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ATMOSPHERE: Efficacy and Safety of Aliskiren and Aliskiren/Enalapril Combination on Morbidity-mortality in Patients With Chronic Heart Failure

Sponsor
Novartis Pharmaceuticals (Industry)
Overall Status
Completed
CT.gov ID
NCT00853658
Collaborator
(none)
7,064
Enrollment
808
Locations
3
Arms
79
Duration (Months)
8.7
Patients Per Site
0.1
Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The study will evaluate the efficacy and safety of both aliskiren monotherapy and aliskiren/enalapril combination therapy as compared to enalapril monotherapy, on morbidity and mortality in patients with chronic heart failure (NYHA Class II - IV.

Condition or Disease Intervention/Treatment Phase
Phase 3

Study Design

Study Type:
Interventional
Actual Enrollment :
7064 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
Triple (Participant, Care Provider, Investigator)
Primary Purpose:
Treatment
Official Title:
A Multicenter, Randomized, Double-blind, Parallel Group, Active-controlled Study to Evaluate the Efficacy and Safety of Both Aliskiren Monotherapy and Aliskiren/Enalapril Combination Therapy Compared to Enalapril Monotherapy, on Morbidity and Mortality in Patients With Chronic Heart Failure (NYHA Class II - IV). The Study is Also Known as Aliskiren Trial of Minimizing OutcomeS in Patients With HEart Failure (ATMOSPHERE).
Study Start Date :
Mar 1, 2009
Actual Primary Completion Date :
Oct 1, 2015
Actual Study Completion Date :
Oct 1, 2015

Arms and Interventions

Arm Intervention/Treatment
Experimental: Combination Aliskiren / Enalapril

Aliskiren / Enalapril combination therapy-150 mg/10 mg titrated to 300 mg/ 10 mg film-coated tablets and administered orally.

Drug: Enalapril
Enalapril 10 mg film-coated tablet and administered orally.

Drug: Aliskiren
Aliskiren 150 mg titrated to 300 mg film-coated tablet and administered orally.
Other Names:
  • SPP100

    		•
    Experimental: Aliskiren

    Aliskiren monotherapy - 150 mg titrated to 300 mg film-coated tablets and administered orally.

    Drug: Aliskiren
    Aliskiren 150 mg titrated to 300 mg film-coated tablet and administered orally.
    Other Names:
  • SPP100

    		•
    Active Comparator: Enalapril

    Enalapril monotherapy -10 mg film-coated tablet and administered orally.

    Drug: Enalapril
    Enalapril 10 mg film-coated tablet and administered orally.

    Outcome Measures

    Primary Outcome Measures

    1. Number of Participants That Had First Occurrence of the Composite Endpoint, Which is Defined as Either Cardiovascular (CV) Death or Heart Failure (HF) Hospitalization [up to End of Study (78 months)]

      Number of participants that had first occurrence of the composite endpoint, which is defined as either CV death or HF hospitalization due to HF.

    Secondary Outcome Measures

    1. Change From Baseline to Month 12 for the Kansas City Cardiomyopathy Questionnaire (KCCQ) Clinical Summary Score [Baseline, Month 12]

      Change from baseline to Month 12 for the Kansas City Cardiomyopathy Questionnaire (KCCQ) clinical summary score. 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. KCCQ clinical summary score is a composite assessment of physical limitations and total symptom scores. Scores are transformed to a range of 0-100, in which higher scores reflect better health status.

    2. All Cause Death [up to end of study (78 months)]

      Number of patients - All-cause death. All-cause death is common in Heart Failure HF patients this measures how many patients had this event.

    Eligibility Criteria

    Criteria

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

    Inclusion Criteria

    Patients eligible for inclusion in this study had to fulfill all of the following criteria:

    1. Patients ≥ 18 years of age, male or female.

    2. Patients with a diagnosis of chronic heart failure (NYHA

    Class II - IV):

    1. LVEF ≤ 35% at Visit 1 (local measurement, within the past 6 months assessed by echocardiography, multiple uptake gated acquisition scan (MUGA), computerized tomography(CT) scan, magnetic resonance imaging (MRI) or ventricular angiography)

    2. Elevated BNP or NT-proBNP at Visit 1:

    BNP ≥ 150 pg/mL (or BNP ≥ 100 pg/mL and unplanned hospitalization for HF within the last 12 months prior to Visit 1) (according to local measurement). OR NT-proBNP ≥ 600 pg/mL (or NT-proBNP ≥ 400 pg/mL and unplanned hospitalization for HF within the last 12 months prior to Visit 1) (according to local measurement).

    1. Patients had to be treated with an ACEI at a stable dose enalapril 10 mg daily at least or any other ACEI, e.g. ramipril, quinapril, lisinopril, fosinopril, perindopril, trandolapril; based on equivalent doses, for at least 4 weeks prior to Visit 1

    2. Patients had to be treated with a beta-blocker, unless contraindicated or not tolerated, at a stable dose for at least 4 weeks prior to visit 1 (for patients not on target dose, according to local guidelines, or in absence of that medication, the reason should be documented).

    3. Written informed consent to participate in the study and ability to comply with all requirements.

    Exclusion Criteria

    Patients with any of the following were to be excluded from participation in the study:

    1. History of hypersensitivity to any of the study drugs including history or allergy to ACEIs as well as known or suspected contraindications to the study drugs or previous history of intolerance to high doses of ACEIs during up- titration process.

    2. Patients treated concomitantly with both an ARB and an aldosterone antagonist in addition to study drug at Visit 1.

    3. Current acute decompensated HF (defined as an acute exacerbation of a chronic heart failure status manifested by typical signs and symptoms of HF like dyspnea, fatigue etc., that may require IV therapy with diuretics, vasodilators and/or inotropic drugs).

    4. Symptomatic hypotension and/or less than 95 mmHg systolic blood pressure (SBP) at Visit 1 and/or less than 90 mmHg SBP at Visit 4.

    5. Acute coronary syndrome, stroke, transient ischemic attack, cardiac, carotid or major vascular surgery, percutaneous coronary intervention (PCI) or carotid angioplasty, within the past 3 months prior to Visit 1.

    6. Coronary or carotid artery disease likely to require surgical or percutaneous intervention within the 6 months after Visit 1.

