132 (4.1)
0
1 (0)
140 (4.4)
418 (13.1)
506 (15.9)
Candesartan/
HCTZ Alone
N=3,176
N (%)
142 (4.5)
0
0
178 (5.6)
436 (13.7)
552 (17.4)
Double
Placebo
N=3,168
N (%)
144 (4.5)
1 (0)
0
191 (6.0)
443 (14.0)
573 (18.1)
P
value*
0.58
1.0
0.005
0.52
0.62
* P values refer to the comparison of the double active to the double placebo
Rosuvastatin Alone group refers to the Rosuvastatin Active/ Candesartan/HCTZ Placebo group
Candesartan/HCTZ Alone group refers to the Candesartan/HCTZ Active/ Rosuvastatin Placebo group
64
Total Hospitalizations
Cardiovascular Hospitalizations
Myocardial infarction
Stroke
Transient ischemic attack
Congestive heart failure
Unstable/new/worsening angina
Cardiac arrest
Supraventricular arrhythmia
Sustained ventricular
tachycardia/arrhythmia
Pulmonary embolism
Coronary angiography
CABG
Percutaneous Coronary
Intervention
Peripheral
angioplasty/stent/abdominal
aortic aneurysm/other vascular
surgery
Carotid angioplasty/stent/surgery
Limb amputation due to vascular
insufficiency
Valve surgery
Other cardiovascular
Non-cardiovascular hospitalizations
Eye complications
Laser treatment/vitrectomy
Limb/foot infections
Candesartan/HCTZ+
Rosuvastatin
N=3,180
N (%)
560 (17.6)
141 (4.4)
20 (0.6)
31 (1.0)
5 (0.2)
11 (0.3)
20 (0.6)
2 (0.1)
20 (0.6)
Rosuvastatin
Alone
N=3,181
N (%)
506 (15.9)
140 (4.4)
26 (0.8)
37 (1.2)
9 (0.3)
8 (0.3)
18 (0.6)
5 (0.2)
12 (0.4)
Candesartan/HCTZ
Alone
N=3,176
N (%)
552 (17.4)
178 (5.6)
27 (0.9)
47 (1.5)
8 (0.3)
13 (0.4)
21 (0.7)
4 (0.1)
17 (0.5)
Double
Placebo
N=3,168
N (%)
573 (18.1)
191 (6.0)
37 (1.2)
53 (1.7)
4 (0.1)
14 (0.4)
26 (0.8)
8 (0.3)
25 (0.8)
3 (0.1)
3 (0.1)
3 (0.1)
5 (0.2)
0.51
5 (0.2)
28 (0.9)
8 (0.3)
3 (0.1)
26 (0.8)
5 (0.2)
4 (0.1)
25 (0.8)
10 (0.3)
7 (0.2)
41 (1.3)
14 (0.4)
0.58
0.12
0.21
14 (0.4)
20 (0.6)
26 (0.8)
32 (1.0)
0.01
4 (0.1)
2 (0.1)
2 (0.1)
2 (0.1)
0.69
2 (0.1)
1 (0)
1 (0)
1.0
1 (0)
1 (0)
1.0
2 (0.1)
36 (1.1)
463 (14.6)
1 (0)
1 (0)
4 (0.1)
7 (0.2)
29 (0.9)
418 (13.1)
4 (0.1)
2 (0.1)
2 (0.1)
7 (0.2)
40 (1.3)
436 (13.7)
0
0
0
2 (0.1)
38 (1.2)
443 (14.0)
0
0
1 (0)
1.0
0.82
0.52
1.0
1.0
0.37
P value
0.62
0.005
0.02
0.02
1.0
0.56
0.38
0.06
0.46
65
Candesartan/HCTZ+
Rosuvastatin
N=3,180
N (%)
5 (0.2)
84 (2.6)
18 (0.6)
41 (1.3)
0
0
5 (0.2)
11 (0.3)
2 (0.1)
37 (1.2)
59 (1.9)
296 (9.3)
Rosuvastatin
Alone
N=3,181
N (%)
3 (0.1)
81 (2.5)
12 (0.4)
28 (0.9)
0
2 (0.1)
8 (0.3)
13 (0.4)
0
44 (1.4)
57 (1.8)
271 (8.5)
Candesartan/HCTZ
Alone
N=3,176
N (%)
5 (0.2)
76 (2.4)
10 (0.3)
32 (1.0)
0
2 (0.1)
2 (0.1)
16 (0.5)
1 (0)
43 (1.4)
57 (1.8)
282 (8.9)
Double
Placebo
N=3,168
N (%)
2 (0.1)
91 (2.9)
20 (0.6)
