Dyslipidemia
Conditions
Keywords
High cholesterol, Treatment for high cholesterol, Lowering cholesterol, Lowering high cholesterol, Hypercholesterolemia
Brief summary
The primary objective was to evaluate the effect of treatment with evolocumab, compared with placebo, on the risk for cardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina, or coronary revascularization, whichever occurs first, in patients with clinically evident cardiovascular disease.
Interventions
BIOLOGICALEvolocumab
Administered subcutaneously using a spring-based prefilled 1.0 mL autoinjector/pen.
DRUGPlacebo
Administered subcutaneously using a spring-based prefilled 1.0 mL autoinjector/pen.
Sponsors
Amgen
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
40 Years to 85 Years
Healthy volunteers
No
Inclusion criteria
* Male or female ≥ 40 to ≤ 85 years of age * History of clinically evident cardiovascular disease at high risk for a recurrent event * Fasting low-density lipoprotein cholesterol (LDL-C) ≥ 70 mg/dL (≥ 1.8 mmol/L) ) or non-high-density lipoprotein cholesterol (non-HDL-C) ≥ 100 mg/dL (\> 2.6 mmol/L) * Fasting triglycerides ≤ 400 mg/dL (4.5 mmol/L)
Exclusion criteria
* New York Heart Association (NYHA) class III or IV, or last known left ventricular ejection fraction \< 30% * Uncontrolled hypertension * Uncontrolled or recurrent ventricular tachycardia * Untreated hyperthyroidism or hypothyroidism * Homozygous familial hypercholesterolemia * LDL or plasma apheresis
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Time to Cardiovascular Death, Myocardial Infarction, Hospitalization for Unstable Angina, Stroke, or Coronary Revascularization | Events that occurred from randomization to the last confirmed survival status date; the median duration of follow-up was 26 months. KM estimates at 6, 12, 18, 24, 30 and 36 months are reported. | All deaths and potential endpoint events were adjudicated by an independent external Clinical Events Committee (CEC) led by the Thrombolysis in Myocardial Infarction (TIMI) Study Group, using standardized definitions based on the Standardized Definitions for Cardiovascular and Stroke End Point Events in Clinical Trials and the Third Universal Definition of Myocardial Infarction. Time to cardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina, or coronary revascularization was defined as the time from randomization to the first occurrence of any component of the composite endpoint and was analyzed using Kaplan-Meier (KM) survival analysis. KM estimates of the percentage of participants with an event are reported. Participants with no event were censored based on last non-fatal potential endpoint collection date. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to Cardiovascular Death | Events that occurred from randomization to the last confirmed survival status date; the median duration of follow-up was 26 months. KM estimates at 6, 12, 18, 24, 30 and 36 months are reported. | All deaths and potential endpoint events were adjudicated by an independent external CEC led by the TIMI Study Group, using standardized definitions based on the Standardized Definitions for Cardiovascular and Stroke End Point Events in Clinical Trials and the Third Universal Definition of Myocardial Infarction. Cardiovascular death includes death resulting from an acute myocardial infarction (MI), sudden cardiac death, death due to heart failure (HF), death due to stroke, death due to cardiovascular (CV) procedures, death due to CV hemorrhage, and death due to other CV causes. Time to cardiovascular death was defined as the time from randomization to the date of cardiovascular death and was analyzed using Kaplan-Meier (KM) survival analysis. KM estimates of the percentage of participants with an event are reported. Participants with no event were censored based on the last confirmed survival status date. |
| Time to All Cause Death | Events that occurred from randomization to the last confirmed survival status date; the median duration of follow-up was 26 months. KM estimates at 6, 12, 18, 24, 30 and 36 months are reported. | Time to all-cause death was defined as the time from randomization to the date of death and was analyzed using Kaplan-Meier (KM) survival analysis. KM estimates of the percentage of participants with an event are reported. Participants with no event were censored based on the last confirmed survival status date. |
| Time to First Myocardial Infarction | Events that occurred from randomization to the last confirmed survival status date; the median duration of follow-up was 26 months. KM estimates at 6, 12, 18, 24, 30 and 36 months are reported. | All deaths and potential endpoint events were adjudicated by an independent external CEC led by the TIMI Study Group, using standardized definitions based on the Standardized Definitions for Cardiovascular and Stroke End Point Events in Clinical Trials and the Third Universal Definition of Myocardial Infarction. The diagnosis of myocardial infarction required the combination of: * Evidence of myocardial necrosis (either changes in cardiac biomarkers or post-mortem pathological findings); and * Supporting information derived from the clinical presentation, electrocardiographic changes, or the results of myocardial or coronary artery Imaging. Time to first myocardial infarction was defined as the time from randomization to the date of the first MI and was analyzed using Kaplan-Meier survival analysis. KM estimates of the percentage of participants with an event are reported. Participants with no event were censored based on last non-fatal potential endpoint collection date. |