    7. Right heart failure due to severe pulmonary disease.

    8. Patients with Diabetes Mellitus.

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 Novartis Investigative Site Huntsville Alabama United States 35801
    2 Novartis Investigative Site Mobile Alabama United States 36608
    3 Novartis Investigative Site Mobile Alabama United States 36693
    4 Novartis Investigative Site Tucson Arizona United States 85723-0001
    5 Novartis Investigative Site Hot Springs Arkansas United States 71913
    6 Novartis Investigative Site Little Rock Arkansas United States 72204
    7 Novartis Investigative Site Little Rock Arkansas United States 72205
    8 Novartis Investigative Site Pine Bluff Arkansas United States 71603
    9 Novartis Investigative Site Searcy Arkansas United States 72143
    10 Novartis Investigative Site Beverly Hills California United States 90211
    11 Novartis Investigative Site French Camp California United States 95231
    12 Novartis Investigative Site Inglewood California United States 90301
    13 Novartis Investigative Site Los Angeles California United States 90073
    14 Novartis Investigative Site Modesto California United States 95355
    15 Novartis Investigative Site Northridge California United States 91325
    16 Novartis Investigative Site Sacramento California United States 95825
    17 Novartis Investigative Site San Diego California United States 92123
    18 Novartis Investigative Site Santa Monica California United States 90404
    19 Novartis Investigative Site Westlake Village California United States 91361
    20 Novartis Investigative Site Denver Colorado United States 80218
    21 Novartis Investigative Site Littleton Colorado United States 80120
    22 Novartis Investigative Site Boynton Beach Florida United States 33437
    23 Novartis Investigative Site Daytona Beach Florida United States 32117
    24 Novartis Investigative Site Fort Lauderdale Florida United States 33316
    25 Novartis Investigative Site Hollywood Florida United States 33021
    26 Novartis Investigative Site Jacksonville Beach Florida United States 32050
    27 Novartis Investigative Site Miami Lakes Florida United States 33014
    28 Novartis Investigative Site Orlando Florida United States 32803
    29 Novartis Investigative Site Wellington Florida United States 33449
    30 Novartis Investigative Site Athens Georgia United States 30606
    31 Novartis Investigative Site Augusta Georgia United States 30904
    32 Novartis Investigative Site Gillespie Illinois United States 62033
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    34 Novartis Investigative Site Metairie Louisiana United States 70006
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    37 Novartis Investigative Site Auburn Maine United States 04210
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    46 Novartis Investigative Site Durham North Carolina United States 27710
    47 Novartis Investigative Site Marion Ohio United States 43302
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    57 Novartis Investigative Site Everett Washington United States 98208
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    97 Novartis Investigative Site Darlinghurst New South Wales Australia 2010
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    161 Novartis Investigative Site Beijing Beijing China 100730
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    165 Novartis Investigative Site Shijiazhuang Hebei China 050000
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    167 Novartis Investigative Site Nanjing Jiangsu China
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    179 Novartis Investigative Site Beijing China 100020
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    191 Novartis Investigative Site Xian China 710004
    192 Novartis Investigative Site Medellín Antioquia Colombia
    193 Novartis Investigative Site Baranquilla Atlantico Colombia
    194 Novartis Investigative Site Barranquilla Atlantico Colombia
    195 Novartis Investigative Site Cartagena Bolivar Colombia
    196 Novartis Investigative Site Bogota Cundinamarca Colombia 111411
    197 Novartis Investigative Site Bogotá Cundinamarca Colombia 110111
    198 Novartis Investigative Site Barranquilla Colombia
    199 Novartis Investigative Site Bogotá Colombia 00000
    200 Novartis Investigative Site Bogotá Colombia
    201 Novartis Investigative Site Florida Blanca Colombia
    202 Novartis Investigative Site Medellín Colombia
    203 Novartis Investigative Site Goicoechea San Jose, Costa Rica Costa Rica 3184-1000
    204 Novartis Investigative Site Alajuela Costa Rica
    205 Novartis Investigative Site San Jose Costa Rica 1307-1000
    206 Novartis Investigative Site San Jose Costa Rica 272-1225
    207 Novartis Investigative Site Benesov Czech Republic 25601
    208 Novartis Investigative Site Brno Czech Republic 60200
    209 Novartis Investigative Site Cesky Krumlov Czech Republic 381 01
    210 Novartis Investigative Site Jindrichuv Hradec Czech Republic 377 01
    211 Novartis Investigative Site Kolín Czech Republic 280 02
    212 Novartis Investigative Site Kromeriz Czech Republic 767 01
    213 Novartis Investigative Site Louny Czech Republic 440 01
    214 Novartis Investigative Site Louny Czech Republic
    215 Novartis Investigative Site Marianske lazne Czech Republic 353 01
    216 Novartis Investigative Site Ostrava Czech Republic 70200
    217 Novartis Investigative Site Plzen Czech Republic 323 00
    218 Novartis Investigative Site Praha 11 Czech Republic 148 00
    219 Novartis Investigative Site Praha 2 Czech Republic 128 08
    220 Novartis Investigative Site Praha 9 Czech Republic
    221 Novartis Investigative Site Pribram VIII Czech Republic 261 01
    222 Novartis Investigative Site Teplice Czech Republic 415 01
    223 Novartis Investigative Site Vyskov Czech Republic 68001
    224 Novartis Investigative Site Aalborg Denmark DK-9000
    225 Novartis Investigative Site Copenhagen NV Denmark DK-2400
    226 Novartis Investigative Site Copenhagen S Denmark DK-2300
    227 Novartis Investigative Site Copenhagen Denmark 2100
    228 Novartis Investigative Site Esbjerg Denmark DK-6700
    229 Novartis Investigative Site Fredericia Denmark 7000
    230 Novartis Investigative Site Frederiksberg Denmark DK-2000
    231 Novartis Investigative Site Glostrup Denmark DK-2600
    232 Novartis Investigative Site Hellerup Denmark DK-2900
    233 Novartis Investigative Site Helsingoer Denmark DK-3000
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    237 Novartis Investigative Site Hvidovre Denmark DK-2650
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    239 Novartis Investigative Site Næstved Denmark DK-4700
    240 Novartis Investigative Site Odense C Denmark DK-5000
    241 Novartis Investigative Site Randers NØ Denmark DK-8930
    242 Novartis Investigative Site Silkeborg Denmark 8600
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    244 Novartis Investigative Site Viborg Denmark DK-8800
    245 Novartis Investigative Site Århus N Denmark DK-8200
    246 Novartis Investigative Site Santo Domingo Republica Dominicana Dominican Republic
    247 Novartis Investigative Site San Cristobal Dominican Republic
    248 Novartis Investigative Site Parnu Estonia 80010
    249 Novartis Investigative Site Tallinn Estonia 10138
    250 Novartis Investigative Site Tallinn Estonia 13419
    251 Novartis Investigative Site Tartu Estonia 51014
    252 Novartis Investigative Site Hyvinkää Finland FIN-05850
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    254 Novartis Investigative Site Seinajoki Finland 60200
    255 Novartis Investigative Site Tammisaari Finland 10600
    256 Novartis Investigative Site Turku Finland FIN-20520
    257 Novartis Investigative Site Albi France 81013
    258 Novartis Investigative Site Angers France 49000
    259 Novartis Investigative Site Becon Les Granits France 49370
    260 Novartis Investigative Site Clichy France 92110
    261 Novartis Investigative Site Dijon France 21079
    262 Novartis Investigative Site Grenoble France 38043
    263 Novartis Investigative Site Marseille Cedex 05 France 13385
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    265 Novartis Investigative Site Paris France 75013
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    267 Novartis Investigative Site Pessac Cedex France 33604
    268 Novartis Investigative Site Saint-Etienne France 42055
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    270 Novartis Investigative Site Winsen (Luhe) Lower Saxony Germany 21423
    271 Novartis Investigative Site Augsburg Germany 86150
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    291 Novartis Investigative Site Coburg Germany 96450
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    293 Novartis Investigative Site Dessau-Roßlau Germany 06846
    294 Novartis Investigative Site Dinkelsbühl Germany 91550
    295 Novartis Investigative Site Dorsten Germany 46282
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    330 Novartis Investigative Site Königsbrück Germany 01436
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    332 Novartis Investigative Site Lambrecht Germany 67466
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    336 Novartis Investigative Site Lienen Germany 49536
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    338 Novartis Investigative Site Lörrach Germany 79539
    339 Novartis Investigative Site Lüneburg Germany 21339
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    341 Novartis Investigative Site Mainz Germany 55116
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    368 Novartis Investigative Site Athens GR Greece 115 27
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    370 Novartis Investigative Site Thessaloniki GR Greece 570 10
    371 Novartis Investigative Site Athens Greece 115 28
    372 Novartis Investigative Site Athens Greece 124 62
    373 Novartis Investigative Site Athens Greece GR 11527
    374 Novartis Investigative Site Chios Greece 82100
    375 Novartis Investigative Site Edessa Greece 58200
    376 Novartis Investigative Site Guntur Andhra Pradesh India 522001
    377 Novartis Investigative Site Hyderabad Andhra Pradesh India 500012
    378 Novartis Investigative Site Secunderabad Andhra Pradesh India 500003
    379 Novartis Investigative Site Vijayawada Andhra Pradesh India 520 008
    380 Novartis Investigative Site New Delhi Delhi India 110060
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    382 Novartis Investigative Site Bangalore Karnataka India 560 052
    383 Novartis Investigative Site Bangalore Karnataka India 560099
    384 Novartis Investigative Site Manipal Karnataka India 576104
    385 Novartis Investigative Site Trivandrum Kerela India 695002
    386 Novartis Investigative Site Mumbai Maharashtra India 400 022
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    388 Novartis Investigative Site Nagpur Maharashtra India 400 012
    389 Novartis Investigative Site Nagpur Maharashtra India 400012
    390 Novartis Investigative Site Nagpur Maharashtra India 440 010
    391 Novartis Investigative Site Nagpur Maharashtra India 440010
    392 Novartis Investigative Site Nagpur Maharashtra India 440012
    393 Novartis Investigative Site Pune Maharashtra India 411 011
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    398 Novartis Investigative Site Delhi New Delhi India 110065
    399 Novartis Investigative Site Jaipur Rajasthan India 302001
    400 Novartis Investigative Site Jaipur Rajasthan India 302024
    401 Novartis Investigative Site Chennai Tamil Nadu India 600100
    402 Novartis Investigative Site Coimbatore Tamil Nadu India 641014
    403 Novartis Investigative Site Madurai Tamil Nadu India 625107
    404 Novartis Investigative Site Hyderabad Telangana India 500082
    405 Novartis Investigative Site Lucknow Uttar Pradesh India 226005
    406 Novartis Investigative Site Lucknow Uttar Pradesh India 226014
    407 Novartis Investigative Site Bangalore India 560 034
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    409 Novartis Investigative Site Hyderabad India 500044
    410 Novartis Investigative Site Lucknow India 226003
    411 Novartis Investigative Site Mumbai India 400 050
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    413 Novartis Investigative Site Noida India 201301
    414 Novartis Investigative Site Co Dublin Ireland
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    419 Novartis Investigative Site Montescano (pv) Italy 27040
    420 Novartis Investigative Site Pavia (pv) Italy 27100
    421 Novartis Investigative Site Ancona AN Italy 60126
    422 Novartis Investigative Site Arezzo AR Italy 52100
    423 Novartis Investigative Site Cortona AR Italy 52044
    424 Novartis Investigative Site Bergamo BG Italy 24128
    425 Novartis Investigative Site Bologna BO Italy 40138
    426 Novartis Investigative Site Brescia BS Italy 25123
    427 Novartis Investigative Site Lumezzane BS Italy 25065
    428 Novartis Investigative Site Chieti CH Italy 66100
    429 Novartis Investigative Site Cosenza CS Italy 87100
    430 Novartis Investigative Site Forlì FC Italy 47100
    431 Novartis Investigative Site Cona FE Italy 44100
    432 Novartis Investigative Site Foggia FG Italy 71100
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    434 Novartis Investigative Site Pozzilli IS Italy 86077
    435 Novartis Investigative Site Casarano LE Italy 73042
    436 Novartis Investigative Site Cecina LI Italy 57023
    437 Novartis Investigative Site Castelnuovo di Garfagnana LU Italy 55032
    438 Novartis Investigative Site Milano MI Italy 20132
    439 Novartis Investigative Site Milano MI Italy 20138
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    441 Novartis Investigative Site Pieve di Coriano MN Italy
    442 Novartis Investigative Site Massa MS Italy 54100
    443 Novartis Investigative Site Palermo PA Italy 90127
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    445 Novartis Investigative Site Parma PR Italy 43100
    446 Novartis Investigative Site Pavia PV Italy 27100
    447 Novartis Investigative Site Cotignola RA Italy 48010
    448 Novartis Investigative Site Roma RM Italy 00169
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    451 Novartis Investigative Site Rimini RN Italy 47900
    452 Novartis Investigative Site Cava De' Tirreni SA Italy 84013
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    454 Novartis Investigative Site Sondalo SO Italy 23035
    455 Novartis Investigative Site Sarzana SP Italy 19038
    456 Novartis Investigative Site Sassari SS Italy 07100
    457 Novartis Investigative Site Orbassano TO Italy 10043
    458 Novartis Investigative Site Torino TO Italy 10126
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    460 Novartis Investigative Site Trieste TS Italy 34142
    461 Novartis Investigative Site Trieste TS Italy 34149
    462 Novartis Investigative Site Vittorio Veneto TV Italy 31029
    463 Novartis Investigative Site San Daniele Del Friuli UD Italy 33038
    464 Novartis Investigative Site Udine UD Italy 33100
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    466 Novartis Investigative Site San Bonifacio VR Italy 37047
    467 Novartis Investigative Site Nagoya-city Aichi Japan 466-8560
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    477 Novartis Investigative Site Kure Hiroshima Japan 737-0023
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    480 Novartis Investigative Site Amagasaki-city Hyogo Japan 660-8550
    481 Novartis Investigative Site Higashiibaraki-gun Ibaraki Japan 311-3193
    482 Novartis Investigative Site Hitachinaka Ibaraki Japan 312-0057
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    484 Novartis Investigative Site Kanazawa Ishikawa Japan 920-8650
    485 Novartis Investigative Site Kawasaki-city Kanagawa Japan 210-0852
    486 Novartis Investigative Site Sagamihara-city Kanagawa Japan 252-0375
    487 Novartis Investigative Site Yokohama-city Kanagawa Japan 232-0024
    488 Novartis Investigative Site Yokosuka Kanagawa Japan 238-8567
    489 Novartis Investigative Site Kumamoto City Kumamoto Japan 860-8556
    490 Novartis Investigative Site Sendai-city Miyagi Japan 980-8574
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    493 Novartis Investigative Site Izumisano-city Osaka Japan 598-8577
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    498 Novartis Investigative Site Komatsushima-city Tokushima Japan 773-8502
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    500 Novartis Investigative Site Adachi-ku Tokyo Japan 120-0006
    501 Novartis Investigative Site Bunkyo-ku Tokyo Japan 113-8431
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    503 Novartis Investigative Site Bunkyo-ku Tokyo Japan 113-8603
    504 Novartis Investigative Site Bunkyo-ku Tokyo Japan 113-8655
    505 Novartis Investigative Site Shinjuku-ku Tokyo Japan 162-8666
    506 Novartis Investigative Site Hofu Yamaguchi Japan 747-8511
    507 Novartis Investigative Site Shunan-city Yamaguchi Japan 745-8522
    508 Novartis Investigative Site Ube Yamaguchi Japan 755-8505
    509 Novartis Investigative Site Fukushima Japan 960-8251
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    522 Novartis Investigative Site Incheon Korea, Republic of 405-760
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    524 Novartis Investigative Site Taegu Korea, Republic of 700 - 721
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    532 Novartis Investigative Site Vilnius Lithuania 08661
    533 Novartis Investigative Site Guadalajara Jalisco Mexico 44600
    534 Novartis Investigative Site Zapopan Jalisco Mexico 45200
    535 Novartis Investigative Site Monterrey Nuevo León Mexico 64060
    536 Novartis Investigative Site Monterrey Nuevo León Mexico 64710
    537 Novartis Investigative Site Culiacan Sinaloa Mexico CP:83230
    538 Novartis Investigative Site Aguascalientes Mexico 20230
    539 Novartis Investigative Site Querétaro Mexico 76000
    540 Novartis Investigative Site San Luis Potosi Mexico 78200
    541 Novartis Investigative Site Alkmaar Netherlands 1815 JD
    542 Novartis Investigative Site Amsterdam Netherlands 1023 NL
    543 Novartis Investigative Site Amsterdam Netherlands 1061 AE
    544 Novartis Investigative Site Amsterdam Netherlands 1091 HA
    545 Novartis Investigative Site Amsterdam Netherlands 1105 AZ
    546 Novartis Investigative Site Apeldoorn Netherlands 7334 DZ
    547 Novartis Investigative Site Deventer Netherlands 7416 SE
    548 Novartis Investigative Site Dirksland Netherlands 3247 BW
    549 Novartis Investigative Site Enschede Netherlands 7513 ER
    550 Novartis Investigative Site Groningen Netherlands 9713 GZ
    551 Novartis Investigative Site Haarlem Netherlands 2035 RC
    552 Novartis Investigative Site Heerlen Netherlands 6419 PC
    553 Novartis Investigative Site Leeuwarden Netherlands 8934 AD
    554 Novartis Investigative Site Leiderdorp Netherlands NL-2353 GA
    555 Novartis Investigative Site Meppel Netherlands 7943 KA
    556 Novartis Investigative Site Rotterdam Netherlands 3045 PM
    557 Novartis Investigative Site Rotterdam Netherlands 3083 AN
    558 Novartis Investigative Site Venlo Netherlands 5912 BL
    559 Novartis Investigative Site Wildervank Netherlands 9648 BE
    560 Novartis Investigative Site Zutphen Netherlands 7207 AE
    561 Novartis Investigative Site Zwolle Netherlands 8011 JW
    562 Novartis Investigative Site Oslo Norway 0514
    563 Novartis Investigative Site Trondheim Norway 7006
    564 Novartis Investigative Site Tønsberg Norway 3116
    565 Novartis Investigative Site Trujillo La Libertad Peru
    566 Novartis Investigative Site Chiclayo Lambayeque Peru
    567 Novartis Investigative Site Bellavista Lima Peru Callao 02
    568 Novartis Investigative Site Cercado de Lima Lima Peru 01
    569 Novartis Investigative Site Jesus Maria Lima Peru 11
    570 Novartis Investigative Site Miraflores Lima Peru 18
    571 Novartis Investigative Site San Borja Lima Peru 41
    572 Novartis Investigative Site San Isidro Lima Peru 27
    573 Novartis Investigative Site San Juan de Miraflores Lima Peru 29
    574 Novartis Investigative Site Lima Peru Lima 39
    575 Novartis Investigative Site Bytom Poland 41-902
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    577 Novartis Investigative Site Gdansk Poland 80-180
    578 Novartis Investigative Site Gdynia Poland 81-423
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    582 Novartis Investigative Site Katowice Poland 40-040
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    585 Novartis Investigative Site Krakow Poland 30-053
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    589 Novartis Investigative Site Opole Poland 45-706
    590 Novartis Investigative Site Ostrow Wielkopolski Poland 63-400
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    593 Novartis Investigative Site Plock Poland 09-402
    594 Novartis Investigative Site Poznan Poland 61-485
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    596 Novartis Investigative Site Tarnow Poland 33-100
    597 Novartis Investigative Site Torun Poland 87-100
    598 Novartis Investigative Site Warszawa Poland 03-242
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    604 Novartis Investigative Site Zabrze Poland 41-800
    605 Novartis Investigative Site Amadora Portugal 2720-276
    606 Novartis Investigative Site Aveiro Portugal 3814-501
    607 Novartis Investigative Site Carnaxide Portugal 2799-523
    608 Novartis Investigative Site Coimbra Portugal 3000-075
    609 Novartis Investigative Site Faro Portugal 8000-386
    610 Novartis Investigative Site Lisboa Portugal 1495-005
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    613 Novartis Investigative Site Penafiel Portugal 4564-007
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    615 Novartis Investigative Site Humacao Puerto Rico 00791
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    618 Novartis Investigative Site Bucharest District 1 Romania 012051
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    622 Novartis Investigative Site Targu Mures jud Mures Romania 540043
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    624 Novartis Investigative Site Targu Mures Mures Romania 540136
    625 Novartis Investigative Site Baia Mare Romania 430123
    626 Novartis Investigative Site Brasov Romania 500281
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    630 Novartis Investigative Site Iasi Romania 700547
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    632 Novartis Investigative Site Pitesti Romania 110114
    633 Novartis Investigative Site Targu Mures Romania 540096
    634 Novartis Investigative Site Timisoara Romania 300310
    635 Novartis Investigative Site Timisoara Romania 300736
    636 Novartis Investigative Site Barnaul Russian Federation 656055
    637 Novartis Investigative Site Chelyabinsk Russian Federation 454000
    638 Novartis Investigative Site Chelyabinsk Russian Federation 454021
    639 Novartis Investigative Site Chelyabinsk Russian Federation 454047
    640 Novartis Investigative Site Chelyabinsk Russian Federation 454048
    641 Novartis Investigative Site Ekaterinburg Russian Federation 620028
    642 Novartis Investigative Site Ekaterinburg Russian Federation 620137
    643 Novartis Investigative Site Izhevsk Russian Federation 426009
    644 Novartis Investigative Site Kirov Russian Federation 610014
    645 Novartis Investigative Site Krasnodar Russian Federation 350063
    646 Novartis Investigative Site Kursk Russian Federation 305035
    647 Novartis Investigative Site Lubertsi Russian Federation 140006
    648 Novartis Investigative Site Moscow Russian Federation 105229
    649 Novartis Investigative Site Moscow Russian Federation 111020
    650 Novartis Investigative Site Moscow Russian Federation 111539
    651 Novartis Investigative Site Moscow Russian Federation 115432
    652 Novartis Investigative Site Moscow Russian Federation 117292
    653 Novartis Investigative Site Moscow Russian Federation 119992
    654 Novartis Investigative Site Moscow Russian Federation 121359
    655 Novartis Investigative Site Moscow Russian Federation 127473
    656 Novartis Investigative Site Moscow Russian Federation 129301
    657 Novartis Investigative Site Moscow Russian Federation
    658 Novartis Investigative Site Nizhny Novgorod Russian Federation 603018
    659 Novartis Investigative Site Novosibirsk Russian Federation 630047
    660 Novartis Investigative Site Novosibirsk Russian Federation 630075
    661 Novartis Investigative Site Novosibirsk Russian Federation 630089
    662 Novartis Investigative Site Omsk Russian Federation 644018
    663 Novartis Investigative Site Perm Russian Federation 614097
    664 Novartis Investigative Site Pushkin,St-Petersburg Russian Federation 196601
    665 Novartis Investigative Site Ryazan Russian Federation 390026
    666 Novartis Investigative Site S.-Petersburg Russian Federation 196247
    667 Novartis Investigative Site Saint Petersburg Russian Federation 197022
    668 Novartis Investigative Site Saint-Petersburg Russian Federation 194044
    669 Novartis Investigative Site Saint-Petersburg Russian Federation 197341
    670 Novartis Investigative Site Saratov Russian Federation 410012
    671 Novartis Investigative Site Saratov Russian Federation 410028
    672 Novartis Investigative Site St-Petersburg Russian Federation 191119
    673 Novartis Investigative Site St. Petersburg Russian Federation 198013
    674 Novartis Investigative Site Tyumen Russian Federation 625026
    675 Novartis Investigative Site Volgograd Russian Federation 400001
    676 Novartis Investigative Site Volgograd Russian Federation 400008
    677 Novartis Investigative Site Voronezh Russian Federation 394065
    678 Novartis Investigative Site Yaroslavl Russian Federation 150000
    679 Novartis Investigative Site Yaroslavl Russian Federation 150030
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    682 Novartis Investigative Site Bratislava Slovak Republic Slovakia 826 06
    683 Novartis Investigative Site Komarno Slovak Republic Slovakia 94575
    684 Novartis Investigative Site Kosice Slovak Republic Slovakia 040 01
    685 Novartis Investigative Site Kosice Slovak republic Slovakia 04166
    686 Novartis Investigative Site Levice Slovak Republic Slovakia 93401
    687 Novartis Investigative Site Nitra Slovak Republic Slovakia 949 01
    688 Novartis Investigative Site Povazska Bystrica Slovak republic Slovakia 01701
    689 Novartis Investigative Site Presov Slovak republic Slovakia 08101
    690 Novartis Investigative Site Stropkov Slovak republic Slovakia 09101
    691 Novartis Investigative Site Zilina Slovak Republic Slovakia 010 01
    692 Novartis Investigative Site Zilina Slovak Republic Slovakia 08001
    693 Novartis Investigative Site Bardejov Slovakia 085 01
    694 Novartis Investigative Site Bratislava Slovakia 81369
    695 Novartis Investigative Site Kosice Slovakia 040 01
    696 Novartis Investigative Site Kosice Slovakia 04001
    697 Novartis Investigative Site Lucenec Slovakia 98439
    698 Novartis Investigative Site Piestany Slovakia 921 01
    699 Novartis Investigative Site Presov Slovakia 080 01
    700 Novartis Investigative Site Trebisov Slovakia 075 01
    701 Novartis Investigative Site Trencin Slovakia 911 01
    702 Novartis Investigative Site Zilina Slovakia 012 07
    703 Novartis Investigative Site Soweto Gauteng South Africa 2013
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    709 Novartis Investigative Site Worcester South Africa 6850
    710 Novartis Investigative Site Sanlucar de Barrameda Andalucia Spain 11540
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    714 Novartis Investigative Site Hospitalet de Llobregat Barcelona Spain 08907
    715 Novartis Investigative Site Villamartin Cadiz Spain 11650
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    720 Novartis Investigative Site Tortosa Cataluña Spain 43500
    721 Novartis Investigative Site Alicante Comunidad Valenciana Spain 03004
    722 Novartis Investigative Site Valencia Comunidad Valenciana Spain 46014
    723 Novartis Investigative Site Santiago de Compostela Galicia Spain 15706
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    726 Novartis Investigative Site Barcelona Spain 08041
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    728 Novartis Investigative Site Madrid Spain 28040
    729 Novartis Investigative Site Madrid Spain 28041
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    732 Novartis Investigative Site Falun Sweden 791 82
    733 Novartis Investigative Site Göteborg Sweden 416 85
    734 Novartis Investigative Site Karlstad Sweden 681 85
    735 Novartis Investigative Site Linkoping Sweden 581 85
    736 Novartis Investigative Site Lund Sweden SE-222 21
    737 Novartis Investigative Site Malmo Sweden SE 211 36
    738 Novartis Investigative Site Malmö Sweden 205 02
    739 Novartis Investigative Site Malmö Sweden 214 22
    740 Novartis Investigative Site Mölndal Sweden 431 80
    741 Novartis Investigative Site Nässjö Sweden SE 571 31
    742 Novartis Investigative Site Skelleftea Sweden 931 86
    743 Novartis Investigative Site Stockholm Sweden 111 57
    744 Novartis Investigative Site Stockholm Sweden 112 81
    745 Novartis Investigative Site Stockholm Sweden 17176
    746 Novartis Investigative Site Stockholm Sweden SE-111 35
    747 Novartis Investigative Site Sundsvall Sweden 851 86
    748 Novartis Investigative Site Sundsvall Sweden 852 31
    749 Novartis Investigative Site Umeå Sweden 901 85
    750 Novartis Investigative Site Uppsala Sweden SE-751 85
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    753 Novartis Investigative Site Basel Switzerland 4031
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    774 Novartis Investigative Site Ankara Turkey 06100
    775 Novartis Investigative Site Aydin Turkey 09100
    776 Novartis Investigative Site Balcova / Izmir Turkey 35340
    777 Novartis Investigative Site Etlik / Ankara Turkey 06018
    778 Novartis Investigative Site Fatih / Istanbul Turkey 34098
    779 Novartis Investigative Site Istanbul Turkey 34304
    780 Novartis Investigative Site Izmir Turkey 35040
    781 Novartis Investigative Site Kinikli / Denizli Turkey 20070
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    784 Novartis Investigative Site Leicester Leicestershire United Kingdom LE3 9QP
    785 Novartis Investigative Site Dafen Llanelli United Kingdom SA14 8QF
    786 Novartis Investigative Site Addlestone Surrey United Kingdom KT15 2BH
    787 Novartis Investigative Site Chichester West Sussex United Kingdom PO19 6SE
    788 Novartis Investigative Site Worthing West Sussex United Kingdom BN11 2DH
    789 Novartis Investigative Site Cardiff United Kingdom CF5 4AD
    790 Novartis Investigative Site Chesterfield United Kingdom S44 5BL
    791 Novartis Investigative Site Colchester United Kingdom CO4 5JL
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    793 Novartis Investigative Site Glasgow United Kingdom G51 4TF
    794 Novartis Investigative Site Liverpool United Kingdom L14 3PE
    795 Novartis Investigative Site London United Kingdom SE1 7EH
    796 Novartis Investigative Site London United Kingdom SW17 0RE
    797 Novartis Investigative Site Manchester United Kingdom M23 9LT
    798 Novartis Investigative Site Southampton United Kingdom SO16 6YD
    799 Novartis Investigative Site Swindon United Kingdom SN3 6BB
    800 Novartis Investigative Site Caracas Distrito Capital Venezuela 1010
    801 Novartis Investigative Site Caracas Distrito Capital Venezuela 1040
    802 Novartis Investigative Site Caracas Distrito Capital Venezuela 1060
    803 Novartis Investigative Site Valencia Edo. Carabobo Venezuela 2001
    804 Novartis Investigative Site Barcelona Estado Anzoátegui Venezuela 6001
    805 Novartis Investigative Site Puerto Ordaz Estado Bolívar Venezuela 8050
    806 Novartis Investigative Site Caracas Estado Miranda Venezuela 1061
    807 Novartis Investigative Site Cumana Estado Sucre Venezuela 6101
    808 Novartis Investigative Site Maracaibo Estado Zulia Venezuela 4011

    Sponsors and Collaborators

    • Novartis Pharmaceuticals

    Investigators

    • Study Director: Novartis Pharmaceuticals, Novartis Pharmaceuticals

    Study Documents (Full-Text)

    None provided.

    More Information

    Publications

    None provided.
    Responsible Party:
    Novartis Pharmaceuticals
    ClinicalTrials.gov Identifier:
    NCT00853658
    Other Study ID Numbers:
    • CSPP100F2301
    • 2008-004104-31
    First Posted:
    Mar 2, 2009
    Last Update Posted:
    Nov 25, 2016
    Last Verified:
    Oct 1, 2016
    Keywords provided by Novartis Pharmaceuticals
    Chronic Heart Failure
    Cardiovascular death
    CHF hospitalization
    morbi-mortality trial
    outcome study
    endpoint driven
    plasma renin activity
    renin angiotensin aldosterone system
    direct renin inhibitors
    BNP
    KCCQ
    eGFR
    (NYHA class II to IV) with elevated
    BNP and reduced LVEF
    Additional relevant MeSH terms:
    Heart Failure
    Enalapril

    Study Results

    Participant Flow

    Recruitment Details
    Pre-assignment Detail During Active Run-in period, patients received enalapril for step 1 & 2 and then aliskiren on top of the max tolerated dose of enalapril for step 3. Patients who completed the run in were randomized in a 1:1:1 ratio to one of the 3 treatment arms (aliskiren/enalapril combination therapy, aliskiren monotherapy, or enalapril monotherapy).
    Arm/Group Title Combination Aliskiren / Enalapril Aliskiren Enalapril
    Arm/Group Description Aliskiren / Enalapril combination therapy-150 mg/10 mg titrated to 300 mg/ 10 mg film-coated tablets and administered orally. Aliskiren monotherapy - 150 mg titrated to 300 mg film-coated tablets and administered orally. Enalapril monotherapy -10 mg film-coated tablet and administered orally.
    Period Title: Overall Study
    STARTED 2354 2356 2354
    Full Analysis Set (FAS) 2340 2340 2336
    Safety Set 2347 2348 2345
    COMPLETED 1567 1524 1539
    NOT COMPLETED 787 832 815

    Baseline Characteristics

    Arm/Group Title Combination Aliskiren / Enalapril Aliskiren Enalapril Total
    Arm/Group Description Aliskiren / Enalapril combination therapy-150 mg/10 mg titrated to 300 mg/ 10 mg film-coated tablets and administered orally. Aliskiren monotherapy - 150 mg titrated to 300 mg film-coated tablets and administered orally. Enalapril monotherapy -10 mg film-coated tablet and administered orally. Total of all reporting groups
    Overall Participants 2340 2340 2336 7016
    Age (years) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [years]
    63.2
    (11.65)
    63.3
    (12.06)
    63.3
    (11.71)
    63.2
    (11.81)
    Sex: Female, Male (Count of Participants)
    Female
    494
    21.1%
    532
    22.7%
    499
    21.4%
    1525
    21.7%
    Male
    1846
    78.9%
    1808
    77.3%
    1837
    78.6%
    5491
    78.3%

    Outcome Measures

    1. Primary Outcome
    Title Number of Participants That Had First Occurrence of the Composite Endpoint, Which is Defined as Either Cardiovascular (CV) Death or Heart Failure (HF) Hospitalization
    Description Number of participants that had first occurrence of the composite endpoint, which is defined as either CV death or HF hospitalization due to HF.
    Time Frame up to End of Study (78 months)

    Outcome Measure Data

    Analysis Population Description
    Full Analysis Set (FAS) - All randomized patients with exception of mis-randomized patients that took no study drug and patients from the sites with major GCP violations.
    Arm/Group Title Combination Aliskiren / Enalapril Aliskiren Enalapril
    Arm/Group Description Aliskiren / Enalapril combination therapy-150 mg/10 mg titrated to 300 mg/ 10 mg film-coated tablets and administered orally. Aliskiren monotherapy - 150 mg titrated to 300 mg film-coated tablets and administered orally. Enalapril monotherapy -10 mg film-coated tablet and administered orally.
    Measure Participants 2340 2340 2336
    Primary Composite
    770
    32.9%
    791
    33.8%
    808
    34.6%
    CV death
    512
    21.9%
    562
    24%
    547
    23.4%
    1st HF Hospitalization
    430
    18.4%
    442
    18.9%
    452
    19.3%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Combination Aliskiren / Enalapril, Enalapril
    Comments (superiority)
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value 0.1724
    Comments
    Method Regression, Cox
    Comments
    Method of Estimation Estimation Parameter Hazard Ratio (HR)
    Estimated Value 0.93
    Confidence Interval (2-Sided) 95%
    0.85 to 1.03
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Combination Aliskiren / Enalapril, Enalapril
    Comments (superiority) Non-Diabetic patients
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value 0.4579
    Comments
    Method Regression, Cox
    Comments
    Method of Estimation Estimation Parameter Hazard Ratio (HR)
    Estimated Value 0.96
    Confidence Interval (2-Sided) 95%
    0.85 to 1.07
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 3
    Statistical Analysis Overview Comparison Group Selection Aliskiren, Enalapril
    Comments
    Type of Statistical Test Non-Inferiority or Equivalence
    Comments Pre-specified Non-inferiority margin 1.104 is used.
    Statistical Test of Hypothesis p-Value 0.0368
    Comments
    Method Regression, Cox
    Comments
    Method of Estimation Estimation Parameter Hazard Ratio (HR)
    Estimated Value 0.99
    Confidence Interval (2-Sided) 95%
    0.90 to 1.10
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 4
    Statistical Analysis Overview Comparison Group Selection Aliskiren, Enalapril
    Comments (superiority)
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value 0.9118
    Comments
    Method Regression, Cox
    Comments
    Method of Estimation Estimation Parameter Hazard Ratio (HR)
    Estimated Value 0.99
    Confidence Interval (2-Sided) 95%
    0.90 to 1.10
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    2. Secondary Outcome
    Title Change From Baseline to Month 12 for the Kansas City Cardiomyopathy Questionnaire (KCCQ) Clinical Summary Score
    Description Change from baseline to Month 12 for the Kansas City Cardiomyopathy Questionnaire (KCCQ) clinical summary score. 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. KCCQ clinical summary score is a composite assessment of physical limitations and total symptom scores. Scores are transformed to a range of 0-100, in which higher scores reflect better health status.
    Time Frame Baseline, Month 12

