Atherosclerotic Cardiovascular Disease
Conditions
Keywords
vascular disease, lipids, cholesteryl ester transfer protein (CETP) inhibition, anacetrapib
Brief summary
The Randomized EValuation of the Effects of Anacetrapib Through Lipid-modification (REVEAL) trial aims to determine whether lipid modification with anacetrapib 100mg daily reduces the risk of coronary death, myocardial infarction (MI) or coronary revascularization (collectively known as major coronary events) in patients with circulatory problems who have their Low-density Lipoprotein (LDL) cholesterol level treated with a statin.
Detailed description
Sub-study: Does anacetrapib as a CETP inhibitor lead to mobilization of stem cells and enhance myocardial function via neoangiogenesis and tissue regeneration? Following the main on-treatment part of the study, there was a further period of at least 2 years during which participants were followed-up by telephone, off treatment. All participants stopped study treatment prior to February 2017 (results for the main-trial have been reported) and direct participant follow-up was completed in April 2019. In the UK we will continue to collect information on health outcomes via central data registries and NHS sources for many years.
Interventions
DRUGAnacetrapib
tablet, 100mg daily
DRUGPlacebo anacetrapib
tablet, 1 tablet daily
Sponsors
Merck Sharp & Dohme LLC
University of Oxford
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
50 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Patients must be aged at least 50 at the time of initial invitation, and at least one of the following inclusion criteria must be satisfied: * History of MI; or * Cerebrovascular atherosclerotic disease (i.e. history of presumed ischaemic stroke or carotid revascularization); or * Peripheral arterial disease (i.e. history of non-coronary revascularization, including aortic aneurysm repair or graft); or * Diabetes mellitus with other evidence of symptomatic coronary heart disease (i.e. treatment or hospitalization for angina, or a history of coronary revascularization or acute coronary syndrome).
Exclusion criteria
* None of the following must be satisfied: * Acute MI, acute coronary syndrome or stroke within 4 weeks prior to Screening Visit or during Run-in (but such individuals may be entered later, if appropriate); * Planned coronary revascularization procedure within the next 6 months (such individuals may be entered later, if appropriate); * Definite history of chronic liver disease, or abnormal liver function (i.e. alanine transaminase (ALT) \>2x the upper limit of normal (ULN)). Note: Individuals with a history of acute hepatitis are eligible provided this ALT limit is not exceeded; * Severe renal insufficiency (i.e. creatinine \>200 µmol/L \[2.3 mg/dL\], dialysis or functioning renal transplant); * Evidence of active inflammatory muscle disease (e.g. dermatomyositis, polymyositis), or creatine kinase (CK) \>3x ULN; * Previous significant adverse reaction to a statin or anacetrapib; * Current treatment with any of the following lipid-lowering treatments: (i) a regimen considered to produce substantially greater LDL cholesterol reduction than atorvastatin 80 mg daily for individuals in non-Asian countries or 20 mg daily for those in North East Asia; or (ii) fibric acid derivative (fibrate, including gemfibrozil); or (iii) niacin (nicotinic acid) at doses above 100 mg daily * Concurrent treatment with a medication that is contraindicated with anacetrapib or atorvastatin: (i) any potent CYP3A4 inhibitor, such as: 1. macrolide antibiotics (erythromycin, clarithromycin, telithromycin); 2. systemic imidazole or triazole antifungals (e.g. itraconazole, posaconazole); 3. protease inhibitors (e.g. atazanavir); 4. nefazodone (ii) ciclosporin (iii) daptomycin (iv) systemic use of fusidic acid Note: Individuals who are taking such drugs temporarily may be re-screened when they discontinue them, if considered appropriate; * Known to be poorly compliant with clinic visits or prescribed medication; * Medical history that might limit the individual's ability to take trial treatments for the duration of the study (e.g. severe respiratory disease; history of cancer or evidence of spread within last 5 years, other than non-melanoma skin cancer; or recent history of alcohol or substance misuse); * Women of child-bearing potential (unless using adequate contraception); * Current participation in a clinical trial