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AVERROES: A Phase III Study of Apixaban in Patients With Atrial Fibrillation

Sponsor
Bristol-Myers Squibb (Industry)
Overall Status
Completed
CT.gov ID
NCT00496769
Collaborator
Pfizer (Industry)
6,421
Enrollment
503
Locations
2
Arms
116.8
Actual Duration (Months)
12.8
Patients Per Site
0.1
Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The purpose of this clinical research study is to determine whether apixaban is more effective than acetylsalicylic acid in the prevention of strokes associated with patients with atrial fibrillation. The safety of this treatment will also be studied.

Condition or Disease Intervention/Treatment Phase
Phase 3

Detailed Description

An optional Long-term Open-label Extension Phase of treatment with apixaban will be provided for qualifying participants following the conclusion of the double-blind phase

Study Design

Study Type:
Interventional
Actual Enrollment :
6421 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
Double (Participant, Investigator)
Primary Purpose:
Prevention
Official Title:
Apixaban Versus Acetylsalicylic Acid (ASA) to Prevent Stroke in Atrial Fibrillation Patients Who Have Failed or Are Unsuitable for Vitamin K Antagonist Treatment: A Randomized Double-blind Trial
Actual Study Start Date :
Aug 31, 2007
Actual Primary Completion Date :
Nov 30, 2010
Actual Study Completion Date :
May 25, 2017

Arms and Interventions

Arm Intervention/Treatment
Experimental: Apixaban

Drug: Apixaban
Tablets, oral, 5 mg (2.5 mg in patients meeting any 2 of the following criteria: 80 years of age and older, weight of 60 kilograms or less, and a serum creatinine level of 1.5 mg/dL or higher), twice daily, up to 156 weeks
Other Names:
  • BMS-562247

    		•
    Active Comparator: Acetylasalicylic acid

    Drug: Acetylsalicylic acid
    Tablets, oral, 81-324 mg, once daily, up to 156 weeks

    Outcome Measures

    Primary Outcome Measures

    1. Event Rate of Stroke/Systemic Embolism During the Intended-treatment Period [Randomization to efficacy cutoff date of May 28, 2010 (date revised following cessation of study for superior efficacy)]

      Event rate=percent of participants with an event divided by the total participants in the arm. Intended-treatment period=date of randomization to the efficacy cutoff date, which was to be the date on which at least 226 unrefuted original primary efficacy events occurred (date revised to May 28, 2010 following cessation of study for superior efficacy.)

    Secondary Outcome Measures

    1. Event Rate for the Composite of Stroke of Any Type, Systemic Embolism, Myocardial Infarction, or Vascular Death During the Double-blind Treatment Period [Randomization to efficacy cutoff date of May 28, 2010 (date revised following cessation of study for superior efficacy)]

      Event rate=percent of participants with an event divided by the total participants in the arm.

    2. Event Rate of All-cause Death; Net Clinical Benefit-Composite of Stroke, Systemic Embolism, Myocardial Infarction, Vascular Death, and Major Bleeding; and Vascular Death [Randomization to efficacy cutoff date of May 28, 2010 (date revised following cessation of study for superior efficacy)]

      Event rate=percent of participants with an event divided by the total participants in the arm.

    3. Event Rates for Major Bleeding, Major or Clinically Relevant Nonmajor (CNRM) Bleeding, and All Bleeding in the Double-blind Period [First dose of study drug (Day 1) to the earlier of a patient's discontinuation of double-blind study drug or the attainment of at least 226 primary efficacy events up to May 28, 2010]

      Event rate=percent of participants with an event divided by the total participants in the arm.

    4. Rate of Unrefuted Bleeding From First Dose of Double-blind Study Drug to First Occurence of Unrefuted Bleeding During the Double-blind Treatment Period [Day 1 to first bleeding event up to efficacy cutoff date of May 28, 2010 (date revised following cessation of study for superior efficacy)]

      Event rate=percent of participants with an event divided by the total participants in the arm.

    5. Number of Participants With Serious Adverse Events (SAEs), Adverse Events (AEs), Bleeding AEs, Discontinuations Due to AEs, and Death as Outcome [First dose of study drug (Day 1) to 30 days after last dose of blinded study drug]

      AE=any new unfavorable symptom, sign, or disease or worsening of a preexisting condition that may not have a causal relationship with treatment. SAE=a medical event that at any dose results in death, persistent or significant disability/incapacity, or drug dependency/abuse; is life-threatening, an important medical event, or a congenital anomaly/birth defect; or requires or prolongs hospitalization.

    6. Number of Participants With Laboratory Test Results Meeting the Criteria for Marked Abnormality [First dose of study drug (Day 1) to 30 days after last dose of blinded study drug]

      BL=baseline, LLN=lower limit of normal, ULN=upper limit of normal. Hemoglobin (g/dL), low: BL>2 or value ≤8; hematocrit(%), low: <0.75*BL; erythrocytes (*10^6 cells/μL), low: <0.75*BL; platelet count (*10^9 cells/L),low: <100*10^9 cells/L; leukocytes (*10^3 cells/μL), low if <0.8*BL and BL<LLN or <LLN and BL >ULN or <0.75*LLN when BL is missing or LLN ≤BL≤ ULN, high if >1.2*BL and BL>ULN or >ULN when BL and BL<LLN or >1.25*ULN when BL is missing or LLN≤BL≤ULN; neutrophils (absolute), low: <1.0*10^3 cells/μL; eosinophils (absolute), high: >0.750*10^3 cells/μL; basophils (absolute), high: >0.4*10^3 cells/μL; monocytes (absolute), high: 2*10^3 cells/μL; lymphocytes (absolute), low if <0.75*10^3 cells/μL, high if >7.50*10^3 cells/μL; ALP (U/L), high: 2*ULN; AST (U/L), high: 3*ULN; AST (U/L), high: 3*ULN; bilirubin, total (mg/dL), high: >2*ULN; bilirubin, direct (mg/dL), high: 1.5*ULN; BUN (mg/dL), high:>2*ULN; creatinine (mg/dL), high: >1.5*ULN.

    7. Number of Participants With Laboratory Test Results Meeting the Criteria for Marked Abnormality (Continued) [First dose of study drug (Day 1) to 30 days after last dose of blinded study drug]

      LLN=lower limit of normal; ULN=upper limit of normal; BL=baseline. Sodium, serum (mEq/L):low if <0.95*BL and BL<LLN or <LLN and BL>ULN or <0.95*LLN when BL missing or LLN ≤BL≤ULN, high if >1.05*BL and BL>ULN or >ULN and BL<LLN or >1.05*ULN when BL missing or LLN≤BL≤ULN; potassium(mEq/L):low if <0.90*BL and BL<LLN or <LLN and BL>ULN or <0.90*LLN if BL missing or LLN≤BL≤ULN, high if >1.10*BL and BL>ULN or>ULN and BL<LLN or >1.10*ULN when BL missing or LLN≤BL≤ULN; chloride(mEq/L):low if <0.90*BL and BL<LLN or <LLN and BL>ULN or <0.90*LLN if BL missing or LLN≤BL ≤ULN, high if >1.10*BL and BL>ULN or >ULN and BL<LLN or >1.10* ULN if BL missing or LLN≤BL≤ULN; calcium(mg/dL):low if <0.75*BL and BL<LLN or <LLN and BL>ULN or <0.80*LLN if BL missing or LLN≤BL≤ULN, high if >1.25*BL and BL>ULN or >ULN if BL<LLN or >1.20*ULN if BL missing or LLN≤BL≤ULN ; bicarbonate(mEq/L):low if <0.75*BL when BL<LLN or <LLN when BL>ULN or <0.75*LLN if BL missing or LLN≤BL≤ULN, high if >1.25*BL when BL>ULN or >ULN

    8. Number of Participants With Laboratory Test Results Meeting the Criteria for Marked Abnormality (Continued) [First dose of study drug (Day 1) to 30 days after last dose of blinded study drug]

      ULN=upper limit of normal; LLN=lower limit of normal; BL=baseline. Creatine kinase (U/L), high:>5*ULN; protein, total(g/L):low if <0.90*BL when BL<LLN or <LLN when B >ULN or <0.90*LLN when BL is missing or LLN≤BL≤ULN, high if >1.10*BL if BL>ULN or >ULN when BL<LLN or >1.10*ULN if BL missing or LLN≤BL≤ULN.Protein,total(g/L): low if <0.90*BL if BL<LLN or <LLN if BL>ULN or <0.90*LLN if BL missing or LLN≤BL≤ULN, high if >1.10*BL if BL>ULN or >ULN if BL<LLN or >1.10*ULN if BL or LLN≤BL≤ULN; glucose, serum fasting (mg/dL): low if <0.8*BL if BL<LLN or <LLN when BL>ULN or <0.8*LLN when BL missing or LLN≤BL≤ULN, high if >2*BL when BL>ULN or >ULN when BL<LLN or >1.5*ULN if BL missing or LLN≤BL≤ULN; uric acid (mg/dL), high: >2*BL and BL>ULN or>1.5*ULN when BL missing or BL≤ULN; glucose, urine, high; protein, urine, high; blood, urine, high; leukocyte esterase, urine, high; RBC count, urine (Hpf), high; WBC count, urine (Hpf), high: ≥2 if BL=missing,=0 or =0.5 or if ≥3 if BL=1, or if ≥4 and BL≥2.

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    50 Years and Older
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    Key Inclusion Criteria:

    • Male and female

    • Age of 50 years or older

    • Permanent, paroxysmal, or persistent atrial fibrillation (at screening or within 6 months prior to enrollment) documented by 12-lead electrocardiogram)

    • At least 1 of the following risk factors for stroke:

    • Prior stroke or transient ischemic attack

    • Age of 75 years or older

    • Arterial hypertension on treatment

    • Diabetes mellitus

    • Heart failure (New York Health Authority Class 2 or greater at time of enrollment)

    • Left ventricular ejection fraction of 35% or less, documented within 6 months of enrollment

    • Peripheral arterial disease (previous arterial revascularization, limb or foot amputation, or current intermittent claudication with ankle-arm systolic blood pressure ratio <0.9)

    • Not currently receiving vitamin K antagonist therapy for 1 of the following reasons:

    • Previous vitamin K antagonist therapy demonstrated as unsuitable and discontinued

    • Vitamin K antagonist therapy not previously used but expected unsuitable

    Key Exclusion Criteria:

    • Women who are pregnant or breast feeding

    • Women of child bearing potential who are unwilling to meet the study requirements for pregnancy testing or are unwilling or unable to use an acceptable method to avoid pregnancy

    • Atrial fibrillation due to reversible causes, such as thyrotoxicosis or pericarditis

    • Valvular disease requiring surgery

    • Planned ablation procedure for atrial fibrillation to be performed within 3 months

    • Conditions other than atrial fibrillation that require chronic anticoagulation (such as, prosthetic mechanical heart valve, venous thromboembolism)

    • Patients with serious bleeding in the last 6 months or at high risk for bleeding, including but not limited to those with:

    • Active peptic ulcer disease

    • Platelet count <100,000/mm^3 or hemoglobin <10g/dL

    • Recent stroke (within 10 days)

    • Documented hemorrhagic tendencies or blood dyscrasias

    • Current alcohol or drug abuse or psychosocial reasons that make study participation impractical

    • Severe comorbid condition with life expectancy <1 year

    • Severe renal insufficiency; any patient with a serum creatinine level >2.5 mg/dL or a calculated creatinine clearance <25 mL/min is excluded

    • Alanine transaminase or aspartate aminotransferase levels >2 times upper limit of normal (ULN) or a total bilirubin level >1.5 times ULN (unless an alternative causative factor [such as Gilbert's syndrome] is identified)

    • Allergy or adverse reaction to acetylsalicylic acid

    • Required treatment with a thienopyridine (clopidogrel or ticlopidine)

    • Prisoners or participants who are compulsory detained (involuntarily incarcerated)

    • Use of an investigational drug or device within the past 30 days or prior randomization into an apixaban clinical study

    • Patients who are compulsorily detained for treatment for a psychiatric or physical illness