    Outcome Measure Data

    Analysis Population Description
    Full Analysis Set (FAS) - All randomized patients with exception of mis-randomized patients that took no study drug and patients from the sites with major GCP violations.
    Arm/Group Title Combination Aliskiren / Enalapril Aliskiren Enalapril
    Arm/Group Description Aliskiren / Enalapril combination therapy-150 mg/10 mg titrated to 300 mg/ 10 mg film-coated tablets and administered orally. Aliskiren monotherapy - 150 mg titrated to 300 mg film-coated tablets and administered orally. Enalapril monotherapy -10 mg film-coated tablet and administered orally.
    Measure Participants 2340 2340 2336
    Least Squares Mean (Standard Error) [KCCQ Score]
    -5.04
    (0.56)
    -6.03
    (0.57)
    -5.01
    (0.55)
    3. Secondary Outcome
    Title All Cause Death
    Description Number of patients - All-cause death. All-cause death is common in Heart Failure HF patients this measures how many patients had this event.
    Time Frame up to end of study (78 months)

    Outcome Measure Data

    Analysis Population Description
    Full Analysis Set (FAS) - All randomized patients with exception of mis-randomized patients that took no study drug and patients from the sites with major GCP violations
    Arm/Group Title Combination Aliskiren / Enalapril Aliskiren Enalapril
    Arm/Group Description Aliskiren / Enalapril combination therapy-150 mg/10 mg titrated to 300 mg/ 10 mg film-coated tablets and administered orally. Aliskiren monotherapy - 150 mg titrated to 300 mg film-coated tablets and administered orally. Enalapril monotherapy -10 mg film-coated tablet and administered orally.
    Measure Participants 2340 2340 2336
    Number [participants]
    595
    25.4%
    654
    27.9%
    646
    27.7%

