Evolocumab Treatment in Pediatric Patients With Homozygous Familial Hypercholesterolemia: Pooled Data From Three Open-Label Studies.

BACKGROUND: Pediatric patients with homozygous familial hypercholesterolemia (HoFH) have an increased risk of atherosclerotic cardiovascular disease and difficulty meeting low-density lipoprotein cholesterol (LDL-C) goals. In this post hoc analysis, we evaluated pooled safety and efficacy data from 3 studies in pediatric patients with HoFH treated with the PCSK9 (proprotein convertase subtilisin/kexin type 9) monoclonal antibody inhibitor evolocumab. METHODS: Patients with HoFH aged 10 to 17 years received treatment with open-label evolocumab 420 mg subcutaneously monthly or biweekly in the TAUSSIG, RAMAN, or HAUSER-OLE clinical studies. All patients received background statins with or without ezetimibe. Study duration ranged from 12 to 260 weeks. The primary end point was treatment-emergent adverse events per 100 patient-years. Efficacy end points were changes from baseline to week 12 in lipids and PCSK9. RESULTS: Of the 39 patients in the pooled analysis, 69.2% were males, median age was 13.0 years, and 79.5% (31/39) had genotyped HoFH with LDLR pathogenic variants. Overall, median exposure to evolocumab was 18.2 (Q1, Q3: 3.0, 18.5) months. Treatment-emergent adverse events with an exposure-adjusted patient incidence rate of ≥5% were upper respiratory tract infection (6.6%), influenza (5.2%), and acne (5.0%) per 100 patient-years. Exposure-adjusted patient incidence of serious treatment-emergent adverse events was 13.3% per 100 patient-years. Excluding 4 patients receiving lipoprotein apheresis, week 12 median percentage change from baseline in LDL-C was -2.9% (Q1, Q3: -21.7, 1.5); however, 42.9% (15/35) of patients achieved ≥15% reduction in LDL-C from baseline. Residual LDLR (LDL receptor) activity was not associated with a reduction in LDL-C. CONCLUSIONS: In this pooled data analysis from 3 studies in pediatric patients with HoFH, evolocumab was well tolerated, with no new safety signals reported. These safety findings are consistent with findings from previous studies of evolocumab. Patients showed marked variability in LDL-C reduction. Results from this pooled analysis support guidelines suggesting a trial of PCSK9 inhibitor therapy regardless of estimated residual LDLR function. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01624142, NCT03403374, and NCT02624869.

Cardiovascular outcomes in patients with coronary artery disease and elevated lipoprotein(a): implications for the OCEAN(a)-outcomes trial population.

Aims: The ongoing Olpasiran Trials of Cardiovascular Events and Lipoprotein(a) Reduction [OCEAN(a)]-Outcomes trial is evaluating whether Lp(a) lowering can reduce the incidence of cardiovascular events among patients with prior myocardial infarction (MI) or percutaneous coronary intervention (PCI) and elevated Lp(a) (≥200 nmol/L). The purpose of this study is to evaluate the association of elevated Lp(a) with cardiovascular outcomes in an observational cohort resembling the OCEAN(a)-Outcomes trial main enrolment criteria. Methods and results: This study included patients aged 18-85 years with Lp(a) measured as part of their clinical care between 2000 and 2019. While patients were required to have a history of MI, or PCI, those with severe kidney dysfunction or a malignant neoplasm were excluded. Elevated Lp(a) was defined as ≥200 nmol/L consistent with the OCEAN(a)-Outcomes trial. The primary outcome was a composite of coronary heart disease death, MI, or coronary revascularization. Natural language processing algorithms, billing and ICD codes, and laboratory data were employed to identify outcomes and covariates. A total of 3142 patients met the eligibility criteria, the median age was 61 (IQR: 52-73) years, 28.6% were women, and 12.3% had elevated Lp(a). Over a median follow-up of 12.2 years (IQR: 6.2-14.3), the primary composite outcome occurred more frequently in patients with versus without elevated Lp(a) [46.0 vs. 38.0%, unadjHR = 1.30 (95% CI: 1.09-1.53), P = 0.003]. Following adjustment for measured confounders, elevated Lp(a) remained independently associated with the primary outcome [adjHR = 1.33 (95% CI: 1.12-1.58), P = 0.001]. Conclusion: In an observational cohort resembling the main OCEAN(a)-Outcomes Trial enrolment criteria, patients with an Lp(a) ≥200 nmol/L had a higher risk of cardiovascular outcomes.

