RESUMEN
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.
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Inhibidores de Hidroximetilglutaril-CoA Reductasas , Hiperlipoproteinemia Tipo II , Atorvastatina/uso terapéutico , Humanos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Hiperlipoproteinemia Tipo II/diagnóstico , Hiperlipoproteinemia Tipo II/tratamiento farmacológico , Hiperlipoproteinemia Tipo II/genética , Farmacogenética , Simvastatina/uso terapéuticoRESUMEN
AIM: To determine periodontitis prevalence in patients with systemic lupus erythematosus (SLE) and to assess whether periodontitis in SLE patients is associated with a greater subclinical atherosclerosis. METHODS: An observational case-control study was conducted in SLE (cases) and patients without any rheumatic diseases (controls), matched for sex. Sociodemographic and cardiometabolic variables were gathered, and SLE activity was assessed through several indexes. Periodontal examination registered probing pocket depth, clinical attachment level, bleeding on probing, plaque index, and tooth loss. Subclinical atherosclerosis was assessed by measuring the carotid-femoral pulse wave velocity (PWV) by Doppler velocimetry, homocysteine levels, C-reactive protein (CRP), and erythrocyte sedimentation rate (ESR). Bivariate analyses and logistic regression were used to assess the association of any of the studied variables with SLE. RESULTS: Seventy-one cases and 72 controls were included in the study. Thirty-nine SLE patients (54.9%) were diagnosed with periodontitis, compared with 16 controls (22.2%). High levels of PWV (≥7.7 m/s, 75th percentile) were shown by 44.3% of the cases vs. 22.4% of the controls (p = .011). Among SLE patients, those with periodontitis showed higher PWV values (8.1 ± 1.52 vs. 7.16 ± 1.11 m/s, p = .006) and higher homeostasis model assessment index (indicative of insulin resistance) (1.7 ± 0.73 vs. 2.92 ± 3.05, p = .028) compared to those with periodontal health. Logistic regression showed that waist circumference (OR 1.06, 95% CI 1.01-1.12, p = .015); ESR (OR 1.09, 95% CI 1.03-1.16, p = .003); and bleeding on probing (OR 1.1, 95% CI 1.01-1.19, p = .018) were associated with the risk of SLE. CONCLUSION: Systemic lupus erythematosus patients showed a higher periodontitis percentage than controls. Higher PWV values were found in SLE patients with periodontitis, indicating a higher prevalence of subclinical atherosclerosis. Patients with higher gingival bleeding showed a higher risk of SLE.
Asunto(s)
Aterosclerosis , Lupus Eritematoso Sistémico , Periodontitis , Aterosclerosis/complicaciones , Estudios de Casos y Controles , Humanos , Lupus Eritematoso Sistémico/complicaciones , Lupus Eritematoso Sistémico/metabolismo , Periodontitis/complicaciones , Análisis de la Onda del Pulso , Factores de RiesgoRESUMEN
The objective of this study was to determine clinical-epidemiological characteristics of the patients and the genetic characteristics of carbapenemase KPC-3-producing Klebsiella pneumoniae isolates belonging to sequence type ST258. The eligible study population was all patients with isolates detected between October 2015 and March 2017. Clinical-epidemiological and microbiological data were gathered on risk factors associated with infection by this clone. Antimicrobial susceptibility was determined using MicroScan system and diffusion in agar. Genes encoding carbapenemases were detected using PCR and Sanger sequencing. The sequence type was assigned by MLST, and the genetic relationship among clinical isolates was determined by pulsed field electrophoresis and by analysis of the genetic environment. The study included 23 individuals with isolates of KPC-3/ST258; the mean age was 77 year, and mean stay pre-isolation was 32 days; 81% received empirical antimicrobial treatment. Isolates were only susceptible to gentamicin (CIM ≤ 2 mg/L), tigecycline (CIM ≤ 1 mg/L), and colistin (CIM ≤ 2 mg/L). The isolates belonged to ST258, with five pulse types or subgroups. All isolates showed amplification of KPC, which was identified as KPC-3 variant. Gene blaKPC-3 was flanked by insertion sequences Kpn6 and Kpn7 within Tn4401 transposon isoform a. We report, for the first time in Spain, an 18-month outbreak by KPC-3-producing ST258 K. pneumoniae. Its acquisition was associated with a history of antimicrobial therapy, with three treatment options, and with high mortality. The detection of different pulse types is attributable to different introductions of the clone in our setting, supporting the need for multi-resistant isolate surveillance studies.
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Proteínas Bacterianas/genética , Infección Hospitalaria/epidemiología , Infección Hospitalaria/microbiología , Brotes de Enfermedades , Infecciones por Klebsiella/epidemiología , Infecciones por Klebsiella/microbiología , Klebsiella pneumoniae/genética , beta-Lactamasas/genética , Hospitales , Humanos , Klebsiella pneumoniae/clasificación , Klebsiella pneumoniae/aislamiento & purificación , Tipificación de Secuencias Multilocus , Filogenia , Filogeografía , Vigilancia en Salud Pública , Factores de Riesgo , España/epidemiologíaRESUMEN
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.