    Adverse Events

    Time Frame
    Adverse Event Reporting Description Safety set (SAF) (double-blind phase) - All patients who received at least one dose of double-blind study drug. Patients were analyzed according to treatment received. Treatment received was considered identical to the randomized treatment if the patient had received at least one dose of the randomized treatment.
    Arm/Group Title Combination of Aliskiren and Enalapril Aliskiren Enalapril
    Arm/Group Description Aliskiren/Enalapril combination therapy-150 mg/10 mg titrated to 300 mg/ 10 mg Aliskiren monotherapy - 150 mg titrated to 300 mg film-coated tablets and administered orally. Enalapril monotherapy -10 mg film-coated tablet and administered orally.
    All Cause Mortality
    Combination of Aliskiren and Enalapril Aliskiren Enalapril
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total / (NaN) / (NaN) / (NaN)
    Serious Adverse Events
    Combination of Aliskiren and Enalapril Aliskiren Enalapril
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 1466/2347 (62.5%) 1504/2348 (64.1%) 1501/2345 (64%)
    Blood and lymphatic system disorders
    Acquired haemophilia 0/2347 (0%) 0/2348 (0%) 1/2345 (0%)
    Anaemia 36/2347 (1.5%) 28/2348 (1.2%) 28/2345 (1.2%)
    Anaemia vitamin B12 deficiency 1/2347 (0%) 0/2348 (0%) 0/2345 (0%)
    Aplastic anaemia 0/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Bicytopenia 0/2347 (0%) 0/2348 (0%) 1/2345 (0%)
    Bone marrow infiltration 0/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Coagulopathy 1/2347 (0%) 0/2348 (0%) 0/2345 (0%)
    Disseminated intravascular coagulation 0/2347 (0%) 0/2348 (0%) 2/2345 (0.1%)
    Febrile neutropenia 0/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Haemolytic anaemia 1/2347 (0%) 0/2348 (0%) 0/2345 (0%)
    Haemorrhagic anaemia 0/2347 (0%) 2/2348 (0.1%) 0/2345 (0%)
    Haemorrhagic diathesis 0/2347 (0%) 0/2348 (0%) 1/2345 (0%)
    Hypochromic anaemia 0/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Hypocoagulable state 1/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Iron deficiency anaemia 1/2347 (0%) 0/2348 (0%) 3/2345 (0.1%)
    Jaundice acholuric 0/2347 (0%) 0/2348 (0%) 1/2345 (0%)
    Leukocytosis 1/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Leukopenia 1/2347 (0%) 0/2348 (0%) 0/2345 (0%)
    Lymphadenitis 0/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Lymphadenopathy mediastinal 0/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Microcytic anaemia 0/2347 (0%) 0/2348 (0%) 1/2345 (0%)
    Normochromic normocytic anaemia 0/2347 (0%) 0/2348 (0%) 1/2345 (0%)
    Pancytopenia 4/2347 (0.2%) 2/2348 (0.1%) 0/2345 (0%)
    Polycythaemia 0/2347 (0%) 1/2348 (0%) 1/2345 (0%)
    Retroperitoneal lymphadenopathy 0/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Splenic embolism 1/2347 (0%) 0/2348 (0%) 0/2345 (0%)
    Splenic infarction 0/2347 (0%) 2/2348 (0.1%) 0/2345 (0%)
    Splenic vein thrombosis 0/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Thrombocytopenia 3/2347 (0.1%) 1/2348 (0%) 3/2345 (0.1%)
    Cardiac disorders
    Acute coronary syndrome 6/2347 (0.3%) 18/2348 (0.8%) 16/2345 (0.7%)
    Acute left ventricular failure 3/2347 (0.1%) 5/2348 (0.2%) 9/2345 (0.4%)
    Acute myocardial infarction 49/2347 (2.1%) 40/2348 (1.7%) 46/2345 (2%)
    Adams-Stokes syndrome 1/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Angina pectoris 35/2347 (1.5%) 33/2348 (1.4%) 37/2345 (1.6%)
    Angina unstable 47/2347 (2%) 48/2348 (2%) 41/2345 (1.7%)
    Aortic valve disease 0/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Aortic valve incompetence 3/2347 (0.1%) 1/2348 (0%) 3/2345 (0.1%)
    Aortic valve stenosis 3/2347 (0.1%) 3/2348 (0.1%) 1/2345 (0%)
    Arrhythmia 13/2347 (0.6%) 15/2348 (0.6%) 12/2345 (0.5%)
    Arrhythmia supraventricular 0/2347 (0%) 2/2348 (0.1%) 1/2345 (0%)
    Arteriosclerosis coronary artery 4/2347 (0.2%) 0/2348 (0%) 2/2345 (0.1%)
    Atrial fibrillation 89/2347 (3.8%) 98/2348 (4.2%) 97/2345 (4.1%)
    Atrial flutter 15/2347 (0.6%) 21/2348 (0.9%) 11/2345 (0.5%)
    Atrial tachycardia 1/2347 (0%) 4/2348 (0.2%) 2/2345 (0.1%)
    Atrial thrombosis 0/2347 (0%) 1/2348 (0%) 2/2345 (0.1%)
    Atrioventricular block 1/2347 (0%) 1/2348 (0%) 3/2345 (0.1%)
    Atrioventricular block complete 7/2347 (0.3%) 8/2348 (0.3%) 13/2345 (0.6%)
    Atrioventricular block first degree 0/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Atrioventricular block second degree 3/2347 (0.1%) 4/2348 (0.2%) 6/2345 (0.3%)
    Bifascicular block 1/2347 (0%) 0/2348 (0%) 0/2345 (0%)
    Bradyarrhythmia 1/2347 (0%) 3/2348 (0.1%) 2/2345 (0.1%)
    Bradycardia 12/2347 (0.5%) 12/2348 (0.5%) 9/2345 (0.4%)
    Bundle branch block 0/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Bundle branch block left 4/2347 (0.2%) 4/2348 (0.2%) 3/2345 (0.1%)
    Cardiac aneurysm 1/2347 (0%) 0/2348 (0%) 0/2345 (0%)
    Cardiac arrest 59/2347 (2.5%) 61/2348 (2.6%) 59/2345 (2.5%)
    Cardiac asthma 2/2347 (0.1%) 4/2348 (0.2%) 1/2345 (0%)
    Cardiac discomfort 3/2347 (0.1%) 3/2348 (0.1%) 0/2345 (0%)
    Cardiac disorder 1/2347 (0%) 0/2348 (0%) 0/2345 (0%)
    Cardiac failure 480/2347 (20.5%) 521/2348 (22.2%) 503/2345 (21.4%)
    Cardiac failure acute 54/2347 (2.3%) 43/2348 (1.8%) 60/2345 (2.6%)
    Cardiac failure chronic 120/2347 (5.1%) 125/2348 (5.3%) 122/2345 (5.2%)
    Cardiac failure congestive 76/2347 (3.2%) 85/2348 (3.6%) 79/2345 (3.4%)
    Cardiac flutter 0/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Cardiac hypertrophy 0/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Cardiac perforation 0/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Cardiac sarcoidosis 0/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Cardiac tamponade 0/2347 (0%) 1/2348 (0%) 2/2345 (0.1%)
    Cardiac valve disease 1/2347 (0%) 0/2348 (0%) 0/2345 (0%)
    Cardiac ventricular thrombosis 0/2347 (0%) 1/2348 (0%) 1/2345 (0%)
    Cardio-respiratory arrest 24/2347 (1%) 24/2348 (1%) 20/2345 (0.9%)
    Cardiogenic shock 31/2347 (1.3%) 49/2348 (2.1%) 38/2345 (1.6%)
    Cardiomegaly 0/2347 (0%) 2/2348 (0.1%) 0/2345 (0%)
    Cardiomyopathy 2/2347 (0.1%) 2/2348 (0.1%) 4/2345 (0.2%)
    Cardiopulmonary failure 4/2347 (0.2%) 6/2348 (0.3%) 2/2345 (0.1%)
    Cardiorenal syndrome 2/2347 (0.1%) 0/2348 (0%) 1/2345 (0%)
    Cardiovascular disorder 0/2347 (0%) 0/2348 (0%) 2/2345 (0.1%)
    Cardiovascular insufficiency 0/2347 (0%) 1/2348 (0%) 1/2345 (0%)
    Chordae tendinae rupture 0/2347 (0%) 0/2348 (0%) 1/2345 (0%)
    Chronotropic incompetence 0/2347 (0%) 1/2348 (0%) 1/2345 (0%)
    Congestive cardiomyopathy 14/2347 (0.6%) 14/2348 (0.6%) 19/2345 (0.8%)
    Coronary artery disease 28/2347 (1.2%) 27/2348 (1.1%) 22/2345 (0.9%)
    Coronary artery insufficiency 0/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Coronary artery occlusion 0/2347 (0%) 2/2348 (0.1%) 1/2345 (0%)
    Coronary artery stenosis 8/2347 (0.3%) 5/2348 (0.2%) 8/2345 (0.3%)
    Coronary artery thrombosis 0/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Extrasystoles 1/2347 (0%) 0/2348 (0%) 0/2345 (0%)
    Heart valve incompetence 0/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Hypertensive heart disease 0/2347 (0%) 2/2348 (0.1%) 1/2345 (0%)
    Ischaemic cardiomyopathy 13/2347 (0.6%) 7/2348 (0.3%) 13/2345 (0.6%)
    Left ventricular dysfunction 6/2347 (0.3%) 6/2348 (0.3%) 8/2345 (0.3%)
    Left ventricular failure 6/2347 (0.3%) 5/2348 (0.2%) 6/2345 (0.3%)
    Metabolic cardiomyopathy 1/2347 (0%) 0/2348 (0%) 0/2345 (0%)
    Mitral valve incompetence 6/2347 (0.3%) 17/2348 (0.7%) 14/2345 (0.6%)
    Mitral valve prolapse 0/2347 (0%) 0/2348 (0%) 1/2345 (0%)
    Mitral valve stenosis 0/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Myocardial infarction 56/2347 (2.4%) 50/2348 (2.1%) 50/2345 (2.1%)
    Myocardial ischaemia 19/2347 (0.8%) 19/2348 (0.8%) 18/2345 (0.8%)
    Nodal rhythm 1/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Palpitations 2/2347 (0.1%) 1/2348 (0%) 1/2345 (0%)
    Papillary muscle rupture 0/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Pericardial effusion 0/2347 (0%) 3/2348 (0.1%) 2/2345 (0.1%)
    Pericarditis 1/2347 (0%) 0/2348 (0%) 1/2345 (0%)
    Pulmonary valve incompetence 0/2347 (0%) 0/2348 (0%) 1/2345 (0%)
    Pulseless electrical activity 1/2347 (0%) 1/2348 (0%) 3/2345 (0.1%)
    Restrictive cardiomyopathy 0/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Rhythm idioventricular 1/2347 (0%) 0/2348 (0%) 0/2345 (0%)
    Right ventricular failure 2/2347 (0.1%) 1/2348 (0%) 2/2345 (0.1%)
    Sinoatrial block 1/2347 (0%) 0/2348 (0%) 1/2345 (0%)
    Sinus arrhythmia 0/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Sinus bradycardia 0/2347 (0%) 0/2348 (0%) 1/2345 (0%)
    Sinus node dysfunction 6/2347 (0.3%) 3/2348 (0.1%) 5/2345 (0.2%)
    Supraventricular extrasystoles 0/2347 (0%) 0/2348 (0%) 1/2345 (0%)
    Supraventricular tachyarrhythmia 2/2347 (0.1%) 0/2348 (0%) 0/2345 (0%)
    Supraventricular tachycardia 7/2347 (0.3%) 5/2348 (0.2%) 3/2345 (0.1%)
    Systolic dysfunction 1/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Tachyarrhythmia 0/2347 (0%) 2/2348 (0.1%) 0/2345 (0%)
    Tachycardia 9/2347 (0.4%) 5/2348 (0.2%) 4/2345 (0.2%)
    Tachycardia paroxysmal 0/2347 (0%) 0/2348 (0%) 1/2345 (0%)
    Tricuspid valve disease 0/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Tricuspid valve incompetence 1/2347 (0%) 3/2348 (0.1%) 2/2345 (0.1%)
    Ventricular arrhythmia 14/2347 (0.6%) 8/2348 (0.3%) 14/2345 (0.6%)
    Ventricular dysfunction 0/2347 (0%) 2/2348 (0.1%) 2/2345 (0.1%)
    Ventricular dyssynchrony 2/2347 (0.1%) 0/2348 (0%) 0/2345 (0%)
    Ventricular extrasystoles 8/2347 (0.3%) 9/2348 (0.4%) 3/2345 (0.1%)
    Ventricular failure 1/2347 (0%) 0/2348 (0%) 0/2345 (0%)
    Ventricular fibrillation 32/2347 (1.4%) 30/2348 (1.3%) 34/2345 (1.4%)
    Ventricular flutter 2/2347 (0.1%) 2/2348 (0.1%) 0/2345 (0%)
    Ventricular tachyarrhythmia 2/2347 (0.1%) 0/2348 (0%) 1/2345 (0%)
    Ventricular tachycardia 78/2347 (3.3%) 67/2348 (2.9%) 63/2345 (2.7%)
    Congenital, familial and genetic disorders
    Atrial septal defect 0/2347 (0%) 0/2348 (0%) 1/2345 (0%)
    Dermoid cyst 1/2347 (0%) 0/2348 (0%) 0/2345 (0%)
    Hydrocele 0/2347 (0%) 1/2348 (0%) 3/2345 (0.1%)
    Ear and labyrinth disorders
    Deafness neurosensory 0/2347 (0%) 0/2348 (0%) 1/2345 (0%)
    Deafness unilateral 1/2347 (0%) 1/2348 (0%) 1/2345 (0%)
    Haematotympanum 1/2347 (0%) 0/2348 (0%) 0/2345 (0%)
    Meniere's disease 0/2347 (0%) 0/2348 (0%) 1/2345 (0%)
    Sudden hearing loss 1/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Tympanic membrane perforation 1/2347 (0%) 0/2348 (0%) 0/2345 (0%)
    Vertigo 2/2347 (0.1%) 3/2348 (0.1%) 2/2345 (0.1%)
    Vertigo positional 0/2347 (0%) 0/2348 (0%) 1/2345 (0%)
    Endocrine disorders
    Goitre 2/2347 (0.1%) 1/2348 (0%) 0/2345 (0%)
    Hyperthyroidism 2/2347 (0.1%) 5/2348 (0.2%) 2/2345 (0.1%)
    Hypothyroidism 2/2347 (0.1%) 7/2348 (0.3%) 2/2345 (0.1%)
    Thyrotoxic crisis 1/2347 (0%) 0/2348 (0%) 0/2345 (0%)
    Toxic nodular goitre 0/2347 (0%) 0/2348 (0%) 1/2345 (0%)
    Eye disorders
    Amaurosis fugax 1/2347 (0%) 0/2348 (0%) 0/2345 (0%)
    Amblyopia 0/2347 (0%) 0/2348 (0%) 1/2345 (0%)
    Cataract 13/2347 (0.6%) 8/2348 (0.3%) 6/2345 (0.3%)
    Conjunctival haemorrhage 1/2347 (0%) 0/2348 (0%) 1/2345 (0%)
    Diabetic retinopathy 0/2347 (0%) 1/2348 (0%) 1/2345 (0%)
    Glaucoma 0/2347 (0%) 1/2348 (0%) 1/2345 (0%)
    Macular hole 0/2347 (0%) 1/2348 (0%) 1/2345 (0%)
    Ocular fistula 0/2347 (0%) 0/2348 (0%) 1/2345 (0%)
    Ocular retrobulbar haemorrhage 1/2347 (0%) 0/2348 (0%) 0/2345 (0%)
    Ophthalmic vein thrombosis 0/2347 (0%) 0/2348 (0%) 1/2345 (0%)
    Retinal artery embolism 1/2347 (0%) 0/2348 (0%) 0/2345 (0%)
    Retinal artery occlusion 0/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Retinal degeneration 1/2347 (0%) 0/2348 (0%) 0/2345 (0%)
    Retinal detachment 0/2347 (0%) 0/2348 (0%) 2/2345 (0.1%)
    Retinal haemorrhage 0/2347 (0%) 0/2348 (0%) 1/2345 (0%)
    Retinal vein occlusion 0/2347 (0%) 0/2348 (0%) 1/2345 (0%)
    Retinopathy 0/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Visual acuity reduced 0/2347 (0%) 0/2348 (0%) 1/2345 (0%)
    Vitreous haemorrhage 0/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Gastrointestinal disorders
    Abdominal adhesions 1/2347 (0%) 0/2348 (0%) 0/2345 (0%)
    Abdominal discomfort 1/2347 (0%) 2/2348 (0.1%) 0/2345 (0%)
    Abdominal distension 0/2347 (0%) 0/2348 (0%) 2/2345 (0.1%)
    Abdominal hernia 3/2347 (0.1%) 1/2348 (0%) 0/2345 (0%)
    Abdominal pain 14/2347 (0.6%) 10/2348 (0.4%) 11/2345 (0.5%)
    Abdominal pain lower 2/2347 (0.1%) 0/2348 (0%) 0/2345 (0%)
    Abdominal pain upper 4/2347 (0.2%) 5/2348 (0.2%) 4/2345 (0.2%)
    Abdominal strangulated hernia 0/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Abdominal wall haematoma 1/2347 (0%) 0/2348 (0%) 0/2345 (0%)
    Acid peptic disease 0/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Acute abdomen 1/2347 (0%) 1/2348 (0%) 1/2345 (0%)
    Alcoholic pancreatitis 0/2347 (0%) 2/2348 (0.1%) 0/2345 (0%)
    Anal fissure 0/2347 (0%) 1/2348 (0%) 1/2345 (0%)
    Anal fistula 0/2347 (0%) 0/2348 (0%) 1/2345 (0%)
    Anal prolapse 1/2347 (0%) 0/2348 (0%) 0/2345 (0%)
    Ascites 6/2347 (0.3%) 6/2348 (0.3%) 6/2345 (0.3%)
    Autoimmune pancreatitis 1/2347 (0%) 0/2348 (0%) 0/2345 (0%)
    Chronic gastritis 0/2347 (0%) 1/2348 (0%) 1/2345 (0%)
    Colitis 1/2347 (0%) 1/2348 (0%) 3/2345 (0.1%)
    Colitis ischaemic 0/2347 (0%) 0/2348 (0%) 2/2345 (0.1%)
    Colitis ulcerative 0/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Constipation 6/2347 (0.3%) 5/2348 (0.2%) 2/2345 (0.1%)
    Crohn's disease 0/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Dental caries 0/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Diabetic gastroparesis 0/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Diarrhoea 18/2347 (0.8%) 4/2348 (0.2%) 11/2345 (0.5%)
    Dieulafoy's vascular malformation 0/2347 (0%) 0/2348 (0%) 1/2345 (0%)
    Diverticular perforation 0/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Diverticulum 1/2347 (0%) 0/2348 (0%) 1/2345 (0%)
    Diverticulum intestinal 0/2347 (0%) 2/2348 (0.1%) 1/2345 (0%)
    Diverticulum intestinal haemorrhagic 0/2347 (0%) 0/2348 (0%) 1/2345 (0%)
    Duodenal ulcer 1/2347 (0%) 2/2348 (0.1%) 5/2345 (0.2%)
    Duodenal ulcer haemorrhage 3/2347 (0.1%) 0/2348 (0%) 1/2345 (0%)
    Duodenal ulcer perforation 0/2347 (0%) 0/2348 (0%) 2/2345 (0.1%)
    Duodenitis 0/2347 (0%) 1/2348 (0%) 1/2345 (0%)
    Dyspepsia 4/2347 (0.2%) 2/2348 (0.1%) 0/2345 (0%)
    Dysphagia 3/2347 (0.1%) 0/2348 (0%) 1/2345 (0%)
    Enteritis 1/2347 (0%) 0/2348 (0%) 1/2345 (0%)
    Enterocolitis 3/2347 (0.1%) 1/2348 (0%) 0/2345 (0%)
    Enterovesical fistula 1/2347 (0%) 0/2348 (0%) 0/2345 (0%)
    Eosinophilic oesophagitis 1/2347 (0%) 0/2348 (0%) 0/2345 (0%)
    Epigastric discomfort 0/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Erosive duodenitis 1/2347 (0%) 0/2348 (0%) 0/2345 (0%)
    Erosive oesophagitis 0/2347 (0%) 0/2348 (0%) 2/2345 (0.1%)
    Faecaloma 1/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Femoral hernia 0/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Femoral hernia, obstructive 1/2347 (0%) 0/2348 (0%) 0/2345 (0%)
    Gastric haemorrhage 0/2347 (0%) 2/2348 (0.1%) 3/2345 (0.1%)
    Gastric polyps 1/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Gastric ulcer 7/2347 (0.3%) 4/2348 (0.2%) 8/2345 (0.3%)
    Gastric ulcer haemorrhage 6/2347 (0.3%) 2/2348 (0.1%) 5/2345 (0.2%)
    Gastric ulcer perforation 1/2347 (0%) 0/2348 (0%) 0/2345 (0%)
    Gastritis 10/2347 (0.4%) 4/2348 (0.2%) 4/2345 (0.2%)
    Gastritis erosive 1/2347 (0%) 1/2348 (0%) 3/2345 (0.1%)
    Gastritis haemorrhagic 2/2347 (0.1%) 0/2348 (0%) 1/2345 (0%)
    Gastroduodenal ulcer 0/2347 (0%) 0/2348 (0%) 1/2345 (0%)
    Gastrointestinal angiodysplasia 1/2347 (0%) 0/2348 (0%) 1/2345 (0%)
    Gastrointestinal haemorrhage 19/2347 (0.8%) 13/2348 (0.6%) 11/2345 (0.5%)
    Gastrointestinal inflammation 0/2347 (0%) 0/2348 (0%) 1/2345 (0%)
    Gastrointestinal ischaemia 1/2347 (0%) 0/2348 (0%) 0/2345 (0%)
    Gastrointestinal necrosis 0/2347 (0%) 0/2348 (0%) 4/2345 (0.2%)
    Gastrointestinal polyp haemorrhage 0/2347 (0%) 0/2348 (0%) 2/2345 (0.1%)
    Gastrointestinal ulcer 0/2347 (0%) 0/2348 (0%) 1/2345 (0%)
    Gastrooesophageal reflux disease 2/2347 (0.1%) 2/2348 (0.1%) 4/2345 (0.2%)
    Gingival bleeding 0/2347 (0%) 0/2348 (0%) 1/2345 (0%)
    Haematemesis 1/2347 (0%) 0/2348 (0%) 2/2345 (0.1%)
    Haematochezia 2/2347 (0.1%) 0/2348 (0%) 1/2345 (0%)
    Haemorrhagic erosive gastritis 0/2347 (0%) 0/2348 (0%) 1/2345 (0%)
    Haemorrhoidal haemorrhage 1/2347 (0%) 4/2348 (0.2%) 1/2345 (0%)
    Haemorrhoids 0/2347 (0%) 5/2348 (0.2%) 2/2345 (0.1%)
    Hiatus hernia 0/2347 (0%) 2/2348 (0.1%) 0/2345 (0%)
    Ileus 4/2347 (0.2%) 3/2348 (0.1%) 2/2345 (0.1%)
    Ileus paralytic 0/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Incarcerated inguinal hernia 2/2347 (0.1%) 2/2348 (0.1%) 0/2345 (0%)
    Incarcerated umbilical hernia 1/2347 (0%) 2/2348 (0.1%) 0/2345 (0%)
    Inguinal hernia 23/2347 (1%) 21/2348 (0.9%) 14/2345 (0.6%)
    Intestinal fistula 0/2347 (0%) 0/2348 (0%) 1/2345 (0%)
    Intestinal haemorrhage 1/2347 (0%) 2/2348 (0.1%) 0/2345 (0%)
    Intestinal infarction 0/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Intestinal ischaemia 0/2347 (0%) 1/2348 (0%) 4/2345 (0.2%)
    Intestinal obstruction 2/2347 (0.1%) 3/2348 (0.1%) 3/2345 (0.1%)
    Intestinal perforation 0/2347 (0%) 2/2348 (0.1%) 0/2345 (0%)
    Intestinal polyp 0/2347 (0%) 1/2348 (0%) 3/2345 (0.1%)
    Intestinal strangulation 1/2347 (0%) 0/2348 (0%) 0/2345 (0%)
    Irritable bowel syndrome 0/2347 (0%) 1/2348 (0%) 2/2345 (0.1%)
    Large intestinal stenosis 0/2347 (0%) 0/2348 (0%) 1/2345 (0%)
    Large intestine perforation 0/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Large intestine polyp 2/2347 (0.1%) 5/2348 (0.2%) 2/2345 (0.1%)
    Lower gastrointestinal haemorrhage 0/2347 (0%) 1/2348 (0%) 4/2345 (0.2%)
    Mallory-Weiss syndrome 1/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Melaena 3/2347 (0.1%) 4/2348 (0.2%) 4/2345 (0.2%)
    Mesenteric artery embolism 1/2347 (0%) 0/2348 (0%) 0/2345 (0%)
    Mesenteric artery thrombosis 2/2347 (0.1%) 0/2348 (0%) 0/2345 (0%)
    Mesenteritis 1/2347 (0%) 0/2348 (0%) 0/2345 (0%)
    Mouth haemorrhage 1/2347 (0%) 0/2348 (0%) 0/2345 (0%)
    Nausea 5/2347 (0.2%) 4/2348 (0.2%) 3/2345 (0.1%)
    Obstruction gastric 0/2347 (0%) 0/2348 (0%) 1/2345 (0%)
    Oedematous pancreatitis 1/2347 (0%) 0/2348 (0%) 0/2345 (0%)
