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BACKGROUND: Intermittent androgen deprivation therapy (iADT) alleviates some side effects of continuous (c) ADT in patients with prostate cancer (PC), but its relative impact on ADT-associated comorbidities is uncertain. We assessed real-world use of iADT and cADT and associated risk of cardiovascular and endocrine/metabolic events in patients with nonmetastatic (nm) PC. METHODS: This retrospective longitudinal cohort study included patients with nmPC initiating systemic ADT with gonadotropin-releasing hormone agonists (goserelin, histrelin, leuprolide, and triptorelin) or antagonists (degarelix) in the US Surveillance, Epidemiology and End Results-Medicare database (2010-2017), who had ≥ 36 months of continuous insurance coverage, unless death occurred, and did not receive chemotherapy or next-generation hormonal therapies during follow-up (through 2019). Risk of major adverse cardiovascular events (MACE [myocardial infarction, stroke, cardiomyopathy/heart failure, pulmonary embolism, ischemic heart disease, all-cause mortality]) and endocrine/metabolic events (diabetes, hypercholesterolemia, bone fractures, and osteoporosis) were examined between cohorts. Inverse probability of treatment-weighted Cox regression models estimated adjusted hazard ratios (HRs) of the outcomes. RESULTS: Of 10,655 eligible patients, 2,095 (19.7%) received iADT and 8,560 (80.3%) cADT. Median follow-up was 43.9 and 48.4 months and median ADT duration (excluding iADT gaps) was 22.0 and 13.5 months for the iADT and cADT cohorts, respectively. Patients receiving cADT had a lower risk of MACE vs. iADT (HR 0.90; 95% confidence interval [CI] 0.83-0.96). No difference in risk of endocrine/metabolic events was observed (HR 0.97; 95% CI 0.92-1.03). Subgroup analysis found that the difference in MACE was maintained in patients with a history of cardiovascular disease (HR 0.90; 95% CI 0.83-0.98) and eliminated in patients without (HR 0.94; 95% CI 0.82-1.08). CONCLUSIONS: Patients with nmPC who received cADT had a lower risk of MACE and similar risk of endocrine/metabolic events vs. those who received iADT. Further research assessing both regimens is needed to inform treatment decisions.
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To assess the clinical impact of delayed testosterone recovery (TR) following the discontinuation of medical androgen deprivation therapy (ADT), a retrospective, longitudinal analysis was conducted in adult males with prostate cancer using the Optum® de-identified Electronic Health Record data set and Optum® Enriched Oncology Data (2010-2021). Of 3875 patients who initiated and discontinued ADT, 1553 received one or more testosterone-level tests within the 12 mo following discontinuation and were included in this study. These 1553 patients were categorized into two cohorts: 25% as TR (testosterone levels >280 ng/dl at any test within 12 mo following ADT discontinuation) and 75% as non-TR. At baseline, non-TR patients were older, had lower testosterone levels, and were more likely to have diabetes, hyperlipidemia, and hypertension, but less likely to have sexual dysfunction. After adjustment for baseline characteristics, the TR cohort had a lower risk of new-onset diabetes (hazard ratio [HR] 0.47; 95% confidence interval [CI] 0.27-0.79), trended toward a lower risk of new-onset depression (HR 0.58; 95% CI 0.33-1.02), and had a higher likelihood of seeking treatment for sexual dysfunction (HR 1.33; 95% CI 0.99-1.78) versus the non-TR cohort. These findings support monitoring testosterone levels after ADT discontinuation to manage potential long-term comorbidities in patients with prostate cancer. Patient summary: This real-world analysis of males with prostate cancer who were treated with medical androgen deprivation therapy (ADT) found that most patients did not have their testosterone level checked in the 12 mo after stopping ADT. Of those who did, 75% did not achieve normal testosterone levels (>280 ng/dl), and these patients were more likely to experience new-onset diabetes than those who achieved normal testosterone levels. These results suggest that to ensure effective clinical decision-making, physicians should check patients' testosterone levels after stopping ADT.
