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Niacin Plus Statin to Prevent Vascular Events

Sponsor
Axio Research. LLC (Industry)
Overall Status
Terminated
CT.gov ID
NCT00120289
Collaborator
National Heart, Lung, and Blood Institute (NHLBI) (NIH), Abbott (Industry)
3,414
Enrollment
91
Locations
2
Arms
87
Duration (Months)
37.5
Patients Per Site
0.4
Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The purpose of this study is to determine whether raising "good cholesterol" with a drug based on the vitamin niacin, while lowering "bad cholesterol" with a statin drug, can prevent more heart disease than the statin alone.

Condition or Disease Intervention/Treatment Phase
Phase 3

Detailed Description

BACKGROUND:

Coronary heart disease (CHD) remains the leading cause of death and disability in the Western world, with approximately 12.6 million individuals in the United States having a history of myocardial infarction (MI), angina, or both. There is mounting evidence that "conventional" therapies aimed at traditional risk factors have not optimized clinical outcomes. For example, in the Heart Protection Study with 20,536 subjects, the 5-year risk of a first major vascular event (nonfatal MI or CHD death, stroke, or coronary or noncoronary revascularization) among placebo-treated patients was 25%. Treatment with simvastatin reduced this risk to 20% over 5 years, which would project out to a 10-year risk of 40%. (The National Cholesterol Education Program Adult Treatment Panel III considers "high risk" or CHD equivalent a 10-year risk of an event greater than 20%.) Even among patients entering the study with baseline low density lipoprotein cholesterol (LDL-C) already near or at goal (i.e., LDL-C less than 116 mg/dL) and who achieved a mean on-trial LDL-C of 70 mg/dL with simvastatin, the 5-year risk of an event was still 18% (projecting to a 10-year risk of 36%). This residual and unacceptably high risk is likely due to the increasing prevalence of obesity, type II diabetes mellitus, and the metabolic syndrome. These disorders are typically accompanied by a constellation of abnormalities that include impaired glycemic control, hypertension, procoagulant and inflammatory states, and atherogenic dyslipidemia. The latter includes a wide spectrum of lipid abnormalities (low HDL-C, high triglycerides and triglyceride-rich remnant lipoproteins, and a preponderance of small dense, highly-oxidizable LDL particles).

Conventional LDL-C-focused therapies are not effective in targeting this type of dyslipidemia. Evidence that therapy directed at atherogenic dyslipidemia among patients with CHD can lower outcomes was shown with gemfibrozil in the VA-HIT trial, which showed a 22 to 24% cardiovascular (CV) event reduction by raising HDL-C (by an average of 6%) and lowering triglycerides (by an average of 31%). Niacin is an even more effective agent for simultaneously raising HDL-C and lowering triglycerides and levels of small dense LDL, and holds the most promise among existing therapies for substantial risk reduction in this population when added to a statin. This was demonstrated in the HDL Atherosclerosis Treatment Study (HATS) trial in which atherosclerosis progression was virtually halted and CV events were reduced by 60 to 90% using combined niacin plus statin therapy.

DESIGN NARRATIVE:

AIM-HIGH is a multicenter, randomized, double-blind, parallel-group, controlled clinical trial designed to test whether the drug combination of extended release niacin plus simvastatin is superior to simvastatin alone, at comparable levels of on-treatment LDL-C, for delaying the time to a first major CV disease outcome over a 4-year median follow-up in patients with atherogenic dyslipidemia. Prior clinical trials have found only 25 to 35% CV risk reduction using statin monotherapy (i.e., event rate 2/3 to 3/4 of placebo rate). The study is needed to confirm whether statin-niacin combination therapy, designed to target a wider spectrum of dyslipidemic factors in addition to LDL-C, will provide a more substantial (greater than 50%) reduction of CV events. Epidemiologic studies confirm the high prevalence of atherogenic dyslipidemia and its impact on CV event rates. Preliminary clinical trials suggest that targeting these factors with dyslipidemic therapy will reduce CV events. The study will enroll an estimated 3,300 men and women more than 45 years old at high risk of recurrent CV events by virtue of having established CV disease together with the two dyslipidemic elements of metabolic syndrome: low HDL-cholesterol (HDL-C) (less than or equal to 40 mg/dl) and high triglycerides (TG) (greater than or equal to 150 mg/dl). The study specifically aims to test this hypothesis for the primary composite clinical end point of CHD death, nonfatal MI, ischemic stroke, hospitalization for acute coronary syndrome with objective evidence of ischemia (troponin-positive or ST-segment deviation), or symptom-driven coronary or cerebral revascularization. Secondary end points include the composite of CHD death, nonfatal MI, ischemic stroke, or hospitalization for high-risk acute coronary syndrome; the composite of CHD death, nonfatal MI or ischemic stroke; and cardiovascular mortality.

Study Design

Study Type:
Interventional
Actual Enrollment :
3414 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose:
Prevention
Official Title:
AIM HIGH: Niacin Plus Statin to Prevent Vascular Events
Study Start Date :
Sep 1, 2005
Actual Primary Completion Date :
Sep 1, 2012
Actual Study Completion Date :
Dec 1, 2012

Arms and Interventions

Arm Intervention/Treatment
Experimental: Combination Therapy

Extended release niacin plus simvastatin

Drug: Extended release niacin
2,000 mg/day or 1,500 mg/day if higher dose not tolerated
Other Names:
  • Niaspan

    • Drug: Simvastatin
    Dose adjusted to achieve LDL-C 40 mg/dL - 80 mg/dL, adding ezetimibe (10 mg/day) if needed to achieve LDL-C target
    Other Names:
  • Zocor

    		•
    Active Comparator: Monotherapy

    Simvastatin alone

    Drug: Simvastatin
    Dose adjusted to achieve LDL-C 40 mg/dL - 80 mg/dL, adding ezetimibe (10 mg/day) if needed to achieve LDL-C target
    Other Names:
  • Zocor

    		•

    Outcome Measures

    Primary Outcome Measures

    1. Composite End Point of CHD Death, Nonfatal MI, Ischemic Stroke, Hospitalization for Non-ST Segment Elevation Acute Coronary Syndrome (ACS), or Symptom-driven Coronary or Cerebral Revascularization [Time to first event measured from date of randomization through last follow-up visit (common termination) for an average of 36 months follow-up, maximum 66 months.]

    Secondary Outcome Measures

    1. Composite Endpoint of CHD Death, Non-fatal MI, High-risk ACS or Ischemic Stroke [Time to first event measured from date of randomization through last follow-up visit (common termination) for an average of 36 months follow-up, maximum 66 months]

    2. Composite Endpoint of CHD Death, Non-fatal MI, or Ischemic Stroke [Time to first event measured from date of randomization through last follow-up visit (common termination) for an average of 36 months follow-up, maximum 66 months]

    3. Cardiovascular Mortality [Time to first event measured from date of randomization through last follow-up visit (common termination), for an average of 36 months follow-up, maximum 66 months.]

    Eligibility Criteria

    Criteria

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

    • Men and women aged 45 and older with established vascular disease and atherogenic dyslipidemia

    • Established vascular disease defined as one or more of the following: (1) documented coronary artery disease (CAD); (2) documented cerebrovascular or carotid disease; (3) documented symptomatic peripheral arterial disease (PAD)

    • Atherogenic dyslipidemia defined as: (1) LDL-C of less than or equal to 160 mg/dL (4.1 mmol/L); (2) HDL-C of less than or equal to 40 mg/dL (1.0 mmol/L) for men or less than or equal to 50 mg/dL (1.3 mmol/L) for women; (3) TG greater than or equal to 150 mg/dL (1.7 mmol/L) and less than or equal to 400 mg/dL (4.5 mmol/L)

    • For patients entering the trial on a statin: (1) the upper limit for LDL-C is adjusted according to the specific statin and statin dose; (2) HDL-C of less than or equal to 42 mg/dL (1.1 mmol/L) for men or less than or equal to 53 mg/dL (1.4 mmol/L) for women; (3) TG greater than or equal to 125 mg/dL (1.4 mmol/L) and less than or equal to 400 mg/DL (4.5 mmol/L)

    Exclusion Criteria:

    • Coronary artery bypass graft (CABG) surgery within 1 year of planned enrollment (run-in phase)

    • Percutaneous coronary intervention (PCI) within 4 weeks of planned enrollment (run-in phase)

    • Hospitalization for acute coronary syndrome and discharge within 4 weeks of planned enrollment (run-in phase)

    • Fasting glucose greater than 180 mg/dL (10 mmol/L) or hemoglobin A1C greater than 9%

    • For patients with diabetes, inability or refusal to use a glucometer for home monitoring of blood glucose

    • Concomitant use of drugs with a high probability of increasing the risk for hepatotoxicity or myopathy, such as those predominantly metabolized by cytochrome P450 system 3A4, including but not limited to cyclosporine, gemfibrozil, fenofibrate, itraconazole, ketoconazole, HIV protease inhibitors, nefazodone, verapamil, amiodarone; lipid-lowering drugs (other than the investigational drugs) such as statins, bile-acid sequestrants, cholesterol absorption inhibitors (e.g., ezetimibe), fibrates or high-dose, antioxidant vitamins (vitamins C, E, or beta carotene) that can interfere with the HDL-raising effect of niacin