    Oesophageal haemorrhage 0/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Oesophageal ulcer 1/2347 (0%) 2/2348 (0.1%) 2/2345 (0.1%)
    Oesophageal ulcer haemorrhage 0/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Oesophagitis 0/2347 (0%) 1/2348 (0%) 1/2345 (0%)
    Oesophagitis haemorrhagic 0/2347 (0%) 0/2348 (0%) 1/2345 (0%)
    Pancreatic cyst 1/2347 (0%) 0/2348 (0%) 1/2345 (0%)
    Pancreatitis 5/2347 (0.2%) 4/2348 (0.2%) 2/2345 (0.1%)
    Pancreatitis acute 9/2347 (0.4%) 5/2348 (0.2%) 5/2345 (0.2%)
    Pancreatitis chronic 1/2347 (0%) 0/2348 (0%) 0/2345 (0%)
    Pancreatitis necrotising 0/2347 (0%) 0/2348 (0%) 1/2345 (0%)
    Peptic ulcer 0/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Peptic ulcer haemorrhage 0/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Peptic ulcer perforation 0/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Pharyngo-oesophageal diverticulum 0/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Portal hypertensive gastropathy 0/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Proctalgia 0/2347 (0%) 0/2348 (0%) 1/2345 (0%)
    Proctitis 1/2347 (0%) 0/2348 (0%) 0/2345 (0%)
    Rectal haemorrhage 7/2347 (0.3%) 5/2348 (0.2%) 3/2345 (0.1%)
    Rectal polyp 1/2347 (0%) 1/2348 (0%) 1/2345 (0%)
    Rectal prolapse 0/2347 (0%) 0/2348 (0%) 1/2345 (0%)
    Small intestinal obstruction 0/2347 (0%) 1/2348 (0%) 1/2345 (0%)
    Stress ulcer 0/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Subileus 1/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Thrombosis mesenteric vessel 0/2347 (0%) 0/2348 (0%) 1/2345 (0%)
    Tongue oedema 1/2347 (0%) 0/2348 (0%) 0/2345 (0%)
    Tooth disorder 1/2347 (0%) 0/2348 (0%) 0/2345 (0%)
    Umbilical hernia 5/2347 (0.2%) 5/2348 (0.2%) 1/2345 (0%)
    Upper gastrointestinal haemorrhage 6/2347 (0.3%) 12/2348 (0.5%) 7/2345 (0.3%)
    Visceral congestion 0/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Volvulus 0/2347 (0%) 1/2348 (0%) 1/2345 (0%)
    Volvulus of small bowel 0/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Vomiting 5/2347 (0.2%) 5/2348 (0.2%) 4/2345 (0.2%)
    General disorders
    Abasia 0/2347 (0%) 2/2348 (0.1%) 0/2345 (0%)
    Accidental death 0/2347 (0%) 1/2348 (0%) 1/2345 (0%)
    Asthenia 8/2347 (0.3%) 5/2348 (0.2%) 4/2345 (0.2%)
    Brain death 0/2347 (0%) 0/2348 (0%) 1/2345 (0%)
    Cardiac complication associated with device 2/2347 (0.1%) 1/2348 (0%) 0/2345 (0%)
    Cardiac death 51/2347 (2.2%) 68/2348 (2.9%) 87/2345 (3.7%)
    Chest discomfort 2/2347 (0.1%) 0/2348 (0%) 0/2345 (0%)
    Chest pain 2/2347 (0.1%) 3/2348 (0.1%) 1/2345 (0%)
    Death 75/2347 (3.2%) 84/2348 (3.6%) 82/2345 (3.5%)
    Device battery issue 13/2347 (0.6%) 9/2348 (0.4%) 14/2345 (0.6%)
    Device breakage 1/2347 (0%) 0/2348 (0%) 1/2345 (0%)
    Device defective 0/2347 (0%) 0/2348 (0%) 1/2345 (0%)
    Device dislocation 1/2347 (0%) 4/2348 (0.2%) 2/2345 (0.1%)
    Device electrical impedance issue 2/2347 (0.1%) 0/2348 (0%) 0/2345 (0%)
    Device end of service 0/2347 (0%) 0/2348 (0%) 2/2345 (0.1%)
    Device failure 4/2347 (0.2%) 0/2348 (0%) 0/2345 (0%)
    Device inappropriate shock delivery 1/2347 (0%) 4/2348 (0.2%) 3/2345 (0.1%)
    Device issue 1/2347 (0%) 0/2348 (0%) 1/2345 (0%)
    Device lead damage 1/2347 (0%) 3/2348 (0.1%) 2/2345 (0.1%)
    Device lead issue 1/2347 (0%) 1/2348 (0%) 2/2345 (0.1%)
    Device malfunction 7/2347 (0.3%) 10/2348 (0.4%) 9/2345 (0.4%)
    Device signal detection issue 0/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Device stimulation issue 0/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Disease progression 1/2347 (0%) 0/2348 (0%) 0/2345 (0%)
    Drug withdrawal syndrome 0/2347 (0%) 0/2348 (0%) 1/2345 (0%)
    Exercise tolerance decreased 0/2347 (0%) 0/2348 (0%) 1/2345 (0%)
    Fatigue 5/2347 (0.2%) 1/2348 (0%) 2/2345 (0.1%)
    Feeling abnormal 1/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Gait disturbance 0/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    General physical health deterioration 3/2347 (0.1%) 3/2348 (0.1%) 7/2345 (0.3%)
    Generalised oedema 2/2347 (0.1%) 2/2348 (0.1%) 2/2345 (0.1%)
    Hernia 0/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Hypothermia 1/2347 (0%) 0/2348 (0%) 0/2345 (0%)
    Ill-defined disorder 0/2347 (0%) 0/2348 (0%) 1/2345 (0%)
    Impaired healing 0/2347 (0%) 1/2348 (0%) 1/2345 (0%)
    Implant site erosion 0/2347 (0%) 0/2348 (0%) 1/2345 (0%)
    Implant site haemorrhage 1/2347 (0%) 0/2348 (0%) 0/2345 (0%)
    Implant site necrosis 0/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Implant site pain 0/2347 (0%) 0/2348 (0%) 1/2345 (0%)
    Implant site ulcer 1/2347 (0%) 0/2348 (0%) 0/2345 (0%)
    Incarcerated hernia 1/2347 (0%) 0/2348 (0%) 0/2345 (0%)
    Inflammation 0/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Influenza like illness 1/2347 (0%) 0/2348 (0%) 0/2345 (0%)
    Injury associated with device 0/2347 (0%) 0/2348 (0%) 1/2345 (0%)
    Lead dislodgement 1/2347 (0%) 1/2348 (0%) 1/2345 (0%)
    Localised oedema 1/2347 (0%) 0/2348 (0%) 0/2345 (0%)
    Malaise 5/2347 (0.2%) 4/2348 (0.2%) 1/2345 (0%)
    Medical device complication 4/2347 (0.2%) 1/2348 (0%) 1/2345 (0%)
    Medical device site thrombosis 0/2347 (0%) 0/2348 (0%) 1/2345 (0%)
    Metaplasia 1/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Multi-organ failure 21/2347 (0.9%) 15/2348 (0.6%) 12/2345 (0.5%)
    Necrosis 0/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Non-cardiac chest pain 13/2347 (0.6%) 15/2348 (0.6%) 22/2345 (0.9%)
    Oedema 1/2347 (0%) 0/2348 (0%) 0/2345 (0%)
    Oedema peripheral 9/2347 (0.4%) 6/2348 (0.3%) 3/2345 (0.1%)
    Organ failure 1/2347 (0%) 0/2348 (0%) 0/2345 (0%)
    Peripheral swelling 0/2347 (0%) 0/2348 (0%) 2/2345 (0.1%)
    Pyrexia 5/2347 (0.2%) 8/2348 (0.3%) 7/2345 (0.3%)
    Stent-graft endoleak 0/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Sudden cardiac death 38/2347 (1.6%) 39/2348 (1.7%) 50/2345 (2.1%)
    Sudden death 98/2347 (4.2%) 89/2348 (3.8%) 86/2345 (3.7%)
    Thrombosis in device 0/2347 (0%) 0/2348 (0%) 1/2345 (0%)
    Ulcer 1/2347 (0%) 0/2348 (0%) 0/2345 (0%)
    Ulcer haemorrhage 0/2347 (0%) 1/2348 (0%) 1/2345 (0%)
    Undersensing 0/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Vascular stent restenosis 1/2347 (0%) 0/2348 (0%) 0/2345 (0%)
    Vascular stent stenosis 0/2347 (0%) 0/2348 (0%) 1/2345 (0%)
    Vascular stent thrombosis 0/2347 (0%) 1/2348 (0%) 2/2345 (0.1%)
    Hepatobiliary disorders
    Acute hepatic failure 1/2347 (0%) 0/2348 (0%) 0/2345 (0%)
    Bile duct obstruction 0/2347 (0%) 2/2348 (0.1%) 1/2345 (0%)
    Bile duct stenosis 1/2347 (0%) 0/2348 (0%) 2/2345 (0.1%)
    Bile duct stone 3/2347 (0.1%) 3/2348 (0.1%) 0/2345 (0%)
    Biliary cirrhosis 0/2347 (0%) 0/2348 (0%) 1/2345 (0%)
    Biliary colic 0/2347 (0%) 1/2348 (0%) 1/2345 (0%)
    Biliary dilatation 0/2347 (0%) 1/2348 (0%) 1/2345 (0%)
    Cholangitis 2/2347 (0.1%) 5/2348 (0.2%) 3/2345 (0.1%)
    Cholangitis acute 2/2347 (0.1%) 2/2348 (0.1%) 1/2345 (0%)
    Cholecystitis 7/2347 (0.3%) 4/2348 (0.2%) 8/2345 (0.3%)
    Cholecystitis acute 9/2347 (0.4%) 9/2348 (0.4%) 9/2345 (0.4%)
    Cholecystitis chronic 2/2347 (0.1%) 1/2348 (0%) 2/2345 (0.1%)
    Cholelithiasis 18/2347 (0.8%) 15/2348 (0.6%) 13/2345 (0.6%)
    Cholestasis 0/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Chronic hepatitis 0/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Cirrhosis alcoholic 0/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Drug-induced liver injury 0/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Hepatic cirrhosis 3/2347 (0.1%) 2/2348 (0.1%) 6/2345 (0.3%)
    Hepatic congestion 2/2347 (0.1%) 3/2348 (0.1%) 3/2345 (0.1%)
    Hepatic failure 4/2347 (0.2%) 2/2348 (0.1%) 3/2345 (0.1%)
    Hepatic function abnormal 3/2347 (0.1%) 2/2348 (0.1%) 1/2345 (0%)
    Hepatic steatosis 0/2347 (0%) 0/2348 (0%) 1/2345 (0%)
    Hepatitis 3/2347 (0.1%) 0/2348 (0%) 1/2345 (0%)
    Hepatitis acute 1/2347 (0%) 2/2348 (0.1%) 1/2345 (0%)
    Hepatitis alcoholic 2/2347 (0.1%) 0/2348 (0%) 0/2345 (0%)
    Hepatocellular injury 0/2347 (0%) 0/2348 (0%) 1/2345 (0%)
    Hepatomegaly 0/2347 (0%) 0/2348 (0%) 1/2345 (0%)
    Hepatorenal failure 1/2347 (0%) 0/2348 (0%) 0/2345 (0%)
    Hepatorenal syndrome 1/2347 (0%) 1/2348 (0%) 3/2345 (0.1%)
    Hepatotoxicity 0/2347 (0%) 0/2348 (0%) 1/2345 (0%)
    Hyperbilirubinaemia 0/2347 (0%) 1/2348 (0%) 1/2345 (0%)
    Ischaemic hepatitis 0/2347 (0%) 1/2348 (0%) 1/2345 (0%)
    Jaundice 2/2347 (0.1%) 3/2348 (0.1%) 5/2345 (0.2%)
    Jaundice cholestatic 1/2347 (0%) 3/2348 (0.1%) 1/2345 (0%)
    Jaundice hepatocellular 1/2347 (0%) 0/2348 (0%) 0/2345 (0%)
    Liver disorder 0/2347 (0%) 1/2348 (0%) 1/2345 (0%)
    Liver injury 0/2347 (0%) 0/2348 (0%) 1/2345 (0%)
    Non-alcoholic steatohepatitis 1/2347 (0%) 0/2348 (0%) 0/2345 (0%)
    Portal hypertension 1/2347 (0%) 0/2348 (0%) 1/2345 (0%)
    Immune system disorders
    Allergy to venom 1/2347 (0%) 0/2348 (0%) 0/2345 (0%)
    Anaphylactic reaction 0/2347 (0%) 1/2348 (0%) 1/2345 (0%)
    Anaphylactic shock 0/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Drug hypersensitivity 0/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Heart transplant rejection 0/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Transplant rejection 0/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Infections and infestations
    Abdominal abscess 1/2347 (0%) 0/2348 (0%) 0/2345 (0%)
    Abdominal infection 1/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Abdominal sepsis 3/2347 (0.1%) 2/2348 (0.1%) 2/2345 (0.1%)
    Abscess intestinal 1/2347 (0%) 0/2348 (0%) 0/2345 (0%)
    Abscess jaw 1/2347 (0%) 0/2348 (0%) 0/2345 (0%)
    Abscess limb 1/2347 (0%) 0/2348 (0%) 4/2345 (0.2%)
    Abscess oral 0/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Acinetobacter infection 0/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Anal abscess 0/2347 (0%) 1/2348 (0%) 3/2345 (0.1%)
    Appendiceal abscess 0/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Appendicitis 5/2347 (0.2%) 2/2348 (0.1%) 5/2345 (0.2%)
    Appendicitis perforated 2/2347 (0.1%) 2/2348 (0.1%) 2/2345 (0.1%)
    Arthritis bacterial 1/2347 (0%) 3/2348 (0.1%) 1/2345 (0%)
    Arthritis infective 2/2347 (0.1%) 1/2348 (0%) 0/2345 (0%)
    Atypical pneumonia 0/2347 (0%) 2/2348 (0.1%) 1/2345 (0%)
    Bacteraemia 1/2347 (0%) 1/2348 (0%) 1/2345 (0%)
    Bacterial diarrhoea 1/2347 (0%) 0/2348 (0%) 0/2345 (0%)
    Bacterial infection 1/2347 (0%) 1/2348 (0%) 1/2345 (0%)
    Bacterial sepsis 1/2347 (0%) 1/2348 (0%) 2/2345 (0.1%)
    Biliary sepsis 2/2347 (0.1%) 0/2348 (0%) 0/2345 (0%)
    Bone abscess 0/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Bone tuberculosis 0/2347 (0%) 0/2348 (0%) 1/2345 (0%)
    Brain abscess 0/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Bronchitis 22/2347 (0.9%) 16/2348 (0.7%) 11/2345 (0.5%)
    Bronchitis bacterial 0/2347 (0%) 0/2348 (0%) 1/2345 (0%)
    Bronchitis viral 0/2347 (0%) 1/2348 (0%) 1/2345 (0%)
    Burn infection 0/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Bursitis infective 1/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Campylobacter gastroenteritis 0/2347 (0%) 0/2348 (0%) 1/2345 (0%)
    Cardiac valve abscess 0/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Cellulitis 6/2347 (0.3%) 9/2348 (0.4%) 13/2345 (0.6%)
    Cholecystitis infective 3/2347 (0.1%) 0/2348 (0%) 0/2345 (0%)
    Chronic sinusitis 0/2347 (0%) 0/2348 (0%) 1/2345 (0%)
    Clostridial infection 0/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Clostridium difficile colitis 0/2347 (0%) 0/2348 (0%) 2/2345 (0.1%)
    Clostridium difficile infection 1/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Corynebacterium infection 0/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Cystitis 6/2347 (0.3%) 1/2348 (0%) 3/2345 (0.1%)
    Cytomegalovirus infection 1/2347 (0%) 0/2348 (0%) 0/2345 (0%)
    Dengue fever 0/2347 (0%) 0/2348 (0%) 1/2345 (0%)
    Device related infection 6/2347 (0.3%) 6/2348 (0.3%) 4/2345 (0.2%)
    Device related sepsis 0/2347 (0%) 3/2348 (0.1%) 0/2345 (0%)
    Diabetic foot infection 3/2347 (0.1%) 0/2348 (0%) 1/2345 (0%)
    Diarrhoea infectious 0/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Diverticulitis 6/2347 (0.3%) 0/2348 (0%) 4/2345 (0.2%)
    Dysentery 1/2347 (0%) 0/2348 (0%) 0/2345 (0%)
    Empyema 1/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Encephalitis 1/2347 (0%) 2/2348 (0.1%) 0/2345 (0%)
    Endocarditis 5/2347 (0.2%) 5/2348 (0.2%) 4/2345 (0.2%)
    Endocarditis bacterial 0/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Endocarditis staphylococcal 1/2347 (0%) 0/2348 (0%) 0/2345 (0%)
    Enteritis infectious 0/2347 (0%) 1/2348 (0%) 1/2345 (0%)
    Enterococcal sepsis 1/2347 (0%) 0/2348 (0%) 0/2345 (0%)
    Epididymitis 1/2347 (0%) 2/2348 (0.1%) 0/2345 (0%)
    Erysipelas 6/2347 (0.3%) 7/2348 (0.3%) 10/2345 (0.4%)
    Escherichia infection 0/2347 (0%) 0/2348 (0%) 1/2345 (0%)
    Escherichia urinary tract infection 1/2347 (0%) 0/2348 (0%) 0/2345 (0%)
    Febrile infection 0/2347 (0%) 0/2348 (0%) 1/2345 (0%)
    Fungal oesophagitis 1/2347 (0%) 0/2348 (0%) 0/2345 (0%)
    Gangrene 10/2347 (0.4%) 3/2348 (0.1%) 2/2345 (0.1%)
    Gastric ulcer helicobacter 0/2347 (0%) 0/2348 (0%) 1/2345 (0%)
    Gastroenteritis 13/2347 (0.6%) 10/2348 (0.4%) 16/2345 (0.7%)
    Gastroenteritis clostridial 1/2347 (0%) 0/2348 (0%) 0/2345 (0%)
    Gastroenteritis norovirus 0/2347 (0%) 0/2348 (0%) 2/2345 (0.1%)
    Gastroenteritis viral 1/2347 (0%) 0/2348 (0%) 2/2345 (0.1%)
    Gastrointestinal infection 2/2347 (0.1%) 0/2348 (0%) 1/2345 (0%)
    Genitourinary tract infection 0/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Groin abscess 0/2347 (0%) 1/2348 (0%) 2/2345 (0.1%)
    H1N1 influenza 0/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Haematoma infection 1/2347 (0%) 0/2348 (0%) 2/2345 (0.1%)
    Haemophilus sepsis 0/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Helicobacter infection 0/2347 (0%) 0/2348 (0%) 1/2345 (0%)
    Hepatic infection bacterial 0/2347 (0%) 0/2348 (0%) 1/2345 (0%)
    Hepatitis B 0/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Hepatitis viral 1/2347 (0%) 0/2348 (0%) 0/2345 (0%)
    Herpes zoster 1/2347 (0%) 1/2348 (0%) 4/2345 (0.2%)
    Herpes zoster cutaneous disseminated 0/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Human ehrlichiosis 1/2347 (0%) 0/2348 (0%) 0/2345 (0%)
    Implant site infection 3/2347 (0.1%) 1/2348 (0%) 3/2345 (0.1%)
    Incision site abscess 1/2347 (0%) 0/2348 (0%) 0/2345 (0%)
    Incision site infection 1/2347 (0%) 0/2348 (0%) 0/2345 (0%)
    Infected cyst 0/2347 (0%) 0/2348 (0%) 1/2345 (0%)
    Infected seroma 0/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Infected skin ulcer 2/2347 (0.1%) 4/2348 (0.2%) 3/2345 (0.1%)
    Infection 4/2347 (0.2%) 2/2348 (0.1%) 4/2345 (0.2%)
    Infectious colitis 1/2347 (0%) 1/2348 (0%) 1/2345 (0%)
    Infectious pleural effusion 1/2347 (0%) 2/2348 (0.1%) 0/2345 (0%)
    Infective exacerbation of chronic obstructive airways disease 1/2347 (0%) 4/2348 (0.2%) 2/2345 (0.1%)
    Influenza 2/2347 (0.1%) 2/2348 (0.1%) 2/2345 (0.1%)
    Intervertebral discitis 2/2347 (0.1%) 0/2348 (0%) 0/2345 (0%)
    Intestinal sepsis 0/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Klebsiella sepsis 0/2347 (0%) 0/2348 (0%) 1/2345 (0%)
    Laryngitis 0/2347 (0%) 0/2348 (0%) 1/2345 (0%)
    Liver abscess 0/2347 (0%) 1/2348 (0%) 1/2345 (0%)
    Localised infection 5/2347 (0.2%) 4/2348 (0.2%) 3/2345 (0.1%)
    Lower respiratory tract infection 5/2347 (0.2%) 6/2348 (0.3%) 9/2345 (0.4%)
    Lung abscess 0/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Lung infection 10/2347 (0.4%) 6/2348 (0.3%) 13/2345 (0.6%)
    Lyme disease 0/2347 (0%) 0/2348 (0%) 1/2345 (0%)
    Mucormycosis 0/2347 (0%) 0/2348 (0%) 1/2345 (0%)
    Mycobacterial infection 0/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Myiasis 0/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Nasopharyngitis 3/2347 (0.1%) 2/2348 (0.1%) 0/2345 (0%)
    Necrotising fasciitis 2/2347 (0.1%) 1/2348 (0%) 2/2345 (0.1%)
    Ophthalmic herpes zoster 0/2347 (0%) 0/2348 (0%) 1/2345 (0%)
    Oral fungal infection 0/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Oral infection 1/2347 (0%) 0/2348 (0%) 0/2345 (0%)
    Orchitis 2/2347 (0.1%) 1/2348 (0%) 1/2345 (0%)
    Oropharyngitis fungal 0/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Osteomyelitis 0/2347 (0%) 0/2348 (0%) 2/2345 (0.1%)
    Otitis media acute 0/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Otitis media chronic 1/2347 (0%) 0/2348 (0%) 1/2345 (0%)
    Parametritis 0/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Paronychia 0/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Periodontitis 1/2347 (0%) 0/2348 (0%) 1/2345 (0%)
    Peritonitis 2/2347 (0.1%) 3/2348 (0.1%) 6/2345 (0.3%)
    Peritonitis bacterial 0/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Pneumococcal sepsis 2/2347 (0.1%) 5/2348 (0.2%) 1/2345 (0%)
    Pneumocystis jirovecii infection 1/2347 (0%) 0/2348 (0%) 0/2345 (0%)
    Pneumonia 136/2347 (5.8%) 145/2348 (6.2%) 122/2345 (5.2%)
    Pneumonia bacterial 1/2347 (0%) 0/2348 (0%) 0/2345 (0%)
    Pneumonia escherichia 0/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Pneumonia haemophilus 1/2347 (0%) 0/2348 (0%) 0/2345 (0%)
    Pneumonia influenzal 1/2347 (0%) 0/2348 (0%) 0/2345 (0%)
    Pneumonia mycoplasmal 0/2347 (0%) 0/2348 (0%) 1/2345 (0%)
    Pneumonia pneumococcal 1/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Pneumonia pseudomonal 0/2347 (0%) 0/2348 (0%) 1/2345 (0%)
    Pneumonia staphylococcal 0/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Pneumonia viral 0/2347 (0%) 0/2348 (0%) 1/2345 (0%)
    Post procedural infection 1/2347 (0%) 1/2348 (0%) 1/2345 (0%)
    Post procedural sepsis 1/2347 (0%) 0/2348 (0%) 0/2345 (0%)
    Postoperative wound infection 0/2347 (0%) 2/2348 (0.1%) 2/2345 (0.1%)
    Prostatic abscess 0/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Pseudomembranous colitis 1/2347 (0%) 0/2348 (0%) 0/2345 (0%)
    Pseudomonal sepsis 1/2347 (0%) 1/2348 (0%) 1/2345 (0%)
    Pseudomonas infection 0/2347 (0%) 1/2348 (0%) 1/2345 (0%)
    Psoas abscess 1/2347 (0%) 0/2348 (0%) 0/2345 (0%)
    Pulmonary sepsis 8/2347 (0.3%) 6/2348 (0.3%) 4/2345 (0.2%)
    Pulmonary tuberculosis 0/2347 (0%) 2/2348 (0.1%) 0/2345 (0%)
    Pyelonephritis 4/2347 (0.2%) 3/2348 (0.1%) 1/2345 (0%)
    Pyelonephritis acute 1/2347 (0%) 0/2348 (0%) 1/2345 (0%)
    Pyelonephritis chronic 0/2347 (0%) 0/2348 (0%) 1/2345 (0%)
    Rectal abscess 0/2347 (0%) 0/2348 (0%) 2/2345 (0.1%)
    Respiratory tract infection 8/2347 (0.3%) 15/2348 (0.6%) 19/2345 (0.8%)