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INTRODUCTION: Cardiovascular disease (CVD) is the leading cause of death among prostate cancer (PC) patients. Androgen deprivation therapy (ADT) with a gonadotropin-releasing hormone receptor (GnRH) agonist or antagonist is the standard treatment for advanced PC. Since 2010, the Food and Drug Administration has required labeling for GnRH agonists to include warnings about increased risk for diabetes and some CVDs. METHODS: In this observational, retrospective, real-world study, we evaluated time to a first cardiovascular (CV) event within 3 years postinitiation of ADT in PC patients while controlling for CVD history and risk factors. Data from a large administrative US claims dataset (2010-2019) were analyzed using Kaplan-Meier survival analysis to calculate the HR for time to first CV event and Cox regressions to identify factors associated with time to first CV event. RESULTS: Of 10,530 patients, 92% had no history of CVD, 8% had history of CVD, and 95% were exposed to a GnRH agonist during follow-up. Kaplan-Meier analysis indicated that patients with a baseline history of CVD had increased risk of CV events within 3 years of ADT initiation vs those without such history (HR, 3.20; 95% CI, 2.58-3.96; P < .0001). Among covariates associated with higher likelihood of CV event, baseline history of CVD yielded the highest HR (2.83; 95% CI, 2.40-3.32, P < .0001). CONCLUSIONS: PC patients with a history of CVD are at increased risk of a CV event within 3 years of ADT initiation compared with those with no history of CVD.
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Enfermedades Cardiovasculares , Neoplasias de la Próstata , Estados Unidos , Masculino , Humanos , Neoplasias de la Próstata/tratamiento farmacológico , Antagonistas de Andrógenos/efectos adversos , Andrógenos/uso terapéutico , Estudios Retrospectivos , Incidencia , Hormona Liberadora de Gonadotropina/agonistas , Enfermedades Cardiovasculares/inducido químicamente , Factores de RiesgoRESUMEN
Background: This retrospective database analysis describes clinical characteristics and treatment patterns of U.S. women with a diagnosis for uterine fibroids (UF), both with and without heavy menstrual bleeding (HMB). Materials and Methods: Two cohorts aged 18-50 years with an incident UF diagnosis, comprising women with and without claims for HMB (UF-HMB and UF-only), were identified from the IQVIA PharMetrics® Plus database (January 1, 2010-December 31, 2019). The index date was the first UF claim following diagnosis; treatment patterns were documented for postindex years 1 and 2 and the full duration of postindex follow-up. Also identified were claims for symptoms or signs potentially associated with UF. Outcomes were the proportion of patients treated with pharmacologic therapies of interest and gynecologic procedures. Logistic regression was used to identify factors associated with postdiagnosis hysterectomy and hormonal therapy. Results: A total of 66,313 (71.8%) women were included in the UF-HMB cohort (mean age [standard deviation]) 42.6 [5.4] years), and 26,068 (28.2%) in the UF-only cohort (41.8 [6.3]). Median follow-up was â¼4 years. Pain was the most common symptom (42.7% in patients with UF-HMB and 36.6% with UF-only); also common were abnormal bleeding (15.6%, 11.5%) and fatigue (22.2%, 15.5%). Within 1 year of UF diagnosis, 28.8% and 49.2% of women with UF-HMB and UF-only, respectively, had no claims for relevant pharmacologic or surgical treatment. In logistic regression, multiple factors were associated with a higher likelihood of receiving hysterectomy or hormonal therapy. Conclusions: Patients with UF-HMB were more likely to receive UF treatment, either surgical or pharmacologic, than women with UF-only. Apart from HMB, pain was the most commonly documented symptom of UF.