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 Cardiovascular Associates, P.C. Birmingham Alabama United States 35213
    2 University of Alabama, Birmingham Birmingham Alabama United States 35294
    3 Clinical Research Consultants, Inc. Hoover Alabama United States 35216
    4 Carl T. Hayden VAMC Phoenix Medical Service Pheonix Arizona United States 85012
    5 Cardiovascular Consultants Ltd Phoenix Arizona United States 85015
    6 Diabetes Center of Excellence Phoenix Arizona United States 85016
    7 Tucson Clinical Research (Eastside Site) Tucson Arizona United States 85712
    8 Tucson Clinical Research (Northwest Site) Tucson Arizona United States 85741
    9 University of Arkansas Little Rock Arkansas United States 72205
    10 Providence Saint Joseph Medical Center Burbank California United States 91505
    11 VA Long Beach Healthcare System Long Beach California United States 90822
    12 Providence Holy Cross Medical Center Mission Hills California United States 91345
    13 Christiana Care Health Services Newark Delaware United States 19718
    14 University of Miami Miami Florida United States 33136
    15 Heart & Vascular Research Center Sarasota Florida United States 34239
    16 James A. Haley Veteran's Hospital Tampa Florida United States 33612
    17 Idaho State University Pocatello Idaho United States 83201
    18 Parkview Research Center Fort Wayne Indiana United States 46805
    19 Iowa Heart Center, P.C. Des Moines Iowa United States 50314
    20 Lipid Research Clinic, University of Iowa Iowa City Iowa United States 52240
    21 Maine Center for Lipids & Cardiovascular Health Scarborough Maine United States 04074
    22 University of Maryland Baltimore Maryland United States 21201
    23 Johns Hopkins University Baltimore Maryland United States 21205
    24 Pentucket Medical Associates Haverhill Massachusetts United States 01830
    25 Veterans Affairs Health System of Ann Arbor, Michigan Ann Arbor Michigan United States 48105
    26 Grunberger Diabetes Institute Bloomfield Hills Michigan United States 48302
    27 Berman Center for Outcomes and Clinical Research Minneapolis Minnesota United States 55404
    28 HealthPartners Riverside Clinic Minneapolis Minnesota United States 55454
    29 Mayo Clinic Rochester Minnesota United States 55905
    30 Phalen Village Clinic St. Paul Minnesota United States 55106
    31 University of Minnesota Twin Cities Minnesota United States 55414
    32 G.V. (Sonny) Montgomery VAMC Jackson Mississippi United States 39216
    33 St. Louis University St. Louis Missouri United States 63104
    34 Alegent Health Heart & Vascular Specialists Papillion Nebraska United States 68046
    35 Cooper Clinical Trials Center Cherry Hill New Jersey United States 08034
    36 Cardiovascular Associates of the Delaware Valley Elmer New Jersey United States 08318
    37 UMDNJ -Robert Wood Johnson Medical School New Brunswick New Jersey United States 08903
    38 New Mexico VA Healthcare Systems Albuquerque New Mexico United States 87108
    39 Kaleida Health/Diabetes Center Buffalo New York United States 14209
    40 Mid Valley Cardiology Kingston New York United States 12401
    41 VA New York Harbor Healthcare System New York New York United States 10010
    42 Columbia University New York New York United States 10032
    43 Syracuse Preventive Cardiology Syracuse New York United States 13202
    44 Duke University Medical Center Durham North Carolina United States 27710
    45 Wake Forest University - Geriatrics/Gerontology Greensboro North Carolina United States 27157
    46 Wake Forest University Health Sciences - Department of Cardiology Winston-Salem North Carolina United States 27157
    47 Wake Forest University School of Medicine - Internal Medicine/Endocrinology Winston-Salem North Carolina United States 27157
    48 Sterling Research Group, Ltd. Cincinnati Ohio United States 45219
    49 St Vincent Charity Hospital - The Center for Vascular Health Cleveland Ohio United States 44115
    50 North Ohio Research, Ltd. Sandusky Ohio United States 44870
    51 Portland VA Medical Center Portland Oregon United States 97239
    52 Philadelphia VA Medical Center Philadelphia Pennsylvania United States 19104
    53 Pennsylvania Cardiology Associates Philadelphia Pennsylvania United States 19106
    54 Cardiology Consultants of Philadelphia Philadelphia Pennsylvania United States 19148
    55 Women's Cardiac Center at The Miriam Hospital Providence Rhode Island United States 02906
    56 Internal Medicine Associates of Greenville Greenville South Carolina United States 29607
    57 VAMC Memphis - Hypertension/Lipid Research Clinic Memphis Tennessee United States 38104
    58 Kelsey Research Foundation Houston Texas United States 77005
    59 Baylor College of Medicine Houston Texas United States 77030
    60 Methodist Hospital Houston Texas United States 77030
    61 Intermountain Medical Center Murray Utah United States 84157
    62 University of Virginia - UVA Cardiology Charlottesville Virginia United States 22908
    63 McGuire VA Medical Center Richmond Virginia United States 23249
    64 University of Washington, Northwest Lipid Research Center Seattle Washington United States 98104
    65 University of Washington, Coronary Atherosclerosis Research Lab Seattle Washington United States 98105
    66 VA Cardiology Research Seattle Washington United States 98108
    67 Washington State University Spokane Washington United States 99202
    68 CARE Foundation, Inc. Wausau Wisconsin United States 54401
    69 Heart Health Institute Calgary Alberta Canada T2E 7C5
    70 Foothills Medical Centre Calgary Alberta Canada T2N 2T9
    71 Royal Alexandra Hospital Edmonton Alberta Canada T5H 3V9
    72 Vancouver Hospital Vancouver British Columbia Canada V5Z 1M9
    73 Victoria Heart Institute Victoria British Columbia Canada V8R 4R2
    74 Health Sciences Center, Diabetes Research Group Winnipeg Manitoba Canada R3E 3R4
    75 New Brunswick Heart Center St John New Brunswick Canada E2L 4L2
    76 Memorial University of Newfoundland St. John's Newfoundland and Labrador Canada A1B 3V6
    77 Queen Elizabeth II Health Sciences Center Halifax Nova Scotia Canada B3H 3A6
    78 Cardiology Associates VRH Kentville Nova Scotia Canada B4N 5E3
    79 Cambridge Cardiac Care Center Cambridge Ontario Canada N1R 6V6
    80 McConnell Medical Center Cornwall Ontario Canada K6H 4M4
    81 Hamilton Health Sciences - General Site Hamilton Ontario Canada L8L 2X2
    82 LHSC University Hospital London Ontario Canada N6A 5A5
    83 Newmarket Cardiology Research Group Newmarket Ontario Canada L3Y 8C3
    84 Sudbury Cardiovascular Research Sudbury Ontario Canada P3E 2N8
    85 St. Michael's Hospital Health Centre Toronto Ontario Canada M5C 2T2
    86 Clinique de Cardiologie de Lévis Lévis Quebec Canada G6V 4Z5
    87 Montreal Heart Institute Montreal Quebec Canada H1T 1C8
    88 Clinique des maladies lipidiques de Québec Québec Quebec Canada G1V 4M6
    89 CSSS Beauce St-Georges de Beauce Quebec Canada G5Y 4T8
    90 CSSS du Sud de Lanaudière - Hôpital Pierre-Le Gardeur Terrebonne Quebec Canada J6V 2H2
    91 Recherches Clinicar Quebec Canada G1J 1Z6

    Sponsors and Collaborators

    • Axio Research. LLC
    • National Heart, Lung, and Blood Institute (NHLBI)
    • Abbott

    Investigators

    • Study Director: Ruth McBride, Axio Research Corporation
    • Principal Investigator: William E. Boden, MD, Samuel S. Stratton VA Medical Center
    • Principal Investigator: Jeffrey Probstfield, MD, University of Washington

    Study Documents (Full-Text)

    None provided.

    More Information

    Additional Information:

    Publications

    Responsible Party:
    Ruth McBride, Co-Director, Coordinating Center, Axio Research. LLC
    ClinicalTrials.gov Identifier:
    NCT00120289
    Other Study ID Numbers:
    • 226
    • U01HL081649
    • U01HL081616
    First Posted:
    Jul 15, 2005
    Last Update Posted:
    Apr 6, 2016
    Last Verified:
    Mar 1, 2016
    Additional relevant MeSH terms:
    Stroke
    Cardiovascular Diseases
    Myocardial Infarction
    Heart Diseases
    Atherosclerosis
    Coronary Disease
    Infarction
    Niacin
    Simvastatin

    Study Results

    Participant Flow

    Recruitment Details
    Pre-assignment Detail
    Arm/Group Title ERN + Simvastatin Placebo + Simvastatin
    Arm/Group Description Extended release niacin plus simvastatin Extended release niacin: 2,000 mg/day or 1,500 mg/day if higher dose not tolerated Simvastatin: Dose adjusted to achieve LDL-C 40 mg/dL - 80 mg/dL, adding ezetimibe (10 mg/day) if needed to achieve LDL-C target Simvastatin alone Simvastatin: Dose adjusted to achieve LDL-C 40 mg/dL - 80 mg/dL, adding ezetimibe (10 mg/day) if needed to achieve LDL-C target
    Period Title: Overall Study
    STARTED 1718 1696
    COMPLETED 1597 1587
    NOT COMPLETED 121 109

    Baseline Characteristics

    Arm/Group Title ERN + Simvastatin Placebo + Simvastatin Total
    Arm/Group Description Extended release niacin plus simvastatin Extended release niacin: 2,000 mg/day or 1,500 mg/day if higher dose not tolerated Simvastatin: Dose adjusted to achieve LDL-C 40 mg/dL - 80 mg/dL, adding ezetimibe (10 mg/day) if needed to achieve LDL-C target Simvastatin alone Simvastatin: Dose adjusted to achieve LDL-C 40 mg/dL - 80 mg/dL, adding ezetimibe (10 mg/day) if needed to achieve LDL-C target Total of all reporting groups
    Overall Participants 1718 1696 3414
    Age (Count of Participants)
    <=18 years
    0
    0%
    0
    0%
    0
    0%
    Between 18 and 65 years
    917
    53.4%
    915
    54%
    1832
    53.7%
    >=65 years
    801
    46.6%
    781
    46%
    1582
    46.3%
    Age (years) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [years]
    63.7
    (8.8)
    63.7
    (8.7)
    63.7
    (8.7)
    Sex: Female, Male (Count of Participants)
    Female
    253
    14.7%
    251
    14.8%
    504
    14.8%
    Male
    1465
    85.3%
    1445
    85.2%
    2910
    85.2%
    Ethnicity (NIH/OMB) (Count of Participants)
    Hispanic or Latino
    63
    3.7%
    77
    4.5%
    140
    4.1%
    Not Hispanic or Latino
    1654
    96.3%
    1619
    95.5%
    3273
    95.9%
    Unknown or Not Reported
    1
    0.1%
    0
    0%
    1
    0%
    Race (NIH/OMB) (Count of Participants)
    American Indian or Alaska Native
    11
    0.6%
    11
    0.6%
    22
    0.6%
    Asian
    20
    1.2%
    21
    1.2%
    41
    1.2%
    Native Hawaiian or Other Pacific Islander
    7
    0.4%
    5
    0.3%
    12
    0.4%
    Black or African American
    68
    4%
    49
    2.9%
    117
    3.4%
    White
    1572
    91.5%
    1576
    92.9%
    3148
    92.2%
    More than one race
    40
    2.3%
    33
    1.9%
    73
    2.1%
    Unknown or Not Reported
    0
    0%
    1
    0.1%
    1
    0%
    Region of Enrollment (participants) [Number]
    United States
    1179
    68.6%
    1167
    68.8%
    2346
    68.7%
    Canada
    539
    31.4%
    529
    31.2%
    1068
    31.3%
    Lipids and Lipoproteins at Baseline (mg/dL) [Mean (Standard Deviation) ]
    LDL-C
    74.2
    (23.4)
    74.0
    (22.7)
    74.1
    (23)
    HDL-C
    34.5
    (5.6)
    34.9
    (5.6)
    34.7
    (5.6)
    Triglycerides
    183.5
    (66.7)
    181.9
    (66.9)
    182.7
    (66.8)
    non-HDL cholesterol
    110.8
    (27.5)
    110.3
    (26)
    110.6
    (26.8)
    HDL2-C
    6
    (2.3)
    6.2
    (2.4)
    6.1
    (2.3)
    HDL3-C
    28.5
    (4.2)
    28.7
    (4.1)
    28.6
    (4.1)
    Apolipoprotein A-I
    122.4
    (16.2)
    123.7
    (16.3)
    123.1
    (16.2)
    Apolipoprotein B
    83.2
    (20.2)
    82.9
    (20.7)
    83
    (20.4)
    Lipoprotein (a)
    77.3
    (87.8)
    75.5
    (89.6)
    76.4
    (88.7)
    Clinical History (participants) [Number]
    History of myocardial infarction (MI)
    968
    56.3%
    955
    56.3%
    1923
    56.3%
    History of CABG
    600
    34.9%
    627
    37%
    1227
    35.9%
    History of Percutaneous Coronary Intervention
    1057
    61.5%
    1044
    61.6%
    2101
    61.5%
    History of stroke or cerebrovascular disease
    358
    20.8%
    362
    21.3%
    720
    21.1%
    History of peripheral vascular disease
    234
    13.6%
    231
    13.6%
    465
    13.6%
    Metabolic syndrome
    1414
    82.3%
    1353
    79.8%
    2767
    81%
    History of diabetes (Type 1 or 2)
    588
    34.2%
    570
    33.6%
    1158
    33.9%
    Concomitant Medications at Baseline (participants) [Number]
    Statins
    1595
    92.8%
    1601
    94.4%
    3196
    93.6%
    Beta-blockers
    1377
    80.2%
    1342
    79.1%
    2719
    79.6%
    ACE inhibitor or Angiotensin Receptor Blocker
    1258
    73.2%
    1271
    74.9%
    2529
    74.1%
    Aspirin or other antiplatelet or anticoagulant
    1680
    97.8%
    1654
    97.5%
    3334
    97.7%

    Outcome Measures

    1. Primary Outcome
    Title Composite End Point of CHD Death, Nonfatal MI, Ischemic Stroke, Hospitalization for Non-ST Segment Elevation Acute Coronary Syndrome (ACS), or Symptom-driven Coronary or Cerebral Revascularization
    Description
    Time Frame Time to first event measured from date of randomization through last follow-up visit (common termination) for an average of 36 months follow-up, maximum 66 months.