47 (1.5)
0
2 (0.1)
4 (0.1)
5 (0.2)
5 (0.2)
44 (1.4)
56 (1.8)
274 (8.6)
P value
0.45
0.59
0.75
0.52
0.25
1.0
0.21
0.29
0.44
0.85
0.38
* P values refer to the comparison of the double active to the double placebo
Rosuvastatin Alone group refers to the Rosuvastatin Active/ Candesartan/HCTZ Placebo group
Candesartan/HCTZ Alone group refers to the Candesartan/HCTZ Active/ Rosuvastatin Placebo group
66
Candesartan/HCTZ
+Rosuvastatin
N=3,180
N (%)
90 (2.8)
31 (1.0)
67 (2.1)
2 (0.1)
7 (0.2)
0
1 (0)
0
0
0
0
0
0
1 (0)
3 (0.1)
2 (0.1)
1 (0)
0
Rosuvastatin
Alone
N=3,181
N (%)
73 (2.3)
27 (0.8)
40 (1.3)
1 (0)
4 (0.1)
0
3 (0.1)
0
0
3 (0.1)
0
0
0
1 (0)
0
1 (0)
1 (0)
1 (0)
Candesartan/
HCTZ Alone
N=3,176
N (%)
68 (2.1)
26 (0.8)
60 (1.9)
2 (0.1)
12 (0.4)
0
2 (0.1)
2 (0.1)
0
4 (0.1)
0
0
0
1 (0)
0
0
2 (0.1)
0
Double
Placebo
N=3,168
N (%)
50 (1.6)
27 (0.9)
22 (0.7)
1 (0)
5 (0.2)
0
0
0
0
2 (0.1)
0
0
0
0
0
0
2 (0.1)
0
Rosuvastatin Alone group refers to the Rosuvastatin Active/ Candesartan/HCTZ Placebo group
Candesartan/HCTZ Alone group refers to the Candesartan/HCTZ Active/ Rosuvastatin Placebo group
67
Table S21B: Adverse Events Leading to Permanent Study Drug Discontinuation of Rosuvastatin or
Rosuvastatin Placebo ONLY in the Candesartan/HCTZ+Rosuvastatin, Rosuvastatin Alone,
Candesartan/HCTZ Alone and Double Placebo Groups
Candesartan/HCTZ
+Rosuvastatin
N=3,180
N (%)
49 (1.5)
21 (0.7)
3 (0.1)
1 (0)
1 (0)
0
10 (0.3)
0
0
27 (0.8)
0
1 (0)
3 (0.1)
1 (0)
0
50 (1.6)
1 (0)
0
Rosuvastatin
Alone
N=3,181
N (%)
46 (1.4)
23 (0.7)
1 (0)
0
1 (0)
0
8 (0.3)
0
0
26 (0.8)
0
1 (0)
4 (0.1)
2 (0.1)
2 (0.1)
59 (1.9)
2 (0.1)
1 (0)
Candesartan/
HCTZ Alone
N=3,176
N (%)
104 (3.3)
26 (0.8)
5 (0.2)
0
0
0
6 (0.2)
0
0
25 (0.8)
0
0
4 (0.1)
2 (0.1)
6 (0.2)
123 (3.9)
1 (0)
0
Double
Placebo
N=3,168
N (%)
106 (3.3)
33 (1.0)
3 (0.1)
1 (0)
1 (0)
0
6 (0.2)
0
0
21 (0.7)
0
1 (0)
4 (0.1)
1 (0)
3 (0.1)
127 (4.0)
0
0
Rosuvastatin Alone group refers to the Rosuvastatin Active/ Candesartan/HCTZ Placebo group
Candesartan/HCTZ Alone group refers to the Candesartan/HCTZ Active/ Rosuvastatin Placebo group
68
Table S21C: Adverse Events Leading to Permanent Study Drug Discontinuation of Both
Candesartan/HCTZ and Rosuvastatin or Their Placebos in the Candesartan/HCTZ+Rosuvastatin,
Rosuvastatin Alone, Candesartan/HCTZ Alone and Double Placebo Groups
Candesartan/HCTZ
+Rosuvastatin
N=3,180
N (%)
697 (21.9)
518 (16.3)
48 (1.5)
1 (0.1)
6 (0.2)
0
10 (0.3)
0
0
18 (0.6)
1 (0)
0
3 (0.1)
10 (0.3)
5 (0.2)
9 (0.3)
28 (0.9)
0
Rosuvastatin
Alone
N=3,181
N (%)
718 (22.6)
542 (17.0)
28 (0.9)
0
8 (0.3)
0
16 (0.5)
2 (0.1)
1 (0)