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Leiomioma , Menorragia , Humanos , Femenino , Preescolar , Masculino , Menorragia/diagnóstico , Menorragia/epidemiología , Estudios Retrospectivos , Leiomioma/complicaciones , Leiomioma/diagnóstico , Leiomioma/epidemiología , Histerectomía , DolorRESUMEN
Patients with portal hypertension may develop pulmonary hypertension. The economic implications of these comorbidities have not been systematically assessed. We compared healthcare resource utilization and costs in the United States between patients with co-existing portal hypertension and pulmonary hypertension (pulmonary hypertension cohort) and a matched cohort of portal hypertension patients without pulmonary hypertension (control cohort). In this retrospective analysis, adult pulmonary hypertension and control patients were identified from the Optum® Clinformatics® Data Mart database between 1 July 2014 and 30 June 2018. All patients had ≥2 claims with diagnosis codes for portal hypertension; pulmonary hypertension patients had ≥2 claims with diagnosis codes for pulmonary hypertension; controls could not have pulmonary hypertension diagnoses or any claims for pulmonary arterial hypertension-specific medications. Controls were matched to pulmonary hypertension patients by age, sex, Charlson comorbidity index score, and liver diseases. We assessed 12-month healthcare resource utilization and costs. Each cohort included 146 patients. During follow-up, pulmonary hypertension cohort patients were more likely than controls to experience a hospitalization (51% vs. 32%, P = 0.0014) and an emergency room visit (55% vs. 41%, P = 0.026). The average annual total cost was higher in pulmonary hypertension patients than for matched controls ($119,912 vs. $81,839, P < 0.0001). After covariate adjustment, costs for pulmonary hypertension cohort patients were 1.47 times higher than those for controls (P = 0.0197). These findings suggest that patients with portal hypertension and co-existing pulmonary hypertension are at a greater risk for hospitalization and incur higher mean annual total costs than portal hypertension patients without pulmonary hypertension.
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INTRODUCTION: Despite the increasing age of the multiple sclerosis (MS) patient population, data are lacking on MS patients in later life. This retrospective study investigated treatment patterns, healthcare resource utilization (HCRU), and healthcare costs (HCCs) for patients enrolled in Medicare, in relation to disease-modifying therapy (DMT) and corticosteroid treatment as a marker for relapse. METHODS: Medical and pharmacy claims between January 1, 2010 and July 31, 2015 identified MS patients. The anchor date was defined as the most recent MS claim. Analyses were performed on claims in the 12-month baseline period before the anchor date. Outcomes were stratified by DMT use and number (0, 1, or ≥ 2) of corticosteroid treatments. RESULTS: Among Medicare MS patients (n = 7072; mean age 57 years), 66% received DMT during the baseline period; 31% had 1 claim and 16% had ≥ 2 claims for corticosteroids. Compared with patients not receiving DMT, patients on DMT were less likely to receive corticosteroids (39% vs 62%) and had fewer all-cause hospitalization episodes and ER visits. DMT use was associated with lower HCRU but higher HCCs in patients both with and without corticosteroid treatment. DMT switching rates were low, both among patients with no corticosteroid (5.6%) and patients with 1 (9.3%) or ≥ 2 (11.1%) corticosteroid treatments. DMT switches were most frequently from an injectable to an oral therapy. CONCLUSION: In Medicare patients with MS, DMT use was associated with higher HCCs but lower HCRU, indicative of better health outcomes; however, low DMT switching rates may be an indicator of possible clinical inertia. FUNDING: Sanofi. Plain language summary available for this article.
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BACKGROUND: Patients with heterozygous familial hypercholesterolemia (HeFH) who completed the double-blind ODYSSEY LONG TERM parent trial and subsequently enrolled in the open-label extension (OLE) study, ODYSSEY OLE (NCT01954394), provide a unique opportunity to investigate effects of 2 doses of alirocumab, a proprotein convertase subtilisin/kexin type 9 inhibitor, within the same patient cohort. OBJECTIVE: The aim of the study was to characterize long-term efficacy and safety of 2 alirocumab dosages and utility of a dose titration strategy in patients with HeFH. METHODS: After an 8-week washout period, patients with HeFH who completed the LONG TERM study (receiving alirocumab 150 mg every 2 weeks [Q2W]) were eligible to enroll in OLE (n = 214) for up to 40 months' treatment duration. In OLE, patients started on alirocumab 75 mg Q2W. From Week 12, dose adjustment from 75 to 150 mg Q2W or vice versa was possible based on physician's clinical judgment. RESULTS: During the LONG TERM trial, alirocumab 150 mg Q2W reduced mean low-density lipoprotein cholesterol (LDL-C) from baseline (162.3 mg/dL) to Week 8 by 63.1%; during OLE, alirocumab 75 mg Q2W reduced mean LDL-C from baseline (166.6 mg/dL) by 47.3% within the same patient cohort. At Week 96, mean LDL-C reduction from OLE baseline was 55.4% vs 46.8% for patients with or without alirocumab dose increase, respectively. Treatment-emergent adverse events leading to permanent treatment discontinuation were observed in 4 patients (1.9%). CONCLUSIONS: In patients with HeFH, both alirocumab dosages provided consistent LDL-C reductions over a treatment duration of up to 4 years (including 1.5 years of the LONG TERM trial), allowing an individualized approach to LDL-C lowering, depending on baseline LDL-C levels.