    Outcome Measure Data

    Analysis Population Description
    Intention-to-treat
    Arm/Group Title ERN + Simvastatin Placebo + Simvastatin
    Arm/Group Description Extended release niacin plus simvastatin Extended release niacin: 2,000 mg/day or 1,500 mg/day if higher dose not tolerated Simvastatin: Dose adjusted to achieve LDL-C 40 mg/dL - 80 mg/dL, adding ezetimibe (10 mg/day) if needed to achieve LDL-C target Simvastatin alone Simvastatin: Dose adjusted to achieve LDL-C 40 mg/dL - 80 mg/dL, adding ezetimibe (10 mg/day) if needed to achieve LDL-C target
    Measure Participants 1718 1696
    Number [participants]
    282
    16.4%
    274
    16.2%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection ERN + Simvastatin, Placebo + Simvastatin
    Comments
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value 0.80
    Comments
    Method Regression, Cox
    Comments Adjusting for gender and history of diabetes (randomization stratification factors).
    Method of Estimation Estimation Parameter Hazard Ratio (HR)
    Estimated Value 1.02
    Confidence Interval (2-Sided) 95%
    0.87 to 1.21
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    2. Secondary Outcome
    Title Composite Endpoint of CHD Death, Non-fatal MI, High-risk ACS or Ischemic Stroke
    Description
    Time Frame Time to first event measured from date of randomization through last follow-up visit (common termination) for an average of 36 months follow-up, maximum 66 months

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title ERN + Simvastatin Placebo + Simvastatin
    Arm/Group Description Extended release niacin plus simvastatin Extended release niacin: 2,000 mg/day or 1,500 mg/day if higher dose not tolerated Simvastatin: Dose adjusted to achieve LDL-C 40 mg/dL - 80 mg/dL, adding ezetimibe (10 mg/day) if needed to achieve LDL-C target Simvastatin alone Simvastatin: Dose adjusted to achieve LDL-C 40 mg/dL - 80 mg/dL, adding ezetimibe (10 mg/day) if needed to achieve LDL-C target
    Measure Participants 1718 1696
    Number [participants]
    171
    10%
    158
    9.3%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection ERN + Simvastatin, Placebo + Simvastatin
    Comments
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value .49
    Comments
    Method Regression, Cox
    Comments
    Method of Estimation Estimation Parameter Hazard Ratio (HR)
    Estimated Value 1.08
    Confidence Interval (2-Sided) 95%
    0.87 to 1.34
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    3. Secondary Outcome
    Title Composite Endpoint of CHD Death, Non-fatal MI, or Ischemic Stroke
    Description
    Time Frame Time to first event measured from date of randomization through last follow-up visit (common termination) for an average of 36 months follow-up, maximum 66 months

    Outcome Measure Data

    Analysis Population Description
    Intention to treat
    Arm/Group Title ERN + Simvastatin Placebo + Simvastatin
    Arm/Group Description Extended release niacin plus simvastatin Extended release niacin: 2,000 mg/day or 1,500 mg/day if higher dose not tolerated Simvastatin: Dose adjusted to achieve LDL-C 40 mg/dL - 80 mg/dL, adding ezetimibe (10 mg/day) if needed to achieve LDL-C target Simvastatin alone Simvastatin: Dose adjusted to achieve LDL-C 40 mg/dL - 80 mg/dL, adding ezetimibe (10 mg/day) if needed to achieve LDL-C target
    Measure Participants 1718 1696
    Number [participants]
    156
    9.1%
    138
    8.1%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection ERN + Simvastatin, Placebo + Simvastatin
    Comments
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value .30
    Comments
    Method Regression, Cox
    Comments
    Method of Estimation Estimation Parameter Hazard Ratio (HR)
    Estimated Value 1.13
    Confidence Interval (2-Sided) 95%
    0.90 to 1.42
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    4. Secondary Outcome
    Title Cardiovascular Mortality
    Description
    Time Frame Time to first event measured from date of randomization through last follow-up visit (common termination), for an average of 36 months follow-up, maximum 66 months.

    Outcome Measure Data

    Analysis Population Description
    Intention to treat
    Arm/Group Title ERN + Simvastatin Placebo + Simvastatin
    Arm/Group Description Extended release niacin plus simvastatin Extended release niacin: 2,000 mg/day or 1,500 mg/day if higher dose not tolerated Simvastatin: Dose adjusted to achieve LDL-C 40 mg/dL - 80 mg/dL, adding ezetimibe (10 mg/day) if needed to achieve LDL-C target Simvastatin alone Simvastatin: Dose adjusted to achieve LDL-C 40 mg/dL - 80 mg/dL, adding ezetimibe (10 mg/day) if needed to achieve LDL-C target
    Measure Participants 1718 1696
    Number [participants]
    45
    2.6%
    38
    2.2%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection ERN + Simvastatin, Placebo + Simvastatin
    Comments
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value 0.47
    Comments
    Method Regression, Cox
    Comments
    Method of Estimation Estimation Parameter Hazard Ratio (HR)
    Estimated Value 1.17
    Confidence Interval (2-Sided) 95%
    0.76 to 1.80
    Parameter Dispersion Type:
    Value:
    Estimation Comments