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 Mobile Heart Specialists, Pc Mobile Alabama United States 36608
    2 Southwest Heart Tucson Arizona United States 85710
    3 Cardiology Consultants Of Orange County Med. Group Inc Anaheim California United States 92801
    4 Kaiser Permanente Medical Center, West Los Angeles Los Angeles California United States 90034
    5 Desert Med Grp Inc, Dba Desert Oasis Healthcare Med Group Palm Springs California United States 92262
    6 Yogesh K. Paliwal Md Pomona California United States 91767
    7 San Diego Managed Care Group Poway California United States 92064
    8 University Of California, San Diego San Diego California United States 92103
    9 Santa Rosa Cardiology Santa Rosa California United States 95405
    10 North County Internal Medicine Vista California United States 92083
    11 Cardiology Associates Of New Haven,Pc Guilford Connecticut United States 06437
    12 Stamford Therapeutics Consortium Stamford Connecticut United States 06905
    13 Bay Pines Va Healthcare System Bay Pines Florida United States 33744
    14 Research Alliance, Inc. Clearwater Florida United States 33756
    15 The Heart & Vascular Institute Of Florida Clearwater Florida United States 33756
    16 Kim A. Klancke, Md Daytona Beach Florida United States 32114
    17 The Heart Group Pl Fort Myers Florida United States 33908
    18 Baptist Heart Specialists Jacksonville Beach Florida United States 32250
    19 St. Vincent'S Ambulatory Care, Inc Jacksonville Florida United States 32204
    20 Michael F. Lesser, Md, Facc Osler Medical Inc. Melbourne Florida United States 32901
    21 Cardiovascular Center Of Sarasota Sarasota Florida United States 34239
    22 The Broward Heart Group, Pa Tamarac Florida United States 33321
    23 Southeast Regional Research Group Columbus Georgia United States 31904
    24 Southeast Regional Research Group Savannah Georgia United States 31406
    25 Fox Valley Clinical Research Center, Llc Aurora Illinois United States 60504
    26 North Chicago Va Medical Center North Chicago Illinois United States 60064
    27 Indiana Heart Physicians, Inc. Indianapolis Indiana United States 46237
    28 The Care Group, Llc Indianapolis Indiana United States 46290
    29 Hutchinson Clinic, Pa Hutchinson Kansas United States 67502
    30 Dr. Jeffrey Chen Lafayette Louisiana United States 70506
    31 Peninsula Cardiology Associates, P.A. Salisbury Maryland United States 21804
    32 Pentucket Medical Associates Haverhill Massachusetts United States 01830
    33 Great Lakes Heart Center Of Alpena Alpena Michigan United States 49707
    34 Henry Ford Hospital K-15 Detroit Michigan United States 48202
    35 Michigan Heart And Vascular Specialists Petoskey Michigan United States 49770
    36 Academic Cardiology Associates Rochester Hills Michigan United States 48307
    37 Tupelo Neurology Clinic, Pa Tupelo Mississippi United States 38801
    38 Missouri Cardiovascular Specialists Columbia Missouri United States 65201
    39 University Of Missouri Columbia Missouri United States 65212
    40 Glacier View Cardiology, Pc Kalispell Montana United States 59901
    41 Hunterdon Cardiovascular Associates Flemington New Jersey United States 08822
    42 Capital Cardiology Associates Albany New York United States 12211
    43 Nyu Hudson Valley Cardiology Cortlandt Manor New York United States 10567
    44 Long Island Heart Associates Mineola New York United States 11501
    45 Dr William Kufs Saratoga Springs New York United States 12866
    46 Capital Cardiology Associates Troy New York United States 12180
    47 Terry V. Arnold, Md Lexington North Carolina United States 27293
    48 Pinehurst Medical Clinic, Inc Pinehurst North Carolina United States 28374
    49 Sanford Cardiology Sanford North Carolina United States 27330
    50 Ira R. Friedlander, M.D. Canton Ohio United States 44710
    51 Davis Heart & Lung Research Institute Columbus Ohio United States 43210
    52 Integris Cardiovascular Physicians Oklahoma City Oklahoma United States 73112
    53 South Oklahoma Heart Research Oklahoma City Oklahoma United States 73135
    54 Oregon Medical Group - Clinical Research Eugene Oregon United States 97401
    55 Hillsboro Cardiology Pc Hillsboro Oregon United States 97123
    56 The Portland Clinic, Llp Portland Oregon United States 97205
    57 Comprehensive Cardiology Consultants Langhorne Pennsylvania United States 19047
    58 Grand View - Lehigh Valley Health Services Sellersville Pennsylvania United States 18960
    59 West Chester Cardiology West Chester Pennsylvania United States 19380
    60 Cardiology Consultants Of Philadelphia Yardley Pennsylvania United States 19067
    61 Lowcountry Medical Group, Llc Beaufort South Carolina United States 29906
    62 Medical University Of South Carolina Charleston South Carolina United States 29425
    63 Internal Medicine Of Greer Greer South Carolina United States 29650
    64 Knoxville Heart Group Knoxville Tennessee United States 37916
    65 Sentara York Clinical Research Norfolk Virginia United States 23510
    66 Roanoke Heart Institute, Plc Roanoke Virginia United States 24014
    67 Salem Veterans Administration Medical Center Salem Virginia United States 24153
    68 Walla Walla Clinic Walla Walla Washington United States 99362
    69 Marshfield Clinic Marshfield Wisconsin United States 54449
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    326 Local Institution Kuri-city Kyunggi-do Korea, Republic of 471-701
    327 Local Institution Busan Korea, Republic of 602-702
    328 Local Institution Daegu Korea, Republic of 700-721
    329 Local Institution Daejeon Korea, Republic of 302-718
    330 Local Institution Gwangju Korea, Republic of 501-757
    331 Local Institution Seoul Korea, Republic of 110-744
    332 Local Institution Seoul Korea, Republic of 130-709
    333 Local Institution Seoul Korea, Republic of 143-729
    334 Local Institution Johor Bahru Johor Malaysia 80100
    335 Local Institution Cheras Kuala Lumpur Malaysia 56000
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    340 Local Institution Mexico Distrito Federal Mexico 06726
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    348 Local Institution San Luis Potosi, Slp San Luis Potosi Mexico 78240
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    350 Local Institution Hermosillo Sonora Mexico 83190
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    352 Local Institution Aguascalientes Mexico 20127
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    354 Local Institution Chihuahua Mexico 31203
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    358 Local Institution Fyllingsdal Norway 5145
    359 Local Institution Kongsberg Norway 3602
    360 Local Institution Oslo Norway 0264
    361 Local Institution Oslo Norway 0450
    362 Local Institution Naga City Camarines SUR Philippines 4400
    363 Local Institution Binan Laguna Philippines 4024
    364 Local Institution Iligan City Lanao DEL Norte Philippines 9200
    365 Local Institution Cagayan De Oro City Philippines 9000
    366 Local Institution Cavite Philippines 4114
    367 Local Institution Laoag City Philippines 2900
    368 Local Institution Manila Philippines 1000
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    370 Local Institution Czestochowa Poland 42-200
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    388 Local Institution Warsaw Poland 00-217
    389 Local Institution Warszawa Poland 03-242
    390 Local Institution Warszawa Poland 04-073
    391 Local Institution Wegrow Poland 07-100
    392 Local Institution Zabrze Poland 41-800
    393 Local Institution Zarow Poland 58-130
    394 Local Institution Kaluga Anenki Russian Federation 248007
    395 Local Institution Barnaul Russian Federation 656055
    396 Local Institution Chelyabinsk Russian Federation 454136
    397 Local Institution Ekaterinburg Russian Federation 620109
    398 Local Institution Ekaterinburg Russian Federation 620144
    399 Local Institution Kazan Russian Federation 420012
    400 Local Institution Kemerovo Russian Federation 650002
    401 Local Institution Krasnodar Russian Federation 350042
    402 Local Institution Moscow Russian Federation 101990
    403 Local Institution Moscow Russian Federation 105066
    404 Local Institution Moscow Russian Federation 109240
    405 Local Institution Moscow Russian Federation 111539
    406 Local Institution Moscow Russian Federation 117485
    407 Local Institution Moscow Russian Federation 119121
    408 Local Institution Moscow Russian Federation 121356
    409 Local Institution Moscow Russian Federation 121552
    410 Local Institution Moscow Russian Federation 125284
    411 Local Institution Moscow Russian Federation 125367
    412 Local Institution Moscow Russian Federation 127644
    413 Local Institution Moscow Russian Federation 129301
    414 Local Institution Moscow Russian Federation 129336
    415 Local Institution Moscow Russian Federation 143000
    416 Local Institution Nizhniy Novgorod Russian Federation 603035
    417 Local Institution Novosibirsk Russian Federation 630047
    418 Local Institution Perm Russian Federation 614097
    419 Local Institution Perm Russian Federation 614107
    420 Local Institution Ryazan Russian Federation 390026
    421 Local Institution Saint Petersburg Russian Federation 193079
    422 Local Institution Saint-petersburg Russian Federation 190000
    423 Local Institution Saint-petersburg Russian Federation 191025
    424 Local Institution Saint-petersburg Russian Federation 193144
    425 Local Institution Saint-petersburg Russian Federation 194156
    426 Local Institution Saint-petersburg Russian Federation 194291
    427 Local Institution Samara Russian Federation 443070
    428 Local Institution Samara Russian Federation 443095
    429 Local Institution Saratov Russian Federation 410028
    430 Local Institution Saratov Russian Federation 410054
    431 Local Institution St.petersburg Russian Federation 195112
    432 Local Institution St.petersburg Russian Federation 197198
    433 Local Institution Tomsk Russian Federation 634012
    434 Local Institution Tumen Russian Federation 625023
    435 Local Institution Tver Russian Federation 170036
    436 Local Institution Yaroslavl Russian Federation 150062
    437 Local Institution Singapore Singapore 169609
    438 Local Institution Singapore Singapore 308433
    439 Local Institution Singapore Singapore 529889
    440 Local Institution Singapore Singapore 768828
    441 Local Institution Bloemfontein FREE State South Africa 9300
    442 Local Institution Bloemfontein FREE State South Africa 9301
    443 Local Institution Alberton Gauteng South Africa 1450
    444 Local Institution Bellville, Cape Town Western CAPE South Africa 7530
    445 Local Institution Cape Town Western CAPE South Africa 7925
    446 Local Institution Somerset West Western CAPE South Africa 7130
    447 Local Institution Worcester Western CAPE South Africa 6850
    448 Local Institution Pretoria South Africa 0041
    449 Local Institution Torrevieja Alicante Spain 03186
    450 Local Institution Hospitalet De Llobregat Barcelona Spain 08907
    451 Local Institution Lugo Galicia Spain 27003
    452 Local Institution Albacete Spain 02006
    453 Local Institution Madrid Spain 28007
    454 Local Institution Madrid Spain 28034
    455 Local Institution Valencia Spain 46017
    456 Local Institution Goteborg Sweden 416 85
    457 Local Institution Goteborg Sweden 417 17
    458 Local Institution Molndal Sweden 431 80
    459 Local Institution Stockholm Sweden 111 57
    460 Local Institution Stockholm Sweden 118 83
    461 Local Institution Stockholm Sweden 141 86
    462 Local Institution Uppsala Sweden 751 85
    463 Local Institution Kaohsiung Taiwan 807
    464 Local Institution Taichung Taiwan 402
    465 Local Institution Tainan Taiwan 704
    466 Local Institution Taipei Taiwan 10507
    467 Local Institution Taipei Taiwan 111
    468 Local Institution Taipei Taiwan 220
    469 Local Institution Isparta Turkey 32100
    470 Local Institution Istanbul Turkey 34304
    471 Local Institution Istanbul Turkey 34390
    472 Local Institution Kirikkale Turkey 71100
    473 Local Institution Dnipropetrovsk Ukraine 49005
    474 Local Institution Donetsk Ukraine 83114
    475 Local Institution Kharkiv Ukraine 61002
    476 Local Institution Kharkiv Ukraine 61018
    477 Local Institution Kharkiv Ukraine 61029
    478 Local Institution Kharkiv Ukraine 61115
    479 Local Institution Kharkiv Ukraine 61176
    480 Local Institution Kyiv Ukraine 01023
    481 Local Institution Kyiv Ukraine 02091
    482 Local Institution Kyiv Ukraine 02660
    483 Local Institution Kyiv Ukraine 03680
    484 Local Institution Kyiv Ukraine 04107
    485 Local Institution Kyiv Ukraine 04114
    486 Local Institution Aberdeen Aberdeenshire United Kingdom AB25 2ZN
    487 Local Institution Chesterfield Derbyshire United Kingdom S44 5BL
    488 Local Institution Basildon Essex United Kingdom SS16 5NL
    489 Local Institution Romford Essex United Kingdom RM7 0AG
    490 Local Institution Kirkcaldy Fife United Kingdom KY2 5AH
    491 Local Institution London Greater London United Kingdom SW17 ORE
    492 Local Institution Glasgow Lanarkshire United Kingdom G11 6NT
    493 Local Institution Glasgow Lanarkshire United Kingdom G51 4TF
    494 Local Institution Blackpool Lancashire United Kingdom FY3 8NR
    495 Local Institution Northampton Northamptonshire United Kingdom NN1 5BD
    496 Local Institution Worksop Nottinghamshire United Kingdom S18 0BD
    497 Local Institution Craigavon Portadown United Kingdom BT63 5QQ
    498 Local Institution Paisley Renfrewshire United Kingdom PA2 9PN
    499 Local Institution Barnsley South Yorkshire United Kingdom S75 2EP
    500 Local Institution Larbert Stirlingshire United Kingdom FK5 4WR
    501 Local Institution Newcastle Upon Tyne And Wear United Kingdom NE2 4HH
    502 Local Institution Birmingham West Midlands United Kingdom B18 7QH
    503 Local Institution Chichester West Sussex United Kingdom PO19 6SE

    Sponsors and Collaborators

    • Bristol-Myers Squibb
    • Pfizer

    Investigators

    • Study Director: Bristol-Myers Squibb, Bristol-Myers Squibb

    Study Documents (Full-Text)

    None provided.

    More Information

    Additional Information:

    Publications

    None provided.
    Responsible Party:
    Bristol-Myers Squibb
    ClinicalTrials.gov Identifier:
    NCT00496769
    Other Study ID Numbers:
    • CV185-048
    First Posted:
    Jul 4, 2007
    Last Update Posted:
    Jun 15, 2018
    Last Verified:
    May 1, 2018
    Additional relevant MeSH terms:
    Atrial Fibrillation
    Aspirin
    Apixaban

    Study Results

    Participant Flow

    Recruitment Details
    Pre-assignment Detail A total 6421 patients were enrolled in the study. Of these, 5598 were randomized (2807 to apixaban and 2791 to acetylsalicylic acid). Most (435) of the patients who were not randomized (823) no longer met study criteria. Of those randomized, 5578 received treatment (2798 with apixaban, and 2780 with acetylsalicylic acid).
    Arm/Group Title Apixaban, 2.5 or 5 mg Twice Daily Acetylsalicylic Acid, 81-324 mg Once Daily Open Label Apixaban
    Arm/Group Description Patients received 5 mg of apixaban twice daily. Participants who fulfilled any 2 of the following criteria at baseline received apixaban, 2.5 mg twice daily: age older than 80 years, body weight of 60 kg or less, Serum creatinine level ≥1.5 mg/dL. Participants randomized to the 2.5 mg twice daily dose of apixaban continued on this dose throughout the study even if they no longer fulfilled the previous criteria. Patients received 81 to 324 mg of acetylsalicylic acid once daily, with dosage based on investigator discretion Participants who completed the double-blind treatment period and met eligibility criteria had the option of enrolling in the Long Term Open Label Extension to receive open-label apixaban. Participants who completed the double-blind treatment period and met eligibility criteria had the option of enrolling in the Long Term Open Label Extension to receive open-label apixaban.
    Period Title: Double Blind
    STARTED 2807 2791 0
    Received Treatment 2798 2708 0
    COMPLETED 2249 2142 0
    NOT COMPLETED 558 649 0
    Period Title: Double Blind
    STARTED 0 0 3275
    COMPLETED 0 0 2264
    NOT COMPLETED 0 0 1011

    Baseline Characteristics

    Arm/Group Title Apixaban, 2.5 or 5 mg Twice Daily Acetylsalicylic Acid, 81-324 mg Once Daily Total
    Arm/Group Description Patients received 5 mg of apixaban twice daily. Participants who fulfilled any 2 of the following criteria at baseline received apixaban, 2.5 mg twice daily: age older than 80 years, body weight of 60 kg or less, Serum creatinine level ≥1.5 mg/dL. Participants randomized to the 2.5 mg twice daily dose of apixaban continued on this dose throughout the study even if they no longer fulfilled the previous criteria. Patients received 81 to 324 mg of acetylsalicylic acid once daily, with dosage based on investigator discretion Total of all reporting groups
    Overall Participants 2807 2791 5598
    Age (years) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [years]
    69.7
    (9.44)
    70.0
    (9.71)
    69.9
    (9.58)
    Age, Customized (Count of Participants)
    < 65 years
    855
    30.5%
    865
    31%
    1720
    30.7%
    >=65 but <75 years
    1049
    37.4%
    938
    33.6%
    1987
    35.5%
    >=75 years
    903
    32.2%
    988
    35.4%
    1891
    33.8%
    Sex: Female, Male (Count of Participants)
    Female
    1147
    40.9%
    1174
    42.1%
    2321
    41.5%
    Male
    1660
    59.1%
    1617
    57.9%
    3277
    58.5%
    Race/Ethnicity, Customized (Count of Participants)
    American Indian or Alaska Native
    6
    0.2%
    6
    0.2%
    12
    0.2%
    Asian
    541
    19.3%
    544
    19.5%
    1085
    19.4%
    Native Hawaiian or Other Pacific Islander
    3
    0.1%
    1
    0%
    4
    0.1%
    Black or African American
    10
    0.4%
    26
    0.9%
    36
    0.6%
    White
    2221
    79.1%
    2178
    78%
    4399
    78.6%
    Other
    26
    0.9%
    36
    1.3%
    62
    1.1%
    Number of Participants by Number of Risk Factors for Stroke (Count of Participants)
    1 or fewer
    1085
    38.7%
    1077
    38.6%
    2162
    38.6%
    2 or more
    1722
    61.3%
    1714
    61.4%
    3436
    61.4%
    Number of Participants With Risk Factors for Stroke (Count of Participants)
    Age of 75 years or older
    903
    32.2%
    988
    35.4%
    1891
    33.8%
    Prior stroke or transient ischemic attack
    390
    13.9%
    374
    13.4%
    764
    13.6%
    Heart failure (NYHA class ≥2) or LVEF ≤35%
    961
    34.2%
    926
    33.2%
    1887
    33.7%
    Diabetes mellitus
    536
    19.1%
    559
    20%
    1095
    19.6%
    Hypertension requiring pharmacologic treatment
    2408
    85.8%
    2429
    87%
    4837
    86.4%
    Peripheral artery disease
    66
    2.4%
    78
    2.8%
    144
    2.6%

    Outcome Measures

    1. Primary Outcome
    Title Event Rate of Stroke/Systemic Embolism During the Intended-treatment Period
    Description Event rate=percent of participants with an event divided by the total participants in the arm. Intended-treatment period=date of randomization to the efficacy cutoff date, which was to be the date on which at least 226 unrefuted original primary efficacy events occurred (date revised to May 28, 2010 following cessation of study for superior efficacy.)
    Time Frame Randomization to efficacy cutoff date of May 28, 2010 (date revised following cessation of study for superior efficacy)

    Outcome Measure Data

    Analysis Population Description
    Participants who received at least 1 dose of study drug.
    Arm/Group Title Apixaban, 2.5 or 5 mg Twice Daily Acetylsalicylic Acid, 81-324 mg Once Daily
    Arm/Group Description Patients received 5 mg of apixaban twice daily. Participants who fulfilled any 2 of the following criteria at baseline received apixaban, 2.5 mg twice daily: age older than 80 years, body weight of 60 kg or less, Serum creatinine level ≥1.5 mg/dL. Participants randomized to the 2.5 mg twice daily dose of apixaban continued on this dose throughout the study even if they no longer fulfilled the previous criteria. Patients received 81 to 324 mg of acetylsalicylic acid once daily, with dosage based on investigator discretion
    Measure Participants 2807 2791
    Number [Percentage of events]
    1.62
    3.63
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Apixaban, 2.5 or 5 mg Twice Daily, Acetylsalicylic Acid, 81-324 mg Once Daily
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value <0.00001
    Comments
    Method Log Rank
    Comments
    Method of Estimation Estimation Parameter Hazard Ratio (HR)
    Estimated Value 0.45
    Confidence Interval (2-Sided) 95%
    0.32 to 0.62
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    2. Secondary Outcome
    Title Event Rate for the Composite of Stroke of Any Type, Systemic Embolism, Myocardial Infarction, or Vascular Death During the Double-blind Treatment Period
    Description Event rate=percent of participants with an event divided by the total participants in the arm.
    Time Frame Randomization to efficacy cutoff date of May 28, 2010 (date revised following cessation of study for superior efficacy)

    Outcome Measure Data

    Analysis Population Description
    Participants who received at least 1 dose of study drug.
    Arm/Group Title Apixaban, 2.5 or 5 mg Twice Daily Acetylsalicylic Acid, 81-324 mg Once Daily
    Arm/Group Description Patients received 5 mg of apixaban twice daily. Participants who fulfilled any 2 of the following criteria at baseline received apixaban, 2.5 mg twice daily: age older than 80 years, body weight of 60 kg or less, Serum creatinine level ≥1.5 mg/dL. Participants randomized to the 2.5 mg twice daily dose of apixaban continued on this dose throughout the study even if they no longer fulfilled the previous criteria. Participants who completed the double-blind treatment period and met eligibility criteria had the option of enrolling in the Long Term Open Label Extension to receive open-label apixaban. Patients received 81 to 324 mg of acetylsalicylic acid once daily, with dosage based on investigator discretion Participants who completed the double-blind treatment period and met eligibility criteria had the option of enrolling in the Long Term Open Label Extension to receive open-label apixaban.
    Measure Participants 2807 2791
    Number [Percentage of events per year]
    4.21
    6.35
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Apixaban, 2.5 or 5 mg Twice Daily, Acetylsalicylic Acid, 81-324 mg Once Daily
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.00026
    Comments
    Method Log Rank
    Comments
    Method of Estimation Estimation Parameter Hazard Ratio (HR)
    Estimated Value 0.66
    Confidence Interval (2-Sided) 95%
    0.53 to 0.83
    Parameter Dispersion Type:
    Value:
    Estimation Comments Vascular death
    3. Secondary Outcome
    Title Event Rate of All-cause Death; Net Clinical Benefit-Composite of Stroke, Systemic Embolism, Myocardial Infarction, Vascular Death, and Major Bleeding; and Vascular Death
    Description Event rate=percent of participants with an event divided by the total participants in the arm.
    Time Frame Randomization to efficacy cutoff date of May 28, 2010 (date revised following cessation of study for superior efficacy)