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Anticuerpos Monoclonales Humanizados/uso terapéutico , Anticolesterolemiantes/uso terapéutico , LDL-Colesterol/sangre , Hiperlipoproteinemia Tipo II/tratamiento farmacológico , Anciano , Cálculo de Dosificación de Drogas , Femenino , Estudios de Seguimiento , Humanos , Hiperlipoproteinemia Tipo II/genética , Masculino , Persona de Mediana Edad , Medicina de Precisión , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Factores de Tiempo , Resultado del TratamientoRESUMEN
Data presented in this article are supplementary material to our article entitled "Identification and diagnosis of patients with familial chylomicronaemia syndrome (FCS): expert panel recommendations and proposal of an "FCS Score" (Moulin et al., 2018, in press). The data describe the genotypes of patients with familial chylomicronaemia syndrome (FCS) and multifactorial chylomicronaemia syndrome (MCS), from the validation and replication cohorts.
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BACKGROUND: ODYSSEY OLE (NCT01954394) was an open-label extension (OLE) study for patients with heterozygous familial hypercholesterolemia (HeFH) who had completed previous phase 3 clinical trials with alirocumab. Alirocumab dose could be increased or decreased as per physician judgment. OBJECTIVE: To assess how the alirocumab dosing strategy was used by physicians during OLE. METHODS: Patients who entered OLE on a starting dose of alirocumab 75 mg every 2 weeks (Q2W) were included in the analysis (those from FH I, FH II, and LONG TERM trials). Those who completed LONG TERM entered an 8-week washout period before receiving alirocumab 75 mg Q2W at the start of OLE. From week 12, dose adjustment from 75 to 150 mg Q2W, or vice versa, was possible, based on the physician's clinical judgment. RESULTS: In total, 909 patients with HeFH completed the 3 parent studies and were treated during OLE for a duration of up to 40 months. Most patients (56.7%) were maintained on 75 mg Q2W throughout OLE, whereas 43.3% of patients had their dose increased to 150 mg Q2W. The dose was subsequently decreased in 7.4% of the patients in whom alirocumab was initially uptitrated. Overall, treatment-emergent adverse events were similar between those who had received placebo or alirocumab in the parent studies. CONCLUSIONS: In the opinion of physicians, alirocumab 75 mg Q2W enabled over half of patients with HeFH to achieve sufficient low-density lipoprotein cholesterol lowering.
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Anticuerpos Monoclonales/uso terapéutico , Heterocigoto , Hiperlipoproteinemia Tipo II/tratamiento farmacológico , Hiperlipoproteinemia Tipo II/genética , Anticuerpos Monoclonales Humanizados , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
BACKGROUND AND AIMS: ODYSSEY OLE (open-label extension; NCT01954394) included patients diagnosed with heterozygous familial hypercholesterolemia (HeFH), receiving maximally tolerated statins, who had completed one of four Phase 3 double-blind parent studies (all 18 months' duration), with the aim to assess longer-term safety and efficacy of alirocumab. METHODS: Patients received starting dose alirocumab 75â¯mg every 2 weeks (Q2W; patients from FH I, FH II, and LONG TERM) or alirocumab 150â¯mg Q2W (patients from HIGH FH). Low-density lipoprotein cholesterol (LDL-C) levels were blinded to the patient and physician until Week 8; from Week 8, LDL-C levels were communicated to physicians. From Week 12, dose adjustment from 75 to 150â¯mg Q2W, or vice versa, was possible per physician's clinical judgment according to patient's LDL-C levels. RESULTS: Patients who had received alirocumab (nâ¯=â¯655) compared with placebo (nâ¯=â¯330) in the parent studies exhibited similar rates of treatment-emergent adverse events (TEAEs; 87.3% vs. 83.9%) during OLE (2.5 years median alirocumab exposure). Overall, 33 patients (3.4%) experienced TEAEs leading to permanent treatment discontinuation. At Week 8, alirocumab reduced mean LDL-C by 44.2% (reduction from 151.9â¯mg/dL at parent study baseline to 84.9â¯mg/dL); reduction in LDL-C was consistent to Week 96 of OLE. Reductions in lipid parameters were similar regardless of treatment allocation in the parent study. CONCLUSIONS: In patients with HeFH, no unexpected long-term safety concerns were observed with alirocumab compared with previously published data; durability of LDL-C-lowering over 3 years (including 1.5 years of parent trials) was demonstrated.
