Improved lipid-lowering treatment and reduction in cardiovascular disease burden in homozygous familial hypercholesterolemia: The SAFEHEART follow-up study.

AIM: We aimed to describe clinical and genetic characteristics, lipid-lowering treatment and atherosclerotic cardiovascular disease (ASCVD) outcomes over a long-term follow-up in homozygous familial hypercholesterolemia (HoFH). METHODS: SAFEHEART (Spanish Familial Hypercholesterolaemia Cohort Study) is a long-term study in molecularly diagnosed FH. Data analyzed in HoFH were prospectively obtained from 2004 until 2022. ASCVD events, lipid profile and lipid-lowering treatment were determined. RESULTS: Thirty-nine HoFH patients were analyzed. The mean age was 42 ± 20 years and nineteen (49%) were women. Median follow-up was 11 years (IQR 6,18). Median age at genetic diagnosis was 24 years (IQR 8,42). At enrolment, 33% had ASCVD and 18% had aortic valve disease. Patients with new ASCVD events and aortic valve disease at follow-up were six (15%), and one (3%), respectively. Median untreated LDL-C levels were 555 mg/dL (IQ 413,800), and median LDL-C levels at last follow-up was 122 mg/dL (IQR 91,172). Most patients (92%) were on high intensity statins and ezetimibe, 28% with PCSK9i, 26% with lomitapide, and 23% with lipoprotein-apheresis. Fourteen patients (36%) attained an LDL-C level below 100 mg/dL, and 10% attained an LDL-C below 70 mg/dL in secondary prevention. Patients with null/null variants were youngers, had higher untreated LDL-C and had the first ASCVD event earlier. Free-event survival is longer in patients with defective variant compared with those patients with at least one null variant (p=0.02). CONCLUSIONS: HoFH is a severe life threating disease with a high genetic and phenotypic variability. The improvement in lipid-lowering treatment and LDL-C levels have contributed to reduce ASCVD events.

Concentration of low-density lipoproteins (LDL) is significantly reduced after nilotinib discontinuation.

Dyslipidemia is a frequent side effect associated with nilotinib treatment. Patients with chronic myeloid leukemia (CML) under treatment with nilotinib who develop dyslipidemia have been shown to have a higher risk of presenting atherosclerotic cardiovascular disease (ACVD). Therapeutic discontinuation in selected individuals could be a strategy in order to prevent the development of ACVD. Observational study of patients with CML under nilotinib treatment. The lipid values were gathered before starting with nilotinib and after 3 months. Such values were also measured before discontinuation in patients who suspended nilotinib treatment, as well as 3 and 12 months later. 32 patients were included, 19 of them treated in monotherapy with nilotinib. The concentrations of total cholesterol and low-density lipoproteins (LDL) increased significantly after 3 months of treatment (27.29 mg/dL ± 22.88, p < 0.01). Of the total number of patients treated, 12 discontinued the treatment. LDL concentration was significantly reduced after 3 months of the nilotinib discontinuation (- 27.58 mg/dL ± 38.30, p = 0.030), remaining substantially lower after 12 months, compared to the time previous to discontinuation (- 24.58 mg/dL ± 37.31, p = 0.043). Nilotinib suspension reduces significantly LDL concentrations. These data support the strategy of therapeutic discontinuation in order to prevent future cardiovascular complications, especially in patients with prior cardiovascular risk factors.

Persistence with long-term PCSK9 inhibitor treatment and its effectiveness in familial hypercholesterolaemia: data from the SAFEHEART study.

AIMS: Most heterozygous familial hypercholesterolaemia (FH) patients require intensive lipid-lowering therapy (LLT) including PCSK9 inhibitors (PCSK9is) to reach current low-density lipoprotein cholesterol (LDL-C) goals. Persistence with chronic treatment is important to reduce the burden of atherosclerotic cardiovascular disease. We analysed persistence, efficacy, and impact on quality of life (QoL) of PCSK9i in FH patients in clinical practice setting. METHODS AND RESULTS: Spanish Familial Hypercholesterolaemia Cohort Study (SAFEHEART) is an open, prospective study in genetically defined FH patients in Spain. Patients ≥18 years of age (n = 696, 46% females) on stable LLT treated with PCSK9i were analysed. Median LDL-C at starting PCSK9i was 145 mg/dL [interquartile range (IQR), 123-177], 3.8 mmol/L (IQR 3.2-4.6). After a median follow up of 3.7 years (IQR 2.3-4.8), 27 patients (4%) discontinued PCSK9i treatment: 5 temporarily (0.7%) and 22 permanently (3.2%). Persistence with PCSK9i was 96.1% in the whole period. Median LDL-C levels and % LDL-C reduction attained after 1 year of treatment and in the last follow-up visit were 63 mg/dL (IQR 43-88), 1.6 mmol/L (IQR 1.1-2.23); 61 mg/dL (IQR 44-82), 1.6 mmol/L (IQR 1.1-2.1); 57.6% (IQR 39.5-69); and 58% (IQR 44-68), respectively. 2016 and 2019 ESC/EAS LDL-C goals were attained by 77 and 48% of patients, respectively, at the last follow-up visit (P < 0.001). Mean QoL score increased slightly in the first year and remained stable. CONCLUSION: Long-term persistence with PCSK9i in FH patients is very high, with a good QoL. Effectiveness in LDL-C reduction and LDL-C goal achievement dramatically improved with PCSK9i in this high-risk population in clinical practice setting. TRIAL REGISTRATION: ClinicalTrials.gov number NCT02693548.