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Anticolesterolemiantes , LDL-Colesterol , Homocigoto , Hiperlipoproteinemia Tipo II , Humanos , Hiperlipoproteinemia Tipo II/genética , Hiperlipoproteinemia Tipo II/tratamiento farmacológico , Hiperlipoproteinemia Tipo II/sangre , Hiperlipoproteinemia Tipo II/complicaciones , Femenino , Masculino , Adulto , Estudios de Seguimiento , Persona de Mediana Edad , LDL-Colesterol/sangre , Resultado del Tratamiento , Anticolesterolemiantes/uso terapéutico , Estudios Prospectivos , Adulto Joven , España/epidemiología , Factores de Tiempo , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Biomarcadores/sangre , Fenotipo , Proproteína Convertasa 9/genética , Proproteína Convertasa 9/metabolismo , Ezetimiba/uso terapéuticoRESUMEN
BACKGROUND: Sex differences in atherosclerotic cardiovascular disease (ASCVD) in familial hypercholesterolaemia have been reported but are not fully established. We aimed to assess sex differences in the risk of ASCVD and life-time burden of ASCVD in patients with heterozygous familial hypercholesterolaemia. METHODS: SAFEHEART is a nationwide, multicentre, long-term prospective cohort study conducted in 25 tertiary care hospitals and one regional hospital in Spain. Participants in the SAFEHEART study aged 18 years or older with genetically confirmed familial hypercholesterolaemia were included in our analysis. Data were obtained between Jan 26, 2004, and Nov 30, 2022. ASCVD and age at onset were documented at enrolment and at follow-up. Our aim was to investigate the differences by sex in the risk and burden of ASCVD in patients with heterozygous familial hypercholesterolaemia, over the study follow-up and over the life course. The SAFEHEART study is registered with ClinicalTrials.gov, NCT02693548. FINDINGS: Of the 5262 participants in SAFEHEART at the time of analysis, 3506 (1898 [54·1%] female and 1608 [45·9%] male participants) met the inclusion criteria and were included in the current study. Mean age was 46·1 years (SD 15·5) and median follow-up was 10·3 years (IQR 6·4-13·0). Mean on-treatment LDL-cholesterol at follow-up was 3·1 mmol/L (SD 1·4) in females and 3·0 mmol/L (1·5) in males. LDL-cholesterol reductions over time were similar in both sexes (1·39 mmol/L [95% CI 1·30-1·47] absolute reduction in females vs 1·39 mmol/L [1·29-1·48] in males; p=0·98). At enrolment, 130 (6·8%) females and 304 (18·9%) males (p<0·0001) had cardiovascular disease. During follow-up, 134 (7·1%) females and 222 (13·8%) males (p<0·0001) had incident cardiovascular events. Median age at first ASCVD event (mostly due to coronary artery disease) was 61·6 years (IQR 50·0-71·4) in females and 50·6 years (42·0-58·6) in males (p<0·0001). The adjusted hazard ratio for ASCVD in males compared with females during follow-up was 1·90 (95% CI 1·49-2·42) and for cardiovascular death was 1·74 (1·11-2·73). Major adverse cardiovascular disease event (MACE)-free survival from birth was lower in males than females (hazard ratio 3·52 [95% CI 2·98-4·16]; p<0·0001). Median MACE-free survival time was 90·1 years (95% CI 86·5-not estimable) in females and 71·0 years (69·2-74·6) in males. The age at which 25% of female participants have had a MACE event was 74·9 years, this figure was 55·5 years in male participants. INTERPRETATION: Our findings suggest that the burden and risk of ASCVD are markedly lower in females than males with familial hypercholesterolaemia. The impact of sex needs to be considered to improve risk stratification and personalised management in patients with heterozygous familial hypercholesterolaemia. FUNDING: Fundación Hipercolesterolemia Familiar, the Instituto de Salud Carlos III, and Next Generation EU funds from the Recovery and Resilience Mechanism Program. TRANSLATION: For the Spanish translation of the abstract see Supplementary Materials section.
RESUMEN
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.
Asunto(s)
Aterosclerosis , Leucemia Mielógena Crónica BCR-ABL Positiva , Humanos , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Lipoproteínas LDLRESUMEN
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.