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Anticuerpos Monoclonales/farmacología , Hiperlipoproteinemia Tipo II/tratamiento farmacológico , Hiperlipoproteinemia Tipo II/genética , Adulto , Anciano , Anticuerpos Monoclonales Humanizados , Índice de Masa Corporal , LDL-Colesterol/metabolismo , Complicaciones de la Diabetes , Método Doble Ciego , Esquema de Medicación , Femenino , Estudios de Seguimiento , Heterocigoto , Humanos , Masculino , Persona de Mediana Edad , Seguridad del PacienteRESUMEN
BACKGROUND AND AIMS: Familial hypercholesterolemia (FH) is under-diagnosed and under-treated in most of the world, including Canada. National registries play a key role in identifying patients with FH, understanding gaps in care, and advancing the science of FH to better treat these patients. METHODS: FH Canada has established a national registry across 19 academic sites acting as "hubs" in Canada to increase awareness and access to standard-of-care therapies. RESULTS: To-date, more than 3000 patients with FH have been entered into a secure, web-based database. Early outcomes of this initiative include a greater understanding of treatment gaps for patients with FH in Canada, the development of a new, simplified Canadian definition of FH, and tools to aid in the diagnosis of FH, including imputation of baseline levels of LDL cholesterol. CONCLUSIONS: As the national registry expands in size and scope, further learning will emerge with ultimate benefit for the diagnosis and treatment of FH in Canada.
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Anticolesterolemiantes/uso terapéutico , LDL-Colesterol/sangre , Hiperlipoproteinemia Tipo II/tratamiento farmacológico , Adulto , Biomarcadores/sangre , Canadá , Enfermedades Cardiovasculares/epidemiología , Enfermedades Cardiovasculares/prevención & control , Bases de Datos Factuales , Regulación hacia Abajo , Quimioterapia Combinada , Femenino , Predisposición Genética a la Enfermedad , Herencia , Humanos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Hiperlipoproteinemia Tipo II/sangre , Hiperlipoproteinemia Tipo II/epidemiología , Hiperlipoproteinemia Tipo II/genética , Masculino , Persona de Mediana Edad , Inhibidores de PCSK9 , Linaje , Fenotipo , Prevalencia , Proproteína Convertasa 9/metabolismo , Sistema de Registros , Medición de Riesgo , Factores de Riesgo , Inhibidores de Serina Proteinasa/uso terapéutico , Factores de Tiempo , Resultado del Tratamiento , Adulto JovenRESUMEN
BACKGROUND: Evolocumab significantly lowers low-density lipoprotein cholesterol (LDL-C) when dosed 140 mg every 2 weeks (Q2W) or 420 mg monthly (QM) subcutaneously. HYPOTHESIS: LDL-C changes are comparable among different patient subgroups in a pooled analysis of data from phase 3 trials. METHODS: A total of 3146 patients received ≥1 dose of evolocumab or control in four 12-week phase 3 studies. Percent change from baseline in LDL-C for evolocumab 140 mg Q2W or 420 mg QM vs control was reported as the average of week 10 and 12 values. Quantitative and qualitative interactions between treatment group and subgroup by dose regimen were tested. RESULTS: In the pooled analysis, treatment differences vs placebo or ezetimibe were similar for both 140 mg Q2W and 420 mg QM doses across ages (<65 years, ≥65 years); gender; race (Asian, black, white, other); ethnicity (Hispanic, non-Hispanic); region (Europe, North America, Asia Pacific); glucose tolerance status (type 2 diabetes mellitus, metabolic syndrome, neither); National Cholesterol Education Program risk categories (high, moderately high, moderate, low); and European Society of Cardiology/European Atherosclerosis Society risk categories (very high, high, moderate, or low). Certain low-magnitude variations in LDL-C lowering among subgroups led to significant quantitative interaction P values that, when tested by qualitative interaction, were not significant. The incidences of adverse events were similar across groups treated with each evolocumab dosing regimen or control. CONCLUSIONS: Consistent reductions in LDL-C were observed in the evolocumab group regardless of demographic and disease characteristics.