Association Between Achieved Low-Density Lipoprotein Cholesterol Levels and Long-Term Cardiovascular and Safety Outcomes: An Analysis of FOURIER-OLE.

BACKGROUND: Low-density lipoprotein cholesterol (LDL-C) is a well-established risk factor for atherosclerotic cardiovascular disease. However, the optimal achieved LDL-C level with regard to efficacy and safety in the long term remains unknown. METHODS: In FOURIER (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk), 27 564 patients with stable atherosclerotic cardiovascular disease were randomized to evolocumab versus placebo, with a median follow-up of 2.2 years. In the open-label extension (FOURIER-OLE), 6635 of these patients were transitioned to open-label evolocumab regardless of initial treatment allocation in the parent trial and were followed for an additional median of 5 years. In this prespecified analysis, we examined the relationship between achieved LDL-C levels (an average of the first 2 LDL-C levels measured) in FOURIER-OLE (available in 6559 patients) and the incidence of subsequent cardiovascular and safety outcomes. We also performed sensitivity analyses evaluating cardiovascular and safety outcomes in the entire FOURIER and FOURIER-OLE patient population. Multivariable modeling was used to adjust for baseline factors associated with achieved LDL-C levels. RESULTS: In FOURIER-OLE, 1604 (24%), 2627 (40%), 1031 (16%), 486 (7%), and 811 (12%) patients achieved LDL-C levels of <20, 20 to <40, 40 to <55, 55 to <70, and ≥70 mg/dL, respectively. There was a monotonic relationship between lower achieved LDL-C levels-down to very low levels <20 mg/dL-and a lower risk of the primary efficacy end point (composite of cardiovascular death, myocardial infarction, stroke, hospital admission for unstable angina or coronary revascularization) and the key secondary efficacy end point (composite of cardiovascular death, myocardial infarction, or stroke) that persisted after multivariable adjustment (adjusted Ptrend<0.0001 for each end points). No statistically significant associations existed in the primary analyses between lower achieved LDL-C levels and increased risk of the safety outcomes (serious adverse events, new or recurrent cancer, cataract-related adverse events, hemorrhagic stroke, new-onset diabetes, neurocognitive adverse events, muscle-related events, or noncardiovascular death). Similar findings were noted in the entire FOURIER and FOURIER-OLE cohort up to a maximum follow-up of 8.6 years. CONCLUSIONS: In patients with atherosclerotic cardiovascular disease, long-term achievement of lower LDL-C levels, down to <20 mg/dL (<0.5 mmol/L), was associated with a lower risk of cardiovascular outcomes with no significant safety concerns. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT01764633.

Long-Term Evolocumab in Patients With Familial Hypercholesterolemia.

BACKGROUND: Proprotein convertase subtilisin/kexin type 9 inhibitor therapy is a treatment option for patients with familial hypercholesterolemia (FH) who are unable to reach low-density lipoprotein cholesterol (LDL-C) goals. OBJECTIVES: The aim of this study was to provide long-term safety and efficacy data for evolocumab in patients with homozygous FH (HoFH) and severe heterozygous FH (HeFH). METHODS: In this open-label, single-arm study, patients with HoFH or severe HeFH ≥12 years of age and on stable lipid-lowering therapy began subcutaneous evolocumab 420 mg monthly or 420 mg every 2 weeks if on lipoprotein apheresis. After 12 weeks, those not on apheresis could be up-titrated to 420 mg every 2 weeks. The primary endpoint was the incidence of treatment-emergent adverse events; secondary endpoints were changes in LDL-C and other lipids. RESULTS: In total, 300 patients (106 with HoFH, including 14 <18 years of age at enrollment) received evolocumab for a median of 4.1 years. Adverse events occurred in 89.3% of patients, the most common of which were nasopharyngitis, influenza, upper respiratory tract infection, and headache. Mean change in LDL-C from baseline to week 12 was -21.2% (-59.8 mg/dl) in patients with HoFH and -54.9% (-104.4 mg/dl) in those with severe HeFH and was sustained over time. Of 48 patients with HoFH who were up-titrated, mean change in LDL-C improved from -19.6% at week 12 to -29.7% after 12 weeks of 420 mg every 2 weeks. The adjudicated cardiovascular event rate was 2.7% per year. Of 61 patients receiving apheresis at enrollment, 16 discontinued apheresis. CONCLUSIONS: Evolocumab was well tolerated and effectively reduced plasma LDL-C levels in patients with HoFH and severe HeFH over a median of 4.1 years.