    Adverse Events

    Time Frame Randomization through final study visit after recommendation to curtail study (June - September 2011)
    Adverse Event Reporting Description
    Arm/Group Title ERN + Simvastatin Placebo + Simvastatin
    Arm/Group Description Extended release niacin plus simvastatin Extended release niacin: 2,000 mg/day or 1,500 mg/day if higher dose not tolerated Simvastatin: Dose adjusted to achieve LDL-C 40 mg/dL - 80 mg/dL, adding ezetimibe (10 mg/day) if needed to achieve LDL-C target Simvastatin alone Simvastatin: Dose adjusted to achieve LDL-C 40 mg/dL - 80 mg/dL, adding ezetimibe (10 mg/day) if needed to achieve LDL-C target
    All Cause Mortality
    ERN + Simvastatin Placebo + Simvastatin
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total / (NaN) / (NaN)
    Serious Adverse Events
    ERN + Simvastatin Placebo + Simvastatin
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 587/1718 (34.2%) 551/1696 (32.5%)
    Blood and lymphatic system disorders
    Anaemia 17/1718 (1%) 10/1696 (0.6%)
    Chronic lymphocytic leukaemia 1/1718 (0.1%) 0/1696 (0%)
    Iron deficiency anaemia 1/1718 (0.1%) 2/1696 (0.1%)
    Leukocytosis 0/1718 (0%) 3/1696 (0.2%)
    Leukopenia 0/1718 (0%) 1/1696 (0.1%)
    Lymphadenopathy 0/1718 (0%) 1/1696 (0.1%)
    Pancytopenia 1/1718 (0.1%) 0/1696 (0%)
    Thrombocytopenia 5/1718 (0.3%) 2/1696 (0.1%)
    Cardiac disorders
    Acute myocardial infarction 3/1718 (0.2%) 3/1696 (0.2%)
    Acute pulmonary oedema 1/1718 (0.1%) 0/1696 (0%)
    Angina pectoris 16/1718 (0.9%) 21/1696 (1.2%)
    Angina unstable 6/1718 (0.3%) 5/1696 (0.3%)
    Aortic valve calcification 1/1718 (0.1%) 0/1696 (0%)
    Aortic valve disease 1/1718 (0.1%) 0/1696 (0%)
    Arrhythmia 0/1718 (0%) 1/1696 (0.1%)
    Arteriospasm coronary 0/1718 (0%) 1/1696 (0.1%)
    Atrial fibrillation 27/1718 (1.6%) 25/1696 (1.5%)
    Atrial flutter 5/1718 (0.3%) 5/1696 (0.3%)
    Atrial tachycardia 0/1718 (0%) 2/1696 (0.1%)
    Atrial thrombosis 1/1718 (0.1%) 0/1696 (0%)
    Atrioventricular block 1/1718 (0.1%) 1/1696 (0.1%)
    Atrioventricular block third degree 2/1718 (0.1%) 4/1696 (0.2%)
    Bradycardia 2/1718 (0.1%) 8/1696 (0.5%)
    Bundle branch block right 0/1718 (0%) 1/1696 (0.1%)
    Cardiac aneurysm 1/1718 (0.1%) 0/1696 (0%)
    Cardiac arrest 0/1718 (0%) 2/1696 (0.1%)
    Cardiac failure 10/1718 (0.6%) 9/1696 (0.5%)
    Cardiac failure chronic 0/1718 (0%) 1/1696 (0.1%)
    Cardiac failure congestive 21/1718 (1.2%) 30/1696 (1.8%)
    Cardiomyopathy 1/1718 (0.1%) 2/1696 (0.1%)
    Chest discomfort 5/1718 (0.3%) 7/1696 (0.4%)
    Chest pain 43/1718 (2.5%) 57/1696 (3.4%)
    Cor pulmonale 1/1718 (0.1%) 0/1696 (0%)
    Coronary artery disease 5/1718 (0.3%) 1/1696 (0.1%)
    Cyanosis 1/1718 (0.1%) 0/1696 (0%)
    Diastolic dysfunction 0/1718 (0%) 1/1696 (0.1%)
    Dyspnoea 31/1718 (1.8%) 38/1696 (2.2%)
    Dyspnoea exertional 1/1718 (0.1%) 5/1696 (0.3%)
    Dyspnoea paroxysmal nocturnal 1/1718 (0.1%) 0/1696 (0%)
    Extrasystoles 0/1718 (0%) 1/1696 (0.1%)
    Intracardiac thrombus 0/1718 (0%) 1/1696 (0.1%)
    Ischaemic cardiomyopathy 3/1718 (0.2%) 2/1696 (0.1%)
    Left ventricular failure 1/1718 (0.1%) 0/1696 (0%)
    Mitral valve incompetence 0/1718 (0%) 2/1696 (0.1%)
    Myocardial infarction 3/1718 (0.2%) 2/1696 (0.1%)
    Myocardial ischaemia 1/1718 (0.1%) 0/1696 (0%)
    Nodal rhythm 0/1718 (0%) 1/1696 (0.1%)
    Palpitations 0/1718 (0%) 7/1696 (0.4%)
    Presyncope 2/1718 (0.1%) 4/1696 (0.2%)
    Pulmonary oedema 3/1718 (0.2%) 4/1696 (0.2%)
    Restrictive cardiomyopathy 0/1718 (0%) 1/1696 (0.1%)
    Sick sinus syndrome 3/1718 (0.2%) 2/1696 (0.1%)
    Sinus bradycardia 0/1718 (0%) 1/1696 (0.1%)
    Subvalvular aortic stenosis 1/1718 (0.1%) 0/1696 (0%)
    Supraventricular extrasystoles 1/1718 (0.1%) 0/1696 (0%)
    Supraventricular tachycardia 2/1718 (0.1%) 1/1696 (0.1%)
    Syncope 21/1718 (1.2%) 19/1696 (1.1%)
    Tachycardia 3/1718 (0.2%) 2/1696 (0.1%)
    Tachycardia paroxysmal 0/1718 (0%) 1/1696 (0.1%)
    Tricuspid valve incompetence 1/1718 (0.1%) 0/1696 (0%)
    Ventricle rupture 0/1718 (0%) 1/1696 (0.1%)
    Ventricular dysfunction 2/1718 (0.1%) 1/1696 (0.1%)
    Ventricular extrasystoles 1/1718 (0.1%) 0/1696 (0%)
    Ventricular tachycardia 6/1718 (0.3%) 5/1696 (0.3%)
    Congenital, familial and genetic disorders
    Gastrointestinal arteriovenous malformation 1/1718 (0.1%) 0/1696 (0%)
    Hypospadias 1/1718 (0.1%) 0/1696 (0%)
    Sickle cell anaemia with crisis 0/1718 (0%) 1/1696 (0.1%)
    Ear and labyrinth disorders
    Vertigo 1/1718 (0.1%) 1/1696 (0.1%)
    Vestibular neuronitis 0/1718 (0%) 1/1696 (0.1%)
    Endocrine disorders
    Adrenal insufficiency 1/1718 (0.1%) 0/1696 (0%)
    Hypercalcaemia of malignancy 1/1718 (0.1%) 0/1696 (0%)
    Hyperthyroidism 0/1718 (0%) 1/1696 (0.1%)
    Hypothyroidism 0/1718 (0%) 1/1696 (0.1%)
    Eye disorders
    Chorioretinal atrophy 1/1718 (0.1%) 0/1696 (0%)
    Diplopia 1/1718 (0.1%) 1/1696 (0.1%)
    Eye inflammation 0/1718 (0%) 1/1696 (0.1%)
    Optic ischaemic neuropathy 1/1718 (0.1%) 0/1696 (0%)
    Retinal detachment 0/1718 (0%) 1/1696 (0.1%)
    Vision blurred 1/1718 (0.1%) 2/1696 (0.1%)
    Gastrointestinal disorders
    Abdominal adhesions 0/1718 (0%) 1/1696 (0.1%)
    Abdominal discomfort 1/1718 (0.1%) 0/1696 (0%)
    Abdominal distension 2/1718 (0.1%) 1/1696 (0.1%)
    Abdominal hernia 3/1718 (0.2%) 1/1696 (0.1%)
    Abdominal pain 22/1718 (1.3%) 10/1696 (0.6%)
    Abdominal pain lower 5/1718 (0.3%) 3/1696 (0.2%)
    Abdominal pain upper 8/1718 (0.5%) 6/1696 (0.4%)
    Abdominal strangulated hernia 1/1718 (0.1%) 0/1696 (0%)
    Anal fistula 1/1718 (0.1%) 0/1696 (0%)
    Aphthous stomatitis 1/1718 (0.1%) 0/1696 (0%)
    Appendicitis perforated 1/1718 (0.1%) 0/1696 (0%)
    Colitis 3/1718 (0.2%) 0/1696 (0%)
    Colitis ischaemic 1/1718 (0.1%) 2/1696 (0.1%)
    Colonic fistula 0/1718 (0%) 1/1696 (0.1%)
    Colonic polyp 2/1718 (0.1%) 1/1696 (0.1%)
    Constipation 0/1718 (0%) 3/1696 (0.2%)
    Crohn's disease 1/1718 (0.1%) 0/1696 (0%)
    Diarrhoea 9/1718 (0.5%) 6/1696 (0.4%)
    Diarrhoea haemorrhagic 1/1718 (0.1%) 0/1696 (0%)
    Diverticulitis oesophageal 0/1718 (0%) 1/1696 (0.1%)
    Diverticulum 4/1718 (0.2%) 1/1696 (0.1%)
    Diverticulum intestinal haemorrhagic 1/1718 (0.1%) 1/1696 (0.1%)
    Duodenal ulcer haemorrhage 1/1718 (0.1%) 0/1696 (0%)
    Dyspepsia 0/1718 (0%) 2/1696 (0.1%)
    Dysphagia 4/1718 (0.2%) 1/1696 (0.1%)
    Enteritis 0/1718 (0%) 1/1696 (0.1%)
    Epigastric discomfort 0/1718 (0%) 1/1696 (0.1%)
    Faecaloma 1/1718 (0.1%) 0/1696 (0%)
    Faeces discoloured 1/1718 (0.1%) 3/1696 (0.2%)
    Gastric haemorrhage 1/1718 (0.1%) 0/1696 (0%)
    Gastric ulcer 2/1718 (0.1%) 2/1696 (0.1%)
    Gastritis 4/1718 (0.2%) 0/1696 (0%)
    Gastroduodenitis 0/1718 (0%) 1/1696 (0.1%)
    Gastroenteritis 1/1718 (0.1%) 0/1696 (0%)
    Gastrointestinal haemorrhage 7/1718 (0.4%) 13/1696 (0.8%)
    Gastrointestinal motility disorder 1/1718 (0.1%) 0/1696 (0%)
    Gastrointestinal pain 0/1718 (0%) 1/1696 (0.1%)
    Gastrooesophageal reflux disease 0/1718 (0%) 5/1696 (0.3%)
    Haematochezia 3/1718 (0.2%) 2/1696 (0.1%)
    Haemorrhoids 0/1718 (0%) 1/1696 (0.1%)
    Hiatus hernia 1/1718 (0.1%) 1/1696 (0.1%)
    Ileus 2/1718 (0.1%) 2/1696 (0.1%)
    Inguinal hernia 1/1718 (0.1%) 3/1696 (0.2%)
    Inguinal hernia, obstructive 1/1718 (0.1%) 2/1696 (0.1%)
    Intestinal ischaemia 1/1718 (0.1%) 0/1696 (0%)
    Intestinal obstruction 3/1718 (0.2%) 0/1696 (0%)
    Large intestine perforation 1/1718 (0.1%) 0/1696 (0%)
    Lower gastrointestinal haemorrhage 4/1718 (0.2%) 3/1696 (0.2%)
    Mallory-Weiss syndrome 0/1718 (0%) 1/1696 (0.1%)
