Real-life experience with PCSK9 inhibition in familial hypercholesterolaemia
Familial hypercholesteraemia (FH, inherited high cholesterol) is one of the key groups for whom PCSK9 inhibition is indicated. This prospective registry provided data on 44 patients with genetically verified FH attending a specialist lipid clinic in Norway.
On maximal conventional lipid lowering therapy (statin plus ezetimibe), LDL cholesterol levels were 3.7 ±1.9 mmol/L, but still above recommended goals. Addition of PCSK9 monoclonal antibody therapy led to reductions of LDL cholesterol by 54% to 1.7 (1.2) mmol/L (p<0.001) after one month, 62% to 1.4 (0.9) mmol/L (p<0.001) after 3 months, and 54% to 1.7 (1.6) mmol/L (p<0.001) after one year. After 1 year 71% of patients attained an LDL cholesterol level <1.8 mmol/L. The most commonly reported adverse events were fatigue (12%), and abdominal symptoms, skin reactions, nasopharyngitis, flu-like symptoms (each reported by 5% of patients). Five (11 %) patients missed one or more doses of PCSK9-inhibition.
In conclusion, PCSK9 inhibition was efficacious and generally well tolerated in a real-life setting in patients with FH. Regular follow-up is recommended to maximise compliance.
Graesdal A, Dybvig A. Real-Life PCSK9 Experience: Efficacy, Compliance and Side Effects After One Year Treatment in Familial Hypercholesterolemia Patients. 67th Scientific Sessions of the American College of Cardiology, 10th March 2018. Orlando. Florida. Abstract 1129-402.
High cardiovascular risk in patients denied PCSK9 inhibitor therapy
Nearly 2 in 3 prescriptions for PCSK9 inhibitor therapy are rejected in high-risk patients in the USA, according to this retrospective cohort study.
The study evaluated data from 3,472 patients (mean age 58 years, 57% males) requesting access to evolocumab and/or alirocumab in the QuintilesIMS Formulary Impact Analyzer (FIA) database between January 2016 to January 2017. Overall, 64% of prescriptions for PCSK9 inhibitor were denied; these patients had a significantly higher risk of an acute cardiovascular event, defined as myocardial infarction, ischaemic stroke, hospitalisation for unstable angina, and coronary revascularization (7.29 per 100 patient years versus 6.73 per 100 patient years overall).
In conclusion, these findings suggest the renewed efforts to ensure that PCSK9 inhibitor therapy is targeted appropriately in high risk patients to avoid the high risk of a major cardiovascular event with serious implications for clinical outcomes that impact patients’ lives.
Baum SJ, Chen CC, Rane P et al. Cardiovascular Risk in Patients Denied Access to PCSK9i Therapy. 67th Scientific Sessions of the American College of Cardiology, 10th March 2018. Orlando. Florida. Abstract 1129-408.
Unmet clinical needs in ASCVD patients: GOULD registry
According to the Getting to an imprOved Understanding of Low-Density Lipoprotein Cholesterol and Dyslipidemia Management (GOULD) registry of high risk patients with atherosclerotic cardiovascular disease (ASCVD), less than 50% are on high-intensity statin therapy, as recommended by clinical guidelines.
The GOULD registry is a prospective US database describing LDL cholesterol treatment patterns over time in patients with clinical ASCVD receiving lipid lowering therapy. Data from 2397 (mean age 68 years, 60% male, mean LDL cholesterol at entry 89 mg/dl) of a planned 5000 patients indicate that only 75% are receiving statin therapy, less than half on high intensity statins. In addition, ezetimibe treatment was prescribed in less than 10% of patients.
In 295 patients who received a PCSK9 inhibitor, 40% received this alone, suggesting that statin intolerance is a problematic in a substantial proportion of ASCVD patients. Moreover, only 5% of patients were prescribed a PCSK9 inhibitor on top of statin plus ezetimibe, as conventional recommended by clinical guidelines.