Combining familial hypercholesterolemia and statin genetic studies as a strategy for the implementation of pharmacogenomics. A multidisciplinary approach.

The diagnostic process of familial hypercholesterolemia frequently involves the use of genetic studies. Patients are treated with lipid-lowering drugs, frequently statins. Although pharmacogenomic clinical practice guidelines focusing on genotype-based statin prescription have been published, their use in routine clinical practice remains very modest.We have implemented a new NGS strategy that combines a panel of genes related to familial hypercholesterolemia with genomic regions related to the pharmacogenomics of lipid-lowering drugs described in clinical practice guidelines and in EMA and FDA drug labels. A multidisciplinary team of doctors, biologists, and pharmacists creates a clinical report that provides diagnostic and therapeutic findings using a knowledge management and clinical decision support system, as well as an algorithm for treatment selection.For 12 months, a total of 483 genetic diagnostic studies for familial hypercholesterolemia were carried out, of which 221 (45.8%) requested a complementary pharmacogenomic test. Of these 221 patients, 66.5% were carriers of actionable variants in any of the studied pharmacogenomic pathways: 46.6% of patients in one pathway, 19.0% in two pathways, and 0.9% in three pathways. 45.7% of patients could have a response to atorvastatin different from that of the reference population, 45.7% for simvastatin and lovastatin, 29.0% for fluvastatin, and 6.7% patients for pitavastatin.This implementation approach facilitates the incorporation of pharmacogenomic studies in clinical care practice, it does not add complexity nor additional steps to laboratory processes, and improves the pharmacotherapeutic process of patients.

Arterial hypertension assessment in a population with chronic myeloid leukemia.

Treatment of chronic myeloid leukaemia (CML) is based on tyrosine kinase inhibitors (TKI), whose introduction in 2001 improved the survival rate after 5 years from 40 to 90%. The longevity increase has been accompanied by a higher incidence of cardiovascular events (CVE) that can be explained due to the sum of cardiovascular risk factors (CVRF) together with the secondary effects of the TKI. The effect of the TKI over the blood pressure control is still unknown. An observational cross-sectional study of patients with CML under treatment with TKI (imatinib, dasatinib and nilotinib) was conducted. Blood pressure was analyzed through sphygmomanometer and 24-h ambulatory blood pressure monitoring (ABPM). A total of 73 patients were included, 57 treated with a single line of treatment. 32.9% of the total of individuals under this study showed uncontrolled blood pressure according to the ABPM. The factors related to uncontrolled BP were overweight, dyslipidemia, alcohol use, pulse wave velocity a high/very high cardiovascular risk. The subjects who received treatment with nilotinib did present worse control of their blood pressure in ABPM than those treated with imatinib and dasatinib (p = 0.041). This finding could indicate that an uncontrolled blood pressure is implied in the pro-inflammatory and pro-atherogenic mechanism underlying the development of the cardiovascular disease in those patients under treatment with nilotinib. The ABPM is a useful tool in the diagnosis and treatment of HT, being the reason why it should be included in the assessment of patients with CML whose HT diagnosis proves uncertain.

Efficacy of PCSK9 inhibitors in the treatment of heterozygous familial hypercholesterolemia: A clinical practice experience.

BACKGROUND: PCSK9 inhibitors are a treatment option for patients with familial hypercholesterolemia not on low-density lipoprotein cholesterol goals despite the use of maximally tolerated high intensity-statins dose. OBJECTIVE: To evaluate the efficacy of alirocumab and evolocumab in LDL-C reduction and targets attainment in patients with heterozygous familial hypercholesterolemia in clinical practice setting. METHODS: SAFEHEART is an open, long-term prospective study of a cohort of subjects with molecular diagnosis of familial hypercholesterolemia. This study analyze subjects ≥ 20 years of age on stable lipid-lowering therapy, who received PCSK9 inhibitors during the period 2016 to January 2020. RESULTS: 433 patients (mean age 55 years, 53% male, 39% with cardiovascular disease) were included and followed-up for a median of 2.5 years (IQR 1.6-3.0). Median LDL-C level prior to PCSK9 inhibitors was 145 mg/dL (IQR 125-173). The addition of PCSK9 inhibitors (211 alirocumab, 222 evolocumab) reduced LDL-C by 58% (IQR 41-70) p<0.001, in men and women, achieving a median LDL-C level of 62 mg/dL (IQR 44-87) without differences between both PCSK9 inhibitors. Out of them 67% with and 80% without cardiovascular disease reached 2016 ESC/EAS LDL-C targets, and 46% very high risk and 50% high risk patients achieved 2019 ESC/EAS LDL-C goals. Independent predictor factors for attainment of 2019 ESC/EAS LDL-C goals were to be male, smoking and the use of statins with ezetimibe. Both inhibitors were well tolerated. CONCLUSIONS: PCSK9 inhibitors on top of maximum lipid-lowering treatment significantly reduced LDL-C levels in patients with familial hypercholesterolemia and improved the achievement of LDL-C targets.

Progressive cardiovascular disease in a patient under treatment with nilotinib. / Enfermedad cardiovascular progresiva en paciente bajo tratamiento con nilotinib.

The development of cardiovascular disease appears in subjects with several cardiovascular risk factors. However, other agents could be related to the appearance of cardiovascular disease, like chemotherapy drugs. We present a 63 years-old man with very high cardiovascular risk and chronic myeloid leukemia under treatment with nilotinib. Despite a good control of cardiovascular risk factors, he development a severe and accelerated peripheral arterial disease. Peripheral arterial disease occurs in 5-20% patients under treatment with nilotinib and it is more frequently in subjects with several cardiovascular risk factors.