    Melaena 0/1718 (0%) 3/1696 (0.2%)
    Nausea 12/1718 (0.7%) 7/1696 (0.4%)
    Odynophagia 0/1718 (0%) 1/1696 (0.1%)
    Oesophageal stenosis 1/1718 (0.1%) 0/1696 (0%)
    Oesophageal ulcer haemorrhage 1/1718 (0.1%) 0/1696 (0%)
    Oesophagitis 2/1718 (0.1%) 0/1696 (0%)
    Pancreatic mass 0/1718 (0%) 1/1696 (0.1%)
    Pancreatitis 3/1718 (0.2%) 3/1696 (0.2%)
    Pancreatitis acute 2/1718 (0.1%) 2/1696 (0.1%)
    Peptic ulcer 0/1718 (0%) 1/1696 (0.1%)
    Pharyngoesophageal diverticulum 1/1718 (0.1%) 0/1696 (0%)
    Rectal haemorrhage 11/1718 (0.6%) 3/1696 (0.2%)
    Rectal polyp 0/1718 (0%) 1/1696 (0.1%)
    Small intestinal obstruction 5/1718 (0.3%) 4/1696 (0.2%)
    Umbilical hernia 0/1718 (0%) 3/1696 (0.2%)
    Upper gastrointestinal haemorrhage 3/1718 (0.2%) 3/1696 (0.2%)
    Volvulus 2/1718 (0.1%) 0/1696 (0%)
    Vomiting 20/1718 (1.2%) 9/1696 (0.5%)
    General disorders
    Abasia 1/1718 (0.1%) 0/1696 (0%)
    Adverse drug reaction 0/1718 (0%) 1/1696 (0.1%)
    Asthenia 10/1718 (0.6%) 8/1696 (0.5%)
    Chest discomfort 2/1718 (0.1%) 6/1696 (0.4%)
    Chest pain 2/1718 (0.1%) 0/1696 (0%)
    Chills 1/1718 (0.1%) 2/1696 (0.1%)
    Cyst 1/1718 (0.1%) 0/1696 (0%)
    Death 3/1718 (0.2%) 1/1696 (0.1%)
    Face oedema 1/1718 (0.1%) 0/1696 (0%)
    Facial pain 1/1718 (0.1%) 0/1696 (0%)
    Fatigue 11/1718 (0.6%) 6/1696 (0.4%)
    Feeling abnormal 1/1718 (0.1%) 0/1696 (0%)
    Gait disturbance 3/1718 (0.2%) 3/1696 (0.2%)
    General physical health deterioration 1/1718 (0.1%) 1/1696 (0.1%)
    Hernia 1/1718 (0.1%) 2/1696 (0.1%)
    Hyperthermia 2/1718 (0.1%) 0/1696 (0%)
    Hypothermia 1/1718 (0.1%) 0/1696 (0%)
    Impaired healing 1/1718 (0.1%) 0/1696 (0%)
    Influenza like illness 1/1718 (0.1%) 0/1696 (0%)
    Malaise 2/1718 (0.1%) 0/1696 (0%)
    Mass 1/1718 (0.1%) 0/1696 (0%)
    Multi-organ failure 0/1718 (0%) 1/1696 (0.1%)
    Non-cardiac chest pain 12/1718 (0.7%) 18/1696 (1.1%)
    Oedema 0/1718 (0%) 2/1696 (0.1%)
    Oedema peripheral 4/1718 (0.2%) 5/1696 (0.3%)
    Pain 3/1718 (0.2%) 1/1696 (0.1%)
    Pyrexia 6/1718 (0.3%) 8/1696 (0.5%)
    Sudden death 1/1718 (0.1%) 0/1696 (0%)
    Thirst 1/1718 (0.1%) 0/1696 (0%)
    Hepatobiliary disorders
    Bile duct stone 1/1718 (0.1%) 0/1696 (0%)
    Biliary colic 1/1718 (0.1%) 0/1696 (0%)
    Cholangitis 1/1718 (0.1%) 0/1696 (0%)
    Cholecystitis 5/1718 (0.3%) 4/1696 (0.2%)
    Cholecystitis acute 6/1718 (0.3%) 2/1696 (0.1%)
    Cholelithiasis 8/1718 (0.5%) 7/1696 (0.4%)
    Gallbladder pain 1/1718 (0.1%) 1/1696 (0.1%)
    Hepatic cirrhosis 1/1718 (0.1%) 0/1696 (0%)
    Hepatic congestion 0/1718 (0%) 1/1696 (0.1%)
    Hepatic function abnormal 0/1718 (0%) 1/1696 (0.1%)
    Hepatic lesion 1/1718 (0.1%) 0/1696 (0%)
    Hyperbilirubinaemia 1/1718 (0.1%) 0/1696 (0%)
    Jaundice 1/1718 (0.1%) 1/1696 (0.1%)
    Jaundice cholestatic 2/1718 (0.1%) 1/1696 (0.1%)
    Portal vein thrombosis 1/1718 (0.1%) 0/1696 (0%)
    Immune system disorders
    Anaphylactic shock 1/1718 (0.1%) 0/1696 (0%)
    Infections and infestations
    Abdominal abscess 1/1718 (0.1%) 0/1696 (0%)
    Abscess intestinal 0/1718 (0%) 1/1696 (0.1%)
    Abscess limb 0/1718 (0%) 1/1696 (0.1%)
    Abscess neck 2/1718 (0.1%) 0/1696 (0%)
    Appendicitis 8/1718 (0.5%) 1/1696 (0.1%)
    Arthritis bacterial 1/1718 (0.1%) 0/1696 (0%)
    Bacteraemia 2/1718 (0.1%) 2/1696 (0.1%)
    Bacterial infection 0/1718 (0%) 1/1696 (0.1%)
    Bacterial sepsis 1/1718 (0.1%) 0/1696 (0%)
    Biliary sepsis 1/1718 (0.1%) 0/1696 (0%)
    Bronchitis 7/1718 (0.4%) 1/1696 (0.1%)
    Bronchitis acute 1/1718 (0.1%) 0/1696 (0%)
    Cellulitis 26/1718 (1.5%) 13/1696 (0.8%)
    Clostridium difficile colitis 1/1718 (0.1%) 3/1696 (0.2%)
    Device related infection 1/1718 (0.1%) 2/1696 (0.1%)
    Diverticulitis 6/1718 (0.3%) 4/1696 (0.2%)
    Endocarditis 0/1718 (0%) 2/1696 (0.1%)
    Enterocolitis infectious 0/1718 (0%) 2/1696 (0.1%)
    Gangrene 0/1718 (0%) 2/1696 (0.1%)
    Gastroenteritis 4/1718 (0.2%) 2/1696 (0.1%)
    Gastroenteritis cryptosporidial 0/1718 (0%) 1/1696 (0.1%)
    Gastroenteritis viral 1/1718 (0.1%) 0/1696 (0%)
    Hepatitis B 0/1718 (0%) 1/1696 (0.1%)
    Herpes zoster 0/1718 (0%) 1/1696 (0.1%)
    Incision site infection 0/1718 (0%) 1/1696 (0.1%)
    Infected insect bite 1/1718 (0.1%) 0/1696 (0%)
    Infection 2/1718 (0.1%) 0/1696 (0%)
    Influenza 1/1718 (0.1%) 0/1696 (0%)
    Intervertebral discitis 0/1718 (0%) 1/1696 (0.1%)
    Labyrinthitis 1/1718 (0.1%) 0/1696 (0%)
    Liver abscess 1/1718 (0.1%) 0/1696 (0%)
    Lobar pneumonia 4/1718 (0.2%) 0/1696 (0%)
    Localised infection 2/1718 (0.1%) 1/1696 (0.1%)
    Lung infection 1/1718 (0.1%) 0/1696 (0%)
    Meningitis aseptic 1/1718 (0.1%) 0/1696 (0%)
    Necrotising fasciitis 0/1718 (0%) 1/1696 (0.1%)
    Oesophageal candidiasis 1/1718 (0.1%) 0/1696 (0%)
    Osteomyelitis 4/1718 (0.2%) 4/1696 (0.2%)
    Perianal abscess 0/1718 (0%) 1/1696 (0.1%)
    Pneumonia 38/1718 (2.2%) 27/1696 (1.6%)
    Pneumonia bacterial 0/1718 (0%) 1/1696 (0.1%)
    Pneumonia klebsiella 0/1718 (0%) 1/1696 (0.1%)
    Pneumonia primary atypical 1/1718 (0.1%) 0/1696 (0%)
    Pneumonia viral 0/1718 (0%) 1/1696 (0.1%)
    Postoperative infection 1/1718 (0.1%) 3/1696 (0.2%)
    Postoperative wound infection 0/1718 (0%) 3/1696 (0.2%)
    Pyelonephritis 1/1718 (0.1%) 2/1696 (0.1%)
    Rectal abscess 1/1718 (0.1%) 0/1696 (0%)
    Respiratory tract infection 0/1718 (0%) 1/1696 (0.1%)
    Sepsis 8/1718 (0.5%) 10/1696 (0.6%)
    Septic embolus 1/1718 (0.1%) 0/1696 (0%)
    Septic shock 2/1718 (0.1%) 1/1696 (0.1%)
    Sinusitis 0/1718 (0%) 3/1696 (0.2%)
    Staphylococcal bacteraemia 1/1718 (0.1%) 0/1696 (0%)
    Staphylococcal infection 2/1718 (0.1%) 1/1696 (0.1%)
    Staphylococcal sepsis 0/1718 (0%) 1/1696 (0.1%)
    Sweat gland infection 1/1718 (0.1%) 0/1696 (0%)
    Tracheobronchitis 0/1718 (0%) 1/1696 (0.1%)
    Upper respiratory tract infection 3/1718 (0.2%) 3/1696 (0.2%)
    Urinary tract infection 19/1718 (1.1%) 10/1696 (0.6%)
    Urosepsis 5/1718 (0.3%) 2/1696 (0.1%)
    Wound infection 0/1718 (0%) 3/1696 (0.2%)
    Injury, poisoning and procedural complications
    Accidental overdose 0/1718 (0%) 1/1696 (0.1%)
    Anastomotic leak 1/1718 (0.1%) 0/1696 (0%)
    Anastomotic stenosis 1/1718 (0.1%) 0/1696 (0%)
    Ankle fracture 4/1718 (0.2%) 1/1696 (0.1%)
    Cervical vertebral fracture 1/1718 (0.1%) 1/1696 (0.1%)
    Clavicle fracture 0/1718 (0%) 1/1696 (0.1%)
    Excoriation 0/1718 (0%) 1/1696 (0.1%)
    Fall 6/1718 (0.3%) 9/1696 (0.5%)
    Femur fracture 1/1718 (0.1%) 1/1696 (0.1%)
    Foreign body trauma 1/1718 (0.1%) 0/1696 (0%)
    Fracture of penis 1/1718 (0.1%) 0/1696 (0%)
    Hand fracture 0/1718 (0%) 2/1696 (0.1%)
    Head injury 2/1718 (0.1%) 1/1696 (0.1%)
    Hip fracture 3/1718 (0.2%) 6/1696 (0.4%)
    Humerus fracture 1/1718 (0.1%) 1/1696 (0.1%)
    Incision site complication 2/1718 (0.1%) 1/1696 (0.1%)
    Incision site haemorrhage 1/1718 (0.1%) 0/1696 (0%)
    Incisional hernia 1/1718 (0.1%) 1/1696 (0.1%)
    Injury 0/1718 (0%) 1/1696 (0.1%)
    Injury asphyxiation 1/1718 (0.1%) 0/1696 (0%)
    Intentional overdose 0/1718 (0%) 1/1696 (0.1%)
    Jaw fracture 0/1718 (0%) 1/1696 (0.1%)
    Joint dislocation 0/1718 (0%) 1/1696 (0.1%)
    Joint injury 1/1718 (0.1%) 1/1696 (0.1%)
    Joint sprain 0/1718 (0%) 1/1696 (0.1%)
    Lower limb fracture 2/1718 (0.1%) 3/1696 (0.2%)
    Multiple drug overdose 1/1718 (0.1%) 0/1696 (0%)
    Multiple fractures 2/1718 (0.1%) 2/1696 (0.1%)
    Narcotic intoxication 0/1718 (0%) 1/1696 (0.1%)
    Pelvic fracture 0/1718 (0%) 1/1696 (0.1%)
    Pharyngeal injury 0/1718 (0%) 1/1696 (0.1%)
    Polytraumatism 1/1718 (0.1%) 0/1696 (0%)