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Anticuerpos Monoclonales/administración & dosificación , LDL-Colesterol/sangre , Hipercolesterolemia/tratamiento farmacológico , Anciano , Anticuerpos Monoclonales Humanizados , Anticolesterolemiantes/administración & dosificación , Asia/epidemiología , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Europa (Continente)/epidemiología , Femenino , Estudios de Seguimiento , Humanos , Hipercolesterolemia/sangre , Hipercolesterolemia/epidemiología , Incidencia , Inyecciones Subcutáneas , Masculino , Persona de Mediana Edad , América del Norte/epidemiología , Factores de Tiempo , Resultado del TratamientoRESUMEN
Familial hypercholesterolemia (FH) is an autosomal codominant lipoprotein disorder characterized by elevated low-density lipoprotein cholesterol (LDL-C) and high risk of premature atherosclerotic cardiovascular disease. Definitions for FH rely on complex algorithms that are on the basis of levels of total or LDL-C, clinical features, family history, and DNA analysis that are often difficult to obtain. We propose a novel simplified definition for FH. Definite FH includes: (1) elevated LDL-C (≥ 8.50 mmol/L); or (2) LDL-C ≥ 5.0 mmol/L (for age 40 years or older; ≥ 4.0 mmol/L if age younger than 18 years; and ≥ 4.5 mmol/L if age is between 18 and 39 years) when associated with at least 1 of: (1) tendon xanthomas; or (2) causal DNA mutation in the LDLR, APOB, or PCSK9 genes in the proband or first-degree relative. Probable FH is defined as subjects with an elevated LDL-C (≥ 5.0 mmol/L) and the presence of premature atherosclerotic cardiovascular disease in the patient or a first-degree relative or an elevated LDL-C in a first-degree relative. LDL-C cut points were determined from a large database comprising > 3.3 million subjects. To compare the proposed definition with currently used algorithms (ie, the Simon Broome Register and Dutch Lipid Clinic Network), we performed concordance analyses in 5987 individuals from Canada. The new FH definition showed very good agreement compared with the Simon Broome Register and Dutch Lipid Clinic Network criteria (κ = 0.969 and 0.966, respectively). In conclusion, the proposed FH definition has diagnostic performance comparable to existing criteria, but adapted to the Canadian population, and will facilitate the diagnosis of FH patients.
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LDL-Colesterol/sangre , Enfermedad de la Arteria Coronaria , Hiperlipoproteinemia Tipo II , Linaje , Xantomatosis , Adolescente , Adulto , Edad de Inicio , Algoritmos , Apolipoproteína B-100/genética , Canadá/epidemiología , Niño , Enfermedad de la Arteria Coronaria/epidemiología , Enfermedad de la Arteria Coronaria/etiología , Femenino , Humanos , Hiperlipoproteinemia Tipo II/diagnóstico , Hiperlipoproteinemia Tipo II/epidemiología , Hiperlipoproteinemia Tipo II/genética , Masculino , Mutación , Proproteína Convertasa 9/genética , Receptores de LDL/genética , Xantomatosis/diagnóstico , Xantomatosis/etiologíaRESUMEN
Familial chylomicronaemia syndrome (FCS) is a rare, inherited disorder characterised by impaired clearance of triglyceride (TG)-rich lipoproteins from plasma, leading to severe hypertriglyceridaemia (HTG) and a markedly increased risk of acute pancreatitis. It is due to the lack of lipoprotein lipase (LPL) function, resulting from recessive loss of function mutations in the genes coding LPL or its modulators. A large overlap in the phenotype between FCS and multifactorial chylomicronaemia syndrome (MCS) contributes to the inconsistency in how patients are diagnosed and managed worldwide, whereas the incidence of acute hypertriglyceridaemic pancreatitis is more frequent in FCS. A panel of European experts provided guidance on the diagnostic strategy surrounding FCS and proposed an algorithm-based diagnosis tool for identification of these patients, which can be readily translated into practice. Features included in this FCS score comprise: severe elevation of plasma TGs (fasting TG levels >10â¯mmol/L [885â¯mg/dL] on multiple occasions), refractory to standard TG-lowering therapies, a young age at onset, the lack of secondary factors (except for pregnancy and oral oestrogens) and a history of episodes of acute pancreatitis. Considering 53 FCS patients from three cohorts and 52 MCS patients from three cohorts, the overall sensitivity of the FCS score (≥10) was 88% (95% confidence interval [CI]: 0.76, 0.97) with an overall specificity of 85% (95% CI: 0.75, 0.94). Receiver operating characteristic curve area was 0.91. Pragmatic clinical scoring, by standardising diagnosis, may help differentiate FCS from MCS, may alleviate the need for systematic genotyping in patients with severe HTG and may help identify high-priority candidates for genotyping.