| Time to Cardiovascular Death, Myocardial Infarction, or Stroke | Events that occurred from randomization to the last confirmed survival status date; the median duration of follow-up was 26 months. KM estimates at 6, 12, 18, 24, 30 and 36 months are reported. | All deaths and potential endpoint events were adjudicated by an independent external CEC led by the TIMI Study Group, using standardized definitions based on the Standardized Definitions for Cardiovascular and Stroke End Point Events in Clinical Trials and the Third Universal Definition of Myocardial Infarction. Time to cardiovascular death, myocardial infarction, or stroke was defined as the time from randomization to the first occurrence of any component of the composite endpoint and was analyzed using Kaplan-Meier (KM) survival analysis. KM estimates of the percentage of participants with an event are reported. Participants with no event were censored based on last non-fatal potential endpoint collection date. |
| Time to First Coronary Revascularization | Events that occurred from randomization to the last confirmed survival status date; the median duration of follow-up was 26 months. KM estimates at 6, 12, 18, 24, 30 and 36 months are reported. | All deaths and potential endpoint events were adjudicated by an independent external CEC led by the TIMI Study Group, using standardized definitions based on the Standardized Definitions for Cardiovascular and Stroke End Point Events in Clinical Trials and the Third Universal Definition of Myocardial Infarction. Time to first coronary revascularization was defined as the time from randomization to the date of the coronary revascularization and was analyzed using Kaplan-Meier (KM) survival analysis. KM estimates of the percentage of participants with an event are reported. Participants with no event were censored based on last non-fatal potential endpoint collection date. |
| Time to Cardiovascular Death or First Hospitalization for Worsening Heart Failure | Events that occurred from randomization to the last confirmed survival status date; the median duration of follow-up was 26 months. KM estimates at 6, 12, 18, 24, 30 and 36 months are reported. | All events were adjudicated by an independent external CEC led by the TIMI Study Group, using standardized definitions. HF hospitalization was defined as an event that met all of the following criteria: 1. Admitted to hospital with a primary diagnosis of HF 2. In hospital for at least 24 hours 3. Documented new or worsening symptoms due to HF, including at least 1 of the following: * Dyspnea * Decreased exercise tolerance * Fatigue * Other symptoms of worsened end-organ perfusion or volume overload 4. Evidence of new or worsening HF consisting of at least 2 physical exam findings or 1 physical exam finding and at least 1 laboratory criterion 5. Received new or increased treatment for HF. Time to CV death or first hospitalization for worsening HF was defined as the time from randomization to the first occurrence of any component of the endpoint analyzed using KM survival analysis. Participants with no event were censored based on last non-fatal potential endpoint collection date. |
| Time to First Ischemic Fatal or Non-Fatal Stroke or Transient Ischemic Attack | Events that occurred from randomization to the last confirmed survival status date; the median duration of follow-up was 26 months. KM estimates at 6, 12, 18, 24, 30 and 36 months are reported. | All deaths and potential endpoint events were adjudicated by an independent external CEC led by the TIMI Study Group, using standardized definitions. Ischemic stroke was defined as an acute episode of focal cerebral, spinal, or retinal dysfunction caused by infarction of central nervous system tissue. Transient ischemic attack (TIA) was defined as a transient episode of focal neurological dysfunction caused by brain, spinal cord, or retinal ischemia, without acute infarction. Time to first ischemic fatal or non-fatal stroke or TIA was defined as the time from randomization to the first occurrence of any component of the composite endpoint and was analyzed using KM analysis. KM estimates of the percentage of participants with an event are reported. Participants with no event were censored based on last non-fatal potential endpoint collection date. |
| Time to First Stroke | Events that occurred from randomization to the last confirmed survival status date; the median duration of follow-up was 26 months. KM estimates at 6, 12, 18, 24, 30 and 36 months are reported. | All deaths and potential endpoint events were adjudicated by an independent external CEC led by the TIMI Study Group, using standardized definitions based on the Standardized Definitions for Cardiovascular and Stroke End Point Events in Clinical Trials and the Third Universal Definition of Myocardial Infarction. Stroke was defined as an acute episode of focal or global neurological dysfunction caused by brain, spinal cord, or retinal vascular injury as a result of hemorrhage or infarction. Time to first stroke was defined as the time from randomization to the date of the stroke and was analyzed using Kaplan-Meier (KM) survival analysis. KM estimates of the percentage of participants with an event are reported. Participants with no event were censored based on last non-fatal potential endpoint collection date. |
Countries
Argentina, Australia, Austria, Belgium, Brazil, Bulgaria, Canada, Chile, China, Colombia, Czechia, Denmark, Estonia, Finland, France, Germany, Greece, Hong Kong, Hungary, Iceland, India, Ireland, Israel, Italy, Japan, Latvia, Lithuania, Malaysia, Mexico, Netherlands, New Zealand, Norway, Philippines, Poland, Portugal, Romania, Russia, Singapore, Slovakia, South Africa, South Korea, Spain, Sweden, Switzerland, Taiwan, Turkey (Türkiye), Ukraine, United Kingdom, United States
Participant flow
Recruitment details
Participants were enrolled at 1242 clinical centers in 49 countries in the regions of Europe (62.9%), North America (16.6%), Asia Pacific (13.9%), and Latin America (6.6%) from 08 February 2013 to 05 June 2015.