12 (0.4)
1 (0)
0
6 (0.2)
12 (0.4)
3 (0.1)
5 (0.2)
19 (0.6)
2 (0.1)
Candesartan/
HCTZ Alone
N=3,176
N (%)
697 (21.9)
497 (15.6)
42 (1.3)
2 (0.1)
7 (0.2)
0
15 (0.5)
0
1 (0)
17 (0.5)
0
0
0
13 (0.4)
5 (0.2)
12 (0.4)
25 (0.8)
1 (0)
Double
Placebo
N=3,168
N (%)
757 (23.9)
532 (16.8)
40 (1.3)
2 (0.1)
3 (0.1)
0
14 (0.4)
0
0
13 (0.4)
0
0
1 (0)
13 (0.4)
5 (0.2)
22 (0.7)
31 (1.0)
0
Rosuvastatin Alone group refers to the Rosuvastatin Active/ Candesartan/HCTZ Placebo group
Candesartan/HCTZ Alone group refers to the Candesartan/HCTZ Active/ Rosuvastatin Placebo group
69
Candesartan/HCTZ
+Rosuvastatin
N=3,180
N (%)
84 (2.6)
23 (0.7)
56 (1.8)
2 (0.1)
5 (0.2)
0
0
0
0
2 (0.1)
0
0
0
0
0
0
0
0
Rosuvastatin
Alone
N=3,181
N (%)
61 (1.9)
18 (0.6)
18 (0.6)
0
1 (0)
0
2 (0.1)
1 (0)
0
0
0
0
0
3 (0.1)
0
1 (0)
1 (0)
1 (0)
Candesartan/
HCTZ Alone
N=3,176
N (%)
73 (2.3)
26 (0.8)
25 (0.8)
1 (0)
1 (0)
0
1 (0)
0
0
1 (0)
0
0
0
0
0
1 (0)
1 (0)
0
Double
Placebo
N=3,168
N (%)
66 (2.1)
23 (0.7)
16 (0.5)
0
2 (0.1)
0
5 (0.2)
0
0
4 (0.1)
0
0
1 (0)
2 (0.1)
0
0
2 (0.1)
0
Rosuvastatin Alone group refers to the Rosuvastatin Active/ Candesartan/HCTZ Placebo group
Candesartan/HCTZ Alone group refers to the Candesartan/HCTZ Active/ Rosuvastatin Placebo group
70
Table S22B: Adverse Events Leading to Temporary Study Drug Discontinuation of Rosuvastatin or
Rosuvastatin Placebo ONLY in the Candesartan/HCTZ+Rosuvastatin, Rosuvastatin Alone,
Candesartan/HCTZ Alone and Double Placebo Groups
Candesartan/HCTZ
+Rosuvastatin
N=3,180
N (%)
89 (2.8)
39 (1.2)
9 (0.3)
0
2 (0.1)
0
4 (0.1)
0
0
35 (1.1)
1 (0)
0
3 (0.1)
1 (0)
1 (0)
14 (0.4)
0
2 (0.1)
Rosuvastatin
Alone
N=3,181
N (%)
93 (2.9)
17 (0.5)
4 (0.1)
0
1(0)
0
10 (0.3)
0
0
26 (0.8)
0
0
4 (0.1)
0
1 (0)
11 (0.3)
0
1 (0)
Candesartan/
HCTZ Alone
N=3,176
N (%)
94 (3.0)
28 (0.9)
8 (0.3)
0
0
0
3 (0.1)
0
1 (0)
16 (0.5)
0
0
4 (0.1)
0
1 (0)
33 (1.0)
0
1 (0)
Double
Placebo
N=3,168
N (%)
79 (2.5)
26 (0.8)
5 (0.2)
1 (0)
1 (0)
0
4 (0.1)
0
0
10 (0.3)
0
0
1 (0)
0
1 (0)
33 (1.0)
0
1 (0)
Rosuvastatin Alone group refers to the Rosuvastatin Active/ Candesartan/HCTZ Placebo group
Candesartan/HCTZ Alone group refers to the Candesartan/HCTZ Active/ Rosuvastatin Placebo group
71
Table S22C: Adverse Events Leading to Temporary Study Drug Discontinuation of Both
Candesartan/HCTZ and Rosuvastatin or Their Placebos in the Candesartan/HCTZ+Rosuvastatin,
Rosuvastatin Alone, Candesartan/HCTZ Alone and Double Placebo Groups
CandesartanHCTZ/Rosuvastatin
N=3,180
N (%)
768 (24.2)
239 (7.5)
47 (1.5)
1 (0)
3 (0.1)
0
32 (1.0)
0
0
11 (0.3)
1 (0)
0
1 (0)
10 (0.3)
1 (0)
1 (0)
3 (0.1)
3 (0.1)