    Outcome Measure Data

    Analysis Population Description
    Participants who received at least 1 dose of study drug.
    Arm/Group Title Apixaban, 2.5 or 5 mg Twice Daily Acetylsalicylic Acid, 81-324 mg Once Daily
    Arm/Group Description Patients received 5 mg of apixaban twice daily. Participants who fulfilled any 2 of the following criteria at baseline received apixaban, 2.5 mg twice daily: age older than 80 years, body weight of 60 kg or less, Serum creatinine level ≥1.5 mg/dL. Participants randomized to the 2.5 mg twice daily dose of apixaban continued on this dose throughout the study even if they no longer fulfilled the previous criteria. Participants who completed the double-blind treatment period and met eligibility criteria had the option of enrolling in the Long Term Open Label Extension to receive open-label apixaban. Patients received 81 to 324 mg of acetylsalicylic acid once daily, with dosage based on investigator discretion Participants who completed the double-blind treatment period and met eligibility criteria had the option of enrolling in the Long Term Open Label Extension to receive open-label apixaban.
    Measure Participants 2807 2791
    All-cause death (n=111, 140)
    3.51
    4.42
    Net clinical benefit (n=163, 220)
    5.23
    7.13
    Vascular death (n=84, 96)
    2.65
    3.03
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Apixaban, 2.5 or 5 mg Twice Daily, Acetylsalicylic Acid, 81-324 mg Once Daily
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.06782
    Comments
    Method Log Rank
    Comments
    Method of Estimation Estimation Parameter Hazard Ratio (HR)
    Estimated Value 0.79
    Confidence Interval (2-Sided) 95%
    0.62 to 1.02
    Parameter Dispersion Type:
    Value:
    Estimation Comments All-cause death
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Apixaban, 2.5 or 5 mg Twice Daily, Acetylsalicylic Acid, 81-324 mg Once Daily
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.00280
    Comments
    Method Log Rank
    Comments
    Method of Estimation Estimation Parameter Hazard Ratio (HR)
    Estimated Value 0.73
    Confidence Interval (2-Sided) 95%
    0.60 to 0.90
    Parameter Dispersion Type:
    Value:
    Estimation Comments Composite endpoint of major vascular events and major bleeding-net clinical benefit
    Statistical Analysis 3
    Statistical Analysis Overview Comparison Group Selection Apixaban, 2.5 or 5 mg Twice Daily, Acetylsalicylic Acid, 81-324 mg Once Daily
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.36586
    Comments
    Method Log Rank
    Comments
    Method of Estimation Estimation Parameter Hazard Ratio (HR)
    Estimated Value 0.87
    Confidence Interval (2-Sided) 95%
    0.65 to 1.17
    Parameter Dispersion Type:
    Value:
    Estimation Comments Vascular death
    4. Secondary Outcome
    Title Event Rates for Major Bleeding, Major or Clinically Relevant Nonmajor (CNRM) Bleeding, and All Bleeding in the Double-blind Period
    Description Event rate=percent of participants with an event divided by the total participants in the arm.
    Time Frame First dose of study drug (Day 1) to the earlier of a patient's discontinuation of double-blind study drug or the attainment of at least 226 primary efficacy events up to May 28, 2010

    Outcome Measure Data

    Analysis Population Description
    Participants who received at least 1 dose of study drug.
    Arm/Group Title Apixaban, 2.5 or 5 mg Twice Daily Acetylsalicylic Acid, 81-324 mg Once Daily
    Arm/Group Description Patients received 5 mg of apixaban twice daily. Participants who fulfilled any 2 of the following criteria at baseline received apixaban, 2.5 mg twice daily: age older than 80 years, body weight of 60 kg or less, Serum creatinine level ≥1.5 mg/dL. Participants randomized to the 2.5 mg twice daily dose of apixaban continued on this dose throughout the study even if they no longer fulfilled the previous criteria. Participants who completed the double-blind treatment period and met eligibility criteria had the option of enrolling in the Long Term Open Label Extension to receive open-label apixaban. Patients received 81 to 324 mg of acetylsalicylic acid once daily, with dosage based on investigator discretion Participants who completed the double-blind treatment period and met eligibility criteria had the option of enrolling in the Long Term Open Label Extension to receive open-label apixaban.
    Measure Participants 2798 2780
    Major bleeding
    1.41
    0.92
    Major or CRNM bleeding
    4.46
    3.24
    All bleeding
    10.85
    8.32
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Apixaban, 2.5 or 5 mg Twice Daily, Acetylsalicylic Acid, 81-324 mg Once Daily
    Comments
    Type of Statistical Test Other
    Comments
    Statistical Test of Hypothesis p-Value 0.0716
    Comments
    Method Log Rank
    Comments
    Method of Estimation Estimation Parameter Hazard Ratio (HR)
    Estimated Value 1.54
    Confidence Interval (2-Sided) 95%
    0.96 to 2.45
    Parameter Dispersion Type:
    Value:
    Estimation Comments Major bleeding
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Apixaban, 2.5 or 5 mg Twice Daily, Acetylsalicylic Acid, 81-324 mg Once Daily
    Comments
    Type of Statistical Test Other
    Comments
    Statistical Test of Hypothesis p-Value 0.0017
    Comments
    Method Log Rank
    Comments
    Method of Estimation Estimation Parameter Hazard Ratio (HR)
    Estimated Value 1.30
    Confidence Interval (2-Sided) 95%
    1.10 to 1.53
    Parameter Dispersion Type:
    Value:
    Estimation Comments All bleeding
    Statistical Analysis 3
    Statistical Analysis Overview Comparison Group Selection Apixaban, 2.5 or 5 mg Twice Daily, Acetylsalicylic Acid, 81-324 mg Once Daily
    Comments
    Type of Statistical Test Other
    Comments
    Statistical Test of Hypothesis p-Value 0.0144
    Comments
    Method Log Rank
    Comments
    Method of Estimation Estimation Parameter Hazard Ratio (HR)
    Estimated Value 1.38
    Confidence Interval (2-Sided) 95%
    1.07 to 1.78
    Parameter Dispersion Type:
    Value:
    Estimation Comments Major or CNRM bleeding
    5. Secondary Outcome
    Title Rate of Unrefuted Bleeding From First Dose of Double-blind Study Drug to First Occurence of Unrefuted Bleeding During the Double-blind Treatment Period
    Description Event rate=percent of participants with an event divided by the total participants in the arm.
    Time Frame Day 1 to first bleeding event up to efficacy cutoff date of May 28, 2010 (date revised following cessation of study for superior efficacy)

    Outcome Measure Data

    Analysis Population Description
    Participants who received at least 1 dose of study drug.
    Arm/Group Title Apixaban, 2.5 or 5 mg Twice Daily Acetylsalicylic Acid, 81-324 mg Once Daily
    Arm/Group Description Patients received 5 mg of apixaban twice daily. Participants who fulfilled any 2 of the following criteria at baseline received apixaban, 2.5 mg twice daily: age older than 80 years, body weight of 60 kg or less, Serum creatinine level ≥1.5 mg/dL. Participants randomized to the 2.5 mg twice daily dose of apixaban continued on this dose throughout the study even if they no longer fulfilled the previous criteria. Participants who completed the double-blind treatment period and met eligibility criteria had the option of enrolling in the Long Term Open Label Extension to receive open-label apixaban. Patients received 81 to 324 mg of acetylsalicylic acid once daily, with dosage based on investigator discretion Participants who completed the double-blind treatment period and met eligibility criteria had the option of enrolling in the Long Term Open Label Extension to receive open-label apixaban.
    Measure Participants 2798 2780
    Number [Percentage of events per year]
    10.85
    8.32
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Apixaban, 2.5 or 5 mg Twice Daily, Acetylsalicylic Acid, 81-324 mg Once Daily
    Comments
    Type of Statistical Test Other
    Comments
    Statistical Test of Hypothesis p-Value 0.0017
    Comments
    Method Log Rank
    Comments
    Method of Estimation Estimation Parameter Hazard Ratio (HR)
    Estimated Value 1.30
    Confidence Interval (2-Sided) 95%
    1.10 to 1.53
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    6. Secondary Outcome
    Title Number of Participants With Serious Adverse Events (SAEs), Adverse Events (AEs), Bleeding AEs, Discontinuations Due to AEs, and Death as Outcome
    Description AE=any new unfavorable symptom, sign, or disease or worsening of a preexisting condition that may not have a causal relationship with treatment. SAE=a medical event that at any dose results in death, persistent or significant disability/incapacity, or drug dependency/abuse; is life-threatening, an important medical event, or a congenital anomaly/birth defect; or requires or prolongs hospitalization.
    Time Frame First dose of study drug (Day 1) to 30 days after last dose of blinded study drug

    Outcome Measure Data

    Analysis Population Description
    Participants who received at least 1 dose of study drug.
    Arm/Group Title Apixaban, 2.5 or 5 mg Twice Daily Acetylsalicylic Acid, 81-324 mg Once Daily
    Arm/Group Description Patients received 5 mg of apixaban twice daily. Participants who fulfilled any 2 of the following criteria at baseline received apixaban, 2.5 mg twice daily: age older than 80 years, body weight of 60 kg or less, Serum creatinine level ≥1.5 mg/dL. Participants randomized to the 2.5 mg twice daily dose of apixaban continued on this dose throughout the study even if they no longer fulfilled the previous criteria. Participants who completed the double-blind treatment period and met eligibility criteria had the option of enrolling in the Long Term Open Label Extension to receive open-label apixaban. Patients received 81 to 324 mg of acetylsalicylic acid once daily, with dosage based on investigator discretion Participants who completed the double-blind treatment period and met eligibility criteria had the option of enrolling in the Long Term Open Label Extension to receive open-label apixaban.
    Measure Participants 2798 2780
    AEs
    1833
    65.3%
    1925
    69%
    SAEs
    657
    23.4%
    804
    28.8%
    Bleeding AEs
    281
    10%
    259
    9.3%
    Discontinuations due to AE
    266
    9.5%
    362
    13%
    Deaths
    91
    3.2%
    115
    4.1%
    7. Secondary Outcome
    Title Number of Participants With Laboratory Test Results Meeting the Criteria for Marked Abnormality
    Description BL=baseline, LLN=lower limit of normal, ULN=upper limit of normal. Hemoglobin (g/dL), low: BL>2 or value ≤8; hematocrit(%), low: <0.75*BL; erythrocytes (*10^6 cells/μL), low: <0.75*BL; platelet count (*10^9 cells/L),low: <100*10^9 cells/L; leukocytes (*10^3 cells/μL), low if <0.8*BL and BL<LLN or <LLN and BL >ULN or <0.75*LLN when BL is missing or LLN ≤BL≤ ULN, high if >1.2*BL and BL>ULN or >ULN when BL and BL<LLN or >1.25*ULN when BL is missing or LLN≤BL≤ULN; neutrophils (absolute), low: <1.0*10^3 cells/μL; eosinophils (absolute), high: >0.750*10^3 cells/μL; basophils (absolute), high: >0.4*10^3 cells/μL; monocytes (absolute), high: 2*10^3 cells/μL; lymphocytes (absolute), low if <0.75*10^3 cells/μL, high if >7.50*10^3 cells/μL; ALP (U/L), high: 2*ULN; AST (U/L), high: 3*ULN; AST (U/L), high: 3*ULN; bilirubin, total (mg/dL), high: >2*ULN; bilirubin, direct (mg/dL), high: 1.5*ULN; BUN (mg/dL), high:>2*ULN; creatinine (mg/dL), high: >1.5*ULN.
    Time Frame First dose of study drug (Day 1) to 30 days after last dose of blinded study drug

    Outcome Measure Data

    Analysis Population Description
    Participants who received at least 1 dose of study drug. n=number evaluable
    Arm/Group Title Apixaban, 2.5 or 5 mg Twice Daily Acetylsalicylic Acid, 81-324 mg Once Daily
    Arm/Group Description Patients received 5 mg of apixaban twice daily. Participants who fulfilled any 2 of the following criteria at baseline received apixaban, 2.5 mg twice daily: age older than 80 years, body weight of 60 kg or less, Serum creatinine level ≥1.5 mg/dL. Participants randomized to the 2.5 mg twice daily dose of apixaban continued on this dose throughout the study even if they no longer fulfilled the previous criteria. Participants who completed the double-blind treatment period and met eligibility criteria had the option of enrolling in the Long Term Open Label Extension to receive open-label apixaban. Patients received 81 to 324 mg of acetylsalicylic acid once daily, with dosage based on investigator discretion Participants who completed the double-blind treatment period and met eligibility criteria had the option of enrolling in the Long Term Open Label Extension to receive open-label apixaban.
    Measure Participants 2798 2780
    Hemoglobin, low (n=1956, 1893)
    131
    4.7%
    120
    4.3%
    Hemoglobin, high (n=1956, 1893)
    0
    0%
    0
    0%
    Hematocrit, low (n=1728, 1687)
    13
    0.5%
    9
    0.3%
    Hematocrit, high (n=1728, 1687)
    0
    0%
    0
    0%
    Erythrocytes, low (n=1728, 1687)
    12
    0.4%
    12
    0.4%
    Erythrocytes, high (n=1728, 1687)
    0
    0%
    0
    0%
    Platelet count, low (n=2148, 2098)
    7
    0.2%
    10
    0.4%
    Platelet count, high (n=2148, 2098)
    0
    0%
    0
    0%
    Leukocytes, low (n=1738, 1698)
    12
    0.4%
    14
    0.5%
    Leukocytes, high (n=1738, 1698)
    14
    0.5%
    18
    0.6%
    Neutrophils (absolute), low (n=2170, 2138)
    2
    0.1%
    1
    0%
    Neutrophils (absolute), high (n=2170, 2138)
    0
    0%
    0
    0%
    Eosinophils (absolute), low (n=2170, 2138)
    0
    0%
    0
    0%
    Eosinophils (absolute), high (n=2170, 2138)
    48
    1.7%
    68
    2.4%
    Basophils (absolute), low (n=2170, 2138)
    0
    0%
    0
    0%
    Basophils (absolute), high (n=2170, 2138)
    0
    0%
    0
    0%
    Monocytes (absolute), low (n=2170, 2138)
    0
    0%
    0
    0%
    Monocytes (absolute), high (n=2170, 2138)
    0
    0%
    2
    0.1%
    Lymphocytes (absolute), low (n=2170, 2138)
    52
    1.9%
    62
    2.2%
    Lymphocytes (absolute), high (n=2170, 2138)
    4
    0.1%
    5
    0.2%
    Alkaline phosphatase (ALP), low (n=2781, 2758)
    0
    0%
    0
    0%
    ALP, high (n=2781, 2758)
    34
    1.2%
    27
    1%
    Aspartate phosphatase (AST), low (n=2779, 2753)
    0
    0%
    0
    0%
    AST, high (n=2779, 2753)
    28
    1%
    33
    1.2%
    Alanine aminotransferase (ALT), low (n=2779, 2753)
    0
    0%
    0
    0%
    ALT, high (n=2779, 2753)
    23
    0.8%
    31
    1.1%
    Bilirubin (total), low (n=2781, 2758)
    0
    0%
    0
    0%
    Bilirubin (total), high (n=2781, 2758)
    30
    1.1%
    43
    1.5%
    Bilirubin (direct), low (n=2773, 2750)
    0
    0%
    0
    0%
    Bilirubin (direct), high (n=2773, 2750)
    241
    8.6%
    248
    8.9%
    Blood urea nitrogen (BUN), low (n=2201, 2172)
    0
    0%
    0
    0%
    BUN, high (n=2201, 2172)
    42
    1.5%
    50
    1.8%
    Creatinine, low (n=2209, 2178)
    0
    0%
    0
    0%
    Creatinine, high (n=2209, 2178)
    67
    2.4%
    71
    2.5%
    8. Secondary Outcome
    Title Number of Participants With Laboratory Test Results Meeting the Criteria for Marked Abnormality (Continued)
    Description LLN=lower limit of normal; ULN=upper limit of normal; BL=baseline. Sodium, serum (mEq/L):low if <0.95*BL and BL<LLN or <LLN and BL>ULN or <0.95*LLN when BL missing or LLN ≤BL≤ULN, high if >1.05*BL and BL>ULN or >ULN and BL<LLN or >1.05*ULN when BL missing or LLN≤BL≤ULN; potassium(mEq/L):low if <0.90*BL and BL<LLN or <LLN and BL>ULN or <0.90*LLN if BL missing or LLN≤BL≤ULN, high if >1.10*BL and BL>ULN or>ULN and BL<LLN or >1.10*ULN when BL missing or LLN≤BL≤ULN; chloride(mEq/L):low if <0.90*BL and BL<LLN or <LLN and BL>ULN or <0.90*LLN if BL missing or LLN≤BL ≤ULN, high if >1.10*BL and BL>ULN or >ULN and BL<LLN or >1.10* ULN if BL missing or LLN≤BL≤ULN; calcium(mg/dL):low if <0.75*BL and BL<LLN or <LLN and BL>ULN or <0.80*LLN if BL missing or LLN≤BL≤ULN, high if >1.25*BL and BL>ULN or >ULN if BL<LLN or >1.20*ULN if BL missing or LLN≤BL≤ULN ; bicarbonate(mEq/L):low if <0.75*BL when BL<LLN or <LLN when BL>ULN or <0.75*LLN if BL missing or LLN≤BL≤ULN, high if >1.25*BL when BL>ULN or >ULN
    Time Frame First dose of study drug (Day 1) to 30 days after last dose of blinded study drug