Pre-assignment details
Eligible participants were randomized in a 1:1 ratio to receive either subcutaneous (SC) evolocumab or placebo. Randomization was stratified by the final screening low-density lipoprotein cholesterol (LDL-C) level (\< 85 mg/dL vs ≥ 85 mg/dL) and by geographical region.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Participants received placebo subcutaneous injections either once every 2 weeks (Q2W) or once a month (QM) according to their own preference. | 13,780 |
| Evolocumab Participants received evolocumab subcutaneous injections either 140 mg Q2W or 420 mg QM according to their own preference. | 13,784 |
| Total | 27,564 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lost to Follow-up | 13 | 5 |
| Overall Study | Withdrawal by Subject | 105 | 88 |
Baseline characteristics
| Characteristic | Total | Placebo | Evolocumab |
|---|---|---|---|
| Age, Continuous | 62.5 years STANDARD_DEVIATION 9 | 62.5 years STANDARD_DEVIATION 8.9 | 62.5 years STANDARD_DEVIATION 9.1 |
| Age, Customized < 65 years | 15310 Participants | 7687 Participants | 7623 Participants |
| Age, Customized ≥ 65 years | 12254 Participants | 6093 Participants | 6161 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2177 Participants | 1084 Participants | 1093 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 25382 Participants | 12694 Participants | 12688 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 5 Participants | 2 Participants | 3 Participants |
| Geographical Region Asia Pacific | 3835 Participants | 1917 Participants | 1918 Participants |
| Geographical Region Europe | 17336 Participants | 8669 Participants | 8667 Participants |
| Geographical Region Latin America | 1823 Participants | 910 Participants | 913 Participants |
| Geographical Region North America | 4570 Participants | 2284 Participants | 2286 Participants |
| Low-density Lipoprotein Cholesterol < 85 mg/dL | 9612 Participants | 4803 Participants | 4809 Participants |
| Low-density Lipoprotein Cholesterol ≥ 85 mg/dL | 17952 Participants | 8977 Participants | 8975 Participants |
| Race/Ethnicity, Customized American Indian or Alaska Native | 140 Participants | 80 Participants | 60 Participants |
| Race/Ethnicity, Customized Asian | 2723 Participants | 1349 Participants | 1374 Participants |
| Race/Ethnicity, Customized Black or African American | 669 Participants | 352 Participants | 317 Participants |
| Race/Ethnicity, Customized Multiple | 31 Participants | 12 Participants | 19 Participants |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander | 26 Participants | 11 Participants | 15 Participants |
| Race/Ethnicity, Customized Other | 517 Participants | 266 Participants | 251 Participants |
| Race/Ethnicity, Customized White | 23458 Participants | 11710 Participants | 11748 Participants |
| Sex: Female, Male Female | 6769 Participants | 3382 Participants | 3387 Participants |
| Sex: Female, Male Male | 20795 Participants | 10398 Participants | 10397 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 3,438 / 13,756 | 3,500 / 13,769 |
| serious Total, serious adverse events | 3,404 / 13,756 | 3,410 / 13,769 |
Outcome results
Primary
Time to Cardiovascular Death, Myocardial Infarction, Hospitalization for Unstable Angina, Stroke, or Coronary Revascularization
All deaths and potential endpoint events were adjudicated by an independent external Clinical Events Committee (CEC) led by the Thrombolysis in Myocardial Infarction (TIMI) Study Group, using standardized definitions based on the Standardized Definitions for Cardiovascular and Stroke End Point Events in Clinical Trials and the Third Universal Definition of Myocardial Infarction. Time to cardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina, or coronary revascularization was defined as the time from randomization to the first occurrence of any component of the composite endpoint and was analyzed using Kaplan-Meier (KM) survival analysis. KM estimates of the percentage of participants with an event are reported. Participants with no event were censored based on last non-fatal potential endpoint collection date.
Time frame: Events that occurred from randomization to the last confirmed survival status date; the median duration of follow-up was 26 months. KM estimates at 6, 12, 18, 24, 30 and 36 months are reported.