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Quilomicrones/sangre , Técnicas de Apoyo para la Decisión , Hiperlipoproteinemia Tipo I/diagnóstico , Lipoproteína Lipasa/genética , Mutación con Pérdida de Función , Triglicéridos/sangre , Edad de Inicio , Algoritmos , Biomarcadores/sangre , Consenso , Diagnóstico Diferencial , Predisposición Genética a la Enfermedad , Humanos , Hiperlipoproteinemia Tipo I/sangre , Hiperlipoproteinemia Tipo I/tratamiento farmacológico , Hiperlipoproteinemia Tipo I/genética , Hipolipemiantes , Lipoproteína Lipasa/metabolismo , Pancreatitis/diagnóstico , Pancreatitis/genética , Fenotipo , Valor Predictivo de las Pruebas , Pronóstico , Reproducibilidad de los Resultados , Factores de Riesgo , Regulación hacia ArribaRESUMEN
BACKGROUND: Familial hypercholesterolemia (FH) is the most frequent autosomal codominant disease worldwide and is characterized by elevated low-density lipoprotein cholesterol and premature coronary artery disease (CAD). Polymorphisms in phosphatase and actin regulator 1 (PHACTR1) have been shown to be associated with cardiovascular risk in large genome-wide association studies studies. OBJECTIVE: The aim of the present study is to evaluate the association between the rs12526453 polymorphism in the PHACTR1 gene and the prevalence of CAD in FH patients. METHODS: A cohort of 668 adult genetically confirmed heterozygous FH subjects were included in the present study. Logistic regression models were used to evaluate the strength of the association between rs12526453 genotype and CAD prevalence. RESULTS: Noncarriers (CC) of the rs12526453 represented 41% of the cohort, whereas heterozygous (CG) and homozygous (GG) carriers represented 44% and 15%, respectively. The prevalence of CAD was significantly higher in non-carriers of the rs12526453 polymorphism compared to heterozygous and homozygous carriers (38.0%, 25.8%, 24.5%, respectively, P = .001). When a dominant logistic regression model was studied, the association between this single-nucleotide polymorphism and CAD prevalence was significant even after correction for all classical cardiovascular risk factors (odds ratio 0.48, 95% confidence intervals 0.31-0.74, P = .001). CONCLUSION: In the present study, we have shown that the rs12526453 single-nucleotide polymorphism of the PHACTR1 gene is significantly associated with a 50% reduction in the odds of CAD events in FH subjects. Because the protective G allele is frequent in the Caucasian population (allelic frequency of 0.26), screening for this polymorphism in Caucasian FH subjects could further help to stratify risk of CAD in this population.