    Post laminectomy syndrome 1/1718 (0.1%) 0/1696 (0%)
    Post procedural bile leak 0/1718 (0%) 1/1696 (0.1%)
    Post procedural complication 1/1718 (0.1%) 0/1696 (0%)
    Post procedural haematoma 0/1718 (0%) 1/1696 (0.1%)
    Post procedural haematuria 1/1718 (0.1%) 0/1696 (0%)
    Post procedural haemorrhage 2/1718 (0.1%) 1/1696 (0.1%)
    Post procedural urine leak 1/1718 (0.1%) 0/1696 (0%)
    Postoperative fever 1/1718 (0.1%) 0/1696 (0%)
    Postoperative renal failure 1/1718 (0.1%) 0/1696 (0%)
    Postoperative wound complication 1/1718 (0.1%) 0/1696 (0%)
    Procedural hypotension 1/1718 (0.1%) 1/1696 (0.1%)
    Radius fracture 1/1718 (0.1%) 0/1696 (0%)
    Renal injury 0/1718 (0%) 1/1696 (0.1%)
    Rib fracture 4/1718 (0.2%) 2/1696 (0.1%)
    Road traffic accident 1/1718 (0.1%) 1/1696 (0.1%)
    Skeletal injury 1/1718 (0.1%) 0/1696 (0%)
    Skin laceration 2/1718 (0.1%) 0/1696 (0%)
    Spinal compression fracture 1/1718 (0.1%) 0/1696 (0%)
    Spinal fracture 1/1718 (0.1%) 2/1696 (0.1%)
    Splenic injury 1/1718 (0.1%) 0/1696 (0%)
    Stent-graft endoleak 1/1718 (0.1%) 0/1696 (0%)
    Subdural haematoma 4/1718 (0.2%) 2/1696 (0.1%)
    Tendon injury 1/1718 (0.1%) 0/1696 (0%)
    Traumatic brain injury 1/1718 (0.1%) 0/1696 (0%)
    Traumatic fracture 0/1718 (0%) 1/1696 (0.1%)
    Traumatic haematoma 0/1718 (0%) 1/1696 (0.1%)
    Traumatic intracranial haemorrhage 0/1718 (0%) 1/1696 (0.1%)
    Upper limb fracture 0/1718 (0%) 3/1696 (0.2%)
    Wound decomposition 0/1718 (0%) 1/1696 (0.1%)
    Investigations
    Arteriogram coronary 0/1718 (0%) 1/1696 (0.1%)
    Arteriogram coronary normal 1/1718 (0.1%) 0/1696 (0%)
    Aspartate aminotransferase increased 1/1718 (0.1%) 1/1696 (0.1%)
    Blood creatine phosphokinase increased 1/1718 (0.1%) 0/1696 (0%)
    Blood creatinine increased 1/1718 (0.1%) 0/1696 (0%)
    Blood glucose decreased 2/1718 (0.1%) 0/1696 (0%)
    Blood glucose increased 2/1718 (0.1%) 2/1696 (0.1%)
    Blood potassium increased 0/1718 (0%) 1/1696 (0.1%)
    Blood pressure increased 0/1718 (0%) 3/1696 (0.2%)
    Cardiac stress test abnormal 1/1718 (0.1%) 0/1696 (0%)
    Ejection fraction abnormal 0/1718 (0%) 1/1696 (0.1%)
    Ejection fraction decreased 1/1718 (0.1%) 1/1696 (0.1%)
    Haematocrit decreased 2/1718 (0.1%) 0/1696 (0%)
    Haemoglobin decreased 2/1718 (0.1%) 2/1696 (0.1%)
    Heart rate decreased 0/1718 (0%) 1/1696 (0.1%)
    Heart rate increased 2/1718 (0.1%) 1/1696 (0.1%)
    Hepatic enzyme increased 3/1718 (0.2%) 0/1696 (0%)
    International normalised ratio increased 1/1718 (0.1%) 1/1696 (0.1%)
    Intraocular pressure increased 0/1718 (0%) 1/1696 (0.1%)
    Oxygen consumption increased 0/1718 (0%) 1/1696 (0.1%)
    Prostatic specific antigen increased 1/1718 (0.1%) 0/1696 (0%)
    Transaminases increased 1/1718 (0.1%) 0/1696 (0%)
    Weight decreased 3/1718 (0.2%) 0/1696 (0%)
    Weight increased 0/1718 (0%) 1/1696 (0.1%)
    Metabolism and nutrition disorders
    Decreased appetite 1/1718 (0.1%) 0/1696 (0%)
    Dehydration 15/1718 (0.9%) 6/1696 (0.4%)
    Diabetes mellitus 2/1718 (0.1%) 1/1696 (0.1%)
    Diabetes mellitus inadequate control 0/1718 (0%) 1/1696 (0.1%)
    Diabetes mellitus non-insulin-dependent 0/1718 (0%) 1/1696 (0.1%)
    Diabetic foot 2/1718 (0.1%) 1/1696 (0.1%)
    Diabetic ketoacidosis 1/1718 (0.1%) 0/1696 (0%)
    Diabetic ulcer 1/1718 (0.1%) 0/1696 (0%)
    Electrolyte imbalance 1/1718 (0.1%) 0/1696 (0%)
    Failure to thrive 1/1718 (0.1%) 0/1696 (0%)
    Fluid overload 1/1718 (0.1%) 3/1696 (0.2%)
    Fluid retention 1/1718 (0.1%) 0/1696 (0%)
    Gout 1/1718 (0.1%) 2/1696 (0.1%)
    Hypercalcaemia 0/1718 (0%) 1/1696 (0.1%)
    Hyperglycaemia 2/1718 (0.1%) 2/1696 (0.1%)
    Hyperkalaemia 4/1718 (0.2%) 5/1696 (0.3%)
    Hypoglycaemia 6/1718 (0.3%) 2/1696 (0.1%)
    Hypokalaemia 1/1718 (0.1%) 1/1696 (0.1%)
    Hyponatraemia 0/1718 (0%) 3/1696 (0.2%)
    Hypovolaemia 1/1718 (0.1%) 1/1696 (0.1%)
    Malnutrition 1/1718 (0.1%) 0/1696 (0%)
    Metabolic acidosis 1/1718 (0.1%) 1/1696 (0.1%)
    Oral intake reduced 2/1718 (0.1%) 0/1696 (0%)
    Musculoskeletal and connective tissue disorders
    Arthralgia 13/1718 (0.8%) 18/1696 (1.1%)
    Arthritis 0/1718 (0%) 1/1696 (0.1%)
    Back pain 7/1718 (0.4%) 7/1696 (0.4%)
    Bunion 1/1718 (0.1%) 0/1696 (0%)
    Bursitis 1/1718 (0.1%) 0/1696 (0%)
    Cervical spinal stenosis 1/1718 (0.1%) 3/1696 (0.2%)
    Costochondritis 0/1718 (0%) 1/1696 (0.1%)
    Flank pain 0/1718 (0%) 2/1696 (0.1%)
    Foot deformity 0/1718 (0%) 1/1696 (0.1%)
    Haemarthrosis 0/1718 (0%) 1/1696 (0.1%)
    Intervertebral disc compression 0/1718 (0%) 1/1696 (0.1%)
    Intervertebral disc degeneration 1/1718 (0.1%) 2/1696 (0.1%)
    Intervertebral disc disorder 1/1718 (0.1%) 0/1696 (0%)
    Intervertebral disc protrusion 2/1718 (0.1%) 2/1696 (0.1%)
    Joint effusion 1/1718 (0.1%) 0/1696 (0%)
    Joint swelling 1/1718 (0.1%) 0/1696 (0%)
    Lumbar spinal stenosis 2/1718 (0.1%) 3/1696 (0.2%)
    Mobility decreased 0/1718 (0%) 1/1696 (0.1%)
    Muscle spasms 1/1718 (0.1%) 0/1696 (0%)
    Muscle twitching 0/1718 (0%) 1/1696 (0.1%)
    Muscular weakness 3/1718 (0.2%) 4/1696 (0.2%)
    Musculoskeletal chest pain 1/1718 (0.1%) 1/1696 (0.1%)
    Musculoskeletal discomfort 2/1718 (0.1%) 0/1696 (0%)
    Musculoskeletal pain 4/1718 (0.2%) 6/1696 (0.4%)
    Musculoskeletal stiffness 0/1718 (0%) 1/1696 (0.1%)
    Myalgia 2/1718 (0.1%) 0/1696 (0%)
    Neck pain 2/1718 (0.1%) 2/1696 (0.1%)
    Neuropathic arthropathy 0/1718 (0%) 2/1696 (0.1%)
    Osteoarthritis 24/1718 (1.4%) 28/1696 (1.7%)
    Osteonecrosis 1/1718 (0.1%) 0/1696 (0%)
    Pain in extremity 11/1718 (0.6%) 7/1696 (0.4%)
    Rhabdomyolysis 4/1718 (0.2%) 1/1696 (0.1%)
    Rotator cuff syndrome 1/1718 (0.1%) 3/1696 (0.2%)
    Sensation of heaviness 1/1718 (0.1%) 0/1696 (0%)
    Spinal column stenosis 3/1718 (0.2%) 1/1696 (0.1%)
    Spinal osteoarthritis 1/1718 (0.1%) 0/1696 (0%)
    Spondylitis 0/1718 (0%) 1/1696 (0.1%)
    Synovial cyst 0/1718 (0%) 1/1696 (0.1%)
    Tendonitis 1/1718 (0.1%) 0/1696 (0%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Acute myeloid leukaemia 1/1718 (0.1%) 1/1696 (0.1%)
    Adenocarcinoma pancreas 0/1718 (0%) 1/1696 (0.1%)
    Basal cell carcinoma 2/1718 (0.1%) 1/1696 (0.1%)
    Benign neoplasm of ureter 1/1718 (0.1%) 0/1696 (0%)
    Benign salivary gland neoplasm 0/1718 (0%) 1/1696 (0.1%)
    Bladder cancer 4/1718 (0.2%) 4/1696 (0.2%)
    Bladder cancer recurrent 0/1718 (0%) 1/1696 (0.1%)
    Bladder cancer stage IV 0/1718 (0%) 1/1696 (0.1%)
    Bladder neoplasm 0/1718 (0%) 2/1696 (0.1%)
    Bone cancer metastatic 1/1718 (0.1%) 0/1696 (0%)
    Bone neoplasm malignant 1/1718 (0.1%) 0/1696 (0%)
    Brain neoplasm 0/1718 (0%) 1/1696 (0.1%)
    Brain neoplasm malignant 1/1718 (0.1%) 0/1696 (0%)
    Breast cancer 1/1718 (0.1%) 0/1696 (0%)
    Breast cancer stage I 0/1718 (0%) 1/1696 (0.1%)
    Carcinoid tumour of the caecum 1/1718 (0.1%) 0/1696 (0%)
    Carcinoid tumour of the gastrointestinal tract 1/1718 (0.1%) 0/1696 (0%)
    Choroid melanoma 0/1718 (0%) 1/1696 (0.1%)
    Colon adenoma 2/1718 (0.1%) 0/1696 (0%)
    Colon cancer 1/1718 (0.1%) 2/1696 (0.1%)
    Endometrial cancer stage I 1/1718 (0.1%) 0/1696 (0%)
    Gastric cancer 2/1718 (0.1%) 1/1696 (0.1%)
    Gastrointestinal neoplasm 1/1718 (0.1%) 0/1696 (0%)
    Gastrointestinal stromal tumour 0/1718 (0%) 1/1696 (0.1%)
    Glioblastoma 1/1718 (0.1%) 0/1696 (0%)
    Hepatic neoplasm malignant 2/1718 (0.1%) 0/1696 (0%)
    Hypopharyngeal cancer 1/1718 (0.1%) 0/1696 (0%)
    Laryngeal cancer 2/1718 (0.1%) 0/1696 (0%)
    Laryngeal cancer recurrent 1/1718 (0.1%) 0/1696 (0%)
    Lung adenocarcinoma 0/1718 (0%) 1/1696 (0.1%)