    Respiratory tract infection bacterial 0/2347 (0%) 1/2348 (0%) 1/2345 (0%)
    Respiratory tract infection fungal 0/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Respiratory tract infection viral 1/2347 (0%) 2/2348 (0.1%) 2/2345 (0.1%)
    Sepsis 14/2347 (0.6%) 18/2348 (0.8%) 12/2345 (0.5%)
    Septic necrosis 1/2347 (0%) 0/2348 (0%) 0/2345 (0%)
    Septic shock 13/2347 (0.6%) 21/2348 (0.9%) 13/2345 (0.6%)
    Sialoadenitis 0/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Sinusitis 1/2347 (0%) 0/2348 (0%) 0/2345 (0%)
    Skin bacterial infection 1/2347 (0%) 0/2348 (0%) 0/2345 (0%)
    Skin infection 2/2347 (0.1%) 1/2348 (0%) 1/2345 (0%)
    Soft tissue infection 0/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Spinal cord infection 0/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Staphylococcal bacteraemia 1/2347 (0%) 0/2348 (0%) 0/2345 (0%)
    Staphylococcal infection 0/2347 (0%) 0/2348 (0%) 2/2345 (0.1%)
    Staphylococcal sepsis 0/2347 (0%) 2/2348 (0.1%) 3/2345 (0.1%)
    Streptococcal endocarditis 0/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Streptococcal sepsis 0/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Subcutaneous abscess 0/2347 (0%) 0/2348 (0%) 3/2345 (0.1%)
    Thrombophlebitis septic 1/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Tooth abscess 0/2347 (0%) 0/2348 (0%) 2/2345 (0.1%)
    Tooth infection 0/2347 (0%) 1/2348 (0%) 1/2345 (0%)
    Tracheitis 1/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Tracheobronchitis 6/2347 (0.3%) 5/2348 (0.2%) 2/2345 (0.1%)
    Upper respiratory tract infection 4/2347 (0.2%) 5/2348 (0.2%) 6/2345 (0.3%)
    Upper respiratory tract infection bacterial 0/2347 (0%) 0/2348 (0%) 1/2345 (0%)
    Urethritis 0/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Urinary tract infection 22/2347 (0.9%) 21/2348 (0.9%) 19/2345 (0.8%)
    Urinary tract infection bacterial 0/2347 (0%) 1/2348 (0%) 1/2345 (0%)
    Urinary tract infection pseudomonal 1/2347 (0%) 0/2348 (0%) 0/2345 (0%)
    Urosepsis 5/2347 (0.2%) 7/2348 (0.3%) 3/2345 (0.1%)
    Viral infection 0/2347 (0%) 3/2348 (0.1%) 0/2345 (0%)
    Viral pericarditis 1/2347 (0%) 0/2348 (0%) 0/2345 (0%)
    Viral upper respiratory tract infection 1/2347 (0%) 0/2348 (0%) 1/2345 (0%)
    Viral vasculitis 1/2347 (0%) 0/2348 (0%) 0/2345 (0%)
    Wound infection 2/2347 (0.1%) 1/2348 (0%) 1/2345 (0%)
    Wound infection bacterial 1/2347 (0%) 0/2348 (0%) 0/2345 (0%)
    Wound infection staphylococcal 1/2347 (0%) 0/2348 (0%) 0/2345 (0%)
    Wound sepsis 1/2347 (0%) 0/2348 (0%) 0/2345 (0%)
    Injury, poisoning and procedural complications
    Accident 1/2347 (0%) 0/2348 (0%) 0/2345 (0%)
    Accidental exposure to product 0/2347 (0%) 0/2348 (0%) 1/2345 (0%)
    Accidental overdose 0/2347 (0%) 0/2348 (0%) 1/2345 (0%)
    Acetabulum fracture 1/2347 (0%) 0/2348 (0%) 1/2345 (0%)
    Alcohol poisoning 0/2347 (0%) 1/2348 (0%) 1/2345 (0%)
    Anastomotic complication 0/2347 (0%) 0/2348 (0%) 1/2345 (0%)
    Anastomotic ulcer 1/2347 (0%) 0/2348 (0%) 0/2345 (0%)
    Ankle fracture 0/2347 (0%) 4/2348 (0.2%) 1/2345 (0%)
    Avulsion fracture 1/2347 (0%) 0/2348 (0%) 0/2345 (0%)
    Bone contusion 1/2347 (0%) 0/2348 (0%) 1/2345 (0%)
    Brain contusion 3/2347 (0.1%) 1/2348 (0%) 0/2345 (0%)
    Burns third degree 1/2347 (0%) 0/2348 (0%) 0/2345 (0%)
    Carbon monoxide poisoning 1/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Cardiac function disturbance postoperative 0/2347 (0%) 2/2348 (0.1%) 1/2345 (0%)
    Cardiac procedure complication 0/2347 (0%) 3/2348 (0.1%) 0/2345 (0%)
    Carotid artery restenosis 0/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Cervical vertebral fracture 0/2347 (0%) 1/2348 (0%) 1/2345 (0%)
    Chest injury 2/2347 (0.1%) 0/2348 (0%) 0/2345 (0%)
    Clavicle fracture 0/2347 (0%) 0/2348 (0%) 1/2345 (0%)
    Closed globe injury 1/2347 (0%) 0/2348 (0%) 0/2345 (0%)
    Comminuted fracture 1/2347 (0%) 0/2348 (0%) 1/2345 (0%)
    Complications of transplanted heart 1/2347 (0%) 0/2348 (0%) 0/2345 (0%)
    Concussion 3/2347 (0.1%) 0/2348 (0%) 1/2345 (0%)
    Contusion 5/2347 (0.2%) 2/2348 (0.1%) 0/2345 (0%)
    Coronary artery reocclusion 1/2347 (0%) 0/2348 (0%) 0/2345 (0%)
    Coronary artery restenosis 1/2347 (0%) 0/2348 (0%) 1/2345 (0%)
    Coronary vascular graft occlusion 1/2347 (0%) 0/2348 (0%) 0/2345 (0%)
    Craniocerebral injury 2/2347 (0.1%) 3/2348 (0.1%) 0/2345 (0%)
    Excoriation 1/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Extradural haematoma 0/2347 (0%) 0/2348 (0%) 1/2345 (0%)
    Facial bones fracture 1/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Fall 9/2347 (0.4%) 8/2348 (0.3%) 11/2345 (0.5%)
    Femoral neck fracture 5/2347 (0.2%) 3/2348 (0.1%) 3/2345 (0.1%)
    Femur fracture 9/2347 (0.4%) 10/2348 (0.4%) 6/2345 (0.3%)
    Fibula fracture 0/2347 (0%) 0/2348 (0%) 1/2345 (0%)
    Foot fracture 1/2347 (0%) 0/2348 (0%) 2/2345 (0.1%)
    Forearm fracture 0/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Foreign body 0/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Fracture displacement 3/2347 (0.1%) 0/2348 (0%) 1/2345 (0%)
    Fractured ischium 0/2347 (0%) 0/2348 (0%) 1/2345 (0%)
    Fractured sacrum 0/2347 (0%) 0/2348 (0%) 2/2345 (0.1%)
    Gastrointestinal stoma complication 0/2347 (0%) 0/2348 (0%) 1/2345 (0%)
    Hand fracture 0/2347 (0%) 0/2348 (0%) 1/2345 (0%)
    Head injury 7/2347 (0.3%) 3/2348 (0.1%) 3/2345 (0.1%)
    Hip fracture 4/2347 (0.2%) 5/2348 (0.2%) 2/2345 (0.1%)
    Humerus fracture 3/2347 (0.1%) 2/2348 (0.1%) 1/2345 (0%)
    Incision site haematoma 1/2347 (0%) 0/2348 (0%) 0/2345 (0%)
    Incisional hernia 0/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Injury 1/2347 (0%) 0/2348 (0%) 1/2345 (0%)
    Intestinal anastomosis complication 1/2347 (0%) 0/2348 (0%) 0/2345 (0%)
    Joint dislocation 1/2347 (0%) 0/2348 (0%) 2/2345 (0.1%)
    Joint injury 0/2347 (0%) 1/2348 (0%) 1/2345 (0%)
    Laceration 0/2347 (0%) 2/2348 (0.1%) 0/2345 (0%)
    Ligament injury 1/2347 (0%) 0/2348 (0%) 0/2345 (0%)
    Ligament sprain 1/2347 (0%) 0/2348 (0%) 1/2345 (0%)
    Limb injury 0/2347 (0%) 0/2348 (0%) 1/2345 (0%)
    Limb traumatic amputation 0/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Lip injury 0/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Lower limb fracture 3/2347 (0.1%) 2/2348 (0.1%) 1/2345 (0%)
    Lumbar vertebral fracture 0/2347 (0%) 0/2348 (0%) 3/2345 (0.1%)
    Meniscus injury 1/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Mouth injury 0/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Multiple fractures 1/2347 (0%) 0/2348 (0%) 0/2345 (0%)
    Multiple injuries 0/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Muscle injury 1/2347 (0%) 0/2348 (0%) 0/2345 (0%)
    Muscle rupture 1/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Overdose 4/2347 (0.2%) 9/2348 (0.4%) 0/2345 (0%)
    Patella fracture 2/2347 (0.1%) 0/2348 (0%) 0/2345 (0%)
    Pelvic fracture 2/2347 (0.1%) 2/2348 (0.1%) 3/2345 (0.1%)
    Periorbital haemorrhage 1/2347 (0%) 0/2348 (0%) 0/2345 (0%)
    Peripheral artery restenosis 1/2347 (0%) 0/2348 (0%) 0/2345 (0%)
    Periprosthetic fracture 1/2347 (0%) 0/2348 (0%) 0/2345 (0%)
    Pneumothorax traumatic 0/2347 (0%) 3/2348 (0.1%) 2/2345 (0.1%)
    Poisoning 0/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Post procedural bile leak 0/2347 (0%) 0/2348 (0%) 1/2345 (0%)
    Post procedural complication 2/2347 (0.1%) 1/2348 (0%) 1/2345 (0%)
    Post procedural haematoma 1/2347 (0%) 0/2348 (0%) 1/2345 (0%)
    Post procedural haematuria 0/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Post procedural haemorrhage 1/2347 (0%) 4/2348 (0.2%) 1/2345 (0%)
    Post-traumatic pain 0/2347 (0%) 0/2348 (0%) 1/2345 (0%)
    Postoperative hernia 0/2347 (0%) 0/2348 (0%) 1/2345 (0%)
    Postoperative ileus 0/2347 (0%) 0/2348 (0%) 1/2345 (0%)
    Postoperative thoracic procedure complication 0/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Postoperative wound complication 0/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Procedural complication 1/2347 (0%) 0/2348 (0%) 0/2345 (0%)
    Procedural pain 0/2347 (0%) 2/2348 (0.1%) 0/2345 (0%)
    Product name confusion 0/2347 (0%) 0/2348 (0%) 1/2345 (0%)
    Pubis fracture 0/2347 (0%) 0/2348 (0%) 1/2345 (0%)
    Pulmonary contusion 0/2347 (0%) 0/2348 (0%) 1/2345 (0%)
    Radius fracture 5/2347 (0.2%) 5/2348 (0.2%) 1/2345 (0%)
    Respiratory fume inhalation disorder 0/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Rib fracture 8/2347 (0.3%) 6/2348 (0.3%) 8/2345 (0.3%)
    Road traffic accident 2/2347 (0.1%) 3/2348 (0.1%) 2/2345 (0.1%)
    Sacroiliac fracture 1/2347 (0%) 0/2348 (0%) 0/2345 (0%)
    Scrotal haematoma 0/2347 (0%) 0/2348 (0%) 1/2345 (0%)
    Shunt stenosis 1/2347 (0%) 0/2348 (0%) 0/2345 (0%)
    Skin abrasion 0/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Skin injury 0/2347 (0%) 0/2348 (0%) 1/2345 (0%)
    Skull fracture 0/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Soft tissue injury 0/2347 (0%) 0/2348 (0%) 1/2345 (0%)
    Spinal compression fracture 1/2347 (0%) 4/2348 (0.2%) 2/2345 (0.1%)
    Spinal cord injury 0/2347 (0%) 0/2348 (0%) 1/2345 (0%)
    Spinal fracture 1/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Subdural haematoma 2/2347 (0.1%) 5/2348 (0.2%) 5/2345 (0.2%)
    Subdural haemorrhage 1/2347 (0%) 2/2348 (0.1%) 1/2345 (0%)
    Tendon rupture 0/2347 (0%) 0/2348 (0%) 2/2345 (0.1%)
    Thermal burn 2/2347 (0.1%) 0/2348 (0%) 1/2345 (0%)
    Thoracic vertebral fracture 3/2347 (0.1%) 0/2348 (0%) 0/2345 (0%)
    Tibia fracture 1/2347 (0%) 2/2348 (0.1%) 3/2345 (0.1%)
    Tooth fracture 0/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Toxicity to various agents 6/2347 (0.3%) 3/2348 (0.1%) 3/2345 (0.1%)
    Transplant failure 0/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Traumatic fracture 0/2347 (0%) 0/2348 (0%) 1/2345 (0%)
    Traumatic haematoma 2/2347 (0.1%) 0/2348 (0%) 0/2345 (0%)
    Traumatic haemothorax 0/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Traumatic intracranial haemorrhage 0/2347 (0%) 1/2348 (0%) 1/2345 (0%)
    Traumatic liver injury 0/2347 (0%) 0/2348 (0%) 1/2345 (0%)
    Traumatic shock 0/2347 (0%) 0/2348 (0%) 1/2345 (0%)
    Ulna fracture 0/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Underdose 0/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Upper limb fracture 1/2347 (0%) 4/2348 (0.2%) 1/2345 (0%)
    Urethral stricture traumatic 0/2347 (0%) 0/2348 (0%) 1/2345 (0%)
    Vascular bypass dysfunction 1/2347 (0%) 0/2348 (0%) 0/2345 (0%)
    Vascular graft occlusion 1/2347 (0%) 0/2348 (0%) 1/2345 (0%)
    Vascular pseudoaneurysm 0/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Vasoplegia syndrome 0/2347 (0%) 0/2348 (0%) 1/2345 (0%)
    Wound 1/2347 (0%) 2/2348 (0.1%) 1/2345 (0%)
    Wound haemorrhage 0/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Investigations
    Anticoagulation drug level below therapeutic 0/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Anticoagulation drug level increased 0/2347 (0%) 0/2348 (0%) 1/2345 (0%)
    Blood alkaline phosphatase increased 1/2347 (0%) 0/2348 (0%) 0/2345 (0%)
    Blood creatine phosphokinase increased 1/2347 (0%) 0/2348 (0%) 2/2345 (0.1%)
    Blood creatinine increased 7/2347 (0.3%) 4/2348 (0.2%) 5/2345 (0.2%)
    Blood ethanol increased 1/2347 (0%) 0/2348 (0%) 0/2345 (0%)
    Blood glucose increased 1/2347 (0%) 0/2348 (0%) 2/2345 (0.1%)
    Blood magnesium decreased 1/2347 (0%) 0/2348 (0%) 0/2345 (0%)
    Blood potassium decreased 0/2347 (0%) 2/2348 (0.1%) 0/2345 (0%)
    Blood potassium increased 0/2347 (0%) 0/2348 (0%) 1/2345 (0%)
    Blood urine 1/2347 (0%) 0/2348 (0%) 0/2345 (0%)
    Blood urine present 1/2347 (0%) 0/2348 (0%) 0/2345 (0%)
    Brain natriuretic peptide increased 0/2347 (0%) 0/2348 (0%) 1/2345 (0%)
    C-reactive protein increased 1/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Cardiac murmur 0/2347 (0%) 0/2348 (0%) 1/2345 (0%)
    Cardiac output decreased 1/2347 (0%) 0/2348 (0%) 0/2345 (0%)
    Cardioactive drug level increased 0/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Chest X-ray abnormal 0/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Coagulation test abnormal 1/2347 (0%) 0/2348 (0%) 0/2345 (0%)
    Coagulation time prolonged 1/2347 (0%) 0/2348 (0%) 0/2345 (0%)
    Ejection fraction abnormal 1/2347 (0%) 2/2348 (0.1%) 1/2345 (0%)
    Ejection fraction decreased 1/2347 (0%) 0/2348 (0%) 1/2345 (0%)
    Electrocardiogram QRS complex prolonged 1/2347 (0%) 2/2348 (0.1%) 1/2345 (0%)
    Enterobacter test positive 0/2347 (0%) 0/2348 (0%) 1/2345 (0%)
    Gamma-glutamyltransferase increased 1/2347 (0%) 0/2348 (0%) 0/2345 (0%)
    Heart rate decreased 1/2347 (0%) 0/2348 (0%) 0/2345 (0%)
    Heart rate irregular 1/2347 (0%) 0/2348 (0%) 0/2345 (0%)
    Hepatic enzyme increased 2/2347 (0.1%) 0/2348 (0%) 2/2345 (0.1%)
    International normalised ratio abnormal 1/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    International normalised ratio increased 5/2347 (0.2%) 3/2348 (0.1%) 6/2345 (0.3%)
    Lipase increased 1/2347 (0%) 0/2348 (0%) 0/2345 (0%)
    Oxygen saturation decreased 1/2347 (0%) 0/2348 (0%) 0/2345 (0%)
    Prostatic specific antigen increased 0/2347 (0%) 0/2348 (0%) 1/2345 (0%)
    Transaminases increased 1/2347 (0%) 0/2348 (0%) 0/2345 (0%)
    Urine output decreased 1/2347 (0%) 0/2348 (0%) 0/2345 (0%)
    Viral load increased 0/2347 (0%) 0/2348 (0%) 1/2345 (0%)
    Weight decreased 3/2347 (0.1%) 3/2348 (0.1%) 1/2345 (0%)
    Weight increased 1/2347 (0%) 0/2348 (0%) 3/2345 (0.1%)
    White blood cell count increased 1/2347 (0%) 0/2348 (0%) 0/2345 (0%)
    Metabolism and nutrition disorders
    Acidosis 0/2347 (0%) 0/2348 (0%) 3/2345 (0.1%)
    Cachexia 1/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Carbohydrate intolerance 0/2347 (0%) 2/2348 (0.1%) 1/2345 (0%)
    Decreased appetite 7/2347 (0.3%) 6/2348 (0.3%) 1/2345 (0%)
    Dehydration 27/2347 (1.2%) 21/2348 (0.9%) 14/2345 (0.6%)
    Diabetes mellitus 15/2347 (0.6%) 16/2348 (0.7%) 10/2345 (0.4%)
    Diabetes mellitus inadequate control 7/2347 (0.3%) 6/2348 (0.3%) 4/2345 (0.2%)
    Diabetic ketoacidosis 0/2347 (0%) 0/2348 (0%) 2/2345 (0.1%)
    Electrolyte imbalance 3/2347 (0.1%) 0/2348 (0%) 3/2345 (0.1%)
    Fluid overload 3/2347 (0.1%) 0/2348 (0%) 1/2345 (0%)
    Fluid retention 0/2347 (0%) 0/2348 (0%) 1/2345 (0%)
    Glucose tolerance impaired 0/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Gout 11/2347 (0.5%) 11/2348 (0.5%) 5/2345 (0.2%)
    Hypercalcaemia 2/2347 (0.1%) 1/2348 (0%) 0/2345 (0%)
    Hyperglycaemia 6/2347 (0.3%) 1/2348 (0%) 3/2345 (0.1%)
    Hyperkalaemia 21/2347 (0.9%) 13/2348 (0.6%) 20/2345 (0.9%)
    Hyperosmolar hyperglycaemic state 0/2347 (0%) 0/2348 (0%) 1/2345 (0%)
    Hyperosmolar state 0/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Hypertriglyceridaemia 1/2347 (0%) 0/2348 (0%) 0/2345 (0%)
    Hyperuricaemia 1/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Hypervolaemia 0/2347 (0%) 0/2348 (0%) 1/2345 (0%)
    Hypoalbuminaemia 0/2347 (0%) 0/2348 (0%) 1/2345 (0%)
    Hypocalcaemia 0/2347 (0%) 0/2348 (0%) 2/2345 (0.1%)
    Hypoglycaemia 10/2347 (0.4%) 5/2348 (0.2%) 5/2345 (0.2%)
    Hypokalaemia 10/2347 (0.4%) 12/2348 (0.5%) 10/2345 (0.4%)
    Hypomagnesaemia 0/2347 (0%) 0/2348 (0%) 2/2345 (0.1%)
    Hyponatraemia 5/2347 (0.2%) 7/2348 (0.3%) 10/2345 (0.4%)
    Hypophagia 0/2347 (0%) 0/2348 (0%) 1/2345 (0%)
    Hypoproteinaemia 0/2347 (0%) 0/2348 (0%) 2/2345 (0.1%)
    Hypovolaemia 0/2347 (0%) 2/2348 (0.1%) 2/2345 (0.1%)
    Insulin resistance 0/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Iron deficiency 0/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Ketoacidosis 1/2347 (0%) 0/2348 (0%) 1/2345 (0%)
    Malnutrition 1/2347 (0%) 0/2348 (0%) 0/2345 (0%)
    Marasmus 0/2347 (0%) 0/2348 (0%) 1/2345 (0%)
    Metabolic acidosis 2/2347 (0.1%) 0/2348 (0%) 2/2345 (0.1%)
    Metabolic disorder 0/2347 (0%) 0/2348 (0%) 1/2345 (0%)
    Mineral deficiency 1/2347 (0%) 0/2348 (0%) 0/2345 (0%)
    Obesity 1/2347 (0%) 0/2348 (0%) 0/2345 (0%)
    Polydipsia 0/2347 (0%) 0/2348 (0%) 1/2345 (0%)
    Type 1 diabetes mellitus 1/2347 (0%) 1/2348 (0%) 1/2345 (0%)
    Type 2 diabetes mellitus 12/2347 (0.5%) 10/2348 (0.4%) 8/2345 (0.3%)
    Musculoskeletal and connective tissue disorders
    Arthralgia 6/2347 (0.3%) 3/2348 (0.1%) 4/2345 (0.2%)
    Arthritis 2/2347 (0.1%) 2/2348 (0.1%) 3/2345 (0.1%)
    Back pain 4/2347 (0.2%) 4/2348 (0.2%) 3/2345 (0.1%)
    Bursitis 0/2347 (0%) 3/2348 (0.1%) 0/2345 (0%)
    Cervical spinal stenosis 1/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Chondropathy 0/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Compartment syndrome 1/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Connective tissue inflammation 0/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Costochondritis 0/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Diabetic amyotrophy 0/2347 (0%) 0/2348 (0%) 1/2345 (0%)
    Fistula 0/2347 (0%) 0/2348 (0%) 1/2345 (0%)
    Flank pain 1/2347 (0%) 2/2348 (0.1%) 0/2345 (0%)
    Foot deformity 0/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Fracture malunion 1/2347 (0%) 0/2348 (0%) 0/2345 (0%)
    Gouty arthritis 6/2347 (0.3%) 3/2348 (0.1%) 1/2345 (0%)
    Haemarthrosis 1/2347 (0%) 1/2348 (0%) 2/2345 (0.1%)
    Intervertebral disc degeneration 1/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Intervertebral disc protrusion 1/2347 (0%) 3/2348 (0.1%) 3/2345 (0.1%)
    Joint effusion 1/2347 (0%) 0/2348 (0%) 0/2345 (0%)
    Joint instability 1/2347 (0%) 0/2348 (0%) 0/2345 (0%)
    Lumbar spinal stenosis 2/2347 (0.1%) 3/2348 (0.1%) 1/2345 (0%)
    Muscle atrophy 0/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Muscle haemorrhage 0/2347 (0%) 0/2348 (0%) 2/2345 (0.1%)
    Muscular weakness 0/2347 (0%) 5/2348 (0.2%) 2/2345 (0.1%)
    Musculoskeletal chest pain 3/2347 (0.1%) 2/2348 (0.1%) 2/2345 (0.1%)
    Musculoskeletal pain 1/2347 (0%) 1/2348 (0%) 2/2345 (0.1%)
    Musculoskeletal stiffness 0/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Myalgia 0/2347 (0%) 0/2348 (0%) 3/2345 (0.1%)
    Myopathy 0/2347 (0%) 0/2348 (0%) 1/2345 (0%)
    Myopathy toxic 1/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Myositis 0/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Neck pain 0/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Osteitis 1/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Osteoarthritis 9/2347 (0.4%) 12/2348 (0.5%) 10/2345 (0.4%)
    Osteochondritis 1/2347 (0%) 0/2348 (0%) 0/2345 (0%)
    Osteochondrosis 2/2347 (0.1%) 1/2348 (0%) 1/2345 (0%)
    Osteonecrosis 2/2347 (0.1%) 0/2348 (0%) 2/2345 (0.1%)