    Outcome Measure Data

    Analysis Population Description
    Participants who received at least 1 dose of study drug. n=number evaluable
    Arm/Group Title Apixaban, 2.5 or 5 mg Twice Daily Acetylsalicylic Acid, 81-324 mg Once Daily
    Arm/Group Description Patients received 5 mg of apixaban twice daily. Participants who fulfilled any 2 of the following criteria at baseline received apixaban, 2.5 mg twice daily: age older than 80 years, body weight of 60 kg or less, Serum creatinine level ≥1.5 mg/dL. Participants randomized to the 2.5 mg twice daily dose of apixaban continued on this dose throughout the study even if they no longer fulfilled the previous criteria. Participants who completed the double-blind treatment period and met eligibility criteria had the option of enrolling in the Long Term Open Label Extension to receive open-label apixaban. Patients received 81 to 324 mg of acetylsalicylic acid once daily, with dosage based on investigator discretion Participants who completed the double-blind treatment period and met eligibility criteria had the option of enrolling in the Long Term Open Label Extension to receive open-label apixaban.
    Measure Participants 2798 2780
    Sodium (serum), low (n=1768, 1740)
    2
    0.1%
    6
    0.2%
    Sodium (serum), high (n=1768, 1740)
    1
    0%
    2
    0.1%
    Potassium (serum), low (n=1763, 1737)
    6
    0.2%
    8
    0.3%
    Potassium (serum), high (n=1763, 1737)
    20
    0.7%
    28
    1%
    Chloride (serum), low (n=1768, 1740)
    0
    0%
    3
    0.1%
    Chloride (serum), high (n=1768, 1740)
    0
    0%
    1
    0%
    Calcium (total), low (n=106, 109)
    0
    0%
    0
    0%
    Calcium (total), high (n=106, 109)
    0
    0%
    0
    0%
    Bicarbonate, low (n=1664, 1619)
    0
    0%
    0
    0%
    Bicarbonate, high (n=1664, 1619)
    0
    0%
    0
    0%
    9. Secondary Outcome
    Title Number of Participants With Laboratory Test Results Meeting the Criteria for Marked Abnormality (Continued)
    Description ULN=upper limit of normal; LLN=lower limit of normal; BL=baseline. Creatine kinase (U/L), high:>5*ULN; protein, total(g/L):low if <0.90*BL when BL<LLN or <LLN when B >ULN or <0.90*LLN when BL is missing or LLN≤BL≤ULN, high if >1.10*BL if BL>ULN or >ULN when BL<LLN or >1.10*ULN if BL missing or LLN≤BL≤ULN.Protein,total(g/L): low if <0.90*BL if BL<LLN or <LLN if BL>ULN or <0.90*LLN if BL missing or LLN≤BL≤ULN, high if >1.10*BL if BL>ULN or >ULN if BL<LLN or >1.10*ULN if BL or LLN≤BL≤ULN; glucose, serum fasting (mg/dL): low if <0.8*BL if BL<LLN or <LLN when BL>ULN or <0.8*LLN when BL missing or LLN≤BL≤ULN, high if >2*BL when BL>ULN or >ULN when BL<LLN or >1.5*ULN if BL missing or LLN≤BL≤ULN; uric acid (mg/dL), high: >2*BL and BL>ULN or>1.5*ULN when BL missing or BL≤ULN; glucose, urine, high; protein, urine, high; blood, urine, high; leukocyte esterase, urine, high; RBC count, urine (Hpf), high; WBC count, urine (Hpf), high: ≥2 if BL=missing,=0 or =0.5 or if ≥3 if BL=1, or if ≥4 and BL≥2.
    Time Frame First dose of study drug (Day 1) to 30 days after last dose of blinded study drug

    Outcome Measure Data

    Analysis Population Description
    Participants who received at least 1 dose of study drug. n=number evaluable
    Arm/Group Title Apixaban, 2.5 or 5 mg Twice Daily Acetylsalicylic Acid, 81-324 mg Once Daily
    Arm/Group Description Patients received 5 mg of apixaban twice daily. Participants who fulfilled any 2 of the following criteria at baseline received apixaban, 2.5 mg twice daily: age older than 80 years, body weight of 60 kg or less, Serum creatinine level ≥1.5 mg/dL. Participants randomized to the 2.5 mg twice daily dose of apixaban continued on this dose throughout the study even if they no longer fulfilled the previous criteria. Participants who completed the double-blind treatment period and met eligibility criteria had the option of enrolling in the Long Term Open Label Extension to receive open-label apixaban. Patients received 81 to 324 mg of acetylsalicylic acid once daily, with dosage based on investigator discretion Participants who completed the double-blind treatment period and met eligibility criteria had the option of enrolling in the Long Term Open Label Extension to receive open-label apixaban.
    Measure Participants 2798 2780
    Creatine kinase, low (n=2780, 2758)
    0
    0%
    0
    0%
    Creatine kinase, high (n=2780, 2758)
    13
    0.5%
    25
    0.9%
    Protein (total), low (n=103, 109)
    0
    0%
    0
    0%
    Protein (total), high (n=103, 109)
    0
    0%
    0
    0%
    Uric acid, low (n=386, 390)
    0
    0%
    0
    0%
    Uric acid, high (n=386, 390)
    1
    0%
    0
    0%
    Glucose (urine), low (n=2, 3)
    0
    0%
    0
    0%
    Glucose (urine), high (n=2, 3)
    0
    0%
    1
    0%
    Protein (urine), low (n=3, 5)
    0
    0%
    0
    0%
    Protein (urine), high (n=3, 5)
    1
    0%
    1
    0%
    Blood (urine), low (n=3, 5)
    0
    0%
    0
    0%
    Blood (urine), high (n=3, 5)
    1
    0%
    0
    0%
    Leukocyte esterase (urine), low (n=3,5)
    0
    0%
    0
    0%
    Leukocyte esterase (urine), high (n=3,5)
    0
    0%
    0
    0%
    Red blood cells (RBC) (urine), low (n=2,2)
    0
    0%
    0
    0%
    RBC (urine), high (n=2,2)
    1
    0%
    0
    0%
    White blood cells (urine), low (n=2,2)
    0
    0%
    0
    0%
    WBC (urine), high (n=2,2)
    0
    0%
    0
    0%