    Lung adenocarcinoma metastatic 0/1718 (0%) 1/1696 (0.1%)
    Lung cancer metastatic 3/1718 (0.2%) 2/1696 (0.1%)
    Lung neoplasm 0/1718 (0%) 2/1696 (0.1%)
    Lung neoplasm malignant 8/1718 (0.5%) 14/1696 (0.8%)
    Lung squamous cell carcinoma stage unspecified 1/1718 (0.1%) 0/1696 (0%)
    Lymphoma 1/1718 (0.1%) 0/1696 (0%)
    Malignant lymphoid neoplasm 0/1718 (0%) 1/1696 (0.1%)
    Malignant melanoma 1/1718 (0.1%) 4/1696 (0.2%)
    Malignant palate neoplasm 0/1718 (0%) 1/1696 (0.1%)
    Malignant urinary tract neoplasm 0/1718 (0%) 1/1696 (0.1%)
    Melanocytic naevus 0/1718 (0%) 1/1696 (0.1%)
    Meningioma 1/1718 (0.1%) 0/1696 (0%)
    Mesothelioma 1/1718 (0.1%) 0/1696 (0%)
    Metastases to central nervous system 1/1718 (0.1%) 0/1696 (0%)
    Metastatic neoplasm 1/1718 (0.1%) 0/1696 (0%)
    Metastatic renal cell carcinoma 1/1718 (0.1%) 0/1696 (0%)
    Metastatic squamous cell carcinoma 0/1718 (0%) 1/1696 (0.1%)
    Multiple myeloma 0/1718 (0%) 1/1696 (0.1%)
    Myelodysplastic syndrome 1/1718 (0.1%) 0/1696 (0%)
    Neoplasm malignant 1/1718 (0.1%) 0/1696 (0%)
    Neoplasm prostate 1/1718 (0.1%) 0/1696 (0%)
    Non-Hodgkin's lymphoma 1/1718 (0.1%) 1/1696 (0.1%)
    Non-small cell lung cancer 0/1718 (0%) 4/1696 (0.2%)
    Non-small cell lung cancer metastatic 0/1718 (0%) 1/1696 (0.1%)
    Non-small cell lung cancer stage I 1/1718 (0.1%) 0/1696 (0%)
    Non-small cell lung cancer stage IIIA 0/1718 (0%) 1/1696 (0.1%)
    Oesophageal carcinoma 1/1718 (0.1%) 1/1696 (0.1%)
    Pancreatic carcinoma 3/1718 (0.2%) 2/1696 (0.1%)
    Pancreatic neoplasm 0/1718 (0%) 1/1696 (0.1%)
    Pituitary tumour benign 2/1718 (0.1%) 0/1696 (0%)
    Prostate cancer 8/1718 (0.5%) 10/1696 (0.6%)
    Prostate cancer metastatic 1/1718 (0.1%) 0/1696 (0%)
    Rectal adenoma 0/1718 (0%) 1/1696 (0.1%)
    Renal cancer metastatic 0/1718 (0%) 1/1696 (0.1%)
    Renal cell carcinoma stage II 0/1718 (0%) 1/1696 (0.1%)
    Renal cell carcinoma stage unspecified 3/1718 (0.2%) 2/1696 (0.1%)
    Renal neoplasm 0/1718 (0%) 1/1696 (0.1%)
    Salivary gland cancer 1/1718 (0.1%) 0/1696 (0%)
    Skin cancer 1/1718 (0.1%) 0/1696 (0%)
    Small cell lung cancer stage unspecified 0/1718 (0%) 2/1696 (0.1%)
    Small intestine carcinoma 0/1718 (0%) 1/1696 (0.1%)
    Spinal cord neoplasm 1/1718 (0.1%) 0/1696 (0%)
    Squamous cell carcinoma 1/1718 (0.1%) 2/1696 (0.1%)
    Testis cancer 1/1718 (0.1%) 0/1696 (0%)
    Thyroid cancer 1/1718 (0.1%) 1/1696 (0.1%)
    Tongue neoplasm malignant stage unspecified 2/1718 (0.1%) 0/1696 (0%)
    Tonsillar neoplasm 1/1718 (0.1%) 0/1696 (0%)
    Nervous system disorders
    Amnesia 1/1718 (0.1%) 0/1696 (0%)
    Aphasia 2/1718 (0.1%) 0/1696 (0%)
    Balance disorder 1/1718 (0.1%) 1/1696 (0.1%)
    Cerebral haemorrhage 0/1718 (0%) 1/1696 (0.1%)
    Cerebrovascular accident 1/1718 (0.1%) 2/1696 (0.1%)
    Cervicobrachial syndrome 0/1718 (0%) 1/1696 (0.1%)
    Convulsion 1/1718 (0.1%) 4/1696 (0.2%)
    Coordination abnormal 1/1718 (0.1%) 0/1696 (0%)
    Dementia 2/1718 (0.1%) 1/1696 (0.1%)
    Dementia Alzheimer's type 1/1718 (0.1%) 2/1696 (0.1%)
    Depressed level of consciousness 1/1718 (0.1%) 2/1696 (0.1%)
    Dizziness 21/1718 (1.2%) 19/1696 (1.1%)
    Drooling 0/1718 (0%) 1/1696 (0.1%)
    Dysarthria 0/1718 (0%) 2/1696 (0.1%)
    Essential tremor 0/1718 (0%) 1/1696 (0.1%)
    Facial palsy 0/1718 (0%) 3/1696 (0.2%)
    Haemorrhage intracranial 1/1718 (0.1%) 1/1696 (0.1%)
    Headache 3/1718 (0.2%) 4/1696 (0.2%)
    Hemiparesis 1/1718 (0.1%) 1/1696 (0.1%)
    Hypertensive encephalopathy 1/1718 (0.1%) 1/1696 (0.1%)
    Hypoaesthesia 5/1718 (0.3%) 2/1696 (0.1%)
    Intracranial aneurysm 1/1718 (0.1%) 1/1696 (0.1%)
    Lethargy 1/1718 (0.1%) 1/1696 (0.1%)
    Loss of consciousness 4/1718 (0.2%) 4/1696 (0.2%)
    Lumbar radiculopathy 0/1718 (0%) 1/1696 (0.1%)
    Migraine 1/1718 (0.1%) 2/1696 (0.1%)
    Migraine with aura 0/1718 (0%) 1/1696 (0.1%)
    Myelitis transverse 0/1718 (0%) 1/1696 (0.1%)
    Myoclonus 1/1718 (0.1%) 0/1696 (0%)
    Nerve compression 0/1718 (0%) 1/1696 (0.1%)
    Neuritis 1/1718 (0.1%) 0/1696 (0%)
    Normal pressure hydrocephalus 1/1718 (0.1%) 1/1696 (0.1%)
    Paraesthesia 0/1718 (0%) 5/1696 (0.3%)
    Paresis 0/1718 (0%) 1/1696 (0.1%)
    Parkinson's disease 2/1718 (0.1%) 0/1696 (0%)
    Partial seizures 1/1718 (0.1%) 0/1696 (0%)
    Post herpetic neuralgia 1/1718 (0.1%) 0/1696 (0%)
    Presyncope 2/1718 (0.1%) 1/1696 (0.1%)
    Radicular pain 0/1718 (0%) 1/1696 (0.1%)
    Sciatica 1/1718 (0.1%) 0/1696 (0%)
    Simple partial seizures 1/1718 (0.1%) 0/1696 (0%)
    Somnolence 0/1718 (0%) 1/1696 (0.1%)
    Spinal claudication 0/1718 (0%) 1/1696 (0.1%)
    Subarachnoid haemorrhage 3/1718 (0.2%) 0/1696 (0%)
    Syncope vasovagal 1/1718 (0.1%) 2/1696 (0.1%)
    Transient ischaemic attack 5/1718 (0.3%) 6/1696 (0.4%)
    Tremor 1/1718 (0.1%) 0/1696 (0%)
    Psychiatric disorders
    Affective disorder 0/1718 (0%) 1/1696 (0.1%)
    Alcohol withdrawal syndrome 0/1718 (0%) 1/1696 (0.1%)
    Anger 1/1718 (0.1%) 0/1696 (0%)
    Anxiety 3/1718 (0.2%) 1/1696 (0.1%)
    Bipolar I disorder 1/1718 (0.1%) 0/1696 (0%)
    Confusional state 7/1718 (0.4%) 8/1696 (0.5%)
    Delirium 2/1718 (0.1%) 1/1696 (0.1%)
    Depression 4/1718 (0.2%) 5/1696 (0.3%)
    Depression suicidal 1/1718 (0.1%) 0/1696 (0%)
    Depressive symptom 0/1718 (0%) 1/1696 (0.1%)
    Disorientation 1/1718 (0.1%) 0/1696 (0%)
    Dysphasia 0/1718 (0%) 1/1696 (0.1%)
    Hallucination 1/1718 (0.1%) 1/1696 (0.1%)
    Impaired self-care 1/1718 (0.1%) 0/1696 (0%)
    Insomnia 0/1718 (0%) 1/1696 (0.1%)
    Major depression 1/1718 (0.1%) 0/1696 (0%)
    Mental disorder 1/1718 (0.1%) 0/1696 (0%)
    Mental status changes 3/1718 (0.2%) 3/1696 (0.2%)
    Panic attack 0/1718 (0%) 1/1696 (0.1%)
    Post-traumatic stress disorder 1/1718 (0.1%) 0/1696 (0%)
    Psychotic disorder 0/1718 (0%) 1/1696 (0.1%)
    Stress 1/1718 (0.1%) 0/1696 (0%)
    Suicidal ideation 4/1718 (0.2%) 2/1696 (0.1%)
    Renal and urinary disorders
    Acute prerenal failure 0/1718 (0%) 1/1696 (0.1%)
    Calculus ureteric 1/1718 (0.1%) 4/1696 (0.2%)
    Calculus urinary 0/1718 (0%) 1/1696 (0.1%)
    Cystitis haemorrhagic 0/1718 (0%) 1/1696 (0.1%)
    Dysuria 1/1718 (0.1%) 2/1696 (0.1%)
    Glomerulonephritis 0/1718 (0%) 1/1696 (0.1%)
    Haematuria 5/1718 (0.3%) 6/1696 (0.4%)
    Hydronephrosis 0/1718 (0%) 2/1696 (0.1%)
    Nephrolithiasis 4/1718 (0.2%) 7/1696 (0.4%)
    Neurogenic bladder 1/1718 (0.1%) 0/1696 (0%)
    Obstructive uropathy 0/1718 (0%) 1/1696 (0.1%)
    Pollakiuria 1/1718 (0.1%) 0/1696 (0%)
    Pyuria 0/1718 (0%) 1/1696 (0.1%)
    Renal colic 0/1718 (0%) 1/1696 (0.1%)
    Renal cyst 1/1718 (0.1%) 0/1696 (0%)
    Renal disorder 0/1718 (0%) 1/1696 (0.1%)
    Renal failure 7/1718 (0.4%) 4/1696 (0.2%)
    Renal failure acute 18/1718 (1%) 15/1696 (0.9%)
    Renal failure chronic 3/1718 (0.2%) 3/1696 (0.2%)
    Stress urinary incontinence 1/1718 (0.1%) 0/1696 (0%)
    Ureteric obstruction 2/1718 (0.1%) 1/1696 (0.1%)
    Ureteric stenosis 0/1718 (0%) 1/1696 (0.1%)
    Urethral obstruction 1/1718 (0.1%) 0/1696 (0%)
    Urethral perforation 1/1718 (0.1%) 0/1696 (0%)
    Urinary bladder haemorrhage 0/1718 (0%) 1/1696 (0.1%)
    Urinary retention 4/1718 (0.2%) 2/1696 (0.1%)
    Reproductive system and breast disorders
    Benign prostatic hyperplasia 2/1718 (0.1%) 3/1696 (0.2%)
    Breast cancer in situ 1/1718 (0.1%) 0/1696 (0%)
    Endometrial cancer recurrent 1/1718 (0.1%) 0/1696 (0%)
    Pelvic haematoma 0/1718 (0%) 1/1696 (0.1%)
    Pelvic pain 1/1718 (0.1%) 1/1696 (0.1%)
    Penile pain 1/1718 (0.1%) 0/1696 (0%)
    Postmenopausal haemorrhage 1/1718 (0.1%) 0/1696 (0%)