Familial Hypercholesterolemia Among Young Adults With Myocardial Infarction.

BACKGROUND: There are limited data on the prevalence and treatment of familial hypercholesterolemia (FH) among U.S. adults who experience a myocardial infarction (MI) at a young age. OBJECTIVES: This study aimed to evaluate the prevalence of clinically defined FH and examine the rates of statin utilization and low-density lipoprotein cholesterol (LDL-C) achieved 1-year post MI. METHODS: The YOUNG-MI registry is a retrospective cohort study that includes patients who experience an MI at or below age 50 years between 2000 and 2016 at 2 academic centers. Probable or definite FH was defined by the Dutch Lipid Clinic criteria. Outcomes included the proportion of patients classified as probable or definite FH, use of lipid-lowering therapy, and LDL-C achieved 1-year post MI. RESULTS: The cohort consisted of 1,996 adults with a median age of 45 years; 19% were women, and 54% had ST-segment elevation MI. Probable/definite FH was present in 180 (9%) of whom 42.8% were not on statins prior to their MI. Of the 1,966 patients surviving until hospital discharge, 89.4% of FH patients and 89.9% of non-FH patients were discharged on statin therapy (p = 0.82). Among FH patients, 63.3% were discharged on high-intensity statin compared with 48.4% for non-FH patients (p < 0.001). At 1-year follow-up, the percent reduction in LDL-C among FH patients was -44.4% compared with -34.5% (p = 0.006) in non-FH patients. The proportion of patients with LDL-C ≥70 mg/dl was higher among FH patients (82.2%) compared with non-FH patients (64.5%; p < 0.001). CONCLUSIONS: Clinically defined FH was present in nearly 1 of 10 patients with MI at a young age. Only two-thirds of FH patients were discharged on high-intensity statin therapy, and the vast majority had elevated LDL-C at 1 year. These findings reinforce the need for more aggressive lipid-lowering therapy in young FH and non-FH patients post-MI.

Residual atherosclerotic cardiovascular disease risk in statin-treated adults: The Multi-Ethnic Study of Atherosclerosis.

BACKGROUND: Residual atherosclerotic cardiovascular disease (ASCVD) risk in statin-treated US adults without known ASCVD is not well described. OBJECTIVE: To quantitate residual ASCVD risk and its predictors in statin-treated adults. METHODS: We studied 1014 statin-treated adults (53.3% female, mean 66.0 years) free of clinical ASCVD in the Multi-Ethnic Study of Atherosclerosis. We examined ASCVD event rates by National Lipid Association risk groups over 11-year follow-up and the relation of standard risk factors, biomarkers, and subclinical atherosclerosis measures with residual ASCVD event risk. RESULTS: Overall, 5.3% of participants were at low, 12.2% at moderate, 60.3% at high, and 22.2% at very high baseline risk. Despite statin therapy, age- and race-standardized ASCVD rates per 1000 person-years for men and women were both 4.9 for low/moderate risk, 19.1 and 14.2 for high risk, and 35.6 and 26.7 for very high risk, respectively. Specific independent predictors of residual risk included current smoking, family history, diabetes, high-sensitivity C-reactive protein, low-density lipoprotein particle number, carotid intimal medial thickness, and especially coronary artery calcium score. Those on moderate- or high-intensity statins at baseline (compared with low intensity) had 39% lower risks and those who increased statin intensity 62% lower ASCVD event risks (P < .01). CONCLUSION: Residual risk of ASCVD remains high despite statin treatment and is predicted by specific risk factors and subclinical atherosclerosis. These findings may be helpful for identifying those at highest risk needing more aggressive treatment.