Acute Coronary Syndrome
Conditions
Brief summary
Reduction of low-density lipoprotein cholesterol (LDL-C) levels effectively reduces the risk of adverse events in patients with established atherosclerotic cardiovascular disease. The clinical benefit of statins in improving clinical outcomes is proportional to the magnitude of LDL-C reduction, is more pronounced in patients with acute coronary syndromes (ACS) compared with stable coronary artery disease, and emerges at very early stages (as early as 4 weeks) after ACS when statins are administered in the acute phase of the event. On the basis of this evidence, early initiation of statin therapy is currently recommended in patients presenting with ACS. Because many patients cannot achieve adequate reduction of LDL-C levels despite treatment with high doses of statins or non-statin lipid-modifying medications, substantial residual risk remains. Moreover, the time of onset of LDL-C reduction takes 2 weeks following initiation of statin therapy. Proprotein convertase subtilisin/kexin type-9 (PCSK9) inhibitors represent a novel class of lipid-lowering drugs leading to rapid, profound, and consistent reductions in LDL-C levels. While the effectiveness of PCSK9 monoclonal antibodies for LDL-C lowering has been established across patient populations without atherosclerotic cardiovascular disease or with stable ischemic heart disease, reduction and attainment of LDL-C target levels has not been explored in the acute setting of ACS - a clinical setting with highest risk of early event recurrence (within the first month). In this study the investigators want to evaluate the safety and effectiveness of the PCSK9 inhibitor evolocumab as compared with placebo, administered in the acute phase of ACS, for reduction of LDL-C levels within 8 weeks in patients receiving guideline-recommended high-intensity statin treatment (atorvastatin 40mg QD).
Interventions
Three injections with pre-filled auto-injector pen at day 1 and at week 4.
DRUGPlacebo
Three injections with pre-filled auto-injector pen at day 1 and at week 4.
Sponsors
Amgen
University of Bern
Insel Gruppe AG, University Hospital Bern
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Male or female ≥ 18 years of age; * Hospitalized for a recent ACS; * LDL-C levels defined as follows: * LDL-C ≥70 mg/dL (≥1.8 mmol/L) or non-HDL-C ≥100 mg/dL (≥2.6 mmol/) in patients who have been receiving stable treatment with high-intensity statin within ≥ 4 weeks prior to enrollment (i.e. continuous treatment that has not changed with regard to statin intensity over the past 4 weeks) or, LDL-C ≥90 mg/dL (≥2.3 mmol/L) or non-HDL-C ≥120 mg/dL (≥3.1 mmol/) in patients who have been receiving stable treatment with low- or moderate-intensity statin within ≥ 4 weeks prior to enrollment (i.e. continuous treatment that has not changed with regard to statin intensity over the past 4 weeks), or LDL-C ≥125 mg/dL (≥3.2 mmol/L) or non-HDL-C ≥155 mg/dL (≥4.0 mmol/) in patients who are statin-naïve or have not been on a stable (unchanged) statin regimen for at least 4 weeks prior to enrollment; * Ability to understand the requirements of the study and to provide informed consent.
Exclusion criteria
* Unstable clinical status (hemodynamic or electrical instability; * Uncontrolled cardiac arrhythmia, defined as recurrent and symptomatic ventricular tachycardia or atrial fibrillation with rapid ventricular response not controlled by medications in the past 3 months prior to screening; * Severe renal dysfunction, defined by estimated glomerular filtration rate \<30 ml/min/1.73m2; * Active liver disease or hepatic dysfunction, either reported in patient medical record or defined by asparate aminotransferase (AST) or alanine aminotransferase (ALT) levels \> 3x the upper limit of normal; * Reported intolerance to atorvastatin (any dose) OR statin intolerance; * Known allergy to contrast medium, heparin, aspirin, ticagrelor or prasugrel; * Known sensitivity to any substances to be administered; * Patients who previously received evolocumab or other PCSK9 inhibitor; * Patient who received cholesterol ester transfer protein inhibitors in the past 12 months prior to screening; * Treatment with systemic steroids or systemic cyclosporine in the past 3 months systemic cyclosporine, systemic steroids (eg. intravenous, intramuscular or per os); * Known active infection or major hematologic, metabolic, or endocrine dysfunction in the judgment of the Investigator; * Patients who will not be available for study-required procedures in the judgment of the Investigator; * Current enrollment in another investigational device or drug study; * Active malignancy requiring treatment; * Female of childbearing potential (age \<50 years and last menstruation within the last 12 months), who did not undergo tubal ligation, ovariectomy or hysterectomy.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Percent change in calculated LDL-C in the intent to treat (ITT) population | Baseline to week 8 |
Secondary
| Measure | Time frame |
|---|---|
| Number of patients with adverse events and serious adverse events | Baseline to week 8 |
Other
| Measure | Time frame | Description |
|---|---|---|
| Change in high-sensitivity Troponin T | Baseline to 72 hours | — |
| Nominal change in calculated LDL-C | Baseline to week 8 | — |
| Proportion of patients with LDL-C level <70 mg/dL (<1.8 mmol/L) at week 8 | Baseline to week 8 | — |
| Change in total cholesterol in the ITT population | Baseline to week 8 | — |
| Change in HDL-C in the ITT population | Baseline to week 8 | — |
| Change in lipoprotein-a in the ITT population | Baseline to week 8 | — |
| Change in triglycerides in the ITT population | Baseline to week 8 | — |
| Change in non-HDL-C in the ITT population | Baseline to week 8 | — |
| Proportion of patients with LDL-C <70 mg/dL and hs-CRP <2 mg/dL at week 8 in the ITT population | Baseline to week 8 | — |
| Change in apolipoprotein A-1 in the ITT population | Baseline to week 8 | — |
| Percent change in high-sensitivity CRP (hs-CRP) in the ITT population | Baseline to week 8 | — |
| Proportion of patients with hs-CRP level <2 mg/dL at week 8 in the ITT population | Baseline to week 8 | — |
| Area under the curve (AUC) at Multiplate with Adenosinediphosphate (ADP) test | Baseline to 72 hours and to week 8 | Platelet inhibition assessed with Multiplate ADP test at 72 hours and 8 weeks |
| Area under the curve (AUC) at Multiplate with Thrombin receptor activating peptide (TRAP) test | Baseline to 72 hours and to week 8 | Platelet inhibition assessed with Multiplate TRAP test at 72 hours and 8 weeks |
| Number of patients with contrast-induced acute kidney injury (CI-AKI) at 72 hours among patients who undergo coronary angiography at baseline | Baseline to 72 hours | — |
| Number of patients with adjudicated events (death, cardiovascular death, myocardial infarction, hospitalization for recurrent ACS, hospitalization for heart failure, coronary revascularization, stroke | Baseline to week 8 | — |
| Change in apolipoprotein B in the ITT population | Baseline to week 8 | — |
| Nominal change in Interleukin (IL)-1b and IL-6 in the ITT population | Baseline to week 8 | — |
Countries
Switzerland
Outcome results
None listed