    Adverse Events

    Time Frame From first dose to last dose plus 30 days (assessed up to May 2017, approximately 95 months)
    Adverse Event Reporting Description
    Arm/Group Title Apixaban, 2.5 or 5 mg Twice Daily Acetylsalicylic Acid, 81-324 mg Once Daily Open Label Apixaban
    Arm/Group Description Patients received 5 mg of apixaban twice daily. Participants who fulfilled any 2 of the following criteria at baseline received apixaban, 2.5 mg twice daily: age older than 80 years, body weight of 60 kg or less, Serum creatinine level ≥1.5 mg/dL. Participants randomized to the 2.5 mg twice daily dose of apixaban continued on this dose throughout the study even if they no longer fulfilled the previous criteria. Patients received 81 to 324 mg of acetylsalicylic acid once daily, with dosage based on investigator discretion Participants who completed the double-blind treatment period and met eligibility criteria had the option of enrolling in the Long Term Open Label Extension to receive open-label apixaban. Participants who completed the double-blind treatment period and met eligibility criteria had the option of enrolling in the Long Term Open Label Extension to receive open-label apixaban.
    All Cause Mortality
    Apixaban, 2.5 or 5 mg Twice Daily Acetylsalicylic Acid, 81-324 mg Once Daily Open Label Apixaban
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 111/2798 (4%) 140/2780 (5%) 286/3275 (8.7%)
    Serious Adverse Events
    Apixaban, 2.5 or 5 mg Twice Daily Acetylsalicylic Acid, 81-324 mg Once Daily Open Label Apixaban
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 657/2798 (23.5%) 804/2780 (28.9%) 1228/3275 (37.5%)
    Blood and lymphatic system disorders
    Anaemia 12/2798 (0.4%) 11/2780 (0.4%) 23/3275 (0.7%)
    Lymphadenopathy 1/2798 (0%) 0/2780 (0%) 0/3275 (0%)
    Thrombocytopenia 1/2798 (0%) 1/2780 (0%) 1/3275 (0%)
    Aplastic anaemia 0/2798 (0%) 1/2780 (0%) 1/3275 (0%)
    Coagulopathy 1/2798 (0%) 0/2780 (0%) 0/3275 (0%)
    Haemorrhagic diathesis 0/2798 (0%) 1/2780 (0%) 0/3275 (0%)
    Iron deficiency anaemia 1/2798 (0%) 0/2780 (0%) 3/3275 (0.1%)
    Leukocytosis 0/2798 (0%) 1/2780 (0%) 0/3275 (0%)
    Anaemia megaloblastic 0/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Haemolytic anaemia 0/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Leukopenia 0/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Pancytopenia 0/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Cardiac disorders
    Acute myocardial infarction 11/2798 (0.4%) 19/2780 (0.7%) 25/3275 (0.8%)
    Atrial flutter 7/2798 (0.3%) 6/2780 (0.2%) 8/3275 (0.2%)
    Cardiac failure 60/2798 (2.1%) 76/2780 (2.7%) 116/3275 (3.5%)
    Cardiogenic shock 1/2798 (0%) 0/2780 (0%) 5/3275 (0.2%)
    Palpitations 4/2798 (0.1%) 2/2780 (0.1%) 2/3275 (0.1%)
    Pericardial effusion 0/2798 (0%) 1/2780 (0%) 2/3275 (0.1%)
    Atrioventricular block 1/2798 (0%) 2/2780 (0.1%) 3/3275 (0.1%)
    Bradycardia 5/2798 (0.2%) 4/2780 (0.1%) 11/3275 (0.3%)
    Conduction disorder 0/2798 (0%) 1/2780 (0%) 0/3275 (0%)
    Left ventricular dysfunction 0/2798 (0%) 1/2780 (0%) 3/3275 (0.1%)
    Mitral valve prolapse 0/2798 (0%) 1/2780 (0%) 0/3275 (0%)
    Ventricular failure 1/2798 (0%) 0/2780 (0%) 0/3275 (0%)
    Atrial fibrillation 72/2798 (2.6%) 70/2780 (2.5%) 113/3275 (3.5%)
    Cardio-respiratory arrest 1/2798 (0%) 0/2780 (0%) 7/3275 (0.2%)
    Cardiovascular insufficiency 0/2798 (0%) 1/2780 (0%) 1/3275 (0%)
    Myocardial ischaemia 3/2798 (0.1%) 2/2780 (0.1%) 4/3275 (0.1%)
    Sinoatrial block 0/2798 (0%) 1/2780 (0%) 0/3275 (0%)
    Supraventricular tachycardia 3/2798 (0.1%) 5/2780 (0.2%) 1/3275 (0%)
    Tachyarrhythmia 1/2798 (0%) 1/2780 (0%) 0/3275 (0%)
    Acute coronary syndrome 3/2798 (0.1%) 6/2780 (0.2%) 7/3275 (0.2%)
    Arrhythmia supraventricular 1/2798 (0%) 2/2780 (0.1%) 0/3275 (0%)
    Atrial tachycardia 1/2798 (0%) 0/2780 (0%) 2/3275 (0.1%)
    Cardiopulmonary failure 2/2798 (0.1%) 3/2780 (0.1%) 4/3275 (0.1%)
    Carditis 0/2798 (0%) 1/2780 (0%) 0/3275 (0%)
    Coronary artery disease 4/2798 (0.1%) 6/2780 (0.2%) 16/3275 (0.5%)
    Coronary artery insufficiency 1/2798 (0%) 0/2780 (0%) 0/3275 (0%)
    Intracardiac thrombus 3/2798 (0.1%) 3/2780 (0.1%) 0/3275 (0%)
    Sick sinus syndrome 8/2798 (0.3%) 11/2780 (0.4%) 0/3275 (0%)
    Ventricular tachycardia 3/2798 (0.1%) 3/2780 (0.1%) 4/3275 (0.1%)
    Angina unstable 20/2798 (0.7%) 12/2780 (0.4%) 17/3275 (0.5%)
    Atrioventricular block complete 3/2798 (0.1%) 2/2780 (0.1%) 1/3275 (0%)
    Cardiac failure congestive 39/2798 (1.4%) 28/2780 (1%) 53/3275 (1.6%)
    Cardiomyopathy 1/2798 (0%) 1/2780 (0%) 1/3275 (0%)
    Ischaemic cardiomyopathy 1/2798 (0%) 0/2780 (0%) 3/3275 (0.1%)
    Tachycardia 1/2798 (0%) 2/2780 (0.1%) 2/3275 (0.1%)
    Tricuspid valve incompetence 1/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Ventricular arrhythmia 1/2798 (0%) 0/2780 (0%) 4/3275 (0.1%)
    Ventricular fibrillation 1/2798 (0%) 2/2780 (0.1%) 3/3275 (0.1%)
    Arrhythmia 0/2798 (0%) 2/2780 (0.1%) 4/3275 (0.1%)
    Nodal arrhythmia 0/2798 (0%) 1/2780 (0%) 0/3275 (0%)
    Sinus arrhythmia 1/2798 (0%) 0/2780 (0%) 0/3275 (0%)
    Sinus bradycardia 1/2798 (0%) 1/2780 (0%) 1/3275 (0%)
    Angina pectoris 4/2798 (0.1%) 9/2780 (0.3%) 14/3275 (0.4%)
    Bradyarrhythmia 2/2798 (0.1%) 1/2780 (0%) 3/3275 (0.1%)
    Cardiac arrest 3/2798 (0.1%) 7/2780 (0.3%) 10/3275 (0.3%)
    Cardiac failure chronic 0/2798 (0%) 3/2780 (0.1%) 6/3275 (0.2%)
    Cor pulmonale 1/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Mitral valve incompetence 1/2798 (0%) 3/2780 (0.1%) 5/3275 (0.2%)
    Myocardial infarction 11/2798 (0.4%) 12/2780 (0.4%) 24/3275 (0.7%)
    Aortic valve incompetence 1/2798 (0%) 0/2780 (0%) 0/3275 (0%)
    Cardiac failure acute 3/2798 (0.1%) 7/2780 (0.3%) 3/3275 (0.1%)
    Coronary artery occlusion 0/2798 (0%) 1/2780 (0%) 0/3275 (0%)
    Left ventricular failure 0/2798 (0%) 3/2780 (0.1%) 6/3275 (0.2%)
    Microvascular angina 1/2798 (0%) 0/2780 (0%) 0/3275 (0%)
    Right ventricular failure 0/2798 (0%) 1/2780 (0%) 0/3275 (0%)
    Acute left ventricular failure 0/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Aortic valve stenosis 0/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Arteriosclerosis coronary artery 0/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Cardiac asthma 0/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Cardiac disorder 0/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Congestive cardiomyopathy 0/2798 (0%) 0/2780 (0%) 3/3275 (0.1%)
    Defect conduction intraventricular 0/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Hypertensive heart disease 0/2798 (0%) 0/2780 (0%) 2/3275 (0.1%)
    Mitral valve disease 0/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Mitral valve stenosis 0/2798 (0%) 0/2780 (0%) 4/3275 (0.1%)
    Nodal rhythm 0/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Pericarditis 0/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Pericarditis constrictive 0/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Prinzmetal angina 0/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Rheumatic heart disease 0/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Sinus arrest 0/2798 (0%) 0/2780 (0%) 2/3275 (0.1%)
    Sinus node dysfunction 0/2798 (0%) 0/2780 (0%) 18/3275 (0.5%)
    Ventricular extrasystoles 0/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Congenital, familial and genetic disorders
    Atrial septal defect 0/2798 (0%) 2/2780 (0.1%) 0/3275 (0%)
    Congenital cystic kidney disease 0/2798 (0%) 1/2780 (0%) 0/3275 (0%)
    Liddle's syndrome 0/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Ear and labyrinth disorders
    Ear disorder 0/2798 (0%) 1/2780 (0%) 0/3275 (0%)
    Vertigo 1/2798 (0%) 3/2780 (0.1%) 5/3275 (0.2%)
    Vertigo positional 0/2798 (0%) 1/2780 (0%) 1/3275 (0%)
    Ear haemorrhage 0/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Endocrine disorders
    Hyperparathyroidism 0/2798 (0%) 1/2780 (0%) 0/3275 (0%)
    Hyperthyroidism 1/2798 (0%) 1/2780 (0%) 4/3275 (0.1%)
    Thyroid haemorrhage 0/2798 (0%) 1/2780 (0%) 0/3275 (0%)
    Hypothyroidism 1/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Goitre 0/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Thyroid mass 0/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Eye disorders
    Eye haemorrhage 2/2798 (0.1%) 0/2780 (0%) 0/3275 (0%)
    Vitreous haemorrhage 2/2798 (0.1%) 0/2780 (0%) 0/3275 (0%)
    Retinal artery occlusion 0/2798 (0%) 1/2780 (0%) 1/3275 (0%)
    Retinal detachment 0/2798 (0%) 2/2780 (0.1%) 0/3275 (0%)
    Amaurosis fugax 1/2798 (0%) 0/2780 (0%) 0/3275 (0%)
    Retinal artery embolism 1/2798 (0%) 0/2780 (0%) 0/3275 (0%)
    Cataract 2/2798 (0.1%) 0/2780 (0%) 6/3275 (0.2%)
    Eye pain 0/2798 (0%) 0/2780 (0%) 2/3275 (0.1%)
    Eyelid ptosis 0/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Keratitis 0/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Tolosa-hunt syndrome 0/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Gastrointestinal disorders
    Abdominal pain upper 1/2798 (0%) 1/2780 (0%) 0/3275 (0%)
    Diverticulum 0/2798 (0%) 1/2780 (0%) 2/3275 (0.1%)
    Gastroduodenitis 0/2798 (0%) 1/2780 (0%) 0/3275 (0%)
    Haematochezia 0/2798 (0%) 1/2780 (0%) 0/3275 (0%)
    Intestinal ischaemia 0/2798 (0%) 2/2780 (0.1%) 0/3275 (0%)
    Pancreatitis chronic 1/2798 (0%) 1/2780 (0%) 0/3275 (0%)
    Abdominal hernia 0/2798 (0%) 1/2780 (0%) 2/3275 (0.1%)
    Colitis 2/2798 (0.1%) 0/2780 (0%) 1/3275 (0%)
    Duodenal ulcer 1/2798 (0%) 1/2780 (0%) 3/3275 (0.1%)
    Gastric disorder 0/2798 (0%) 1/2780 (0%) 0/3275 (0%)
    Gastritis 5/2798 (0.2%) 6/2780 (0.2%) 3/3275 (0.1%)
    Gastritis erosive 1/2798 (0%) 2/2780 (0.1%) 2/3275 (0.1%)
    Haematemesis 1/2798 (0%) 0/2780 (0%) 4/3275 (0.1%)
    Intestinal obstruction 1/2798 (0%) 2/2780 (0.1%) 6/3275 (0.2%)
    Lumbar hernia 0/2798 (0%) 1/2780 (0%) 0/3275 (0%)
    Mouth haemorrhage 1/2798 (0%) 0/2780 (0%) 0/3275 (0%)
    Peptic ulcer 1/2798 (0%) 2/2780 (0.1%) 1/3275 (0%)
    Retroperitoneal haematoma 0/2798 (0%) 1/2780 (0%) 1/3275 (0%)
    Colonic polyp 1/2798 (0%) 0/2780 (0%) 0/3275 (0%)
    Dyspepsia 0/2798 (0%) 1/2780 (0%) 1/3275 (0%)
    Dysphagia 1/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Gastrooesophageal reflux disease 0/2798 (0%) 1/2780 (0%) 1/3275 (0%)
    Gingival bleeding 2/2798 (0.1%) 1/2780 (0%) 0/3275 (0%)
    Mesenteric artery embolism 1/2798 (0%) 0/2780 (0%) 0/3275 (0%)
    Oesophageal achalasia 0/2798 (0%) 1/2780 (0%) 0/3275 (0%)
    Rectal haemorrhage 7/2798 (0.3%) 1/2780 (0%) 8/3275 (0.2%)
    Reflux oesophagitis 0/2798 (0%) 1/2780 (0%) 0/3275 (0%)
    Subileus 2/2798 (0.1%) 0/2780 (0%) 0/3275 (0%)
    Gastric ulcer haemorrhage 1/2798 (0%) 0/2780 (0%) 2/3275 (0.1%)
    Gastrointestinal haemorrhage 2/2798 (0.1%) 9/2780 (0.3%) 20/3275 (0.6%)
    Gastrointestinal hypomotility 0/2798 (0%) 1/2780 (0%) 0/3275 (0%)
    Ileus 0/2798 (0%) 1/2780 (0%) 0/3275 (0%)
    Oesophagitis 1/2798 (0%) 0/2780 (0%) 0/3275 (0%)
    Pancreatitis acute 1/2798 (0%) 1/2780 (0%) 3/3275 (0.1%)
    Proctitis ulcerative 1/2798 (0%) 0/2780 (0%) 0/3275 (0%)
    Duodenal ulcer haemorrhage 2/2798 (0.1%) 0/2780 (0%) 1/3275 (0%)
    Duodenitis 1/2798 (0%) 1/2780 (0%) 0/3275 (0%)
    Gastric haemorrhage 1/2798 (0%) 0/2780 (0%) 0/3275 (0%)
    Gastrointestinal disorder 0/2798 (0%) 1/2780 (0%) 0/3275 (0%)
    Intestinal haemorrhage 0/2798 (0%) 1/2780 (0%) 0/3275 (0%)
    Large intestinal obstruction 0/2798 (0%) 1/2780 (0%) 0/3275 (0%)
    Melaena 5/2798 (0.2%) 1/2780 (0%) 5/3275 (0.2%)
    Oesophageal varices haemorrhage 1/2798 (0%) 0/2780 (0%) 0/3275 (0%)
    Spigelian hernia 0/2798 (0%) 1/2780 (0%) 0/3275 (0%)
    Abdominal adhesions 1/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Constipation 1/2798 (0%) 2/2780 (0.1%) 6/3275 (0.2%)
    Food poisoning 0/2798 (0%) 1/2780 (0%) 2/3275 (0.1%)
    Gastric ulcer 1/2798 (0%) 1/2780 (0%) 4/3275 (0.1%)
    Gastrointestinal perforation 0/2798 (0%) 1/2780 (0%) 0/3275 (0%)
    Mesenteric artery thrombosis 0/2798 (0%) 1/2780 (0%) 0/3275 (0%)
    Nausea 1/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Abdominal pain 4/2798 (0.1%) 3/2780 (0.1%) 6/3275 (0.2%)
    Diarrhoea 0/2798 (0%) 5/2780 (0.2%) 11/3275 (0.3%)
    Faecaloma 1/2798 (0%) 0/2780 (0%) 2/3275 (0.1%)
    Inguinal hernia 3/2798 (0.1%) 6/2780 (0.2%) 12/3275 (0.4%)
    Oesophageal stenosis 1/2798 (0%) 0/2780 (0%) 0/3275 (0%)
    Pancreatitis 2/2798 (0.1%) 3/2780 (0.1%) 2/3275 (0.1%)
    Small intestinal obstruction 1/2798 (0%) 0/2780 (0%) 2/3275 (0.1%)
    Abdominal strangulated hernia 1/2798 (0%) 0/2780 (0%) 0/3275 (0%)
    Acute abdomen 0/2798 (0%) 1/2780 (0%) 1/3275 (0%)
    Duodenal ulcer perforation 0/2798 (0%) 1/2780 (0%) 0/3275 (0%)
    Gastritis haemorrhagic 1/2798 (0%) 0/2780 (0%) 0/3275 (0%)
    Hiatus hernia 1/2798 (0%) 0/2780 (0%) 0/3275 (0%)
    Splenic artery aneurysm 1/2798 (0%) 0/2780 (0%) 0/3275 (0%)
    Tooth loss 0/2798 (0%) 1/2780 (0%) 0/3275 (0%)
    Vomiting 2/2798 (0.1%) 1/2780 (0%) 1/3275 (0%)
    Abdominal distension 0/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Abdominal mass 0/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Abdominal wall haematoma 0/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Ascites 0/2798 (0%) 0/2780 (0%) 3/3275 (0.1%)
    Barrett's oesophagus 0/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Chronic gastritis 0/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Colitis ulcerative 0/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Diverticulum intestinal 0/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Haemorrhoidal haemorrhage 0/2798 (0%) 0/2780 (0%) 3/3275 (0.1%)
    Haemorrhoids 0/2798 (0%) 0/2780 (0%) 3/3275 (0.1%)
    Ileus paralytic 0/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Incarcerated umbilical hernia 0/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Large intestine perforation 0/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Large intestine polyp 0/2798 (0%) 0/2780 (0%) 3/3275 (0.1%)
    Lower gastrointestinal haemorrhage 0/2798 (0%) 0/2780 (0%) 2/3275 (0.1%)
    Mallory-weiss syndrome 0/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Oesophageal dilatation 0/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Proctitis 0/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Umbilical hernia 0/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Upper gastrointestinal haemorrhage 0/2798 (0%) 0/2780 (0%) 14/3275 (0.4%)
    Volvulus 0/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    General disorders
    Chest pain 16/2798 (0.6%) 24/2780 (0.9%) 28/3275 (0.9%)
    Gait disturbance 0/2798 (0%) 2/2780 (0.1%) 1/3275 (0%)
    Malaise 1/2798 (0%) 0/2780 (0%) 0/3275 (0%)
    Pain 0/2798 (0%) 1/2780 (0%) 0/3275 (0%)
    Device pacing issue 0/2798 (0%) 1/2780 (0%) 0/3275 (0%)
    Implant site effusion 0/2798 (0%) 1/2780 (0%) 0/3275 (0%)
    Device lead damage 1/2798 (0%) 0/2780 (0%) 0/3275 (0%)
    Generalised oedema 1/2798 (0%) 1/2780 (0%) 1/3275 (0%)
    Hernia pain 0/2798 (0%) 1/2780 (0%) 1/3275 (0%)
    Sudden cardiac death 3/2798 (0.1%) 1/2780 (0%) 6/3275 (0.2%)
    Asthenia 4/2798 (0.1%) 1/2780 (0%) 9/3275 (0.3%)
    Cardiac death 1/2798 (0%) 1/2780 (0%) 3/3275 (0.1%)
    General physical health deterioration 3/2798 (0.1%) 1/2780 (0%) 1/3275 (0%)
    Medical device complication 1/2798 (0%) 0/2780 (0%) 0/3275 (0%)
    Oedema peripheral 2/2798 (0.1%) 1/2780 (0%) 7/3275 (0.2%)
    Systemic inflammatory response syndrome 1/2798 (0%) 1/2780 (0%) 1/3275 (0%)
    Adverse drug reaction 0/2798 (0%) 1/2780 (0%) 3/3275 (0.1%)
    Chest discomfort 1/2798 (0%) 0/2780 (0%) 2/3275 (0.1%)
    Device malfunction 0/2798 (0%) 1/2780 (0%) 0/3275 (0%)
    Pelvic mass 0/2798 (0%) 1/2780 (0%) 0/3275 (0%)
    Fatigue 0/2798 (0%) 1/2780 (0%) 1/3275 (0%)
    Hernia 0/2798 (0%) 1/2780 (0%) 0/3275 (0%)
    Multi-organ failure 1/2798 (0%) 0/2780 (0%) 0/3275 (0%)
    Oedema 1/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Pyrexia 3/2798 (0.1%) 3/2780 (0.1%) 7/3275 (0.2%)
    Death 14/2798 (0.5%) 9/2780 (0.3%) 38/3275 (1.2%)
    Non-cardiac chest pain 3/2798 (0.1%) 5/2780 (0.2%) 2/3275 (0.1%)
    Sudden death 9/2798 (0.3%) 12/2780 (0.4%) 32/3275 (1%)
    Swelling 0/2798 (0%) 1/2780 (0%) 0/3275 (0%)