with an unlicensed drug or device. Individuals will also be excluded at the Screening visit if it is considered unlikely that they will achieve total cholesterol \<3.5 mmol/L (135 mg/dL) on the highest atorvastatin dose available in their region (atorvastatin 80 mg daily in non-Asian countries or 20 mg daily in North East Asia). In addition, individuals will be excluded at the Randomization visit if any of the following are true: * Total cholesterol above 4 mmol/L \[155 mg/dL\] * Non-compliant with run-in treatment (\<90% scheduled run-in medication taken) * Individual is no longer willing to be randomized into the 4-5 year trial * The individual's doctor is of the view that their patient should not be randomized.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Major Coronary Event | Randomized treatment phase during median follow-up period of 4.1years | Primary assessment involves an intention-to-treat comparison among all randomized participants of the effects of allocation to anacetrapib versus placebo on major coronary events (defined as the occurrence of coronary death, myocardial infarction or coronary revascularization procedure) during the scheduled treatment period. Data reported is for the first major coronary event. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Major Atherosclerotic Event | Randomized treatment phase during median follow-up period of 4.1years | Major atherosclerotic events (defined as coronary death, myocardial infarction or presumed ischaemic stroke; the key secondary outcome). Secondary assessments involve intention-to-treat comparisons among all randomized participants of the effects of allocation to anacetrapib versus placebo during the scheduled treatment period. |
| Number of Participants With Presumed Ischaemic Stroke | Randomized treatment phase during median follow-up period of 4.1years | Presumed ischaemic stroke (i.e. not known to be haemorrhagic). Secondary assessments involve intention-to-treat comparisons among all randomized participants of the effects of allocation to anacetrapib versus placebo during the scheduled treatment period. |
| Number of Participants With Major Vascular Event | Randomized treatment phase during median follow-up period of 4.1years | Major vascular events (defined as coronary death, myocardial infarction, coronary revascularization or presumed ischaemic stroke). Secondary assessments involve intention-to-treat comparisons among all randomized participants of the effects of allocation to anacetrapib versus placebo during the scheduled treatment period |
Countries
United Kingdom
Participant flow
Recruitment details
Participants were randomized between August 2011 and October 2013. Follow-up continued until 31st January 2017.
Pre-assignment details
Successfully screened participants were entered into a run-in period. Attendees were discouraged from continuing to randomization if it was thought unlikely they would be able to continue attending follow-up visits for at least 4-5years. During run-in participants were issued atorvastatin (1 tablet/day) and placebo anacetrapib (1 tablet/day).
Participants by arm
| Arm | Count |
|---|---|
| Anacetrapib Anacetrapib: 100mg tablet daily | 15,225 |
| Placebo Anacetrapib Placebo anacetrapib: 1 tablet daily | 15,224 |
| Total | 30,449 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lost to Follow-up | 22 | 21 |
| Overall Study | Withdrawal by Subject | 16 | 17 |
Baseline characteristics
| Characteristic | Total | Placebo Anacetrapib | Anacetrapib |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 17172 Participants | 8581 Participants | 8591 Participants |
| Age, Categorical Between 18 and 65 years | 13277 Participants | 6643 Participants | 6634 Participants |
| Age, Continuous | 67 years STANDARD_DEVIATION 8 | 67 years STANDARD_DEVIATION 8 | 67 years STANDARD_DEVIATION 8 |
| Body Mass Index, Categorical <25 kg/m^2 | 6808 Participants | 3361 Participants | 3447 Participants |
| Body Mass Index, Categorical ≥25 to < 30 kg/m^2 | 13944 Participants | 6995 Participants | 6949 Participants |
| Body Mass Index, Categorical ≥ 30 kg/m^2 | 9697 Participants | 4868 Participants | 4829 Participants |
| Body Mass Index, Continuous | 28.6 kg/m^2 STANDARD_DEVIATION 5.1 | 28.6 kg/m^2 STANDARD_DEVIATION 5.1 | 28.6 kg/m^2 STANDARD_DEVIATION 5 |
| Diastolic Blood Pressure, Categorical < 75 mmHg | 11446 Participants | 5790 Participants | 5656 Participants |