Asunto(s)
Anticolesterolemiantes , Inhibidores de Hidroximetilglutaril-CoA Reductasas , Hiperlipoproteinemia Tipo II , Femenino , Humanos , Masculino , Inhibidores de PCSK9 , LDL-Colesterol , Anticolesterolemiantes/uso terapéutico , Proproteína Convertasa 9 , Calidad de Vida , Estudios de Cohortes , Estudios Prospectivos , Hiperlipoproteinemia Tipo II/tratamiento farmacológico , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéuticoRESUMEN
Migrant patients arriving in Spain often come from countries where there is no universal access to healthcare. Although the prevalence of arterial hypertension (HTN) is lower in West Africa than in Spain, there is a higher prevalence of masked HT due to the absence of health screening. Furthermore, patients with secondary hypertension may not be diagnosed. We present the case of a 36-year-old Senegalese man, with no known pathological history, resident for a year in Spain, who debuted with a hypertensive emergency. At the time of diagnosis, the patient had severe end-organ damage (hypertensive heart disease, hypertensive retinopathy). After the study, he was diagnosed with arterial hypertension secondary to malformation of the renal artery. After performing angioplasty, blood pressure normalized and, at 18 months, target organ damage had reduced. Migrants who arrive in our country must be incorporated into health screening systems to diagnose and treat possible unknown pathologies. In our case, the clue to secondary hypertension was the development of resistant hypertension with target organ damage in a young subject.
Asunto(s)
Cardiopatías , Hipertensión , Migrantes , Adulto , Presión Sanguínea , Humanos , Hipertensión/complicaciones , Hipertensión/diagnóstico , Hipertensión/epidemiología , Masculino , España/epidemiologíaRESUMEN
Renal infarction is a rare disease whose incidence is less than 1%. The symptoms can be abdominal or flank pain, nausea, vomiting, fever or hypertension. The diagnosis is complex, and it is based on symptoms, blood analysis with an elevated level of lactate dehydrogenase and computed tomography angiography. The two major causes of renal infarction are thromboembolism and in situ thrombosis. The treatment depends on an adequate etiological diagnosis.
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Hipertensión , Infarto/etiología , Riñón , Humanos , Incidencia , Infarto/diagnóstico , Riñón/patología , Tomografía Computarizada por Rayos XRESUMEN
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.
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Hipertensión/epidemiología , Leucemia Mielógena Crónica BCR-ABL Positiva/epidemiología , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Monitoreo Ambulatorio de la Presión Arterial , Enfermedades Cardiovasculares/inducido químicamente , Enfermedades Cardiovasculares/epidemiología , Estudios Transversales , Femenino , Factores de Riesgo de Enfermedad Cardiaca , Humanos , Hipertensión/inducido químicamente , Hipertensión/diagnóstico , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Leucemia Mielógena Crónica BCR-ABL Positiva/fisiopatología , Masculino , Persona de Mediana Edad , Inhibidores de Proteínas Quinasas/administración & dosificación , Inhibidores de Proteínas Quinasas/efectos adversos , España/epidemiologíaRESUMEN
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.
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Anticuerpos Monoclonales Humanizados/administración & dosificación , Hiperlipoproteinemia Tipo II/sangre , Hiperlipoproteinemia Tipo II/tratamiento farmacológico , Inhibidores de PCSK9/administración & dosificación , Anciano , LDL-Colesterol/antagonistas & inhibidores , LDL-Colesterol/sangre , Estudios de Cohortes , Femenino , Estudios de Seguimiento , Humanos , Hiperlipoproteinemia Tipo II/diagnóstico , Inyecciones Subcutáneas , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Resultado del TratamientoRESUMEN
Background and aims: The benefits of the PCSK9 inhibitors, alirocumab and evolocumab, in lowering LDL-cholesterol and preventing major adverse cardiac events (MACE) have been demonstrated in pivotal clinical trials. However, few studies of routine clinical practice have been conducted to analyse and compare the efficacy and safety of the two drugs. Methods: Retrospective observational study of patients treated with a PCSK9 inhibitor in five hospitals in Andalusia (southern Spain). Baseline demographic and clinical data, LDL-cholesterol levels and the occurrence of MACEs during the follow-up period were recorded. Results: A total of 141 patients were included in the study: 90 were treated with alirocumab and 51 with evolocumab. The patients' mean age (IQR) was 58 (11) years and 58 (41%) were women. The most frequent concomitant medications were statins, 94 (66.7%), followed by antiplatelet therapy (66%) and ezetimibe (65.2%). The median (IQR) follow-up period was 18 (18) months, with 18 (24) for alirocumab and 11 (18) for evolocumab. At the six-month follow-up visit, LDL-cholesterol values had decreased to pre-treatment levels and remained significantly decreased (p < 0.05) over time, for both drugs, and a greater reduction was achieved in patients with established cardiovascular disease and concomitant treatment with statins. With respect to adverse effects, there were nine MACEs (6.4%), of which seven were with alirocumab (7.8%) and two with evolocumab (3.9%) (p NS). Other adverse effects (9.2%) included local erythema (3.5%), muscle cramps (2.1%), respiratory symptoms (2.1%) and asthaenia (1.4%). Conclusions: The efficacy and safety of alirocumab and evolocumab in routine clinical practice are consistent with the findings of the pivotal clinical trials.
RESUMEN
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.