    Unassigned 4/2798 (0.1%) 6/2780 (0.2%) 7/3275 (0.2%)
    Exercise tolerance decreased 0/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Incarcerated hernia 0/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Multiple organ dysfunction syndrome 0/2798 (0%) 0/2780 (0%) 5/3275 (0.2%)
    Peripheral swelling 0/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Unevaluable event 0/2798 (0%) 0/2780 (0%) 2/3275 (0.1%)
    Hepatobiliary disorders
    Cholecystitis 5/2798 (0.2%) 6/2780 (0.2%) 4/3275 (0.1%)
    Bile duct stone 1/2798 (0%) 3/2780 (0.1%) 3/3275 (0.1%)
    Cholestasis 1/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Hepatitis 2/2798 (0.1%) 0/2780 (0%) 0/3275 (0%)
    Cholecystitis chronic 1/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Hepatic failure 1/2798 (0%) 0/2780 (0%) 0/3275 (0%)
    Jaundice cholestatic 0/2798 (0%) 1/2780 (0%) 1/3275 (0%)
    Cholelithiasis 3/2798 (0.1%) 2/2780 (0.1%) 7/3275 (0.2%)
    Bile duct stenosis 0/2798 (0%) 1/2780 (0%) 0/3275 (0%)
    Cholangitis 2/2798 (0.1%) 0/2780 (0%) 3/3275 (0.1%)
    Cholecystitis acute 5/2798 (0.2%) 2/2780 (0.1%) 4/3275 (0.1%)
    Hyperbilirubinaemia 0/2798 (0%) 1/2780 (0%) 0/3275 (0%)
    Liver disorder 0/2798 (0%) 1/2780 (0%) 1/3275 (0%)
    Acute hepatic failure 0/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Cholangitis acute 0/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Hepatic cirrhosis 0/2798 (0%) 0/2780 (0%) 2/3275 (0.1%)
    Hepatic cyst 0/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Hepatitis fulminant 0/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Hepatomegaly 0/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Portal hypertension 0/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Immune system disorders
    Anaphylactic reaction 0/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Infections and infestations
    Abdominal wall abscess 0/2798 (0%) 1/2780 (0%) 0/3275 (0%)
    Bronchitis 7/2798 (0.3%) 7/2780 (0.3%) 15/3275 (0.5%)
    Chronic sinusitis 1/2798 (0%) 0/2780 (0%) 0/3275 (0%)
    Dengue fever 0/2798 (0%) 1/2780 (0%) 0/3275 (0%)
    Hepatitis C 1/2798 (0%) 0/2780 (0%) 0/3275 (0%)
    Infection 0/2798 (0%) 1/2780 (0%) 0/3275 (0%)
    Infective exacerbation of chronic obstructive airways disease 1/2798 (0%) 2/2780 (0.1%) 1/3275 (0%)
    Lobar pneumonia 1/2798 (0%) 1/2780 (0%) 0/3275 (0%)
    Postoperative wound infection 1/2798 (0%) 2/2780 (0.1%) 2/3275 (0.1%)
    Septic shock 4/2798 (0.1%) 2/2780 (0.1%) 12/3275 (0.4%)
    Wound infection 2/2798 (0.1%) 0/2780 (0%) 1/3275 (0%)
    Bronchopneumonia 2/2798 (0.1%) 5/2780 (0.2%) 0/3275 (0%)
    Helicobacter gastritis 0/2798 (0%) 1/2780 (0%) 0/3275 (0%)
    Hepatic amoebiasis 1/2798 (0%) 0/2780 (0%) 0/3275 (0%)
    Influenza 0/2798 (0%) 1/2780 (0%) 0/3275 (0%)
    Meningitis 1/2798 (0%) 0/2780 (0%) 0/3275 (0%)
    Skin infection 0/2798 (0%) 1/2780 (0%) 0/3275 (0%)
    Tracheitis 1/2798 (0%) 0/2780 (0%) 0/3275 (0%)
    Vestibular neuronitis 1/2798 (0%) 1/2780 (0%) 0/3275 (0%)
    Abscess 0/2798 (0%) 1/2780 (0%) 1/3275 (0%)
    Abscess limb 0/2798 (0%) 1/2780 (0%) 2/3275 (0.1%)
    Amoebic dysentery 0/2798 (0%) 1/2780 (0%) 0/3275 (0%)
    Lung infection 0/2798 (0%) 1/2780 (0%) 2/3275 (0.1%)
    Psoas abscess 1/2798 (0%) 0/2780 (0%) 0/3275 (0%)
    Staphylococcal sepsis 0/2798 (0%) 1/2780 (0%) 0/3275 (0%)
    Viral infection 1/2798 (0%) 3/2780 (0.1%) 0/3275 (0%)
    Arthritis bacterial 2/2798 (0.1%) 0/2780 (0%) 0/3275 (0%)
    Endocarditis 1/2798 (0%) 1/2780 (0%) 3/3275 (0.1%)
    Escherichia bacteraemia 1/2798 (0%) 0/2780 (0%) 0/3275 (0%)
    Gastroenteritis 8/2798 (0.3%) 5/2780 (0.2%) 14/3275 (0.4%)
    Klebsiella bacteraemia 1/2798 (0%) 0/2780 (0%) 0/3275 (0%)
    Lower respiratory tract infection 2/2798 (0.1%) 2/2780 (0.1%) 5/3275 (0.2%)
    Osteomyelitis 0/2798 (0%) 1/2780 (0%) 0/3275 (0%)
    Pneumonia 37/2798 (1.3%) 55/2780 (2%) 99/3275 (3%)
    Pneumonia klebsiella 1/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Pneumonia pneumococcal 1/2798 (0%) 0/2780 (0%) 0/3275 (0%)
    Pyelonephritis 1/2798 (0%) 0/2780 (0%) 2/3275 (0.1%)
    Pyometra 0/2798 (0%) 1/2780 (0%) 0/3275 (0%)
    Cellulitis 6/2798 (0.2%) 5/2780 (0.2%) 13/3275 (0.4%)
    Clostridium colitis 1/2798 (0%) 0/2780 (0%) 0/3275 (0%)
    Diverticulitis 0/2798 (0%) 3/2780 (0.1%) 7/3275 (0.2%)
    Gangrene 0/2798 (0%) 1/2780 (0%) 1/3275 (0%)
    Localised infection 0/2798 (0%) 1/2780 (0%) 2/3275 (0.1%)
    Pneumonia viral 0/2798 (0%) 2/2780 (0.1%) 0/3275 (0%)
    Respiratory tract infection 3/2798 (0.1%) 5/2780 (0.2%) 6/3275 (0.2%)
    Sepsis 4/2798 (0.1%) 4/2780 (0.1%) 17/3275 (0.5%)
    Sinusitis 0/2798 (0%) 1/2780 (0%) 1/3275 (0%)
    Urinary tract infection 11/2798 (0.4%) 15/2780 (0.5%) 24/3275 (0.7%)
    Bronchiectasis 1/2798 (0%) 0/2780 (0%) 0/3275 (0%)
    Clostridium difficile colitis 0/2798 (0%) 2/2780 (0.1%) 1/3275 (0%)
    Gastroenteritis salmonella 1/2798 (0%) 0/2780 (0%) 0/3275 (0%)
    Herpes zoster 0/2798 (0%) 2/2780 (0.1%) 3/3275 (0.1%)
    Pyelonephritis acute 1/2798 (0%) 2/2780 (0.1%) 1/3275 (0%)
    Upper respiratory tract infection 3/2798 (0.1%) 1/2780 (0%) 3/3275 (0.1%)
    Urosepsis 1/2798 (0%) 1/2780 (0%) 4/3275 (0.1%)
    Appendicitis 0/2798 (0%) 1/2780 (0%) 6/3275 (0.2%)
    Helicobacter infection 1/2798 (0%) 0/2780 (0%) 0/3275 (0%)
    Oral candidiasis 1/2798 (0%) 0/2780 (0%) 0/3275 (0%)
    Urinary tract infection bacterial 1/2798 (0%) 0/2780 (0%) 0/3275 (0%)
    Abdominal wall infection 0/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Colonic abscess 0/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Cystitis 0/2798 (0%) 0/2780 (0%) 2/3275 (0.1%)
    Diabetic foot infection 0/2798 (0%) 0/2780 (0%) 2/3275 (0.1%)
    Disseminated tuberculosis 0/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Diverticulitis intestinal haemorrhagic 0/2798 (0%) 0/2780 (0%) 2/3275 (0.1%)
    Empyema 0/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Encephalitis viral 0/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Endophthalmitis 0/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Erysipelas 0/2798 (0%) 0/2780 (0%) 8/3275 (0.2%)
    Escherichia infection 0/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Gastroenteritis viral 0/2798 (0%) 0/2780 (0%) 3/3275 (0.1%)
    Gastrointestinal infection 0/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Groin infection 0/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Hepatitis E 0/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Infectious pleural effusion 0/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Listeriosis 0/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Liver abscess 0/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Nasopharyngitis 0/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Nosocomial infection 0/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Oesophageal candidiasis 0/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Ophthalmic herpes zoster 0/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Orchitis 0/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Periorbital cellulitis 0/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Peritonitis 0/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Pneumonia escherichia 0/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Pneumonia influenzal 0/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Prostate infection 0/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Pulmonary tuberculosis 0/2798 (0%) 0/2780 (0%) 2/3275 (0.1%)
    Sepsis syndrome 0/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Staphylococcal infection 0/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Tracheobronchitis 0/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Tuberculosis 0/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Tuberculous pleurisy 0/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Viral upper respiratory tract infection 0/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Injury, poisoning and procedural complications
    Concussion 1/2798 (0%) 1/2780 (0%) 0/3275 (0%)
    Hand fracture 2/2798 (0.1%) 0/2780 (0%) 0/3275 (0%)
    Multiple fractures 2/2798 (0.1%) 0/2780 (0%) 2/3275 (0.1%)
    Skull fracture 0/2798 (0%) 1/2780 (0%) 0/3275 (0%)
    Traumatic brain injury 0/2798 (0%) 1/2780 (0%) 0/3275 (0%)
    Upper limb fracture 0/2798 (0%) 1/2780 (0%) 4/3275 (0.1%)
    Cerebral haemorrhage traumatic 0/2798 (0%) 1/2780 (0%) 0/3275 (0%)
    Drug toxicity 1/2798 (0%) 0/2780 (0%) 0/3275 (0%)
    Foot fracture 0/2798 (0%) 1/2780 (0%) 1/3275 (0%)
    Joint dislocation 1/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Limb traumatic amputation 1/2798 (0%) 0/2780 (0%) 0/3275 (0%)
    Lumbar vertebral fracture 1/2798 (0%) 2/2780 (0.1%) 7/3275 (0.2%)
    Muscle strain 1/2798 (0%) 0/2780 (0%) 0/3275 (0%)
    Ulna fracture 0/2798 (0%) 2/2780 (0.1%) 0/3275 (0%)
    Fall 4/2798 (0.1%) 6/2780 (0.2%) 12/3275 (0.4%)
    Jaw fracture 1/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Muscle rupture 0/2798 (0%) 1/2780 (0%) 0/3275 (0%)
    Post procedural diarrhoea 0/2798 (0%) 1/2780 (0%) 0/3275 (0%)
    Procedural pain 0/2798 (0%) 1/2780 (0%) 1/3275 (0%)
    Road traffic accident 1/2798 (0%) 2/2780 (0.1%) 1/3275 (0%)
    Head injury 0/2798 (0%) 1/2780 (0%) 2/3275 (0.1%)
    Lower limb fracture 1/2798 (0%) 1/2780 (0%) 1/3275 (0%)
    Meniscus lesion 0/2798 (0%) 1/2780 (0%) 0/3275 (0%)
    Pubis fracture 2/2798 (0.1%) 1/2780 (0%) 2/3275 (0.1%)
    Spinal column injury 1/2798 (0%) 0/2780 (0%) 0/3275 (0%)
    Therapeutic agent toxicity 2/2798 (0.1%) 1/2780 (0%) 0/3275 (0%)
    Femur fracture 5/2798 (0.2%) 6/2780 (0.2%) 11/3275 (0.3%)
    Patella fracture 1/2798 (0%) 1/2780 (0%) 0/3275 (0%)
    Post procedural fistula 1/2798 (0%) 0/2780 (0%) 0/3275 (0%)
    Rib fracture 1/2798 (0%) 1/2780 (0%) 2/3275 (0.1%)
    Incisional hernia 1/2798 (0%) 0/2780 (0%) 3/3275 (0.1%)
    Traumatic haematoma 0/2798 (0%) 2/2780 (0.1%) 0/3275 (0%)
    Wound secretion 1/2798 (0%) 0/2780 (0%) 0/3275 (0%)
    Animal bite 0/2798 (0%) 1/2780 (0%) 0/3275 (0%)
    Ankle fracture 1/2798 (0%) 1/2780 (0%) 3/3275 (0.1%)
    Cervical vertebral fracture 1/2798 (0%) 0/2780 (0%) 0/3275 (0%)
    Femoral neck fracture 2/2798 (0.1%) 0/2780 (0%) 8/3275 (0.2%)
    Humerus fracture 1/2798 (0%) 1/2780 (0%) 0/3275 (0%)
    In-stent arterial restenosis 0/2798 (0%) 1/2780 (0%) 0/3275 (0%)
    In-stent coronary artery restenosis 0/2798 (0%) 1/2780 (0%) 0/3275 (0%)
    Radius fracture 0/2798 (0%) 1/2780 (0%) 1/3275 (0%)
    Spinal compression fracture 0/2798 (0%) 1/2780 (0%) 2/3275 (0.1%)
    Contusion 2/2798 (0.1%) 1/2780 (0%) 0/3275 (0%)
    Facial bones fracture 1/2798 (0%) 0/2780 (0%) 0/3275 (0%)
    Hip fracture 5/2798 (0.2%) 4/2780 (0.1%) 12/3275 (0.4%)
    Injury 1/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Multiple injuries 1/2798 (0%) 0/2780 (0%) 2/3275 (0.1%)
    Overdose 3/2798 (0.1%) 5/2780 (0.2%) 3/3275 (0.1%)
    Subdural haematoma 4/2798 (0.1%) 2/2780 (0.1%) 5/3275 (0.2%)
    Thoracic vertebral fracture 1/2798 (0%) 0/2780 (0%) 0/3275 (0%)
    Abdominal wound dehiscence 0/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Accidental overdose 0/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Aortic injury 0/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Brain contusion 0/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Chest injury 0/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Confusion postoperative 0/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Craniocerebral injury 0/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Fibula fracture 0/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Fractured sacrum 0/2798 (0%) 0/2780 (0%) 2/3275 (0.1%)
    Incarcerated incisional hernia 0/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Laceration 0/2798 (0%) 0/2780 (0%) 3/3275 (0.1%)
    Ligament sprain 0/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Meniscus injury 0/2798 (0%) 0/2780 (0%) 2/3275 (0.1%)
    Pelvic fracture 0/2798 (0%) 0/2780 (0%) 2/3275 (0.1%)
    Periorbital haematoma 0/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Post procedural haematoma 0/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Post procedural haematuria 0/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Post procedural haemorrhage 0/2798 (0%) 0/2780 (0%) 2/3275 (0.1%)
    Procedural haemorrhage 0/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Scapula fracture 0/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Spinal fracture 0/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Stomal hernia 0/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Subarachnoid haemorrhage 0/2798 (0%) 0/2780 (0%) 2/3275 (0.1%)
    Tendon rupture 0/2798 (0%) 0/2780 (0%) 2/3275 (0.1%)
    Tibia fracture 0/2798 (0%) 0/2780 (0%) 3/3275 (0.1%)
    Toxicity to various agents 0/2798 (0%) 0/2780 (0%) 5/3275 (0.2%)
    Traumatic haemorrhage 0/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Wound evisceration 0/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Wrist fracture 0/2798 (0%) 0/2780 (0%) 2/3275 (0.1%)
    Investigations
    Blood magnesium decreased 0/2798 (0%) 1/2780 (0%) 0/3275 (0%)
    Cystoscopy 1/2798 (0%) 0/2780 (0%) 0/3275 (0%)
    Ejection fraction decreased 1/2798 (0%) 0/2780 (0%) 0/3275 (0%)
    Hepatic enzyme increased 1/2798 (0%) 1/2780 (0%) 0/3275 (0%)
    Angiogram 1/2798 (0%) 3/2780 (0.1%) 1/3275 (0%)
    Arteriogram coronary 1/2798 (0%) 1/2780 (0%) 1/3275 (0%)
    Heart rate irregular 1/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Red blood cell sedimentation rate increased 1/2798 (0%) 0/2780 (0%) 0/3275 (0%)
    Liver function test abnormal 1/2798 (0%) 2/2780 (0.1%) 0/3275 (0%)
    Prostatic specific antigen increased 0/2798 (0%) 1/2780 (0%) 0/3275 (0%)
    Weight decreased 0/2798 (0%) 1/2780 (0%) 0/3275 (0%)
    Arthroscopy 0/2798 (0%) 0/2780 (0%) 2/3275 (0.1%)
    Blood creatinine increased 0/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Ecg signs of myocardial ischaemia 0/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Haemoglobin decreased 0/2798 (0%) 0/2780 (0%) 2/3275 (0.1%)
    Heart rate abnormal 0/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Liver function test increased 0/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Platelet count decreased 0/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Metabolism and nutrition disorders
    Hypoglycaemia 8/2798 (0.3%) 3/2780 (0.1%) 12/3275 (0.4%)
    Diabetes mellitus inadequate control 0/2798 (0%) 2/2780 (0.1%) 3/3275 (0.1%)
    Gout 2/2798 (0.1%) 2/2780 (0.1%) 1/3275 (0%)
    Hyperkalaemia 0/2798 (0%) 2/2780 (0.1%) 5/3275 (0.2%)
    Malnutrition 0/2798 (0%) 1/2780 (0%) 0/3275 (0%)
    Decreased appetite 1/2798 (0%) 1/2780 (0%) 2/3275 (0.1%)
    Starvation 1/2798 (0%) 0/2780 (0%) 0/3275 (0%)
    Type 2 diabetes mellitus 1/2798 (0%) 1/2780 (0%) 2/3275 (0.1%)
    Cachexia 0/2798 (0%) 2/2780 (0.1%) 0/3275 (0%)
    Dehydration 7/2798 (0.3%) 5/2780 (0.2%) 11/3275 (0.3%)
    Hypokalaemia 0/2798 (0%) 3/2780 (0.1%) 2/3275 (0.1%)
    Hyponatraemia 4/2798 (0.1%) 3/2780 (0.1%) 6/3275 (0.2%)
    Obesity 0/2798 (0%) 1/2780 (0%) 1/3275 (0%)
    Electrolyte imbalance 1/2798 (0%) 0/2780 (0%) 2/3275 (0.1%)
    Hyperglycaemia 3/2798 (0.1%) 1/2780 (0%) 2/3275 (0.1%)
    Hypovolaemia 1/2798 (0%) 0/2780 (0%) 0/3275 (0%)
    Diabetes mellitus 5/2798 (0.2%) 4/2780 (0.1%) 6/3275 (0.2%)
    Diabetes with hyperosmolarity 0/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Hypernatraemia 0/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Hypomagnesaemia 0/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Hypophosphataemia 0/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Lactic acidosis 0/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Metabolic acidosis 0/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Musculoskeletal and connective tissue disorders
    Lumbar spinal stenosis 0/2798 (0%) 1/2780 (0%) 4/3275 (0.1%)
    Musculoskeletal stiffness 1/2798 (0%) 0/2780 (0%) 0/3275 (0%)
    Osteochondrosis 1/2798 (0%) 0/2780 (0%) 0/3275 (0%)
    Spinal column stenosis 1/2798 (0%) 0/2780 (0%) 0/3275 (0%)
    Myopathy 1/2798 (0%) 0/2780 (0%) 0/3275 (0%)