| Diastolic Blood Pressure, Categorical ≥ 75 to < 85 mmHg | 10685 Participants | 5277 Participants | 5408 Participants |
| Diastolic Blood Pressure, Categorical ≥ 85 mmHg | 8318 Participants | 4157 Participants | 4161 Participants |
| Diastolic Blood Pressure, Continuous | 78.1 mmHg STANDARD_DEVIATION 11 | 78.0 mmHg STANDARD_DEVIATION 11 | 78.1 mmHg STANDARD_DEVIATION 10.9 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 235 Participants | 114 Participants | 121 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 5082 Participants | 2522 Participants | 2560 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 25132 Participants | 12588 Participants | 12544 Participants |
| Glomerular Filtration Rate, Categorical < 60 ml/min/1.73m^2 | 3353 Participants | 1698 Participants | 1655 Participants |
| Glomerular Filtration Rate, Categorical ≥ 60 ml/min/1.73m^2 | 27096 Participants | 13526 Participants | 13570 Participants |
| Glomerular Filtration Rate, Continuous | 83 ml/min/1.73m^2 STANDARD_DEVIATION 17 | 83 ml/min/1.73m^2 STANDARD_DEVIATION 17 | 83 ml/min/1.73m^2 STANDARD_DEVIATION 17 |
| HDL Cholesterol, Categorical < 35 mg/dl | 9173 Participants | 4590 Participants | 4583 Participants |
| HDL Cholesterol, Categorical ≥ 35 to < 43 mg/dl | 10707 Participants | 5269 Participants | 5438 Participants |
| HDL Cholesterol, Categorical ≥ 43 mg/dl | 10569 Participants | 5365 Participants | 5204 Participants |
| HDL Cholesterol, Continuous | 40 mg/dl STANDARD_DEVIATION 10 | 40 mg/dl STANDARD_DEVIATION 10 | 40 mg/dl STANDARD_DEVIATION 10 |
| LDL Cholesterol, Categorical < 54 mg/dl | 10100 Participants | 5077 Participants | 5023 Participants |
| LDL Cholesterol, Categorical ≥ 54 to < 66 mg/dl | 9348 Participants | 4705 Participants | 4643 Participants |
| LDL Cholesterol, Categorical ≥ 66 mg/dl | 11001 Participants | 5442 Participants | 5559 Participants |
| LDL Cholesterol, Continuous | 61 mg/dl STANDARD_DEVIATION 15 | 61 mg/dl STANDARD_DEVIATION 15 | 61 mg/dl STANDARD_DEVIATION 15 |
| Non-HDL Cholesterol, Categorical ≥ 101 mg/dl | 9357 Participants | 4670 Participants | 4687 Participants |
| Non-HDL Cholesterol, Categorical < 85 mg/dl | 11343 Participants | 5701 Participants | 5642 Participants |
| Non-HDL Cholesterol, Categorical ≥ 85 to <101 mg/dl | 9749 Participants | 4853 Participants | 4896 Participants |
| Non-HDL Cholesterol, Continuous | 92 mg/dl STANDARD_DEVIATION 19 | 92 mg/dl STANDARD_DEVIATION 19 | 92 mg/dl STANDARD_DEVIATION 19 |
| Previous disease Cerebrovascular disease | 6781 Participants | 3396 Participants | 3385 Participants |
| Previous disease Coronary heart disease | 26679 Participants | 13354 Participants | 13325 Participants |
| Previous disease Diabetes | 11320 Participants | 5666 Participants | 5654 Participants |
| Previous disease Heart failure | 1771 Participants | 869 Participants | 902 Participants |
| Previous disease Peripheral-artery disease | 2435 Participants | 1206 Participants | 1229 Participants |
| Race/Ethnicity, Customized Race Black or African American | 328 Participants | 168 Participants | 160 Participants |
| Race/Ethnicity, Customized Race Chinese | 8646 Participants | 4323 Participants | 4323 Participants |
| Race/Ethnicity, Customized Race Mixed | 33 Participants | 12 Participants | 21 Participants |
| Race/Ethnicity, Customized Race Other | 96 Participants | 49 Participants | 47 Participants |
| Race/Ethnicity, Customized Race Other North East Asian | 11 Participants | 6 Participants | 5 Participants |
| Race/Ethnicity, Customized Race South Asian | 192 Participants | 97 Participants | 95 Participants |
| Race/Ethnicity, Customized Race South East Asian | 22 Participants | 11 Participants | 11 Participants |
| Race/Ethnicity, Customized Race Unknown | 2 Participants | 0 Participants | 2 Participants |
| Race/Ethnicity, Customized Race White | 21119 Participants | 10558 Participants | 10561 Participants |
| Region China | 8629 Participants | 4315 Participants | 4314 Participants |
| Region Europe | 15738 Participants | 7875 Participants | 7863 Participants |
| Region North America | 6082 Participants | 3034 Participants | 3048 Participants |
| Region of Enrollment Canada | 752 participants | 391 participants | 361 participants |
| Region of Enrollment China | 8629 participants | 4315 participants | 4314 participants |
| Region of Enrollment Denmark | 1850 participants | 932 participants | 918 participants |
| Region of Enrollment Finland | 613 participants | 306 participants | 307 participants |
