Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk - FOURIER
Contribution To Literature:
Highlighted text has been updated as of August 29, 2022.
The FOURIER trial showed that evolocumab was superior to placebo at reducing adverse cardiovascular events.
The goal of the trial was to evaluate the efficacy and safety of evolocumab, a PCSK9 inhibitor, among participants with elevated cardiovascular risk on statin therapy.
Participants with established cardiovascular disease on statin therapy were randomized to evolocumab 140 mg subcutaneous every 2 weeks or 420 mg monthly (n = 13,784) versus placebo every 2 weeks (n = 13,780).
- Total number of enrollees: 27,564 patients
- Duration of follow-up: median 26 months
- Mean patient age: 63 years
- Percentage female: 25%
- Percentage with diabetes: 37%
- Participants with established cardiovascular disease defined as prior myocardial infarction (MI), prior stroke, or symptomatic peripheral artery disease (PAD)
- On statin therapy with low-density lipoprotein cholesterol (LDL-C) ≥70 mg/dl
- MI or stroke within 4 weeks
- New York Heart Association class III or IV heart failure symptoms or left ventricular ejection fraction <30%
- Hemorrhagic stroke
- Uncontrolled ventricular tachycardia
- Planned revascularization within the next 3 months
- Uncontrolled hypertension
- Chronic kidney disease
- Organ transplant
- Major active infection
Other salient features/characteristics:
- 69% were on a high-intensity statin, while 30% were on a moderate-intensity statin
- Median LDL-C = 92 mg/dl
The primary outcome, incidence of cardiovascular death, MI, stroke, hospitalization for unstable angina, or coronary revascularization, occurred in 12.6% of the evolocumab group versus 14.6% of the placebo group (p < 0.0001). This finding was consistent among all tested subgroups. Benefit was enhanced among higher-risk subgroups (those with recent MI, multiple prior MIs, and residual multivessel coronary artery disease) compared to those without such characteristics.
Evolocumab reduced total cardiovascular events (hazard ratio [HR] 0.82, 95% confidence interval [CI] 0.75-0.90, p < 0.001), first cardiovascular events (HR 0.85, 95% CI 0.79-0.92, p < 0.001), and subsequent events (HR 0.74, 95% CI 0.65-0.85).
- Absolute reduction in LDL-C was 56 mg/dl with evolocumab versus placebo (median LDL-C = 30 mg/dl)
- Any serious adverse event: 24.8% with evolocumab versus 24.7% with placebo
- Complex coronary revascularization (>1 of: multivessel percutaneous coronary intervention [PCI], ≥3 stents, ≥3 lesions treated, bifurcation PCI, or total stent length >60 mm) or coronary artery bypass grafting surgery (CABG): evolocumab vs. placebo (HR 0.71, 95% CI 0.61-0.84, p < 0.001)
A proportion of patients underwent cognitive testing (n = 1,204). Among this cohort, there was no difference between evolocumab versus placebo for a battery of cognitive tests, patient-reported everyday cognition, and physician-reported adverse cognitive events.
As the proportion of LDL-C lowering below 40 mg/dl increased, there was no evidence of attenuation in treatment effect (p value for treatment interaction = 0.78). Ten percent of participants had LDL-C <20 mg/dl, while 31% had LDL-C between 20 and 50 mg/dl. There was a linear relationship between LDL-C and adverse cardiovascular events, such that adverse events continued to decline to the lowest levels of LDL-C (p = 0.0012). There was no notable increase in any safety events, including cancer and cognition, with very low LDL-C levels.
Among those with baseline LDL-C <70 mg/dl, evolocumab reduced the primary endpoint (HR 0.80, 95% CI 0.60-1.07) to a similar degree as those with baseline LDL-C ≥70 mg/dl (HR 0.86, 95% CI 0.79-0.92; p = 0.65 for interaction).
PAD subset: A total of 13.2% of patients had established PAD. Patients with PAD had an 81% higher risk of cardiovascular disease/MI/stroke compared with those without (p < 0.001). There was a significant reduction in cardiovascular disease/MI/stroke with evolocumab versus placebo among patients with PAD (9.5% vs. 13.0%, p = 0.004) and those without (6.2% vs. 7.6%, p < 0.001) (p for interaction = 0.41). The absolute risk reduction was greater among PAD patients due to the higher event rates. There was a significant reduction in the incidence of major adverse limb events with evolocumab (0.27% vs. 0.45%, p = 0.0093), with greater net reductions among patients with PAD (1.5% vs. 2.4%). There appeared to be a monotonic relationship between reduction in LDL-C and reduction in adverse limb events (p = 0.026).