    Rotator cuff syndrome 0/2798 (0%) 2/2780 (0.1%) 1/3275 (0%)
    Spinal osteoarthritis 1/2798 (0%) 0/2780 (0%) 4/3275 (0.1%)
    Joint swelling 1/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Musculoskeletal chest pain 1/2798 (0%) 0/2780 (0%) 3/3275 (0.1%)
    Osteoarthritis 11/2798 (0.4%) 3/2780 (0.1%) 17/3275 (0.5%)
    Polyarthritis 0/2798 (0%) 1/2780 (0%) 1/3275 (0%)
    Intervertebral disc protrusion 0/2798 (0%) 4/2780 (0.1%) 4/3275 (0.1%)
    Muscle spasms 1/2798 (0%) 0/2780 (0%) 0/3275 (0%)
    Pain in extremity 1/2798 (0%) 1/2780 (0%) 0/3275 (0%)
    Systemic lupus erythematosus 0/2798 (0%) 1/2780 (0%) 0/3275 (0%)
    Back pain 5/2798 (0.2%) 3/2780 (0.1%) 9/3275 (0.3%)
    Gouty arthritis 1/2798 (0%) 2/2780 (0.1%) 2/3275 (0.1%)
    Haemarthrosis 1/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Muscle haemorrhage 1/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Osteopenia 0/2798 (0%) 1/2780 (0%) 0/3275 (0%)
    Arthralgia 1/2798 (0%) 2/2780 (0.1%) 2/3275 (0.1%)
    Musculoskeletal pain 0/2798 (0%) 1/2780 (0%) 1/3275 (0%)
    Arthritis 0/2798 (0%) 0/2780 (0%) 2/3275 (0.1%)
    Bursitis 0/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Inguinal mass 0/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Intervertebral disc degeneration 0/2798 (0%) 0/2780 (0%) 2/3275 (0.1%)
    Muscular weakness 0/2798 (0%) 0/2780 (0%) 2/3275 (0.1%)
    Myalgia 0/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Plantar fasciitis 0/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Polymyalgia rheumatica 0/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Rhabdomyolysis 0/2798 (0%) 0/2780 (0%) 2/3275 (0.1%)
    Rheumatoid arthritis 0/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Spinal pain 0/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Tendon pain 0/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Breast cancer 9/2798 (0.3%) 1/2780 (0%) 10/3275 (0.3%)
    Cholesteatoma 0/2798 (0%) 1/2780 (0%) 0/3275 (0%)
    Colon cancer metastatic 1/2798 (0%) 1/2780 (0%) 0/3275 (0%)
    Gastric cancer 1/2798 (0%) 2/2780 (0.1%) 2/3275 (0.1%)
    Laryngeal cancer 0/2798 (0%) 2/2780 (0.1%) 0/3275 (0%)
    Lip and/or oral cavity cancer 1/2798 (0%) 0/2780 (0%) 0/3275 (0%)
    Lung neoplasm malignant 3/2798 (0.1%) 5/2780 (0.2%) 15/3275 (0.5%)
    Neoplasm prostate 1/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Non-Hodgkin's lymphoma stage III 1/2798 (0%) 0/2780 (0%) 0/3275 (0%)
    Pancreatic carcinoma 0/2798 (0%) 1/2780 (0%) 6/3275 (0.2%)
    Prostatic adenoma 2/2798 (0.1%) 0/2780 (0%) 3/3275 (0.1%)
    Uterine leiomyoma 0/2798 (0%) 2/2780 (0.1%) 2/3275 (0.1%)
    Bladder cancer 1/2798 (0%) 0/2780 (0%) 4/3275 (0.1%)
    Brain neoplasm benign 1/2798 (0%) 0/2780 (0%) 0/3275 (0%)
    Omentum neoplasm 0/2798 (0%) 1/2780 (0%) 0/3275 (0%)
    Renal cell carcinoma 1/2798 (0%) 0/2780 (0%) 2/3275 (0.1%)
    Breast cancer metastatic 0/2798 (0%) 1/2780 (0%) 1/3275 (0%)
    Bronchial carcinoma 0/2798 (0%) 2/2780 (0.1%) 0/3275 (0%)
    Leukaemia 2/2798 (0.1%) 0/2780 (0%) 1/3275 (0%)
    Metastases to abdominal cavity 0/2798 (0%) 1/2780 (0%) 0/3275 (0%)
    Biliary neoplasm 0/2798 (0%) 1/2780 (0%) 0/3275 (0%)
    Hepatic neoplasm malignant 1/2798 (0%) 1/2780 (0%) 0/3275 (0%)
    Malignant melanoma 1/2798 (0%) 2/2780 (0.1%) 2/3275 (0.1%)
    Lipoma 1/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Lung adenocarcinoma metastatic 1/2798 (0%) 0/2780 (0%) 0/3275 (0%)
    Lung cancer metastatic 0/2798 (0%) 1/2780 (0%) 0/3275 (0%)
    Lymph node cancer metastatic 1/2798 (0%) 0/2780 (0%) 0/3275 (0%)
    Metastases to central nervous system 1/2798 (0%) 0/2780 (0%) 0/3275 (0%)
    Neoplasm malignant 1/2798 (0%) 1/2780 (0%) 1/3275 (0%)
    Rectal cancer metastatic 1/2798 (0%) 0/2780 (0%) 0/3275 (0%)
    Sebaceous carcinoma 0/2798 (0%) 1/2780 (0%) 0/3275 (0%)
    Squamous cell carcinoma 2/2798 (0.1%) 4/2780 (0.1%) 7/3275 (0.2%)
    Cervix carcinoma stage 0 1/2798 (0%) 0/2780 (0%) 0/3275 (0%)
    Gastrointestinal carcinoma 1/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Leiomyoma 0/2798 (0%) 1/2780 (0%) 0/3275 (0%)
    Malignant melanoma stage I 0/2798 (0%) 1/2780 (0%) 0/3275 (0%)
    Pelvic neoplasm 0/2798 (0%) 1/2780 (0%) 0/3275 (0%)
    Renal cancer stage III 1/2798 (0%) 0/2780 (0%) 0/3275 (0%)
    Squamous cell carcinoma of skin 2/2798 (0.1%) 0/2780 (0%) 4/3275 (0.1%)
    Basal cell carcinoma 5/2798 (0.2%) 5/2780 (0.2%) 12/3275 (0.4%)
    Basosquamous carcinoma 1/2798 (0%) 0/2780 (0%) 0/3275 (0%)
    Colon cancer 2/2798 (0.1%) 1/2780 (0%) 5/3275 (0.2%)
    Liposarcoma 1/2798 (0%) 0/2780 (0%) 0/3275 (0%)
    Prostate cancer recurrent 0/2798 (0%) 1/2780 (0%) 0/3275 (0%)
    Renal neoplasm 1/2798 (0%) 1/2780 (0%) 0/3275 (0%)
    Colon neoplasm 1/2798 (0%) 0/2780 (0%) 0/3275 (0%)
    Endometrial cancer 1/2798 (0%) 0/2780 (0%) 0/3275 (0%)
    Gallbladder cancer 0/2798 (0%) 1/2780 (0%) 0/3275 (0%)
    Lymphoma 1/2798 (0%) 0/2780 (0%) 2/3275 (0.1%)
    Metastases to liver 0/2798 (0%) 1/2780 (0%) 0/3275 (0%)
    Prostate cancer 7/2798 (0.3%) 10/2780 (0.4%) 12/3275 (0.4%)
    Rectal cancer 0/2798 (0%) 1/2780 (0%) 0/3275 (0%)
    Renal cancer 0/2798 (0%) 1/2780 (0%) 1/3275 (0%)
    Squamous cell carcinoma of the cervix 0/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Acute myeloid leukaemia 0/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Adenocarcinoma gastric 0/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Adenocarcinoma of colon 0/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Adrenal adenoma 0/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    B-cell lymphoma 0/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    B-cell small lymphocytic lymphoma stage iv 0/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Bladder cancer stage 0, with cancer in situ 0/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Bladder neoplasm 0/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Bowen's disease 0/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Brain cancer metastatic 0/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Brain neoplasm 0/2798 (0%) 0/2780 (0%) 4/3275 (0.1%)
    Carcinoid tumour of the caecum 0/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Cholangiocarcinoma 0/2798 (0%) 0/2780 (0%) 2/3275 (0.1%)
    Chronic lymphocytic leukaemia 0/2798 (0%) 0/2780 (0%) 2/3275 (0.1%)
    Colorectal cancer 0/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Diffuse large b-cell lymphoma 0/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Gastrointestinal stromal tumour 0/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Hepatocellular carcinoma 0/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Intraductal papillary mucinous neoplasm 0/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Intraocular melanoma 0/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Invasive ductal breast carcinoma 0/2798 (0%) 0/2780 (0%) 2/3275 (0.1%)
    Leiomyosarcoma metastatic 0/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Light chain disease 0/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Lung adenocarcinoma 0/2798 (0%) 0/2780 (0%) 2/3275 (0.1%)
    Lung neoplasm 0/2798 (0%) 0/2780 (0%) 2/3275 (0.1%)
    Meningioma 0/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Metastases to bone 0/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Metastases to pleura 0/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Metastatic neoplasm 0/2798 (0%) 0/2780 (0%) 2/3275 (0.1%)
    Metastatic renal cell carcinoma 0/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Myeloproliferative neoplasm 0/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Neoplasm 0/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Neuroendocrine tumour 0/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Non-hodgkin's lymphoma 1/2798 (0%) 0/2780 (0%) 2/3275 (0.1%)
    Oesophageal adenocarcinoma 0/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Oesophageal cancer metastatic 0/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Ovarian cancer 0/2798 (0%) 0/2780 (0%) 3/3275 (0.1%)
    Paraneoplastic syndrome 0/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Plasma cell myeloma 0/2798 (0%) 0/2780 (0%) 2/3275 (0.1%)
    Prostate cancer metastatic 0/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Rectal adenocarcinoma 0/2798 (0%) 0/2780 (0%) 2/3275 (0.1%)
    Seborrhoeic keratosis 0/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Skin cancer 0/2798 (0%) 0/2780 (0%) 3/3275 (0.1%)
    Throat cancer 0/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Thyroid adenoma 0/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Transitional cell carcinoma 0/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Tumour haemorrhage 0/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Uterine cancer 0/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Vocal cord neoplasm 0/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Nervous system disorders
    Cerebral infarction 1/2798 (0%) 6/2780 (0.2%) 10/3275 (0.3%)
    Dementia 0/2798 (0%) 1/2780 (0%) 1/3275 (0%)
    Dizziness 1/2798 (0%) 10/2780 (0.4%) 6/3275 (0.2%)
    Haemorrhagic cerebral infarction 0/2798 (0%) 1/2780 (0%) 0/3275 (0%)
    Lethargy 0/2798 (0%) 1/2780 (0%) 1/3275 (0%)
    Loss of consciousness 0/2798 (0%) 1/2780 (0%) 2/3275 (0.1%)
    Metabolic encephalopathy 0/2798 (0%) 2/2780 (0.1%) 1/3275 (0%)
    Peripheral nerve palsy 0/2798 (0%) 1/2780 (0%) 0/3275 (0%)
    Tremor 1/2798 (0%) 0/2780 (0%) 0/3275 (0%)
    Vertebrobasilar insufficiency 1/2798 (0%) 0/2780 (0%) 0/3275 (0%)
    Migraine 0/2798 (0%) 1/2780 (0%) 0/3275 (0%)
    Parkinson's disease 0/2798 (0%) 4/2780 (0.1%) 4/3275 (0.1%)
    Subarachnoid haemorrhage 0/2798 (0%) 2/2780 (0.1%) 0/3275 (0%)
    Cerebral haemorrhage 3/2798 (0.1%) 1/2780 (0%) 10/3275 (0.3%)
    Cubital tunnel syndrome 1/2798 (0%) 0/2780 (0%) 0/3275 (0%)
    Depressed level of consciousness 0/2798 (0%) 1/2780 (0%) 1/3275 (0%)
    Embolic stroke 0/2798 (0%) 2/2780 (0.1%) 3/3275 (0.1%)
    Hemiparesis 1/2798 (0%) 1/2780 (0%) 0/3275 (0%)
    Partial seizures 0/2798 (0%) 1/2780 (0%) 0/3275 (0%)
    Presyncope 5/2798 (0.2%) 2/2780 (0.1%) 4/3275 (0.1%)
    Sciatica 0/2798 (0%) 1/2780 (0%) 1/3275 (0%)
    VIIth nerve paralysis 1/2798 (0%) 0/2780 (0%) 0/3275 (0%)
    Cerebral microhaemorrhage 1/2798 (0%) 0/2780 (0%) 0/3275 (0%)
    Cerebral thrombosis 1/2798 (0%) 0/2780 (0%) 0/3275 (0%)
    Cervical root pain 1/2798 (0%) 0/2780 (0%) 0/3275 (0%)
    Encephalopathy 0/2798 (0%) 1/2780 (0%) 0/3275 (0%)
    Epilepsy 2/2798 (0.1%) 1/2780 (0%) 3/3275 (0.1%)
    Lumbar radiculopathy 1/2798 (0%) 0/2780 (0%) 0/3275 (0%)
    Neuropathy peripheral 1/2798 (0%) 1/2780 (0%) 0/3275 (0%)
    Paraesthesia 1/2798 (0%) 1/2780 (0%) 0/3275 (0%)
    Cerebral haematoma 0/2798 (0%) 1/2780 (0%) 0/3275 (0%)
    Convulsion 1/2798 (0%) 2/2780 (0.1%) 0/3275 (0%)
    Headache 1/2798 (0%) 1/2780 (0%) 2/3275 (0.1%)
    Ischaemic stroke 19/2798 (0.7%) 46/2780 (1.7%) 22/3275 (0.7%)
    Lacunar infarction 0/2798 (0%) 1/2780 (0%) 1/3275 (0%)
    Transient ischaemic attack 10/2798 (0.4%) 29/2780 (1%) 13/3275 (0.4%)
    Vascular encephalopathy 0/2798 (0%) 1/2780 (0%) 0/3275 (0%)
    Diabetic hyperglycaemic coma 0/2798 (0%) 1/2780 (0%) 0/3275 (0%)
    Haemorrhagic stroke 5/2798 (0.2%) 6/2780 (0.2%) 8/3275 (0.2%)
    Aphasia 0/2798 (0%) 1/2780 (0%) 1/3275 (0%)
    Brain stem infarction 0/2798 (0%) 1/2780 (0%) 0/3275 (0%)
    Carotid arterial embolus 1/2798 (0%) 0/2780 (0%) 0/3275 (0%)
    Cerebral cyst 0/2798 (0%) 1/2780 (0%) 0/3275 (0%)
    Cerebrovascular disorder 0/2798 (0%) 1/2780 (0%) 2/3275 (0.1%)
    Ischaemic cerebral infarction 0/2798 (0%) 1/2780 (0%) 0/3275 (0%)
    Syncope 8/2798 (0.3%) 18/2780 (0.6%) 26/3275 (0.8%)
    Altered state of consciousness 0/2798 (0%) 1/2780 (0%) 2/3275 (0.1%)
    Brain stem haemorrhage 0/2798 (0%) 1/2780 (0%) 0/3275 (0%)
    Cerebellar ataxia 0/2798 (0%) 1/2780 (0%) 0/3275 (0%)
    Cerebrovascular accident 16/2798 (0.6%) 40/2780 (1.4%) 15/3275 (0.5%)
    Cerebrovascular insufficiency 0/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Cognitive disorder 0/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Dementia alzheimer's type 0/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Diabetic neuropathy 0/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Dysarthria 0/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Dyskinesia 0/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Haemorrhage intracranial 0/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Hydrocephalus 0/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Hypoaesthesia 0/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Hypoglycaemic coma 0/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Hyponatraemic encephalopathy 0/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Intraventricular haemorrhage 0/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Myoclonus 0/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Neuritis 0/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Neuroglycopenia 0/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Paraplegia 0/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Seizure 0/2798 (0%) 0/2780 (0%) 3/3275 (0.1%)
    Simple partial seizures 0/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Status epilepticus 0/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Subdural effusion 0/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Thrombotic stroke 0/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Uraemic encephalopathy 0/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Vascular dementia 0/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Autonomic nervous system imbalance 0/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Balance disorder 0/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Basal ganglia haemorrhage 0/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Carotid artery stenosis 0/2798 (0%) 0/2780 (0%) 4/3275 (0.1%)
    Carpal tunnel syndrome 0/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Cerebellar infarction 0/2798 (0%) 0/2780 (0%) 2/3275 (0.1%)
    Cerebral artery embolism 0/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Pregnancy, puerperium and perinatal conditions
    Cephalhaematoma 0/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Product Issues
    Lead dislodgement 0/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Psychiatric disorders
    Alcohol abuse 0/2798 (0%) 2/2780 (0.1%) 0/3275 (0%)
    Anxiety 0/2798 (0%) 1/2780 (0%) 0/3275 (0%)
    Panic attack 0/2798 (0%) 1/2780 (0%) 0/3275 (0%)
    Confusional state 3/2798 (0.1%) 0/2780 (0%) 2/3275 (0.1%)
    Bipolar disorder 0/2798 (0%) 1/2780 (0%) 0/3275 (0%)
    Delirium 0/2798 (0%) 3/2780 (0.1%) 0/3275 (0%)
    Psychotic disorder 1/2798 (0%) 0/2780 (0%) 0/3275 (0%)
    Alcohol withdrawal syndrome 0/2798 (0%) 1/2780 (0%) 0/3275 (0%)
    Depression 2/2798 (0.1%) 1/2780 (0%) 3/3275 (0.1%)
    Adjustment disorder 0/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Bipolar i disorder 0/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Completed suicide 0/2798 (0%) 0/2780 (0%) 2/3275 (0.1%)
    Hallucination 0/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Insomnia 0/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Mental disorder 0/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Stress 0/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Suicidal ideation 0/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Suicide attempt 0/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Renal and urinary disorders
    Calculus ureteric 0/2798 (0%) 1/2780 (0%) 0/3275 (0%)
    Hypertensive nephropathy 0/2798 (0%) 1/2780 (0%) 0/3275 (0%)
    Renal failure acute 8/2798 (0.3%) 9/2780 (0.3%) 0/3275 (0%)
    Urinary incontinence 2/2798 (0.1%) 0/2780 (0%) 0/3275 (0%)
    Dysuria 1/2798 (0%) 0/2780 (0%) 0/3275 (0%)
    Renal failure 1/2798 (0%) 6/2780 (0.2%) 6/3275 (0.2%)
    Urinary retention 3/2798 (0.1%) 2/2780 (0.1%) 2/3275 (0.1%)
    Renal impairment 0/2798 (0%) 1/2780 (0%) 2/3275 (0.1%)
    Renal infarct 0/2798 (0%) 1/2780 (0%) 0/3275 (0%)
    Bladder mass 1/2798 (0%) 0/2780 (0%) 0/3275 (0%)
    Haematuria 5/2798 (0.2%) 4/2780 (0.1%) 13/3275 (0.4%)
    Renal failure chronic 1/2798 (0%) 1/2780 (0%) 0/3275 (0%)