Population: All randomized participants; The number of participants entered at each time point represents the number of participants at risk.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | Time to Cardiovascular Death, Myocardial Infarction, Hospitalization for Unstable Angina, Stroke, or Coronary Revascularization | KM estimate at 6 months | 3.11 percentage of participants |
| Placebo | Time to Cardiovascular Death, Myocardial Infarction, Hospitalization for Unstable Angina, Stroke, or Coronary Revascularization | KM estimate at 12 months | 6.01 percentage of participants |
| Placebo | Time to Cardiovascular Death, Myocardial Infarction, Hospitalization for Unstable Angina, Stroke, or Coronary Revascularization | KM estimate at 18 months | 8.32 percentage of participants |
| Placebo | Time to Cardiovascular Death, Myocardial Infarction, Hospitalization for Unstable Angina, Stroke, or Coronary Revascularization | KM estimate at 24 months | 10.66 percentage of participants |
| Placebo | Time to Cardiovascular Death, Myocardial Infarction, Hospitalization for Unstable Angina, Stroke, or Coronary Revascularization | KM estimate at 30 months | 12.72 percentage of participants |
| Placebo | Time to Cardiovascular Death, Myocardial Infarction, Hospitalization for Unstable Angina, Stroke, or Coronary Revascularization | KM estimate at 36 months | 14.64 percentage of participants |
| Evolocumab | Time to Cardiovascular Death, Myocardial Infarction, Hospitalization for Unstable Angina, Stroke, or Coronary Revascularization | KM estimate at 30 months | 10.91 percentage of participants |
| Evolocumab | Time to Cardiovascular Death, Myocardial Infarction, Hospitalization for Unstable Angina, Stroke, or Coronary Revascularization | KM estimate at 6 months | 2.74 percentage of participants |
| Evolocumab | Time to Cardiovascular Death, Myocardial Infarction, Hospitalization for Unstable Angina, Stroke, or Coronary Revascularization | KM estimate at 24 months | 9.13 percentage of participants |
| Evolocumab | Time to Cardiovascular Death, Myocardial Infarction, Hospitalization for Unstable Angina, Stroke, or Coronary Revascularization | KM estimate at 12 months | 5.31 percentage of participants |
| Evolocumab | Time to Cardiovascular Death, Myocardial Infarction, Hospitalization for Unstable Angina, Stroke, or Coronary Revascularization | KM estimate at 36 months | 12.57 percentage of participants |
| Evolocumab | Time to Cardiovascular Death, Myocardial Infarction, Hospitalization for Unstable Angina, Stroke, or Coronary Revascularization | KM estimate at 18 months | 7.25 percentage of participants |
Comparison: The primary endpoint was compared between treatment groups at a significance level of 0.05.p-value: <0.000195% CI: [0.79, 0.92]Log Rank
Secondary
Time to All Cause Death
Time to all-cause death was defined as the time from randomization to the date of death and was analyzed using Kaplan-Meier (KM) survival analysis. KM estimates of the percentage of participants with an event are reported. Participants with no event were censored based on the last confirmed survival status date.
Time frame: Events that occurred from randomization to the last confirmed survival status date; the median duration of follow-up was 26 months. KM estimates at 6, 12, 18, 24, 30 and 36 months are reported.
Population: All randomized participants; The number of participants entered at each time point represents the number of participants at risk.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | Time to All Cause Death | KM estimate at 6 months | 0.62 percentage of participants |
| Placebo | Time to All Cause Death | KM estimate at 12 months | 1.29 percentage of participants |
| Placebo | Time to All Cause Death | KM estimate at 18 months | 1.96 percentage of participants |
| Placebo | Time to All Cause Death | KM estimate at 24 months | 2.78 percentage of participants |
| Placebo | Time to All Cause Death | KM estimate at 30 months | 3.48 percentage of participants |
| Placebo | Time to All Cause Death | KM estimate at 36 months | 4.28 percentage of participants |
| Evolocumab | Time to All Cause Death | KM estimate at 30 months | 3.63 percentage of participants |
| Evolocumab | Time to All Cause Death | KM estimate at 6 months | 0.55 percentage of participants |
| Evolocumab | Time to All Cause Death | KM estimate at 24 months | 2.81 percentage of participants |
| Evolocumab | Time to All Cause Death | KM estimate at 12 months | 1.26 percentage of participants |
| Evolocumab | Time to All Cause Death | KM estimate at 36 months | 4.75 percentage of participants |
| Evolocumab | Time to All Cause Death | KM estimate at 18 months | 1.94 percentage of participants |
Comparison: If the primary, key secondary, and endpoint cardiovascular death reached a statistical significance level of 0.05, then the endpoint of all-cause death was tested at a significance level of 0.04 and remaining secondary endpoints at an overall significant level of 0.01 by applying the Hochberg method.p-value: 0.536895% CI: [0.91, 1.19]Log Rank
Secondary
Time to Cardiovascular Death
All deaths and potential endpoint events were adjudicated by an independent external CEC led by the TIMI Study Group, using standardized definitions based on the Standardized Definitions for Cardiovascular and Stroke End Point Events in Clinical Trials and the Third Universal Definition of Myocardial Infarction. Cardiovascular death includes death resulting from an acute myocardial infarction (MI), sudden cardiac death, death due to heart failure (HF), death due to stroke, death due to cardiovascular (CV) procedures, death due to CV hemorrhage, and death due to other CV causes. Time to cardiovascular death was defined as the time from randomization to the date of cardiovascular death and was analyzed using Kaplan-Meier (KM) survival analysis. KM estimates of the percentage of participants with an event are reported. Participants with no event were censored based on the last confirmed survival status date.