    Osteonecrosis of jaw 1/2347 (0%) 0/2348 (0%) 0/2345 (0%)
    Osteoporosis 0/2347 (0%) 1/2348 (0%) 1/2345 (0%)
    Osteoporotic fracture 0/2347 (0%) 1/2348 (0%) 1/2345 (0%)
    Pain in extremity 4/2347 (0.2%) 3/2348 (0.1%) 6/2345 (0.3%)
    Pathological fracture 0/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Polyarthritis 0/2347 (0%) 0/2348 (0%) 1/2345 (0%)
    Rhabdomyolysis 2/2347 (0.1%) 0/2348 (0%) 1/2345 (0%)
    Rheumatic disorder 0/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Rheumatoid arthritis 3/2347 (0.1%) 0/2348 (0%) 0/2345 (0%)
    Rotator cuff syndrome 0/2347 (0%) 4/2348 (0.2%) 0/2345 (0%)
    Scleroderma 0/2347 (0%) 0/2348 (0%) 1/2345 (0%)
    Spinal column stenosis 0/2347 (0%) 3/2348 (0.1%) 2/2345 (0.1%)
    Spinal deformity 0/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Spinal osteoarthritis 2/2347 (0.1%) 2/2348 (0.1%) 0/2345 (0%)
    Spinal pain 2/2347 (0.1%) 0/2348 (0%) 2/2345 (0.1%)
    Synovial cyst 0/2347 (0%) 1/2348 (0%) 1/2345 (0%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Acute myeloid leukaemia 0/2347 (0%) 0/2348 (0%) 1/2345 (0%)
    Adenocarcinoma gastric 2/2347 (0.1%) 1/2348 (0%) 2/2345 (0.1%)
    Adenocarcinoma of appendix 0/2347 (0%) 0/2348 (0%) 1/2345 (0%)
    Adenocarcinoma of colon 3/2347 (0.1%) 8/2348 (0.3%) 2/2345 (0.1%)
    Adrenal adenoma 1/2347 (0%) 0/2348 (0%) 1/2345 (0%)
    Basal cell carcinoma 2/2347 (0.1%) 5/2348 (0.2%) 3/2345 (0.1%)
    Benign ear neoplasm 0/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Benign lung neoplasm 1/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Benign neoplasm of bladder 0/2347 (0%) 2/2348 (0.1%) 0/2345 (0%)
    Benign neoplasm of skin 0/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Benign neoplasm of spinal cord 1/2347 (0%) 0/2348 (0%) 0/2345 (0%)
    Benign neoplasm of thyroid gland 1/2347 (0%) 0/2348 (0%) 0/2345 (0%)
    Benign pancreatic neoplasm 1/2347 (0%) 0/2348 (0%) 0/2345 (0%)
    Benign renal neoplasm 0/2347 (0%) 0/2348 (0%) 1/2345 (0%)
    Benign salivary gland neoplasm 1/2347 (0%) 0/2348 (0%) 1/2345 (0%)
    Bile duct adenocarcinoma 0/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Bile duct cancer 0/2347 (0%) 1/2348 (0%) 1/2345 (0%)
    Bladder cancer 3/2347 (0.1%) 4/2348 (0.2%) 6/2345 (0.3%)
    Bladder cancer recurrent 0/2347 (0%) 0/2348 (0%) 1/2345 (0%)
    Bladder neoplasm 0/2347 (0%) 0/2348 (0%) 1/2345 (0%)
    Bladder papilloma 0/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Bladder transitional cell carcinoma 1/2347 (0%) 0/2348 (0%) 1/2345 (0%)
    Bone cancer 2/2347 (0.1%) 0/2348 (0%) 0/2345 (0%)
    Brain neoplasm 0/2347 (0%) 0/2348 (0%) 1/2345 (0%)
    Brain neoplasm malignant 0/2347 (0%) 0/2348 (0%) 1/2345 (0%)
    Breast cancer 1/2347 (0%) 3/2348 (0.1%) 3/2345 (0.1%)
    Breast cancer female 0/2347 (0%) 0/2348 (0%) 1/2345 (0%)
    Bronchial carcinoma 2/2347 (0.1%) 0/2348 (0%) 7/2345 (0.3%)
    Carcinoma in situ of penis 0/2347 (0%) 0/2348 (0%) 1/2345 (0%)
    Carcinoma in situ of skin 0/2347 (0%) 0/2348 (0%) 1/2345 (0%)
    Cardiac valve fibroelastoma 0/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Cerebellar tumour 0/2347 (0%) 0/2348 (0%) 1/2345 (0%)
    Cholangiocarcinoma 2/2347 (0.1%) 2/2348 (0.1%) 1/2345 (0%)
    Chronic lymphocytic leukaemia 1/2347 (0%) 0/2348 (0%) 0/2345 (0%)
    Colon adenoma 1/2347 (0%) 0/2348 (0%) 2/2345 (0.1%)
    Colon cancer 10/2347 (0.4%) 4/2348 (0.2%) 7/2345 (0.3%)
    Colon cancer metastatic 1/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Colon cancer recurrent 1/2347 (0%) 0/2348 (0%) 0/2345 (0%)
    Colorectal adenocarcinoma 0/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Colorectal cancer 1/2347 (0%) 0/2348 (0%) 0/2345 (0%)
    Extranodal marginal zone B-cell lymphoma (MALT type) 1/2347 (0%) 0/2348 (0%) 0/2345 (0%)
    Gallbladder cancer 1/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Gastric adenoma 0/2347 (0%) 0/2348 (0%) 1/2345 (0%)
    Gastric cancer 6/2347 (0.3%) 3/2348 (0.1%) 3/2345 (0.1%)
    Gastrointestinal cancer metastatic 0/2347 (0%) 0/2348 (0%) 1/2345 (0%)
    Gastrointestinal carcinoma 0/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Glioblastoma 0/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Glioma 0/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Haemangioma 0/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Hepatic cancer 4/2347 (0.2%) 2/2348 (0.1%) 1/2345 (0%)
    Hepatic cancer metastatic 0/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Hepatic neoplasm 0/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Hepatobiliary cancer 0/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Hepatocellular carcinoma 0/2347 (0%) 1/2348 (0%) 1/2345 (0%)
    Hodgkin's disease 0/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Hypopharyngeal cancer 0/2347 (0%) 0/2348 (0%) 1/2345 (0%)
    Infected neoplasm 1/2347 (0%) 0/2348 (0%) 0/2345 (0%)
    Intestinal adenocarcinoma 0/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Invasive ductal breast carcinoma 0/2347 (0%) 0/2348 (0%) 1/2345 (0%)
    Keratoacanthoma 0/2347 (0%) 0/2348 (0%) 1/2345 (0%)
    Large intestine benign neoplasm 0/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Laryngeal cancer 2/2347 (0.1%) 0/2348 (0%) 0/2345 (0%)
    Laryngeal squamous cell carcinoma 0/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Lentigo maligna 0/2347 (0%) 0/2348 (0%) 1/2345 (0%)
    Lip and/or oral cavity cancer 0/2347 (0%) 0/2348 (0%) 1/2345 (0%)
    Lip neoplasm malignant stage unspecified 1/2347 (0%) 0/2348 (0%) 0/2345 (0%)
    Lipoma 1/2347 (0%) 0/2348 (0%) 1/2345 (0%)
    Lung adenocarcinoma 2/2347 (0.1%) 1/2348 (0%) 1/2345 (0%)
    Lung adenocarcinoma metastatic 0/2347 (0%) 0/2348 (0%) 1/2345 (0%)
    Lung cancer metastatic 0/2347 (0%) 2/2348 (0.1%) 0/2345 (0%)
    Lung carcinoma cell type unspecified stage IV 1/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Lung neoplasm 0/2347 (0%) 0/2348 (0%) 1/2345 (0%)
    Lung neoplasm malignant 9/2347 (0.4%) 9/2348 (0.4%) 12/2345 (0.5%)
    Lymphoma 0/2347 (0%) 1/2348 (0%) 1/2345 (0%)
    Malignant melanoma 1/2347 (0%) 3/2348 (0.1%) 2/2345 (0.1%)
    Malignant neoplasm of auricular cartilage 0/2347 (0%) 0/2348 (0%) 1/2345 (0%)
    Malignant neoplasm of renal pelvis 1/2347 (0%) 0/2348 (0%) 0/2345 (0%)
    Malignant palate neoplasm 1/2347 (0%) 0/2348 (0%) 0/2345 (0%)
    Malignant pleural effusion 1/2347 (0%) 0/2348 (0%) 0/2345 (0%)
    Mediastinum neoplasm 0/2347 (0%) 0/2348 (0%) 1/2345 (0%)
    Meningioma 1/2347 (0%) 0/2348 (0%) 0/2345 (0%)
    Meningioma benign 0/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Metastases to bone 0/2347 (0%) 3/2348 (0.1%) 0/2345 (0%)
    Metastases to bone marrow 1/2347 (0%) 0/2348 (0%) 0/2345 (0%)
    Metastases to central nervous system 0/2347 (0%) 2/2348 (0.1%) 1/2345 (0%)
    Metastases to liver 0/2347 (0%) 7/2348 (0.3%) 2/2345 (0.1%)
    Metastases to lung 1/2347 (0%) 1/2348 (0%) 2/2345 (0.1%)
    Metastases to lymph nodes 0/2347 (0%) 1/2348 (0%) 1/2345 (0%)
    Metastases to peritoneum 0/2347 (0%) 0/2348 (0%) 1/2345 (0%)
    Metastases to pleura 0/2347 (0%) 0/2348 (0%) 1/2345 (0%)
    Metastases to spine 0/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Metastatic malignant melanoma 0/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Metastatic pain 0/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Metastatic squamous cell carcinoma 1/2347 (0%) 0/2348 (0%) 1/2345 (0%)
    Myelodysplastic syndrome 0/2347 (0%) 0/2348 (0%) 1/2345 (0%)
    Myeloproliferative disorder 0/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Nasopharyngeal cancer 0/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Neoplasm malignant 1/2347 (0%) 0/2348 (0%) 2/2345 (0.1%)
    Neuroendocrine carcinoma 1/2347 (0%) 0/2348 (0%) 1/2345 (0%)
    Non-Hodgkin's lymphoma 1/2347 (0%) 0/2348 (0%) 0/2345 (0%)
    Non-small cell lung cancer 0/2347 (0%) 0/2348 (0%) 2/2345 (0.1%)
    Non-small cell lung cancer stage IV 1/2347 (0%) 0/2348 (0%) 0/2345 (0%)
    Oesophageal carcinoma 3/2347 (0.1%) 4/2348 (0.2%) 3/2345 (0.1%)
    Ovarian cancer 0/2347 (0%) 0/2348 (0%) 1/2345 (0%)
    Pancreatic carcinoma 4/2347 (0.2%) 2/2348 (0.1%) 5/2345 (0.2%)
    Pancreatic carcinoma metastatic 1/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Pancreatic carcinoma stage IV 0/2347 (0%) 0/2348 (0%) 1/2345 (0%)
    Papillary thyroid cancer 1/2347 (0%) 0/2348 (0%) 0/2345 (0%)
    Penile cancer 0/2347 (0%) 0/2348 (0%) 1/2345 (0%)
    Pineal parenchymal neoplasm malignant 0/2347 (0%) 0/2348 (0%) 1/2345 (0%)
    Plasma cell myeloma 5/2347 (0.2%) 1/2348 (0%) 0/2345 (0%)
    Pleural mesothelioma 0/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Prostate cancer 6/2347 (0.3%) 7/2348 (0.3%) 19/2345 (0.8%)
    Prostate cancer metastatic 1/2347 (0%) 0/2348 (0%) 2/2345 (0.1%)
    Prostatic adenoma 1/2347 (0%) 2/2348 (0.1%) 1/2345 (0%)
    Rectal adenocarcinoma 0/2347 (0%) 1/2348 (0%) 2/2345 (0.1%)
    Rectal cancer 2/2347 (0.1%) 3/2348 (0.1%) 3/2345 (0.1%)
    Rectosigmoid cancer 1/2347 (0%) 1/2348 (0%) 1/2345 (0%)
    Renal cancer 5/2347 (0.2%) 1/2348 (0%) 1/2345 (0%)
    Renal cancer metastatic 0/2347 (0%) 0/2348 (0%) 1/2345 (0%)
    Renal cell carcinoma 2/2347 (0.1%) 4/2348 (0.2%) 3/2345 (0.1%)
    Renal neoplasm 1/2347 (0%) 2/2348 (0.1%) 0/2345 (0%)
    Salivary gland adenoma 0/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Sinus cancer metastatic 0/2347 (0%) 0/2348 (0%) 1/2345 (0%)
    Skin cancer 1/2347 (0%) 1/2348 (0%) 1/2345 (0%)
    Small cell lung cancer recurrent 0/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Squamous cell carcinoma 2/2347 (0.1%) 0/2348 (0%) 5/2345 (0.2%)
    Squamous cell carcinoma of lung 0/2347 (0%) 1/2348 (0%) 2/2345 (0.1%)
    Squamous cell carcinoma of skin 1/2347 (0%) 0/2348 (0%) 1/2345 (0%)
    Thyroid cancer 2/2347 (0.1%) 0/2348 (0%) 0/2345 (0%)
    Thyroid neoplasm 0/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Tongue neoplasm malignant stage unspecified 0/2347 (0%) 2/2348 (0.1%) 0/2345 (0%)
    Transitional cell carcinoma 1/2347 (0%) 0/2348 (0%) 0/2345 (0%)
    Tumour flare 0/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Tumour haemorrhage 0/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Tumour pain 1/2347 (0%) 0/2348 (0%) 0/2345 (0%)
    Uterine cancer 0/2347 (0%) 0/2348 (0%) 1/2345 (0%)
    Uterine leiomyoma 0/2347 (0%) 0/2348 (0%) 1/2345 (0%)
    Nervous system disorders
    Ageusia 1/2347 (0%) 0/2348 (0%) 0/2345 (0%)
    Altered state of consciousness 1/2347 (0%) 0/2348 (0%) 1/2345 (0%)
    Amyotrophic lateral sclerosis 0/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Aphasia 1/2347 (0%) 0/2348 (0%) 0/2345 (0%)
    Atonic seizures 1/2347 (0%) 0/2348 (0%) 0/2345 (0%)
    Balance disorder 0/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Basilar artery stenosis 0/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Brain hypoxia 0/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Brain injury 1/2347 (0%) 0/2348 (0%) 1/2345 (0%)
    Brain oedema 0/2347 (0%) 2/2348 (0.1%) 0/2345 (0%)
    Brain stem infarction 0/2347 (0%) 0/2348 (0%) 1/2345 (0%)
    Brain stem syndrome 0/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Carotid arteriosclerosis 1/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Carotid artery disease 0/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Carotid artery stenosis 3/2347 (0.1%) 5/2348 (0.2%) 0/2345 (0%)
    Carpal tunnel syndrome 1/2347 (0%) 0/2348 (0%) 0/2345 (0%)
    Cerebellar ataxia 1/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Cerebellar haemorrhage 0/2347 (0%) 2/2348 (0.1%) 0/2345 (0%)
    Cerebellar infarction 1/2347 (0%) 0/2348 (0%) 0/2345 (0%)
    Cerebral amyloid angiopathy 0/2347 (0%) 0/2348 (0%) 1/2345 (0%)
    Cerebral arteriosclerosis 0/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Cerebral artery embolism 1/2347 (0%) 0/2348 (0%) 5/2345 (0.2%)
    Cerebral artery occlusion 1/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Cerebral atrophy 0/2347 (0%) 0/2348 (0%) 2/2345 (0.1%)
    Cerebral haematoma 1/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Cerebral haemorrhage 6/2347 (0.3%) 9/2348 (0.4%) 7/2345 (0.3%)
    Cerebral infarction 9/2347 (0.4%) 17/2348 (0.7%) 17/2345 (0.7%)
    Cerebral ischaemia 3/2347 (0.1%) 2/2348 (0.1%) 3/2345 (0.1%)
    Cerebrovascular accident 44/2347 (1.9%) 51/2348 (2.2%) 62/2345 (2.6%)
    Cerebrovascular disorder 0/2347 (0%) 1/2348 (0%) 1/2345 (0%)
    Cerebrovascular insufficiency 1/2347 (0%) 0/2348 (0%) 0/2345 (0%)
    Cervicogenic headache 0/2347 (0%) 0/2348 (0%) 1/2345 (0%)
    Cognitive disorder 1/2347 (0%) 2/2348 (0.1%) 1/2345 (0%)
    Coma 1/2347 (0%) 3/2348 (0.1%) 2/2345 (0.1%)
    Complex partial seizures 0/2347 (0%) 1/2348 (0%) 1/2345 (0%)
    Dementia 6/2347 (0.3%) 1/2348 (0%) 3/2345 (0.1%)
    Depressed level of consciousness 0/2347 (0%) 1/2348 (0%) 1/2345 (0%)
    Diabetic coma 0/2347 (0%) 0/2348 (0%) 1/2345 (0%)
    Diabetic hyperosmolar coma 0/2347 (0%) 0/2348 (0%) 1/2345 (0%)
    Diabetic neuropathy 2/2347 (0.1%) 1/2348 (0%) 0/2345 (0%)
    Dizziness 11/2347 (0.5%) 9/2348 (0.4%) 4/2345 (0.2%)
    Dizziness postural 1/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Dysarthria 1/2347 (0%) 1/2348 (0%) 3/2345 (0.1%)
    Dyslalia 0/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Embolic cerebral infarction 0/2347 (0%) 0/2348 (0%) 1/2345 (0%)
    Embolic stroke 3/2347 (0.1%) 1/2348 (0%) 1/2345 (0%)
    Encephalomalacia 0/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Encephalopathy 1/2347 (0%) 2/2348 (0.1%) 1/2345 (0%)
    Epilepsy 2/2347 (0.1%) 7/2348 (0.3%) 2/2345 (0.1%)
    Generalised tonic-clonic seizure 0/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Haemorrhage intracranial 0/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Haemorrhagic stroke 3/2347 (0.1%) 4/2348 (0.2%) 4/2345 (0.2%)
    Headache 1/2347 (0%) 3/2348 (0.1%) 1/2345 (0%)
    Hemianopia 0/2347 (0%) 0/2348 (0%) 1/2345 (0%)
    Hemianopia homonymous 1/2347 (0%) 0/2348 (0%) 0/2345 (0%)
    Hemiparesis 3/2347 (0.1%) 3/2348 (0.1%) 1/2345 (0%)
    Hemiplegia 0/2347 (0%) 2/2348 (0.1%) 2/2345 (0.1%)
    Hepatic encephalopathy 0/2347 (0%) 2/2348 (0.1%) 0/2345 (0%)
    Hydrocephalus 2/2347 (0.1%) 0/2348 (0%) 2/2345 (0.1%)
    Hypoglycaemic coma 1/2347 (0%) 0/2348 (0%) 2/2345 (0.1%)
    Hypoglycaemic seizure 1/2347 (0%) 0/2348 (0%) 0/2345 (0%)
    Hypoxic-ischaemic encephalopathy 2/2347 (0.1%) 2/2348 (0.1%) 3/2345 (0.1%)
    IIIrd nerve paresis 0/2347 (0%) 0/2348 (0%) 1/2345 (0%)
    Intracranial aneurysm 0/2347 (0%) 1/2348 (0%) 2/2345 (0.1%)
    Intraventricular haemorrhage 0/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Ischaemic cerebral infarction 0/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Ischaemic stroke 45/2347 (1.9%) 45/2348 (1.9%) 29/2345 (1.2%)
    Lacunar infarction 1/2347 (0%) 0/2348 (0%) 1/2345 (0%)
    Leukoencephalopathy 0/2347 (0%) 0/2348 (0%) 1/2345 (0%)
    Loss of consciousness 5/2347 (0.2%) 3/2348 (0.1%) 5/2345 (0.2%)
    Mental retardation 0/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Metabolic encephalopathy 0/2347 (0%) 0/2348 (0%) 2/2345 (0.1%)
    Monoparesis 1/2347 (0%) 1/2348 (0%) 1/2345 (0%)
    Monoplegia 0/2347 (0%) 0/2348 (0%) 2/2345 (0.1%)
    Motor neurone disease 1/2347 (0%) 0/2348 (0%) 0/2345 (0%)
    Myelopathy 0/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Myoclonus 1/2347 (0%) 0/2348 (0%) 0/2345 (0%)
    Narcolepsy 0/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Nervous system disorder 0/2347 (0%) 0/2348 (0%) 2/2345 (0.1%)
    Orthostatic intolerance 0/2347 (0%) 0/2348 (0%) 1/2345 (0%)
    Paraesthesia 0/2347 (0%) 0/2348 (0%) 1/2345 (0%)
    Paraparesis 1/2347 (0%) 0/2348 (0%) 0/2345 (0%)
    Paresis cranial nerve 0/2347 (0%) 0/2348 (0%) 1/2345 (0%)
    Parkinson's disease 0/2347 (0%) 1/2348 (0%) 2/2345 (0.1%)
    Parkinsonism 1/2347 (0%) 0/2348 (0%) 1/2345 (0%)
    Partial seizures 1/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Peripheral sensory neuropathy 0/2347 (0%) 0/2348 (0%) 1/2345 (0%)
    Postresuscitation encephalopathy 1/2347 (0%) 0/2348 (0%) 0/2345 (0%)
    Presyncope 4/2347 (0.2%) 5/2348 (0.2%) 9/2345 (0.4%)
    Psychomotor hyperactivity 0/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Radiculopathy 0/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Restless legs syndrome 0/2347 (0%) 0/2348 (0%) 1/2345 (0%)
    Retrograde amnesia 1/2347 (0%) 0/2348 (0%) 0/2345 (0%)
    Reversible ischaemic neurological deficit 1/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Sciatica 1/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Seizure 1/2347 (0%) 4/2348 (0.2%) 0/2345 (0%)
    Somnolence 0/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Spinal claudication 0/2347 (0%) 2/2348 (0.1%) 0/2345 (0%)
    Spinal epidural haematoma 0/2347 (0%) 0/2348 (0%) 1/2345 (0%)
    Subarachnoid haemorrhage 3/2347 (0.1%) 1/2348 (0%) 3/2345 (0.1%)
    Syncope 48/2347 (2%) 56/2348 (2.4%) 27/2345 (1.2%)
    Tension headache 0/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Thalamus haemorrhage 0/2347 (0%) 0/2348 (0%) 1/2345 (0%)
    Transient global amnesia 0/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Transient ischaemic attack 23/2347 (1%) 20/2348 (0.9%) 15/2345 (0.6%)
    Tremor 1/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Trigeminal nerve disorder 0/2347 (0%) 0/2348 (0%) 1/2345 (0%)
    Uraemic encephalopathy 0/2347 (0%) 0/2348 (0%) 1/2345 (0%)
    VIIth nerve paralysis 0/2347 (0%) 1/2348 (0%) 2/2345 (0.1%)
    Vascular dementia 0/2347 (0%) 2/2348 (0.1%) 1/2345 (0%)
    Vascular encephalopathy 1/2347 (0%) 0/2348 (0%) 1/2345 (0%)
    Vertebrobasilar insufficiency 3/2347 (0.1%) 2/2348 (0.1%) 2/2345 (0.1%)
    Psychiatric disorders
    Abulia 1/2347 (0%) 0/2348 (0%) 0/2345 (0%)
    Acute psychosis 0/2347 (0%) 0/2348 (0%) 1/2345 (0%)
    Adjustment disorder 1/2347 (0%) 0/2348 (0%) 0/2345 (0%)
    Alcohol abuse 0/2347 (0%) 0/2348 (0%) 1/2345 (0%)
    Alcohol withdrawal syndrome 0/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Alcoholism 0/2347 (0%) 2/2348 (0.1%) 2/2345 (0.1%)
    Anxiety 2/2347 (0.1%) 2/2348 (0.1%) 4/2345 (0.2%)
    Anxiety disorder 0/2347 (0%) 0/2348 (0%) 1/2345 (0%)
    Apathy 1/2347 (0%) 0/2348 (0%) 0/2345 (0%)
    Bipolar disorder 0/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Catatonia 1/2347 (0%) 0/2348 (0%) 0/2345 (0%)
    Completed suicide 0/2347 (0%) 2/2348 (0.1%) 2/2345 (0.1%)
    Confusional state 4/2347 (0.2%) 4/2348 (0.2%) 3/2345 (0.1%)
    Delirium 1/2347 (0%) 3/2348 (0.1%) 2/2345 (0.1%)
    Delusion 1/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Depression 2/2347 (0.1%) 6/2348 (0.3%) 2/2345 (0.1%)