    Urethral disorder 0/2798 (0%) 1/2780 (0%) 0/3275 (0%)
    Renal colic 1/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Calculus urinary 3/2798 (0.1%) 0/2780 (0%) 1/3275 (0%)
    Acute kidney injury 0/2798 (0%) 0/2780 (0%) 24/3275 (0.7%)
    Azotaemia 0/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Calculus bladder 0/2798 (0%) 0/2780 (0%) 2/3275 (0.1%)
    Calculus urethral 0/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Chronic kidney disease 0/2798 (0%) 0/2780 (0%) 3/3275 (0.1%)
    Cystitis haemorrhagic 0/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Diabetic nephropathy 0/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Haemorrhage urinary tract 0/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Nephrolithiasis 0/2798 (0%) 0/2780 (0%) 2/3275 (0.1%)
    Postrenal failure 0/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Renal haemorrhage 0/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Renal tubular necrosis 0/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Reproductive system and breast disorders
    Prostatic obstruction 0/2798 (0%) 1/2780 (0%) 0/3275 (0%)
    Menometrorrhagia 1/2798 (0%) 0/2780 (0%) 0/3275 (0%)
    Benign prostatic hyperplasia 2/2798 (0.1%) 3/2780 (0.1%) 8/3275 (0.2%)
    Vaginal haemorrhage 1/2798 (0%) 0/2780 (0%) 0/3275 (0%)
    Breast mass 0/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Metrorrhagia 0/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Postmenopausal haemorrhage 0/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Prostatic hypoplasia 0/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Prostatomegaly 0/2798 (0%) 0/2780 (0%) 2/3275 (0.1%)
    Spermatic cord disorder 0/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Uterine polyp 0/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Respiratory, thoracic and mediastinal disorders
    Emphysema 0/2798 (0%) 1/2780 (0%) 1/3275 (0%)
    Epistaxis 5/2798 (0.2%) 6/2780 (0.2%) 16/3275 (0.5%)
    Lung infiltration 1/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Mediastinal mass 0/2798 (0%) 1/2780 (0%) 0/3275 (0%)
    Haemothorax 0/2798 (0%) 1/2780 (0%) 2/3275 (0.1%)
    Pulmonary fibrosis 0/2798 (0%) 1/2780 (0%) 1/3275 (0%)
    Respiratory arrest 1/2798 (0%) 0/2780 (0%) 0/3275 (0%)
    Sleep apnoea syndrome 1/2798 (0%) 0/2780 (0%) 2/3275 (0.1%)
    Allergic bronchitis 1/2798 (0%) 0/2780 (0%) 0/3275 (0%)
    Chronic obstructive pulmonary disease 12/2798 (0.4%) 9/2780 (0.3%) 24/3275 (0.7%)
    Dyspnoea 13/2798 (0.5%) 11/2780 (0.4%) 22/3275 (0.7%)
    Haemoptysis 3/2798 (0.1%) 2/2780 (0.1%) 6/3275 (0.2%)
    Pulmonary artery thrombosis 1/2798 (0%) 0/2780 (0%) 0/3275 (0%)
    Respiratory failure 4/2798 (0.1%) 9/2780 (0.3%) 5/3275 (0.2%)
    Dyspnoea exertional 0/2798 (0%) 1/2780 (0%) 4/3275 (0.1%)
    Hiccups 1/2798 (0%) 0/2780 (0%) 0/3275 (0%)
    Lung disorder 1/2798 (0%) 2/2780 (0.1%) 3/3275 (0.1%)
    Orthopnoea 1/2798 (0%) 0/2780 (0%) 2/3275 (0.1%)
    Pulmonary embolism 2/2798 (0.1%) 11/2780 (0.4%) 7/3275 (0.2%)
    Pulmonary oedema 2/2798 (0.1%) 2/2780 (0.1%) 3/3275 (0.1%)
    Sinus polyp 0/2798 (0%) 1/2780 (0%) 0/3275 (0%)
    Acute pulmonary oedema 4/2798 (0.1%) 2/2780 (0.1%) 4/3275 (0.1%)
    Acute respiratory distress syndrome 0/2798 (0%) 1/2780 (0%) 0/3275 (0%)
    Cough 1/2798 (0%) 0/2780 (0%) 0/3275 (0%)
    Pleural effusion 1/2798 (0%) 4/2780 (0.1%) 5/3275 (0.2%)
    Acute respiratory failure 4/2798 (0.1%) 0/2780 (0%) 4/3275 (0.1%)
    Asthma 6/2798 (0.2%) 3/2780 (0.1%) 5/3275 (0.2%)
    Bronchitis chronic 1/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Bronchospasm 1/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Pneumonia aspiration 3/2798 (0.1%) 2/2780 (0.1%) 3/3275 (0.1%)
    Pneumothorax 2/2798 (0.1%) 2/2780 (0.1%) 0/3275 (0%)
    Pulmonary hypertension 1/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Respiratory distress 0/2798 (0%) 3/2780 (0.1%) 3/3275 (0.1%)
    Asphyxia 0/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Hyperventilation 0/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Hypoxia 0/2798 (0%) 0/2780 (0%) 2/3275 (0.1%)
    Lung consolidation 0/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Pleurisy 0/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Pulmonary congestion 0/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Pulmonary vascular disorder 0/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Skin and subcutaneous tissue disorders
    Blood blister 0/2798 (0%) 1/2780 (0%) 0/3275 (0%)
    Skin lesion 1/2798 (0%) 0/2780 (0%) 0/3275 (0%)
    Decubitus ulcer 2/2798 (0.1%) 0/2780 (0%) 1/3275 (0%)
    Dermatitis herpetiformis 0/2798 (0%) 1/2780 (0%) 0/3275 (0%)
    Purpura 0/2798 (0%) 1/2780 (0%) 0/3275 (0%)
    Rash erythematous 0/2798 (0%) 1/2780 (0%) 1/3275 (0%)
    Angioedema 1/2798 (0%) 1/2780 (0%) 2/3275 (0.1%)
    Dermatitis 0/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Diabetic foot 0/2798 (0%) 0/2780 (0%) 3/3275 (0.1%)
    Erythema 0/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Skin ulcer 0/2798 (0%) 0/2780 (0%) 3/3275 (0.1%)
    Social circumstances
    Activities of daily living impaired 0/2798 (0%) 1/2780 (0%) 0/3275 (0%)
    Physical assault 1/2798 (0%) 0/2780 (0%) 0/3275 (0%)
    Cardiac assistance device user 0/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Surgical and medical procedures
    Cataract operation 0/2798 (0%) 1/2780 (0%) 2/3275 (0.1%)
    Fasciotomy 0/2798 (0%) 1/2780 (0%) 0/3275 (0%)
    Gallbladder operation 0/2798 (0%) 1/2780 (0%) 1/3275 (0%)
    Genitourinary operation 1/2798 (0%) 0/2780 (0%) 0/3275 (0%)
    Haemorrhoid operation 1/2798 (0%) 1/2780 (0%) 1/3275 (0%)
    Knee arthroplasty 1/2798 (0%) 1/2780 (0%) 6/3275 (0.2%)
    Papilloma excision 1/2798 (0%) 0/2780 (0%) 0/3275 (0%)
    Skin graft 0/2798 (0%) 1/2780 (0%) 0/3275 (0%)
    Abdominoplasty 0/2798 (0%) 1/2780 (0%) 0/3275 (0%)
    Cardiac pacemaker removal 1/2798 (0%) 0/2780 (0%) 0/3275 (0%)
    Cardiac pacemaker replacement 1/2798 (0%) 1/2780 (0%) 2/3275 (0.1%)
    Cholecystectomy 1/2798 (0%) 1/2780 (0%) 0/3275 (0%)
    Implantable defibrillator insertion 0/2798 (0%) 1/2780 (0%) 1/3275 (0%)
    Prostatic operation 1/2798 (0%) 1/2780 (0%) 0/3275 (0%)
    Tarsal tunnel decompression 1/2798 (0%) 0/2780 (0%) 0/3275 (0%)
    Coronary artery bypass 0/2798 (0%) 1/2780 (0%) 1/3275 (0%)
    Hysterectomy 0/2798 (0%) 1/2780 (0%) 0/3275 (0%)
    Implantable defibrillator replacement 1/2798 (0%) 0/2780 (0%) 2/3275 (0.1%)
    Inguinal hernia repair 4/2798 (0.1%) 0/2780 (0%) 4/3275 (0.1%)
    Peripheral artery angioplasty 1/2798 (0%) 1/2780 (0%) 3/3275 (0.1%)
    Therapeutic embolisation 1/2798 (0%) 0/2780 (0%) 0/3275 (0%)
    Transfusion 1/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Vertebroplasty 0/2798 (0%) 1/2780 (0%) 1/3275 (0%)
    Cardiac ablation 1/2798 (0%) 2/2780 (0.1%) 1/3275 (0%)
    Cardiac pacemaker insertion 4/2798 (0.1%) 2/2780 (0.1%) 9/3275 (0.3%)
    Orchidectomy 0/2798 (0%) 1/2780 (0%) 0/3275 (0%)
    Percutaneous coronary intervention 2/2798 (0.1%) 2/2780 (0.1%) 0/3275 (0%)
    Skin neoplasm excision 1/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Spinal fusion surgery 0/2798 (0%) 1/2780 (0%) 0/3275 (0%)
    Toe amputation 0/2798 (0%) 1/2780 (0%) 1/3275 (0%)
    Tooth extraction 0/2798 (0%) 1/2780 (0%) 0/3275 (0%)
    Transurethral prostatectomy 1/2798 (0%) 4/2780 (0.1%) 1/3275 (0%)
    Cardiac pacemaker battery replacement 3/2798 (0.1%) 0/2780 (0%) 1/3275 (0%)
    Coronary angioplasty 0/2798 (0%) 1/2780 (0%) 0/3275 (0%)
    Hip arthroplasty 2/2798 (0.1%) 1/2780 (0%) 8/3275 (0.2%)
    Hip surgery 1/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Uterine dilation and curettage 1/2798 (0%) 0/2780 (0%) 0/3275 (0%)
    Angioplasty 1/2798 (0%) 0/2780 (0%) 0/3275 (0%)
    Eye operation 1/2798 (0%) 0/2780 (0%) 0/3275 (0%)
    Heart valve operation 0/2798 (0%) 2/2780 (0.1%) 0/3275 (0%)
    Hospitalisation 3/2798 (0.1%) 2/2780 (0.1%) 1/3275 (0%)
    Mastectomy 0/2798 (0%) 1/2780 (0%) 1/3275 (0%)
    Salivary gland operation 0/2798 (0%) 1/2780 (0%) 0/3275 (0%)
    Mitral valve repair 0/2798 (0%) 1/2780 (0%) 0/3275 (0%)
    Renal stone removal 1/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Thromboembolectomy 0/2798 (0%) 1/2780 (0%) 0/3275 (0%)
    Appendicectomy 0/2798 (0%) 1/2780 (0%) 0/3275 (0%)
    Bursal operation 0/2798 (0%) 1/2780 (0%) 0/3275 (0%)
    Cardioversion 1/2798 (0%) 0/2780 (0%) 0/3275 (0%)
    Hernia repair 1/2798 (0%) 1/2780 (0%) 2/3275 (0.1%)
    Incisional hernia repair 0/2798 (0%) 1/2780 (0%) 0/3275 (0%)
    Rectal polypectomy 0/2798 (0%) 1/2780 (0%) 0/3275 (0%)
    Aortic aneurysm repair 0/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Aortic valve replacement 0/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Benign tumour excision 0/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Bladder polypectomy 0/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Cancer surgery 0/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Carotid endarterectomy 0/2798 (0%) 0/2780 (0%) 2/3275 (0.1%)
    Choledochoenterostomy 0/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Coronary arterial stent insertion 0/2798 (0%) 0/2780 (0%) 2/3275 (0.1%)
    Endarterectomy 0/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Endovenous ablation 0/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Gastric bypass 0/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Gastrointestinal tube insertion 0/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Heart valve replacement 0/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    High frequency ablation 0/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Hydronephrosis repair 0/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Knee operation 0/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Laparotomy 0/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Liver operation 0/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Lung operation 0/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Medical device implantation 0/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Medical device removal 0/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Mitral valve replacement 0/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Pancreaticoduodenectomy 0/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Plastic surgery to the face 0/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Proctocolectomy 0/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Rehabilitation therapy 0/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Skin lesion removal 0/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Thyroid operation 0/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Thyroidectomy 0/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Tracheostomy 0/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Ureteral stent insertion 0/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Urethral stent insertion 0/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Vascular graft 0/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Ventriculo-peritoneal shunt 0/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Weight loss diet 0/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Wrist surgery 0/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Vascular disorders
    Hypertensive crisis 6/2798 (0.2%) 3/2780 (0.1%) 3/3275 (0.1%)
    Intermittent claudication 0/2798 (0%) 1/2780 (0%) 0/3275 (0%)
    Arteriosclerosis obliterans 0/2798 (0%) 1/2780 (0%) 0/3275 (0%)
    Deep vein thrombosis 2/2798 (0.1%) 6/2780 (0.2%) 2/3275 (0.1%)
    Thrombophlebitis 0/2798 (0%) 1/2780 (0%) 1/3275 (0%)
    Femoral artery embolism 0/2798 (0%) 1/2780 (0%) 0/3275 (0%)
    Haemorrhage 1/2798 (0%) 3/2780 (0.1%) 6/3275 (0.2%)
    Lymphocele 1/2798 (0%) 0/2780 (0%) 0/3275 (0%)
    Peripheral embolism 0/2798 (0%) 1/2780 (0%) 2/3275 (0.1%)
    Venous insufficiency 1/2798 (0%) 0/2780 (0%) 0/3275 (0%)
    Aortic rupture 0/2798 (0%) 1/2780 (0%) 0/3275 (0%)
    Arterial thrombosis limb 1/2798 (0%) 1/2780 (0%) 0/3275 (0%)
    Femoral artery occlusion 0/2798 (0%) 3/2780 (0.1%) 0/3275 (0%)
    Hypertension 4/2798 (0.1%) 9/2780 (0.3%) 13/3275 (0.4%)
    Orthostatic hypotension 1/2798 (0%) 6/2780 (0.2%) 3/3275 (0.1%)
    Thrombosis 1/2798 (0%) 1/2780 (0%) 1/3275 (0%)
    Venous thrombosis 0/2798 (0%) 2/2780 (0.1%) 0/3275 (0%)
    Aortic dissection 1/2798 (0%) 0/2780 (0%) 0/3275 (0%)
    Arterial stenosis 0/2798 (0%) 1/2780 (0%) 0/3275 (0%)
    Shock 1/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Thrombophlebitis superficial 0/2798 (0%) 1/2780 (0%) 1/3275 (0%)
    Aortic aneurysm 0/2798 (0%) 1/2780 (0%) 2/3275 (0.1%)
    Aortic stenosis 2/2798 (0.1%) 0/2780 (0%) 3/3275 (0.1%)
    Arteriosclerosis 1/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Haematoma 1/2798 (0%) 2/2780 (0.1%) 4/3275 (0.1%)
    Pallor 1/2798 (0%) 1/2780 (0%) 0/3275 (0%)
    Peripheral arterial occlusive disease 0/2798 (0%) 4/2780 (0.1%) 2/3275 (0.1%)
    Varicose vein 0/2798 (0%) 1/2780 (0%) 1/3275 (0%)
    Hypotension 3/2798 (0.1%) 4/2780 (0.1%) 4/3275 (0.1%)
    Peripheral ischaemia 0/2798 (0%) 5/2780 (0.2%) 3/3275 (0.1%)
    Phlebitis 0/2798 (0%) 1/2780 (0%) 0/3275 (0%)
    Accelerated hypertension 0/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Aneurysm 0/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Arterial disorder 0/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Arterial occlusive disease 0/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Circulatory collapse 0/2798 (0%) 0/2780 (0%) 2/3275 (0.1%)
    Hypertensive emergency 0/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Hypovolaemic shock 0/2798 (0%) 0/2780 (0%) 2/3275 (0.1%)
    Leriche syndrome 0/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Pelvic venous thrombosis 0/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Peripheral artery stenosis 0/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Peripheral vascular disorder 0/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Peripheral venous disease 0/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Subclavian artery stenosis 0/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Temporal arteritis 0/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Varicose ulceration 0/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Varicose vein ruptured 0/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Venous haemorrhage 0/2798 (0%) 0/2780 (0%) 1/3275 (0%)
    Other (Not Including Serious) Adverse Events
    Apixaban, 2.5 or 5 mg Twice Daily Acetylsalicylic Acid, 81-324 mg Once Daily Open Label Apixaban
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 207/2798 (7.4%) 267/2780 (9.6%) 180/3275 (5.5%)
    Nervous system disorders
    Dizziness 109/2798 (3.9%) 144/2780 (5.2%) 132/3275 (4%)
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea 109/2798 (3.9%) 141/2780 (5.1%) 164/3275 (5%)

    Limitations/Caveats

    On May 28, 2010, after a planned interim analysis for efficacy, the Data Monitoring Committee recommended early termination due to apixaban's superior efficacy over ASA, with an acceptable safety profile. The open-label phase is ongoing.

    More Information

    Certain Agreements

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

    Bristol-Myers Squibb Co. agreements with investigators vary; constant is our right to embargo communications regarding trial results prior to public release for a period ≤60 days from submittal for review. We will not prohibit investigators from publishing, but will prohibit the disclosure of previously undisclosed confidential information other than study results, and request postponement of single-center publications until after disclosure of the clinical trial's primary publication.

    Results Point of Contact

    Name/Title Bristol-Myers Squibb Study Director
    Organization Bristol-Myers Squibb
    Phone
    Email Clinical.Trials@bms.com
    Responsible Party:
    Bristol-Myers Squibb
    ClinicalTrials.gov Identifier:
    NCT00496769
    Other Study ID Numbers:
    • CV185-048
    First Posted:
    Jul 4, 2007
    Last Update Posted:
    Jun 15, 2018
    Last Verified:
    May 1, 2018