Time frame: Events that occurred from randomization to the last confirmed survival status date; the median duration of follow-up was 26 months. KM estimates at 6, 12, 18, 24, 30 and 36 months are reported.
Population: All randomized participants; The number of participants entered at each time point represents the number of participants at risk.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | Time to Cardiovascular Death | KM estimate at 6 months | 0.40 percentage of participants |
| Placebo | Time to Cardiovascular Death | KM estimate at 12 months | 0.82 percentage of participants |
| Placebo | Time to Cardiovascular Death | KM estimate at 18 months | 1.19 percentage of participants |
| Placebo | Time to Cardiovascular Death | KM estimate at 24 months | 1.57 percentage of participants |
| Placebo | Time to Cardiovascular Death | KM estimate at 30 months | 1.99 percentage of participants |
| Placebo | Time to Cardiovascular Death | KM estimate at 36 months | 2.39 percentage of participants |
| Evolocumab | Time to Cardiovascular Death | KM estimate at 30 months | 2.11 percentage of participants |
| Evolocumab | Time to Cardiovascular Death | KM estimate at 6 months | 0.39 percentage of participants |
| Evolocumab | Time to Cardiovascular Death | KM estimate at 24 months | 1.64 percentage of participants |
| Evolocumab | Time to Cardiovascular Death | KM estimate at 12 months | 0.79 percentage of participants |
| Evolocumab | Time to Cardiovascular Death | KM estimate at 36 months | 2.49 percentage of participants |
| Evolocumab | Time to Cardiovascular Death | KM estimate at 18 months | 1.20 percentage of participants |
Comparison: If the primary and key secondary endpoints reached a statistical significance level of 0.05, then the endpoint of cardiovascular death was tested at a significance level of 0.05.p-value: 0.618895% CI: [0.88, 1.25]Log Rank
Secondary
Time to Cardiovascular Death, Myocardial Infarction, or Stroke
All deaths and potential endpoint events were adjudicated by an independent external CEC led by the TIMI Study Group, using standardized definitions based on the Standardized Definitions for Cardiovascular and Stroke End Point Events in Clinical Trials and the Third Universal Definition of Myocardial Infarction. Time to cardiovascular death, myocardial infarction, or stroke was defined as the time from randomization to the first occurrence of any component of the composite endpoint and was analyzed using Kaplan-Meier (KM) survival analysis. KM estimates of the percentage of participants with an event are reported. Participants with no event were censored based on last non-fatal potential endpoint collection date.
Time frame: Events that occurred from randomization to the last confirmed survival status date; the median duration of follow-up was 26 months. KM estimates at 6, 12, 18, 24, 30 and 36 months are reported.
Population: All randomized participants; The number of participants entered at each time point represents the number of participants at risk.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | Time to Cardiovascular Death, Myocardial Infarction, or Stroke | KM estimate at 6 months | 1.86 percentage of participants |
| Placebo | Time to Cardiovascular Death, Myocardial Infarction, or Stroke | KM estimate at 12 months | 3.68 percentage of participants |
| Placebo | Time to Cardiovascular Death, Myocardial Infarction, or Stroke | KM estimate at 18 months | 5.18 percentage of participants |
| Placebo | Time to Cardiovascular Death, Myocardial Infarction, or Stroke | KM estimate at 24 months | 6.83 percentage of participants |
| Placebo | Time to Cardiovascular Death, Myocardial Infarction, or Stroke | KM estimate at 30 months | 8.31 percentage of participants |
| Placebo | Time to Cardiovascular Death, Myocardial Infarction, or Stroke | KM estimate at 36 months | 9.93 percentage of participants |
| Evolocumab | Time to Cardiovascular Death, Myocardial Infarction, or Stroke | KM estimate at 30 months | 6.66 percentage of participants |
| Evolocumab | Time to Cardiovascular Death, Myocardial Infarction, or Stroke | KM estimate at 6 months | 1.65 percentage of participants |
| Evolocumab | Time to Cardiovascular Death, Myocardial Infarction, or Stroke | KM estimate at 24 months | 5.47 percentage of participants |
| Evolocumab | Time to Cardiovascular Death, Myocardial Infarction, or Stroke | KM estimate at 12 months | 3.10 percentage of participants |
| Evolocumab | Time to Cardiovascular Death, Myocardial Infarction, or Stroke | KM estimate at 36 months | 7.90 percentage of participants |
| Evolocumab | Time to Cardiovascular Death, Myocardial Infarction, or Stroke | KM estimate at 18 months | 4.29 percentage of participants |
Comparison: If the primary endpoint reached statistical significance at the 0.05 level, the key secondary endpoint (composite of cardiovascular death, myocardial infarction, and stroke) was tested at a significance level of 0.05.p-value: <0.000195% CI: [0.73, 0.88]Log Rank
Secondary
Time to Cardiovascular Death or First Hospitalization for Worsening Heart Failure
All events were adjudicated by an independent external CEC led by the TIMI Study Group, using standardized definitions. HF hospitalization was defined as an event that met all of the following criteria: 1. Admitted to hospital with a primary diagnosis of HF 2. In hospital for at least 24 hours 3. Documented new or worsening symptoms due to HF, including at least 1 of the following: * Dyspnea * Decreased exercise tolerance * Fatigue * Other symptoms of worsened end-organ perfusion or volume overload 4. Evidence of new or worsening HF consisting of at least 2 physical exam findings or 1 physical exam finding and at least 1 laboratory criterion 5. Received new or increased treatment for HF. Time to CV death or first hospitalization for worsening HF was defined as the time from randomization to the first occurrence of any component of the endpoint analyzed using KM survival analysis. Participants with no event were censored based on last non-fatal potential endpoint collection date.