    Disorientation 0/2347 (0%) 1/2348 (0%) 1/2345 (0%)
    Fear 0/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Insomnia 0/2347 (0%) 0/2348 (0%) 1/2345 (0%)
    Major depression 1/2347 (0%) 0/2348 (0%) 0/2345 (0%)
    Mental status changes 0/2347 (0%) 0/2348 (0%) 1/2345 (0%)
    Mood disorder due to a general medical condition 1/2347 (0%) 0/2348 (0%) 0/2345 (0%)
    Psychotic disorder 2/2347 (0.1%) 3/2348 (0.1%) 0/2345 (0%)
    Restlessness 0/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Schizophrenia 0/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Somatisation disorder 0/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Suicidal ideation 1/2347 (0%) 0/2348 (0%) 0/2345 (0%)
    Suicide attempt 2/2347 (0.1%) 0/2348 (0%) 0/2345 (0%)
    Renal and urinary disorders
    Acute kidney injury 52/2347 (2.2%) 29/2348 (1.2%) 38/2345 (1.6%)
    Acute prerenal failure 1/2347 (0%) 2/2348 (0.1%) 2/2345 (0.1%)
    Anuria 1/2347 (0%) 1/2348 (0%) 1/2345 (0%)
    Azotaemia 1/2347 (0%) 0/2348 (0%) 0/2345 (0%)
    Calculus bladder 0/2347 (0%) 1/2348 (0%) 2/2345 (0.1%)
    Calculus ureteric 1/2347 (0%) 2/2348 (0.1%) 1/2345 (0%)
    Calculus urethral 1/2347 (0%) 0/2348 (0%) 0/2345 (0%)
    Calculus urinary 0/2347 (0%) 0/2348 (0%) 1/2345 (0%)
    Chronic kidney disease 21/2347 (0.9%) 10/2348 (0.4%) 10/2345 (0.4%)
    Diabetic nephropathy 0/2347 (0%) 0/2348 (0%) 1/2345 (0%)
    Dysuria 1/2347 (0%) 0/2348 (0%) 1/2345 (0%)
    Glomerulonephritis membranous 0/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Haematuria 4/2347 (0.2%) 6/2348 (0.3%) 5/2345 (0.2%)
    Hydronephrosis 0/2347 (0%) 0/2348 (0%) 1/2345 (0%)
    Hypertensive nephropathy 0/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Ischaemic nephropathy 1/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Nephritis 0/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Nephrolithiasis 3/2347 (0.1%) 1/2348 (0%) 1/2345 (0%)
    Nephropathy 0/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Nephrotic syndrome 0/2347 (0%) 1/2348 (0%) 1/2345 (0%)
    Polyuria 2/2347 (0.1%) 1/2348 (0%) 0/2345 (0%)
    Postrenal failure 1/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Prerenal failure 0/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Proteinuria 0/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Renal cyst 0/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Renal disorder 0/2347 (0%) 0/2348 (0%) 1/2345 (0%)
    Renal embolism 1/2347 (0%) 0/2348 (0%) 0/2345 (0%)
    Renal failure 33/2347 (1.4%) 26/2348 (1.1%) 27/2345 (1.2%)
    Renal impairment 34/2347 (1.4%) 31/2348 (1.3%) 33/2345 (1.4%)
    Renal infarct 0/2347 (0%) 0/2348 (0%) 2/2345 (0.1%)
    Renal tubular necrosis 0/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Ureteric fistula 0/2347 (0%) 0/2348 (0%) 1/2345 (0%)
    Ureteric stenosis 0/2347 (0%) 0/2348 (0%) 1/2345 (0%)
    Urethral obstruction 1/2347 (0%) 0/2348 (0%) 0/2345 (0%)
    Urethral stenosis 0/2347 (0%) 1/2348 (0%) 2/2345 (0.1%)
    Urinary bladder haemorrhage 0/2347 (0%) 0/2348 (0%) 1/2345 (0%)
    Urinary bladder polyp 1/2347 (0%) 0/2348 (0%) 1/2345 (0%)
    Urinary retention 3/2347 (0.1%) 7/2348 (0.3%) 2/2345 (0.1%)
    Urinary tract obstruction 0/2347 (0%) 2/2348 (0.1%) 0/2345 (0%)
    Urinoma 0/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Reproductive system and breast disorders
    Acquired hydrocele 1/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Benign prostatic hyperplasia 2/2347 (0.1%) 9/2348 (0.4%) 7/2345 (0.3%)
    Breast hyperplasia 1/2347 (0%) 0/2348 (0%) 0/2345 (0%)
    Mammary fistula 0/2347 (0%) 0/2348 (0%) 1/2345 (0%)
    Menorrhagia 1/2347 (0%) 0/2348 (0%) 0/2345 (0%)
    Metrorrhagia 0/2347 (0%) 1/2348 (0%) 1/2345 (0%)
    Ovarian cyst 1/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Postmenopausal haemorrhage 0/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Prostatic obstruction 0/2347 (0%) 1/2348 (0%) 1/2345 (0%)
    Prostatitis 0/2347 (0%) 0/2348 (0%) 1/2345 (0%)
    Prostatomegaly 0/2347 (0%) 1/2348 (0%) 2/2345 (0.1%)
    Rectocele 0/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Scrotal oedema 1/2347 (0%) 0/2348 (0%) 0/2345 (0%)
    Spermatocele 0/2347 (0%) 0/2348 (0%) 1/2345 (0%)
    Uterine polyp 2/2347 (0.1%) 0/2348 (0%) 0/2345 (0%)
    Respiratory, thoracic and mediastinal disorders
    Acute pulmonary oedema 20/2347 (0.9%) 20/2348 (0.9%) 17/2345 (0.7%)
    Acute respiratory distress syndrome 0/2347 (0%) 1/2348 (0%) 1/2345 (0%)
    Acute respiratory failure 13/2347 (0.6%) 8/2348 (0.3%) 14/2345 (0.6%)
    Alveolitis 0/2347 (0%) 0/2348 (0%) 1/2345 (0%)
    Apnoea 1/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Asphyxia 1/2347 (0%) 0/2348 (0%) 0/2345 (0%)
    Asthma 4/2347 (0.2%) 8/2348 (0.3%) 5/2345 (0.2%)
    Asthmatic crisis 0/2347 (0%) 0/2348 (0%) 1/2345 (0%)
    Bronchiectasis 0/2347 (0%) 1/2348 (0%) 1/2345 (0%)
    Bronchitis chronic 2/2347 (0.1%) 1/2348 (0%) 8/2345 (0.3%)
    Bronchopleural fistula 1/2347 (0%) 0/2348 (0%) 0/2345 (0%)
    Bronchospasm 2/2347 (0.1%) 1/2348 (0%) 0/2345 (0%)
    Cheyne-Stokes respiration 1/2347 (0%) 0/2348 (0%) 2/2345 (0.1%)
    Chronic obstructive pulmonary disease 32/2347 (1.4%) 32/2348 (1.4%) 43/2345 (1.8%)
    Chronic respiratory failure 0/2347 (0%) 2/2348 (0.1%) 0/2345 (0%)
    Cough 6/2347 (0.3%) 2/2348 (0.1%) 3/2345 (0.1%)
    Diaphragmatic paralysis 1/2347 (0%) 0/2348 (0%) 0/2345 (0%)
    Dyspnoea 54/2347 (2.3%) 46/2348 (2%) 35/2345 (1.5%)
    Dyspnoea at rest 0/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Dyspnoea exertional 1/2347 (0%) 2/2348 (0.1%) 3/2345 (0.1%)
    Dyspnoea paroxysmal nocturnal 0/2347 (0%) 2/2348 (0.1%) 2/2345 (0.1%)
    Emphysema 0/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Epistaxis 4/2347 (0.2%) 3/2348 (0.1%) 8/2345 (0.3%)
    Haemoptysis 4/2347 (0.2%) 2/2348 (0.1%) 5/2345 (0.2%)
    Haemothorax 1/2347 (0%) 2/2348 (0.1%) 1/2345 (0%)
    Hiccups 0/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Hydrothorax 3/2347 (0.1%) 2/2348 (0.1%) 3/2345 (0.1%)
    Hypercapnia 0/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Hyperventilation 0/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Hypoxia 1/2347 (0%) 0/2348 (0%) 1/2345 (0%)
    Idiopathic pulmonary fibrosis 0/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Interstitial lung disease 2/2347 (0.1%) 0/2348 (0%) 3/2345 (0.1%)
    Laryngeal oedema 1/2347 (0%) 0/2348 (0%) 0/2345 (0%)
    Lung disorder 0/2347 (0%) 0/2348 (0%) 2/2345 (0.1%)
    Lung infiltration 0/2347 (0%) 2/2348 (0.1%) 0/2345 (0%)
    Mediastinal mass 0/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Nasal septum deviation 1/2347 (0%) 0/2348 (0%) 0/2345 (0%)
    Organising pneumonia 1/2347 (0%) 0/2348 (0%) 0/2345 (0%)
    Oropharyngeal pain 1/2347 (0%) 0/2348 (0%) 0/2345 (0%)
    Orthopnoea 3/2347 (0.1%) 0/2348 (0%) 2/2345 (0.1%)
    Pharyngeal oedema 1/2347 (0%) 0/2348 (0%) 0/2345 (0%)
    Pleural effusion 10/2347 (0.4%) 11/2348 (0.5%) 12/2345 (0.5%)
    Pleurisy 2/2347 (0.1%) 2/2348 (0.1%) 3/2345 (0.1%)
    Pleurocutaneous fistula 0/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Pneumomediastinum 0/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Pneumonia aspiration 5/2347 (0.2%) 6/2348 (0.3%) 4/2345 (0.2%)
    Pneumonitis 1/2347 (0%) 3/2348 (0.1%) 1/2345 (0%)
    Pneumothorax 1/2347 (0%) 3/2348 (0.1%) 4/2345 (0.2%)
    Pneumothorax spontaneous 1/2347 (0%) 0/2348 (0%) 0/2345 (0%)
    Productive cough 0/2347 (0%) 1/2348 (0%) 1/2345 (0%)
    Pulmonary alveolar haemorrhage 0/2347 (0%) 0/2348 (0%) 1/2345 (0%)
    Pulmonary arterial hypertension 0/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Pulmonary artery thrombosis 0/2347 (0%) 0/2348 (0%) 1/2345 (0%)
    Pulmonary congestion 3/2347 (0.1%) 1/2348 (0%) 1/2345 (0%)
    Pulmonary embolism 17/2347 (0.7%) 18/2348 (0.8%) 9/2345 (0.4%)
    Pulmonary fibrosis 0/2347 (0%) 0/2348 (0%) 1/2345 (0%)
    Pulmonary haematoma 0/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Pulmonary hypertension 6/2347 (0.3%) 4/2348 (0.2%) 4/2345 (0.2%)
    Pulmonary mass 1/2347 (0%) 0/2348 (0%) 0/2345 (0%)
    Pulmonary oedema 27/2347 (1.2%) 27/2348 (1.1%) 14/2345 (0.6%)
    Pulmonary venous thrombosis 0/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Respiratory arrest 1/2347 (0%) 2/2348 (0.1%) 0/2345 (0%)
    Respiratory distress 0/2347 (0%) 4/2348 (0.2%) 3/2345 (0.1%)
    Respiratory failure 16/2347 (0.7%) 16/2348 (0.7%) 26/2345 (1.1%)
    Sleep apnoea syndrome 3/2347 (0.1%) 2/2348 (0.1%) 1/2345 (0%)
    Snoring 1/2347 (0%) 0/2348 (0%) 0/2345 (0%)
    Suffocation feeling 1/2347 (0%) 0/2348 (0%) 0/2345 (0%)
    Vocal cord leukoplakia 1/2347 (0%) 0/2348 (0%) 0/2345 (0%)
    Skin and subcutaneous tissue disorders
    Acquired epidermolysis bullosa 1/2347 (0%) 0/2348 (0%) 0/2345 (0%)
    Actinic keratosis 0/2347 (0%) 0/2348 (0%) 1/2345 (0%)
    Angioedema 1/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Decubitus ulcer 3/2347 (0.1%) 1/2348 (0%) 1/2345 (0%)
    Dermal cyst 1/2347 (0%) 0/2348 (0%) 0/2345 (0%)
    Dermatitis 1/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Dermatitis allergic 0/2347 (0%) 0/2348 (0%) 1/2345 (0%)
    Dermatitis bullous 1/2347 (0%) 0/2348 (0%) 0/2345 (0%)
    Dermatitis contact 0/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Diabetic foot 5/2347 (0.2%) 1/2348 (0%) 0/2345 (0%)
    Diabetic ulcer 1/2347 (0%) 0/2348 (0%) 0/2345 (0%)
    Drug eruption 0/2347 (0%) 0/2348 (0%) 1/2345 (0%)
    Ecchymosis 0/2347 (0%) 0/2348 (0%) 1/2345 (0%)
    Erythema 0/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Fungating wound 0/2347 (0%) 0/2348 (0%) 1/2345 (0%)
    Henoch-Schonlein purpura 0/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Hyperhidrosis 0/2347 (0%) 0/2348 (0%) 1/2345 (0%)
    Intertrigo 1/2347 (0%) 0/2348 (0%) 0/2345 (0%)
    Lichen sclerosus 1/2347 (0%) 0/2348 (0%) 0/2345 (0%)
    Neuropathic ulcer 0/2347 (0%) 0/2348 (0%) 1/2345 (0%)
    Peau d'orange 0/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Precancerous skin lesion 1/2347 (0%) 0/2348 (0%) 0/2345 (0%)
    Pruritus 0/2347 (0%) 0/2348 (0%) 1/2345 (0%)
    Psoriasis 1/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Purpura 0/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Rash 1/2347 (0%) 0/2348 (0%) 0/2345 (0%)
    Seborrhoeic dermatitis 0/2347 (0%) 0/2348 (0%) 1/2345 (0%)
    Skin necrosis 1/2347 (0%) 0/2348 (0%) 0/2345 (0%)
    Skin ulcer 4/2347 (0.2%) 4/2348 (0.2%) 4/2345 (0.2%)
    Skin ulcer haemorrhage 0/2347 (0%) 0/2348 (0%) 1/2345 (0%)
    Toxic skin eruption 2/2347 (0.1%) 0/2348 (0%) 0/2345 (0%)
    Social circumstances
    Immobile 1/2347 (0%) 0/2348 (0%) 1/2345 (0%)
    Treatment noncompliance 0/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Surgical and medical procedures
    Heart transplant 0/2347 (0%) 1/2348 (0%) 1/2345 (0%)
    Implantable defibrillator insertion 0/2347 (0%) 3/2348 (0.1%) 1/2345 (0%)
    Vascular disorders
    Accelerated hypertension 5/2347 (0.2%) 1/2348 (0%) 1/2345 (0%)
    Aneurysm ruptured 0/2347 (0%) 0/2348 (0%) 1/2345 (0%)
    Aortic aneurysm 0/2347 (0%) 8/2348 (0.3%) 8/2345 (0.3%)
    Aortic aneurysm rupture 2/2347 (0.1%) 1/2348 (0%) 2/2345 (0.1%)
    Aortic arteriosclerosis 1/2347 (0%) 0/2348 (0%) 0/2345 (0%)
    Aortic dilatation 0/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Aortic dissection 1/2347 (0%) 0/2348 (0%) 2/2345 (0.1%)
    Aortic rupture 0/2347 (0%) 2/2348 (0.1%) 0/2345 (0%)
    Aortic stenosis 2/2347 (0.1%) 3/2348 (0.1%) 1/2345 (0%)
    Aortic thrombosis 1/2347 (0%) 0/2348 (0%) 0/2345 (0%)
    Arterial insufficiency 0/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Arterial stenosis 0/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Arterial thrombosis 0/2347 (0%) 0/2348 (0%) 1/2345 (0%)
    Arteriosclerosis 3/2347 (0.1%) 1/2348 (0%) 0/2345 (0%)
    Arteriovenous fistula 0/2347 (0%) 0/2348 (0%) 1/2345 (0%)
    Arteritis 1/2347 (0%) 0/2348 (0%) 0/2345 (0%)
    Bleeding varicose vein 0/2347 (0%) 0/2348 (0%) 1/2345 (0%)
    Circulatory collapse 7/2347 (0.3%) 3/2348 (0.1%) 3/2345 (0.1%)
    Deep vein thrombosis 3/2347 (0.1%) 5/2348 (0.2%) 4/2345 (0.2%)
    Diabetic vascular disorder 0/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Embolism arterial 0/2347 (0%) 0/2348 (0%) 1/2345 (0%)
    Embolism venous 0/2347 (0%) 0/2348 (0%) 1/2345 (0%)
    Extremity necrosis 2/2347 (0.1%) 2/2348 (0.1%) 0/2345 (0%)
    Femoral artery embolism 0/2347 (0%) 0/2348 (0%) 1/2345 (0%)
    Femoral artery occlusion 2/2347 (0.1%) 3/2348 (0.1%) 2/2345 (0.1%)
    Haematoma 5/2347 (0.2%) 1/2348 (0%) 4/2345 (0.2%)
    Haemodynamic instability 0/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Hypertension 17/2347 (0.7%) 13/2348 (0.6%) 10/2345 (0.4%)
    Hypertensive crisis 7/2347 (0.3%) 4/2348 (0.2%) 3/2345 (0.1%)
    Hypertensive emergency 2/2347 (0.1%) 0/2348 (0%) 1/2345 (0%)
    Hypotension 37/2347 (1.6%) 49/2348 (2.1%) 26/2345 (1.1%)
    Hypovolaemic shock 1/2347 (0%) 4/2348 (0.2%) 2/2345 (0.1%)
    Iliac artery embolism 0/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Iliac artery occlusion 0/2347 (0%) 1/2348 (0%) 1/2345 (0%)
    Intermittent claudication 5/2347 (0.2%) 5/2348 (0.2%) 3/2345 (0.1%)
    Ischaemia 0/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Ischaemic limb pain 1/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Orthostatic hypotension 5/2347 (0.2%) 3/2348 (0.1%) 4/2345 (0.2%)
    Peripheral arterial occlusive disease 18/2347 (0.8%) 13/2348 (0.6%) 11/2345 (0.5%)
    Peripheral artery aneurysm 1/2347 (0%) 1/2348 (0%) 1/2345 (0%)
    Peripheral artery stenosis 5/2347 (0.2%) 2/2348 (0.1%) 3/2345 (0.1%)
    Peripheral artery thrombosis 0/2347 (0%) 3/2348 (0.1%) 4/2345 (0.2%)
    Peripheral embolism 4/2347 (0.2%) 2/2348 (0.1%) 3/2345 (0.1%)
    Peripheral ischaemia 5/2347 (0.2%) 8/2348 (0.3%) 3/2345 (0.1%)
    Peripheral vascular disorder 1/2347 (0%) 2/2348 (0.1%) 1/2345 (0%)
    Peripheral venous disease 0/2347 (0%) 4/2348 (0.2%) 4/2345 (0.2%)
    Post thrombotic syndrome 0/2347 (0%) 1/2348 (0%) 2/2345 (0.1%)
    Secondary hypertension 1/2347 (0%) 0/2348 (0%) 0/2345 (0%)
    Shock 2/2347 (0.1%) 1/2348 (0%) 1/2345 (0%)
    Shock haemorrhagic 1/2347 (0%) 1/2348 (0%) 2/2345 (0.1%)
    Subclavian artery stenosis 0/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Thrombophlebitis 1/2347 (0%) 0/2348 (0%) 0/2345 (0%)
    Thrombophlebitis superficial 0/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Thrombosis 2/2347 (0.1%) 1/2348 (0%) 2/2345 (0.1%)
    Varicophlebitis 0/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Varicose ulceration 0/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Varicose vein 0/2347 (0%) 3/2348 (0.1%) 1/2345 (0%)
    Vascular rupture 0/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Venous haemorrhage 0/2347 (0%) 1/2348 (0%) 0/2345 (0%)
    Venous thrombosis 1/2347 (0%) 0/2348 (0%) 0/2345 (0%)
    Venous thrombosis limb 1/2347 (0%) 0/2348 (0%) 0/2345 (0%)
    Other (Not Including Serious) Adverse Events
    Combination of Aliskiren and Enalapril Aliskiren Enalapril
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 1698/2347 (72.3%) 1605/2348 (68.4%) 1623/2345 (69.2%)
    Blood and lymphatic system disorders
    Anaemia 124/2347 (5.3%) 115/2348 (4.9%) 111/2345 (4.7%)
    Cardiac disorders
    Angina pectoris 81/2347 (3.5%) 86/2348 (3.7%) 71/2345 (3%)
    Atrial fibrillation 199/2347 (8.5%) 238/2348 (10.1%) 184/2345 (7.8%)
    Cardiac failure 241/2347 (10.3%) 254/2348 (10.8%) 238/2345 (10.1%)
    Ventricular tachycardia 55/2347 (2.3%) 74/2348 (3.2%) 55/2345 (2.3%)
    Gastrointestinal disorders
    Constipation 96/2347 (4.1%) 79/2348 (3.4%) 82/2345 (3.5%)
    Diarrhoea 145/2347 (6.2%) 117/2348 (5%) 116/2345 (4.9%)
    Nausea 68/2347 (2.9%) 78/2348 (3.3%) 55/2345 (2.3%)
    General disorders
    Fatigue 96/2347 (4.1%) 107/2348 (4.6%) 101/2345 (4.3%)
    Oedema peripheral 182/2347 (7.8%) 183/2348 (7.8%) 176/2345 (7.5%)
    Infections and infestations
    Bronchitis 151/2347 (6.4%) 138/2348 (5.9%) 147/2345 (6.3%)
    Influenza 91/2347 (3.9%) 62/2348 (2.6%) 86/2345 (3.7%)
    Nasopharyngitis 185/2347 (7.9%) 187/2348 (8%) 186/2345 (7.9%)
    Pneumonia 84/2347 (3.6%) 95/2348 (4%) 78/2345 (3.3%)
    Upper respiratory tract infection 84/2347 (3.6%) 74/2348 (3.2%) 79/2345 (3.4%)
    Urinary tract infection 92/2347 (3.9%) 82/2348 (3.5%) 84/2345 (3.6%)
    Investigations
    Blood creatinine increased 97/2347 (4.1%) 70/2348 (3%) 57/2345 (2.4%)
    Glomerular filtration rate decreased 88/2347 (3.7%) 50/2348 (2.1%) 79/2345 (3.4%)
    Metabolism and nutrition disorders
    Diabetes mellitus 99/2347 (4.2%) 96/2348 (4.1%) 84/2345 (3.6%)
    Gout 113/2347 (4.8%) 88/2348 (3.7%) 91/2345 (3.9%)
    Hyperkalaemia 469/2347 (20%) 283/2348 (12.1%) 350/2345 (14.9%)
    Hyperuricaemia 101/2347 (4.3%) 108/2348 (4.6%) 93/2345 (4%)
    Hypokalaemia 130/2347 (5.5%) 149/2348 (6.3%) 116/2345 (4.9%)
    Musculoskeletal and connective tissue disorders
    Arthralgia 72/2347 (3.1%) 86/2348 (3.7%) 71/2345 (3%)
    Back pain 90/2347 (3.8%) 82/2348 (3.5%) 98/2345 (4.2%)
    Nervous system disorders
    Dizziness 179/2347 (7.6%) 140/2348 (6%) 144/2345 (6.1%)
    Headache 55/2347 (2.3%) 71/2348 (3%) 67/2345 (2.9%)
    Psychiatric disorders
    Insomnia 91/2347 (3.9%) 92/2348 (3.9%) 98/2345 (4.2%)
    Renal and urinary disorders
    Renal impairment 414/2347 (17.6%) 298/2348 (12.7%) 328/2345 (14%)
    Respiratory, thoracic and mediastinal disorders
    Cough 285/2347 (12.1%) 223/2348 (9.5%) 286/2345 (12.2%)
    Dyspnoea 204/2347 (8.7%) 216/2348 (9.2%) 213/2345 (9.1%)
    Vascular disorders
    Hypertension 188/2347 (8%) 180/2348 (7.7%) 137/2345 (5.8%)
    Hypotension 409/2347 (17.4%) 308/2348 (13.1%) 332/2345 (14.2%)

    Limitations/Caveats

    [Not Specified]

    More Information

    Certain Agreements

    Principal Investigators are NOT employed by the organization sponsoring the study.

    The terms and conditions of Novartis' agreements with its investigators may vary. However, Novartis does not prohibit any investigator from publishing. Any publications from a single-site are postponed until the publication of the pooled data (i.e., data from all sites) in the clinical trial or disclosure of trial results in their entirety.

    Results Point of Contact

    Name/Title Study Director
    Organization Novartis Pharmaceuticals
    Phone 862-778-8300
    Email
    Responsible Party:
    Novartis Pharmaceuticals
    ClinicalTrials.gov Identifier:
    NCT00853658
    Other Study ID Numbers:
    • CSPP100F2301
    • 2008-004104-31
    First Posted:
    Mar 2, 2009
    Last Update Posted:
    Nov 25, 2016
    Last Verified:
    Oct 1, 2016