Rosuvastatin
Alone
N=3,181
N (%)
693 (21.8)
222 (7.0)
28 (0.9)
0
2 (0.1)
0
33 (1.0)
0
1 (0)
12 (0.4)
2 (0.1)
0
1 (0)
6 (0.2)
0
0
2 (0.1)
2 (0.1)
CandesartanHCTZ Alone
N=3,176
N (%)
729 (33.0)
205 (6.5)
43 (1.4)
1 (0)
1 (0)
0
21 (0.7)
0
0
9 (0.3)
1 (0)
0
0
9 (0.3)
0
0
2 (0.1)
4 (0.1)
Double
Placebo
N=3,168
N (%)
731 (23.1)
220 (6.9)
20 (0.6)
1 (0)
1 (0)
0
23 (0.7)
0
0
6 (0.2)
0
0
0
9 (0.3)
0
4 (0.1)
6 (0.2)
2 (0.1)
Rosuvastatin Alone group refers to the Rosuvastatin Active/ Candesartan/HCTZ Placebo group
Candesartan/HCTZ Alone group refers to the Candesartan/HCTZ Active/ Rosuvastatin Placebo group
72
Table S23: Reported Serious Unexpected Suspected Adverse Reactions (SUSARS) in the
Candesartan/HCTZ+Rosuvastatin, Rosuvastatin Alone, Candesartan-HCTZ Alone and Double
Placebo Groups*
CandesartanRosuvastatin CandesartanHCTZ/Rosuvastatin
Alone
HCTZ Alone
N=3,180
N=3,181
N=3,176
N (%)
N (%)
N (%)
Blood pressure abnormalities
2 (0.1)
1 (0)
1 (0)
Diabetes/glycemia
0
1 (0)
1 (0)
Dizziness/syncope/presyncope
5 (0.2)
0
0
Blood and lymphatic system disorders
2 (0.1)
0
0
Cardiac disorders
2 (0.1)
7 (0.2)
7 (0.2)
Congenital, familial and genetic disorders
0
0
1 (0)
Ear and labyrinth disorders
0
0
0
Endocrine disorders
0
0
1 (0)
Eye disorders
2 (0.1)
1 (0)
0
Gastrointestinal disorders
6 (0.2)
0
5 (0.2)
General disorders & administration site conditions
5 (0.2)
9 (0.3)
6 (0.2)
Hepatobiliary disorders
1 (0)
3 (0.1)
0
Immune system disorders
0
1 (0)
0
Infections and infestations
5 (0.2)
7 (0.2)
3 (0.1)
Injury, poisoning and procedural complications
5 (0.2)
3 (0.1)
4 (0.1)
Investigations
2 (0.1)
0
1 (0)
Metabolism and nutrition disorders
2 (0.1)
2 (0.1)
3 (0.1)
Musculoskeletal and connective tissue disorders
3 (0.1)
3 (0.1)
2 (0.1)
Neoplasms benign, malignant and unspecified
9 (0.3)
3 (0.1)
5 (0.2)
Nervous system disorders
2 (0.1)
3 (0.1)
2 (0.1)
Psychiatric disorders
1 (0)
0
2 (0.1)
Renal and urinary disorders
2 (0.1)
2 (0.1)
4 (0.1)
Reproductive system and breast disorders
2 (0.1)
0
0
Respiratory, thoracic and mediastinal disorders
2 (0.1)
1 (0)
3 (0.1)
Skin and subcutaneous tissue disorders
3 (0.1)
1 (0)
1 (0)
Surgical and medical procedures
2 (0.1)
3 (0.1)
2 (0.1)
Vascular disorders
0
0
1 (0)
Rosuvastatin Alone group refers to the Rosuvastatin Active/ Candesartan/HCTZ Placebo group
Candesartan/HCTZ Alone group refers to the Candesartan/HCTZ Active/ Rosuvastatin Placebo group
Double
Placebo
N=3,168
N (%)
2 (0.1)
1 (0)
3 (0.1)
0
6 (0.2)
0
1 (0)
0
0
0
6 (0.2)
4 (0.1)
0
7 (0.2)
4 (0.1)
1 (0)
1 (0)
1 (0)
4 (0.1)
5 (0.2)
3 (0.1)
2 (0.1)
1 (0)
1 (0)
0
2 (0.1)
2 (0.1)
73