Time frame: Events that occurred from randomization to the last confirmed survival status date; the median duration of follow-up was 26 months. KM estimates at 6, 12, 18, 24, 30 and 36 months are reported.
Population: All randomized participants; the number of participants entered at each time point represents the number of participants at risk.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | Time to Cardiovascular Death or First Hospitalization for Worsening Heart Failure | KM estimate at 6 months | 0.79 percentage of participants |
| Placebo | Time to Cardiovascular Death or First Hospitalization for Worsening Heart Failure | KM estimate at 12 months | 1.35 percentage of participants |
| Placebo | Time to Cardiovascular Death or First Hospitalization for Worsening Heart Failure | KM estimate at 18 months | 1.99 percentage of participants |
| Placebo | Time to Cardiovascular Death or First Hospitalization for Worsening Heart Failure | KM estimate at 36 months | 4.03 percentage of participants |
| Placebo | Time to Cardiovascular Death or First Hospitalization for Worsening Heart Failure | KM estimate at 24 months | 2.70 percentage of participants |
| Placebo | Time to Cardiovascular Death or First Hospitalization for Worsening Heart Failure | KM estimate at 30 months | 3.45 percentage of participants |
| Evolocumab | Time to Cardiovascular Death or First Hospitalization for Worsening Heart Failure | KM estimate at 18 months | 1.99 percentage of participants |
| Evolocumab | Time to Cardiovascular Death or First Hospitalization for Worsening Heart Failure | KM estimate at 6 months | 0.64 percentage of participants |
| Evolocumab | Time to Cardiovascular Death or First Hospitalization for Worsening Heart Failure | KM estimate at 24 months | 2.64 percentage of participants |
| Evolocumab | Time to Cardiovascular Death or First Hospitalization for Worsening Heart Failure | KM estimate at 12 months | 1.29 percentage of participants |
| Evolocumab | Time to Cardiovascular Death or First Hospitalization for Worsening Heart Failure | KM estimate at 30 months | 3.31 percentage of participants |
| Evolocumab | Time to Cardiovascular Death or First Hospitalization for Worsening Heart Failure | KM estimate at 36 months | 4.13 percentage of participants |
Comparison: If the primary, key secondary, and endpoint of cardiovascular death reached a statistical significance level of 0.05, then the endpoint of all-cause death was tested at a significance level of 0.04 and remaining secondary endpoints were tested at an overall significance level of 0.01 by applying the Hochberg method.p-value: 0.817995% CI: [0.86, 1.13]Log Rank
Secondary
Time to First Coronary Revascularization
All deaths and potential endpoint events were adjudicated by an independent external CEC led by the TIMI Study Group, using standardized definitions based on the Standardized Definitions for Cardiovascular and Stroke End Point Events in Clinical Trials and the Third Universal Definition of Myocardial Infarction. Time to first coronary revascularization was defined as the time from randomization to the date of the coronary revascularization and was analyzed using Kaplan-Meier (KM) survival analysis. KM estimates of the percentage of participants with an event are reported. Participants with no event were censored based on last non-fatal potential endpoint collection date.
Time frame: Events that occurred from randomization to the last confirmed survival status date; the median duration of follow-up was 26 months. KM estimates at 6, 12, 18, 24, 30 and 36 months are reported.