| Region of Enrollment Germany | 1529 participants | 774 participants | 755 participants |
| Region of Enrollment Italy | 1660 participants | 834 participants | 826 participants |
| Region of Enrollment Norway | 844 participants | 418 participants | 426 participants |
| Region of Enrollment Sweden | 861 participants | 434 participants | 427 participants |
| Region of Enrollment United Kingdom | 8381 participants | 4177 participants | 4204 participants |
| Region of Enrollment United States | 5330 participants | 2643 participants | 2687 participants |
| Sex: Female, Male Female | 4915 Participants | 2459 Participants | 2456 Participants |
| Sex: Female, Male Male | 25534 Participants | 12765 Participants | 12769 Participants |
| Systolic Blood Pressure, Categorical <125 mmHg | 11438 Participants | 5760 Participants | 5678 Participants |
| Systolic Blood Pressure, Categorical ≥125 to <140 mmHg | 9559 Participants | 4740 Participants | 4819 Participants |
| Systolic Blood Pressure, Categorical ≥140 mmHg | 9452 Participants | 4724 Participants | 4728 Participants |
| Systolic Blood Pressure, Continuous | 131.2 mmHg STANDARD_DEVIATION 18.5 | 131.1 mmHg STANDARD_DEVIATION 18.5 | 131.3 mmHg STANDARD_DEVIATION 18.5 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 1,122 / 15,225 | 1,155 / 15,224 |
| other Total, other adverse events | 2,493 / 3,048 | 2,503 / 3,034 |
| serious Total, serious adverse events | 8,898 / 15,225 | 8,912 / 15,224 |
Outcome results
Primary
Number of Participants With Major Coronary Event
Primary assessment involves an intention-to-treat comparison among all randomized participants of the effects of allocation to anacetrapib versus placebo on major coronary events (defined as the occurrence of coronary death, myocardial infarction or coronary revascularization procedure) during the scheduled treatment period. Data reported is for the first major coronary event.
Time frame: Randomized treatment phase during median follow-up period of 4.1years
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Anacetrapib | Number of Participants With Major Coronary Event | 1640 Participants |
| Placebo Anacetrapib | Number of Participants With Major Coronary Event | 1803 Participants |
p-value: 0.00495% CI: [0.85, 0.97]Log Rank
Secondary
Number of Participants With Major Atherosclerotic Event
Major atherosclerotic events (defined as coronary death, myocardial infarction or presumed ischaemic stroke; the key secondary outcome). Secondary assessments involve intention-to-treat comparisons among all randomized participants of the effects of allocation to anacetrapib versus placebo during the scheduled treatment period.
Time frame: Randomized treatment phase during median follow-up period of 4.1years
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Anacetrapib | Number of Participants With Major Atherosclerotic Event | 1383 Participants |
| Placebo Anacetrapib | Number of Participants With Major Atherosclerotic Event | 1483 Participants |
p-value: 0.05295% CI: [0.86, 1]Log Rank
Secondary
Number of Participants With Major Vascular Event
Major vascular events (defined as coronary death, myocardial infarction, coronary revascularization or presumed ischaemic stroke). Secondary assessments involve intention-to-treat comparisons among all randomized participants of the effects of allocation to anacetrapib versus placebo during the scheduled treatment period
Time frame: Randomized treatment phase during median follow-up period of 4.1years
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Anacetrapib | Number of Participants With Major Vascular Event | 2068 Participants |
| Placebo Anacetrapib | Number of Participants With Major Vascular Event | 2214 Participants |
p-value: 0.0295% CI: [0.88, 0.99]Log Rank
Secondary
Number of Participants With Presumed Ischaemic Stroke
Presumed ischaemic stroke (i.e. not known to be haemorrhagic). Secondary assessments involve intention-to-treat comparisons among all randomized participants of the effects of allocation to anacetrapib versus placebo during the scheduled treatment period.
Time frame: Randomized treatment phase during median follow-up period of 4.1years
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Anacetrapib | Number of Participants With Presumed Ischaemic Stroke | 485 Participants |
| Placebo Anacetrapib | Number of Participants With Presumed Ischaemic Stroke | 489 Participants |
95% CI: [0.87, 1.12]