Outcomes according to inflammatory risk: Among those with high-sensitivity C-reactive protein <1 mg/dl, 1-3 mg/dl, and >3 mg/dl, there was an absolute reduction in the primary outcome of 1.6%, 1.8%, and 2.7%, respectively.
Genetic risk score: A 27–single-nucleotide polymorphism (SNP) genetic risk score was created to categorize subjects into low-risk, intermediate-risk, and high-risk categories. Major vascular events were increased 14% for those categorized as intermediate-risk vs. low-risk and increased 37% for those categorized as high-risk vs. low-risk.
Major vascular events: Among those without multiple clinical risk factors or genetic high-risk, evolocumab vs. placebo was not associated with risk reduction. Among those with multiple clinical risk factors but without genetic high-risk, evolocumab vs. placebo was associated with a 1.4% absolute risk reduction. Among those with genetic high-risk (irrespective of clinical risk), evolocumab vs. placebo was associated with a 4.0% absolute risk reduction (p for trend = 0.04).
Prevention of stroke: The incidence of any stroke was 1.5% for evolocumab vs. 1.9% for placebo (p = 0.01), the incidence of ischemic stroke was 1.2% for evolocumab vs. 1.6% for placebo (p = 0.005), and the incidence of ischemic stroke or transient ischemic attack (TIA) was 1.7% for evolocumab vs. 2.1% for placebo (p = 0.003).
The association between evolocumab vs. placebo on the primary outcome among subjects with prior stroke (HR 0.85, 95% CI 0.72-1.00) and among subjects with no prior stroke (HR 0.85, 95% CI 0.79-0.93) was similar (p for interaction = 0.91).
Open-label extension (median follow-up, 5 years):
- Primary outcome of cardiovascular death, MI, stroke, unstable angina, or coronary revascularization: HR 0.85 (95% CI 0.75-0.96, p = 0.008)
- Serious adverse events: 10% with long-term use of evolocumab
Among patients with elevated cardiovascular risk on statin therapy, evolocumab versus placebo was effective at reducing adverse cardiovascular events. Evolocumab was associated with marked reductions in LDL-C levels. Serious adverse events were similar between treatment groups. Efficacy for evolocumab was similar among those with very low baseline LDL-C levels. There was a greater absolute reduction in major adverse events for evolocumab versus placebo among those with the highest baseline inflammatory risk and genetically determined high-risk status. PCSK9 inhibition represents a novel approach to lower LDL-C levels and improves cardiovascular outcomes. However, for the duration of follow-up, there was no benefit on cardiovascular or all-cause mortality, and cost remains an issue.
Detailed testing did not reveal any adverse cognitive deficits among the evolocumab group. There were no apparent safety issues with very low achieved LDL-C levels. Long-term use of evolocumab appears safe. The benefit of evolocumab accrues over a median follow-up of >7 years.
Presented by Dr. Michelle O'Donoghue at the European Society of Cardiology Congress (ESC 2022), Barcelona, Spain, August 29, 2022.
Presented by Dr. Nicholas Marston at the European Society of Cardiology Virtual Congress, August 28, 2021.
Oyama K, Furtado RH, Fagundes A, et al. Effect of Evolocumab on Complex Coronary Disease Requiring Revascularization. J Am Coll Cardiol 2021;77:259-67.
Presented by Dr. Kazuma Oyama at the American Heart Association Virtual Scientific Sessions, November 13, 2020.
Giugliano RP, Pedersen TJ, Saver JL, et al., on behalf of the FOURIER Investigators. Stroke Prevention With the PCSK9 (Proprotein Convertase Subtilisin-Kexin Type 9) Inhibitor Evolocumab Added to Statin in High-Risk Patients With Stable Atherosclerosis. Stroke 2020;51:1546-54.
Editorial Comment: Alberts MJ, Thompson PD. PCSK9 (Proprotein Convertase Subtilisin-Kexin Type 9) Inhibition and Stroke Prevention: Another Step Forward. Stroke 2020;51:1361-2.
Marston NA, Kamanu FK, Nordio F, et al. Predicting Benefit From Evolocumab Therapy in Patients With Atherosclerotic Disease Using a Genetic Risk Score: Results From the FOURIER Trial. Circulation 2020;141:616-23.