Population: All randomized participants; the number of participants entered at each time point represents the number of participants at risk.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | Time to First Coronary Revascularization | KM estimate at 6 months | 1.87 percentage of participants |
| Placebo | Time to First Coronary Revascularization | KM estimate at 12 months | 3.71 percentage of participants |
| Placebo | Time to First Coronary Revascularization | KM estimate at 18 months | 5.20 percentage of participants |
| Placebo | Time to First Coronary Revascularization | KM estimate at 24 months | 6.57 percentage of participants |
| Placebo | Time to First Coronary Revascularization | KM estimate at 30 months | 7.91 percentage of participants |
| Placebo | Time to First Coronary Revascularization | KM estimate at 36 months | 9.17 percentage of participants |
| Evolocumab | Time to First Coronary Revascularization | KM estimate at 30 months | 6.13 percentage of participants |
| Evolocumab | Time to First Coronary Revascularization | KM estimate at 6 months | 1.60 percentage of participants |
| Evolocumab | Time to First Coronary Revascularization | KM estimate at 24 months | 5.22 percentage of participants |
| Evolocumab | Time to First Coronary Revascularization | KM estimate at 12 months | 3.13 percentage of participants |
| Evolocumab | Time to First Coronary Revascularization | KM estimate at 36 months | 7.01 percentage of participants |
| Evolocumab | Time to First Coronary Revascularization | KM estimate at 18 months | 4.16 percentage of participants |
Comparison: If the primary, key secondary, and endpoint of cardiovascular death reached a statistical significance level of 0.05, then the endpoint of all-cause death was tested at a significance level of 0.04 and remaining secondary endpoints were tested at an overall significance level of 0.01 by applying the Hochberg method.p-value: <0.000195% CI: [0.71, 0.86]Log Rank
Secondary
Time to First Ischemic Fatal or Non-Fatal Stroke or Transient Ischemic Attack
All deaths and potential endpoint events were adjudicated by an independent external CEC led by the TIMI Study Group, using standardized definitions. Ischemic stroke was defined as an acute episode of focal cerebral, spinal, or retinal dysfunction caused by infarction of central nervous system tissue. Transient ischemic attack (TIA) was defined as a transient episode of focal neurological dysfunction caused by brain, spinal cord, or retinal ischemia, without acute infarction. Time to first ischemic fatal or non-fatal stroke or TIA was defined as the time from randomization to the first occurrence of any component of the composite endpoint and was analyzed using KM analysis. KM estimates of the percentage of participants with an event are reported. Participants with no event were censored based on last non-fatal potential endpoint collection date.
Time frame: Events that occurred from randomization to the last confirmed survival status date; the median duration of follow-up was 26 months. KM estimates at 6, 12, 18, 24, 30 and 36 months are reported.
Population: All randomized participants; the number of participants entered at each time point represents the number of participants at risk.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | Time to First Ischemic Fatal or Non-Fatal Stroke or Transient Ischemic Attack | KM estimate at 18 months | 1.52 percentage of participants |
| Placebo | Time to First Ischemic Fatal or Non-Fatal Stroke or Transient Ischemic Attack | KM estimate at 30 months | 2.40 percentage of participants |
| Placebo | Time to First Ischemic Fatal or Non-Fatal Stroke or Transient Ischemic Attack | KM estimate at 12 months | 1.05 percentage of participants |
| Placebo | Time to First Ischemic Fatal or Non-Fatal Stroke or Transient Ischemic Attack | KM estimate at 36 months | 2.81 percentage of participants |
| Placebo | Time to First Ischemic Fatal or Non-Fatal Stroke or Transient Ischemic Attack | KM estimate at 24 months | 2.05 percentage of participants |
| Placebo | Time to First Ischemic Fatal or Non-Fatal Stroke or Transient Ischemic Attack | KM estimate at 6 months | 0.61 percentage of participants |
| Evolocumab | Time to First Ischemic Fatal or Non-Fatal Stroke or Transient Ischemic Attack | KM estimate at 24 months | 1.46 percentage of participants |
| Evolocumab | Time to First Ischemic Fatal or Non-Fatal Stroke or Transient Ischemic Attack | KM estimate at 12 months | 0.83 percentage of participants |
| Evolocumab | Time to First Ischemic Fatal or Non-Fatal Stroke or Transient Ischemic Attack | KM estimate at 18 months | 1.18 percentage of participants |
| Evolocumab | Time to First Ischemic Fatal or Non-Fatal Stroke or Transient Ischemic Attack | KM estimate at 6 months | 0.42 percentage of participants |
| Evolocumab | Time to First Ischemic Fatal or Non-Fatal Stroke or Transient Ischemic Attack | KM estimate at 30 months | 1.92 percentage of participants |
| Evolocumab | Time to First Ischemic Fatal or Non-Fatal Stroke or Transient Ischemic Attack | KM estimate at 36 months | 2.48 percentage of participants |
Comparison: If the primary, key secondary, and endpoint of cardiovascular death reached a statistical significance level of 0.05, then the endpoint of all-cause death was tested at a significance level of 0.04 and remaining secondary endpoints were tested at an overall significance level of 0.01 by applying the Hochberg method.p-value: 0.003595% CI: [0.65, 0.92]Log Rank
Secondary
Time to First Myocardial Infarction
All deaths and potential endpoint events were adjudicated by an independent external CEC led by the TIMI Study Group, using standardized definitions based on the Standardized Definitions for Cardiovascular and Stroke End Point Events in Clinical Trials and the Third Universal Definition of Myocardial Infarction. The diagnosis of myocardial infarction required the combination of: * Evidence of myocardial necrosis (either changes in cardiac biomarkers or post-mortem pathological findings); and * Supporting information derived from the clinical presentation, electrocardiographic changes, or the results of myocardial or coronary artery Imaging. Time to first myocardial infarction was defined as the time from randomization to the date of the first MI and was analyzed using Kaplan-Meier survival analysis. KM estimates of the percentage of participants with an event are reported. Participants with no event were censored based on last non-fatal potential endpoint collection date.