In conclusion, these early findings from the GOULD registry highlight the need for improvement in the management of ASCVD patients, both with respect to conventional lipid lowering therapy and the use of PCSK9 inhibition.
Cannon CP, de Lemos J, Rosenson R et al. Getting to an imprOved Understanding of Low-Density Lipoprotein Cholesterol and Dyslipidemia Management (GOULD): A Registry of High Cardiovascular Risk Patients in the United States. 67th Scientific Sessions of the American College of Cardiology, 10th March 2018. Orlando. Florida. Abstract 1129-415.
The Wits Find-FH Program: Addressing the paucity of data on familial hypercholesterolaemia in black individuals in South Africa
Studies confirm a high prevalence of familial hypercholesterolemia (FH, inherited high cholesterol) in the white and coloured Afrikaner population, the Indian population and the Ashkenazi Jews in South Africa. Yet data for FH prevalence in African populations, both in South Africa and the rest of the Sub-Saharan Africa are lacking. These findings therefore provide a rationale for the Wits Find-FH Program.
To date, 310 family members were screened and 236 suspected FH cases identified, including black and Indian families. Next generation sequencing was performed in these subjects suspected of FH; 130/236 (55.1%) were confirmed with a mutation consistent with FH including 16/236 (6.8%) with homozygous, compound heterozygous or double heterozygous FH. In these patients, mean LDL cholesterol was 188.9 ± 86.4 mg/dL; this compares with a mean LDL cholesterol of 136.4 ± 41.3 mg/dl in those without any variant identified. Five black patients were identified with suspected FH, four of whom had FH-causative mutations identified (all LDLR variants).
The Wits Find-FH Program will hopefully help to address the underrepresentation of African patients in lipid clinics. Whether this is due to lack of awareness, incorrect diagnosis and/or loss-of-function mutations in PCSK9 as described in African Americans, warrants further study.
Raal F, Stevens B, du Toit R et al. Detection of Familial Hypercholesterolemia in South Africa Via Cascade Screening: The Wits Find-FH Program. 67th Scientific Sessions of the American College of Cardiology, 10th March 2018. Orlando. Florida. Abstract 1129-416.
More insights from GLAGOV: Sex differences in regression rates with evolocumab
GLAGOV (Global Assessment of Plaque Regression With a PCSK9 Antibody as Measured by Intravascular Ultrasound) compared the effects of treatment for 78 weeks with evolocumab or placebo on progression of coronary atherosclerosis, measured by serial intravascular ultrasonography, in statin-treated patients with coronary artery disease.1 In this analysis, plaque burden and progression were compared between men (n=614) and women (n=232) at baseline.
At baseline, female patients were older (61.7 vs 58.8 years, p<0.001), more likely to have hypertension (89.2% vs 79.5%, p=0.001), two or more risk factors at baseline (77.2% vs 66.4%, p=0.003) and low HDL-cholesterol (49.6% vs 39.1%, p=0.006) than male patients. Moreover, despite a lower atherosclerotic burden in female patients at baseline (percent atheroma volume 32.4% vs. 38.0% in male patients, p<0.001), atherosclerotic regression was greater on evolocumab treatment (-1.4 vs. -0.8%, p=0.03). These findings may reflect potential gender related differences in the modifiability of coronary atherosclerosis and warrant further study.
Professor Stephen Nicholls (South Australian Health & Medical Research Institute, Adelaide, Australia) gives his interpretation of these findings.
- Nicholls SJ, Puri R, Anderson T et al. Effect of Evolocumab on Progression of Coronary Disease in Statin-Treated Patients: The GLAGOV Randomized Clinical Trial. JAMA. 2016 Dec 13;316(22):2373-2384 PUBMED https://www.ncbi.nlm.nih.gov/pubmed/27846344
King P, Puri R, Ballantyne C et al. Sex-Related Difference in the Regression of Coronary Atherosclerosis With the PCSK9 Inhibitor, Evolocumab: Insights From GLAGOV. 67th Scientific Sessions of the American College of Cardiology, 10th March 2018. Orlando. Florida. Abstract 1115-271.
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