    Prostatitis 1/1718 (0.1%) 0/1696 (0%)
    Vaginal haemorrhage 1/1718 (0.1%) 0/1696 (0%)
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory failure 3/1718 (0.2%) 1/1696 (0.1%)
    Asthma 2/1718 (0.1%) 2/1696 (0.1%)
    Bronchospasm 0/1718 (0%) 1/1696 (0.1%)
    Chronic obstructive pulmonary disease 15/1718 (0.9%) 11/1696 (0.6%)
    Cough 4/1718 (0.2%) 5/1696 (0.3%)
    Cryptogenic organising pneumonia 0/1718 (0%) 1/1696 (0.1%)
    Diaphragmatic paralysis 1/1718 (0.1%) 0/1696 (0%)
    Dysphonia 0/1718 (0%) 1/1696 (0.1%)
    Dyspnoea 1/1718 (0.1%) 5/1696 (0.3%)
    Epistaxis 1/1718 (0.1%) 2/1696 (0.1%)
    Haemoptysis 2/1718 (0.1%) 3/1696 (0.2%)
    Hypercapnia 0/1718 (0%) 1/1696 (0.1%)
    Hypoxia 2/1718 (0.1%) 3/1696 (0.2%)
    Idiopathic pulmonary fibrosis 1/1718 (0.1%) 0/1696 (0%)
    Influenza 4/1718 (0.2%) 1/1696 (0.1%)
    Interstitial lung disease 1/1718 (0.1%) 0/1696 (0%)
    Laryngeal oedema 1/1718 (0.1%) 0/1696 (0%)
    Lung infiltration 0/1718 (0%) 1/1696 (0.1%)
    Nasal septum deviation 0/1718 (0%) 1/1696 (0.1%)
    Orthopnoea 2/1718 (0.1%) 1/1696 (0.1%)
    Pharyngolaryngeal pain 0/1718 (0%) 2/1696 (0.1%)
    Pleural effusion 4/1718 (0.2%) 2/1696 (0.1%)
    Pleurisy 0/1718 (0%) 1/1696 (0.1%)
    Pleuritic pain 1/1718 (0.1%) 2/1696 (0.1%)
    Pneumonia aspiration 0/1718 (0%) 2/1696 (0.1%)
    Pneumothorax 1/1718 (0.1%) 0/1696 (0%)
    Productive cough 2/1718 (0.1%) 1/1696 (0.1%)
    Respiratory acidosis 0/1718 (0%) 1/1696 (0.1%)
    Respiratory distress 2/1718 (0.1%) 2/1696 (0.1%)
    Respiratory failure 7/1718 (0.4%) 3/1696 (0.2%)
    Sinus congestion 1/1718 (0.1%) 0/1696 (0%)
    Sleep apnoea syndrome 0/1718 (0%) 1/1696 (0.1%)
    Throat tightness 1/1718 (0.1%) 0/1696 (0%)
    Skin and subcutaneous tissue disorders
    Angioneurotic oedema 0/1718 (0%) 1/1696 (0.1%)
    Decubitus ulcer 1/1718 (0.1%) 0/1696 (0%)
    Dermatitis contact 0/1718 (0%) 1/1696 (0.1%)
    Erythema 2/1718 (0.1%) 2/1696 (0.1%)
    Hyperhidrosis 3/1718 (0.2%) 4/1696 (0.2%)
    Hypoaesthesia facial 0/1718 (0%) 1/1696 (0.1%)
    Pruritus generalised 1/1718 (0.1%) 0/1696 (0%)
    Rash 0/1718 (0%) 1/1696 (0.1%)
    Rash pruritic 1/1718 (0.1%) 0/1696 (0%)
    Skin ulcer 1/1718 (0.1%) 4/1696 (0.2%)
    Swelling face 1/1718 (0.1%) 2/1696 (0.1%)
    Surgical and medical procedures
    Cardioversion 1/1718 (0.1%) 1/1696 (0.1%)
    Coronary revascularisation 1/1718 (0.1%) 0/1696 (0%)
    Hypotensive anaesthesia procedure 0/1718 (0%) 1/1696 (0.1%)
    Peripheral revascularisation 0/1718 (0%) 1/1696 (0.1%)
    Shoulder arthroplasty 1/1718 (0.1%) 0/1696 (0%)
    Spinal decompression 1/1718 (0.1%) 0/1696 (0%)
    Stent placement 1/1718 (0.1%) 1/1696 (0.1%)
    Therapeutic embolisation 1/1718 (0.1%) 0/1696 (0%)
    Toe amputation 0/1718 (0%) 1/1696 (0.1%)
    Vascular disorders
    Aneurysm 1/1718 (0.1%) 0/1696 (0%)
    Aortic aneurysm 8/1718 (0.5%) 11/1696 (0.6%)
    Aortic aneurysm rupture 1/1718 (0.1%) 0/1696 (0%)
    Aortic stenosis 1/1718 (0.1%) 3/1696 (0.2%)
    Aorto-duodenal fistula 1/1718 (0.1%) 0/1696 (0%)
    Arteriovenous fistula 0/1718 (0%) 1/1696 (0.1%)
    Carotid artery aneurysm 0/1718 (0%) 1/1696 (0.1%)
    Carotid artery disease 0/1718 (0%) 1/1696 (0.1%)
    Carotid artery stenosis 1/1718 (0.1%) 2/1696 (0.1%)
    Circulatory collapse 2/1718 (0.1%) 0/1696 (0%)
    Deep vein thrombosis 9/1718 (0.5%) 6/1696 (0.4%)
    Femoral arterial stenosis 0/1718 (0%) 1/1696 (0.1%)
    Flushing 0/1718 (0%) 1/1696 (0.1%)
    Haematoma 3/1718 (0.2%) 2/1696 (0.1%)
    Hypertension 5/1718 (0.3%) 5/1696 (0.3%)
    Hypertensive crisis 1/1718 (0.1%) 1/1696 (0.1%)
    Hypertensive emergency 2/1718 (0.1%) 0/1696 (0%)
    Hypotension 11/1718 (0.6%) 8/1696 (0.5%)
    Iliac artery stenosis 0/1718 (0%) 2/1696 (0.1%)
    Intermittent claudication 2/1718 (0.1%) 4/1696 (0.2%)
    Orthostatic hypotension 2/1718 (0.1%) 3/1696 (0.2%)
    Peripheral artery aneurysm 0/1718 (0%) 2/1696 (0.1%)
    Peripheral ischaemia 0/1718 (0%) 1/1696 (0.1%)
    Peripheral vascular disorder 3/1718 (0.2%) 3/1696 (0.2%)
    Pulmonary embolism 4/1718 (0.2%) 5/1696 (0.3%)
    Pulmonary hypertension 0/1718 (0%) 1/1696 (0.1%)
    Shock haemorrhagic 1/1718 (0.1%) 0/1696 (0%)
    Thrombosis 0/1718 (0%) 2/1696 (0.1%)
    Vascular pseudoaneurysm 5/1718 (0.3%) 1/1696 (0.1%)
    Vasospasm 1/1718 (0.1%) 0/1696 (0%)
    Other (Not Including Serious) Adverse Events
    ERN + Simvastatin Placebo + Simvastatin
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 1413/1718 (82.2%) 1345/1696 (79.3%)
    Blood and lymphatic system disorders
    Anaemia 41/1718 (2.4%) 34/1696 (2%)
    Cardiac disorders
    Angina pectoris 43/1718 (2.5%) 46/1696 (2.7%)
    Atrial fibrillation 43/1718 (2.5%) 30/1696 (1.8%)
    Chest pain 112/1718 (6.5%) 95/1696 (5.6%)
    Dyspnoea 89/1718 (5.2%) 89/1696 (5.2%)
    Dyspnoea exertional 26/1718 (1.5%) 40/1696 (2.4%)
    Eye disorders
    Cataract 80/1718 (4.7%) 77/1696 (4.5%)
    Gastrointestinal disorders
    Abdominal pain 39/1718 (2.3%) 34/1696 (2%)
    Diarrhoea 136/1718 (7.9%) 63/1696 (3.7%)
    Nausea 55/1718 (3.2%) 40/1696 (2.4%)
    Vomiting 46/1718 (2.7%) 28/1696 (1.7%)
    General disorders
    Fatigue 87/1718 (5.1%) 74/1696 (4.4%)
    Non-cardiac chest pain 27/1718 (1.6%) 42/1696 (2.5%)
    Oedema peripheral 66/1718 (3.8%) 73/1696 (4.3%)
    Infections and infestations
    Bronchitis 82/1718 (4.8%) 68/1696 (4%)
    Cellulitis 36/1718 (2.1%) 30/1696 (1.8%)
    Herpes zoster 53/1718 (3.1%) 29/1696 (1.7%)
    Influenza 61/1718 (3.6%) 62/1696 (3.7%)
    Nasopharyngitis 113/1718 (6.6%) 121/1696 (7.1%)
    Pneumonia 38/1718 (2.2%) 52/1696 (3.1%)
    Sinusitis 80/1718 (4.7%) 71/1696 (4.2%)
    Upper respiratory tract infection 72/1718 (4.2%) 59/1696 (3.5%)
    Urinary tract infection 60/1718 (3.5%) 53/1696 (3.1%)
    Injury, poisoning and procedural complications
    Contusion 29/1718 (1.7%) 36/1696 (2.1%)
    Investigations
    Blood glucose increased 112/1718 (6.5%) 78/1696 (4.6%)
    Metabolism and nutrition disorders
    Diabetes mellitus 67/1718 (3.9%) 41/1696 (2.4%)
    Gout 66/1718 (3.8%) 65/1696 (3.8%)
    Musculoskeletal and connective tissue disorders
    Arthralgia 138/1718 (8%) 158/1696 (9.3%)
    Back pain 120/1718 (7%) 122/1696 (7.2%)
    Muscle spasms 46/1718 (2.7%) 51/1696 (3%)
    Musculoskeletal pain 75/1718 (4.4%) 88/1696 (5.2%)
    Myalgia 53/1718 (3.1%) 53/1696 (3.1%)
    Neck pain 38/1718 (2.2%) 35/1696 (2.1%)
    Osteoarthritis 47/1718 (2.7%) 50/1696 (2.9%)
    Pain in extremity 134/1718 (7.8%) 147/1696 (8.7%)
    Nervous system disorders
    Dizziness 95/1718 (5.5%) 122/1696 (7.2%)
    Headache 61/1718 (3.6%) 51/1696 (3%)
    Hypoaesthesia 36/1718 (2.1%) 35/1696 (2.1%)
    Respiratory, thoracic and mediastinal disorders
    Cough 57/1718 (3.3%) 52/1696 (3.1%)
    Skin and subcutaneous tissue disorders
    Pruritus 47/1718 (2.7%) 27/1696 (1.6%)
    Rash 58/1718 (3.4%) 38/1696 (2.2%)
    Vascular disorders
    Hypertension 59/1718 (3.4%) 58/1696 (3.4%)

    Limitations/Caveats

    [Not Specified]

    More Information

    Certain Agreements

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

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

    Results Point of Contact

    Name/Title Ruth McBride
    Organization Axio Research, LLC
    Phone 206-577-0212
    Email ruthm@axioresearch.com
    Responsible Party:
    Ruth McBride, Co-Director, Coordinating Center, Axio Research. LLC
    ClinicalTrials.gov Identifier:
    NCT00120289
    Other Study ID Numbers:
    • 226
    • U01HL081649
    • U01HL081616
    First Posted:
    Jul 15, 2005
    Last Update Posted:
    Apr 6, 2016
    Last Verified:
    Mar 1, 2016