Time frame: Events that occurred from randomization to the last confirmed survival status date; the median duration of follow-up was 26 months. KM estimates at 6, 12, 18, 24, 30 and 36 months are reported.
Population: All randomized participants; The number of participants entered at each time point represents the number of participants at risk.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | Time to First Myocardial Infarction | KM estimate at 6 months | 1.14 percentage of participants |
| Placebo | Time to First Myocardial Infarction | KM estimate at 12 months | 2.39 percentage of participants |
| Placebo | Time to First Myocardial Infarction | KM estimate at 18 months | 3.33 percentage of participants |
| Placebo | Time to First Myocardial Infarction | KM estimate at 24 months | 4.30 percentage of participants |
| Placebo | Time to First Myocardial Infarction | KM estimate at 30 months | 5.25 percentage of participants |
| Placebo | Time to First Myocardial Infarction | KM estimate at 36 months | 6.28 percentage of participants |
| Evolocumab | Time to First Myocardial Infarction | KM estimate at 30 months | 3.83 percentage of participants |
| Evolocumab | Time to First Myocardial Infarction | KM estimate at 6 months | 1.06 percentage of participants |
| Evolocumab | Time to First Myocardial Infarction | KM estimate at 24 months | 3.21 percentage of participants |
| Evolocumab | Time to First Myocardial Infarction | KM estimate at 12 months | 1.90 percentage of participants |
| Evolocumab | Time to First Myocardial Infarction | KM estimate at 36 months | 4.41 percentage of participants |
| Evolocumab | Time to First Myocardial Infarction | KM estimate at 18 months | 2.55 percentage of participants |
Comparison: If the primary, key secondary, and endpoint of cardiovascular death reached a statistical significance level of 0.05, then the endpoint of all-cause death was tested at a significance level of 0.04 and remaining secondary endpoints were tested at an overall significance level of 0.01 by applying the Hochberg method.p-value: <0.000195% CI: [0.65, 0.82]Log Rank
Secondary
Time to First Stroke
All deaths and potential endpoint events were adjudicated by an independent external CEC led by the TIMI Study Group, using standardized definitions based on the Standardized Definitions for Cardiovascular and Stroke End Point Events in Clinical Trials and the Third Universal Definition of Myocardial Infarction. Stroke was defined as an acute episode of focal or global neurological dysfunction caused by brain, spinal cord, or retinal vascular injury as a result of hemorrhage or infarction. Time to first stroke was defined as the time from randomization to the date of the stroke and was analyzed using Kaplan-Meier (KM) survival analysis. KM estimates of the percentage of participants with an event are reported. Participants with no event were censored based on last non-fatal potential endpoint collection date.
Time frame: Events that occurred from randomization to the last confirmed survival status date; the median duration of follow-up was 26 months. KM estimates at 6, 12, 18, 24, 30 and 36 months are reported.
Population: All randomized participants; The number of participants entered at each time point represents the number of participants at risk.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | Time to First Stroke | KM estimate at 6 months | 0.50 percentage of participants |
| Placebo | Time to First Stroke | KM estimate at 12 months | 0.85 percentage of participants |
| Placebo | Time to First Stroke | KM estimate at 18 months | 1.30 percentage of participants |
| Placebo | Time to First Stroke | KM estimate at 24 months | 1.80 percentage of participants |
| Placebo | Time to First Stroke | KM estimate at 30 months | 2.15 percentage of participants |
| Placebo | Time to First Stroke | KM estimate at 36 months | 2.60 percentage of participants |
| Evolocumab | Time to First Stroke | KM estimate at 30 months | 1.71 percentage of participants |
| Evolocumab | Time to First Stroke | KM estimate at 6 months | 0.31 percentage of participants |
| Evolocumab | Time to First Stroke | KM estimate at 24 months | 1.36 percentage of participants |
| Evolocumab | Time to First Stroke | KM estimate at 12 months | 0.70 percentage of participants |
| Evolocumab | Time to First Stroke | KM estimate at 36 months | 2.18 percentage of participants |
| Evolocumab | Time to First Stroke | KM estimate at 18 months | 1.05 percentage of participants |
Comparison: If the primary, key secondary, and endpoint of cardiovascular death reached a statistical significance level of 0.05, then the endpoint of all-cause death was tested at a significance level of 0.04 and remaining secondary endpoints were tested at an overall significance level of 0.01 by applying the Hochberg method.p-value: 0.010195% CI: [0.66, 0.95]Log Rank