Presented by Dr. Nicholas A. Marston at the American Heart Association Annual Scientific Sessions (AHA 2019), Philadelphia, PA, November 17, 2019.
Murphy SA, Pedersen TR, Gaciong ZA, et al. Effect of the PCSK9 Inhibitor Evolocumab on Total Cardiovascular Events in Patients With Cardiovascular Disease: A Prespecified Analysis From the FOURIER Trial. JAMA Cardiol 2019;May 22:[Epub ahead of print].
Sabatine MS, De Ferrari GM, Giugliano RP, et al. Clinical Benefit of Evolocumab by Severity and Extent of Coronary Artery Disease: An Analysis From FOURIER. Circulation 2018;Apr 6:[Epub ahead of print].
Bohula EA, Giugliano RP, Leiter LA, et al. Inflammatory and Cholesterol Risk in the FOURIER Trial (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Patients With Elevated Risk). Circulation 2018;Mar 12:[Epub ahead of print].
Presented by Dr. Erin A. Bohula at the American College of Cardiology Annual Scientific Session (ACC 2018), Orlando, FL, March 12, 2018.
Giugliano RP, Keech A, Murphy SA, et al. Clinical Efficacy and Safety of Evolocumab in High-Risk Patients Receiving a Statin: Secondary Analysis of Patients With Low LDL Cholesterol Levels and in Those Already Receiving a Maximal-Potency Statin in a Randomized Clinical Trial. JAMA Cardiol 2017;2:1385-91.
Bonaca MP, Nault P, Giugliano RP, et al. Low-Density Lipoprotein Cholesterol Lowering With Evolocumab and Outcomes in Patients With Peripheral Artery Disease: Insights From the FOURIER Trial (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk). Circulation 2017;Nov 13:[Epub ahead of print].
Presented by Drs. Marc C. Bonaca and Marc S. Sabatine at the American Heart Association Annual Scientific Sessions (AHA 2017), Anaheim, CA, November 13, 2017.
Giugliano RP, Pedersen TR, Park JG, et al., on behalf of the FOURIER Investigators. Clinical efficacy and safety of achieving very low LDL-cholesterol concentrations with the PCSK9 inhibitor evolocumab: a prespecified secondary analysis of the FOURIER trial. Lancet 2017;390:1962-71.
Presented by Dr. Robert P. Giugliano at the European Society of Cardiology Congress, Barcelona, Spain, August 28, 2017.
Sabatine MS, Giugliano RP, Keech AC, et al., on behalf of the FOURIER Steering Committee and Investigators. Evolocumab and Clinical Outcomes in Patients with Cardiovascular Disease. N Engl J Med 2017;376:1713-22.
Editorial: Dullaart RP. PCSK9 Inhibition to Reduce Cardiovascular Events. N Engl J Med 2017;376:1790-1.
Presented by Dr. Marc S. Sabatine at the American College of Cardiology Annual Scientific Session (ACC 2017), Washington, DC, March 17, 2017.
Giugliano RP, Mach F, Zavitz K, et al., on behalf of the EBBINGHAUS Investigators. Cognitive Function in a Randomized Trial of Evolocumab. N Engl J Med 2017;377:633-43.
EBBINGHAUS: Presented by Dr. Robert P. Giugliano at the American College of Cardiology Annual Scientific Session (ACC 2017), Washington, DC, March 18, 2017.
Clinical Topics: Diabetes and Cardiometabolic Disease, Dyslipidemia, Invasive Cardiovascular Angiography and Intervention, Prevention, Vascular Medicine, Atherosclerotic Disease (CAD/PAD), Lipid Metabolism, Nonstatins, Novel Agents, Statins, Interventions and Vascular Medicine
Keywords: AHA Annual Scientific Sessions, AHA20, AHA19, ACC18, ACC17, ACC Annual Scientific Session, ESC Congress, ESC22, ESC21, ESC2017, Angina, Unstable, Antibodies, Monoclonal, Cholesterol, Cholesterol, LDL, Dyslipidemias, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Lipoproteins, Metabolic Syndrome, Myocardial Infarction, Percutaneous Coronary Intervention, Peripheral Arterial Disease, Primary Prevention, Proprotein Convertases, Stroke, Subtilisins, Cognition, Inflammation, Vascular Diseases
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