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Enfermedad de la Arteria Coronaria/diagnóstico , Hiperlipoproteinemia Tipo II/patología , Proteínas de Microfilamentos/genética , Adulto , Alelos , Enfermedad de la Arteria Coronaria/epidemiología , Enfermedad de la Arteria Coronaria/etiología , Femenino , Frecuencia de los Genes , Genotipo , Heterocigoto , Homocigoto , Humanos , Hiperlipoproteinemia Tipo II/complicaciones , Hiperlipoproteinemia Tipo II/genética , Modelos Logísticos , Masculino , Persona de Mediana Edad , Oportunidad Relativa , Polimorfismo de Nucleótido Simple , Prevalencia , Factores de RiesgoRESUMEN
BACKGROUND: Hypercholesterolemia is a major risk factor for the late-onset form of Alzheimer disease (AD). Loss-of-function (LOF) mutations of PCSK9 and PCSK9 inhibitors lower low-density lipoprotein cholesterol (LDL-C) and have been associated with a reduced risk of cardiovascular disease. The aim of this study was to examine the effect of PCSK9 LOF variants on risk and age of onset of AD. METHODS: A total of 878 participants (410 controls and 468 AD cases) from the Quebec Founder Population were included in the study. RESULTS: Fifty-four (6.2%) participants carried the R46L mutation, whereas 226 (26.2%) participants carried the InsLEU mutation. There was no protective or no deleterious effect of carrying PCSK9 LOF mutations on AD prevalence nor on age of onset, even when stratified by apolipoprotein E epsilon 4 genotype or by gender. CONCLUSION: Our data indicate that carrying PCSK9 LOF mutations has a neutral effect on neurocognitive health and the prevalence of AD.
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Edad de Inicio , Enfermedad de Alzheimer/genética , Técnicas de Genotipaje/métodos , Mutación , Proproteína Convertasa 9/genética , Enfermedad de Alzheimer/patología , LDL-Colesterol/sangre , Femenino , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple , Proproteína Convertasa 9/sangre , Factores de RiesgoRESUMEN
BACKGROUND: The ABO blood group has been associated with cardiovascular disease (CVD) in observational studies. However, the effect of ABO blood group has never been studied in subjects affected by familial hypercholesterolemia (FH), a severe monogenic disease characterized by accelerated atherosclerotic plaque development. OBJECTIVE: Our aim is to investigate the effect of the ABO blood group on CVD risk in FH patients. METHODS: A total of 668 adult subjects with a heterozygous FH-causing mutation in the low density lipoprotein receptor (LDLR) gene were included in the present study. ABO blood group was determined using 2 functional single-nucleotide polymorphisms in the ABO gene (rs8176719 and rs8176746). RESULTS: Total cholesterol was significantly higher in non-O subjects compared to carriers of the O group (9.48 vs 9.14 mmol/L, P = .02). We observed a greater proportion of subjects carrying the non-O groups (73.4%) in patients with CVD compared to subjects without CVD (63.3%). In a regression model corrected for cardiovascular risk factors, the non-O group was significantly associated with an increased prevalence of CVD (odds ratio = 2.14, 95% confidence interval = 1.25-3.65, P = .005). In average, patients in the non-O blood group experienced more CVD events (0.88 per individual) than those in the O group (0.60 per individual), P = .008. CONCLUSION: Carrying a non-O blood group is associated with an independent twofold increased risk of CVD in FH patients. The ABO blood group represents a novel CVD risk factor in FH subjects that is often known by the patient and could be used to further stratify CVD risk in this population of patients.
Asunto(s)
Antígenos de Grupos Sanguíneos/genética , Enfermedades Cardiovasculares/genética , Hiperlipoproteinemia Tipo II/genética , Mutación , Polimorfismo de Nucleótido Simple , Receptores de LDL/genética , Adulto , Enfermedades Cardiovasculares/sangre , Enfermedades Cardiovasculares/diagnóstico , Estudios de Cohortes , Femenino , Genotipo , Humanos , Hiperlipoproteinemia Tipo II/sangre , Modelos Logísticos , Masculino , Persona de Mediana Edad , Factores de RiesgoRESUMEN
BACKGROUND: Familial hypercholesterolemia (FH) is the most frequent genetic disorder seen clinically and is characterized by increased LDL cholesterol (LDL-C) (>95th percentile), family history of increased LDL-C, premature atherosclerotic cardiovascular disease (ASCVD) in the patient or in first-degree relatives, presence of tendinous xanthomas or premature corneal arcus, or presence of a pathogenic mutation in the LDLR, PCSK9, or APOB genes. A diagnosis of FH has important clinical implications with respect to lifelong risk of ASCVD and requirement for intensive pharmacological therapy. The concentration of baseline LDL-C (untreated) is essential for the diagnosis of FH but is often not available because the individual is already on statin therapy. METHODS: To validate a new algorithm to impute baseline LDL-C, we examined 1297 patients. The baseline LDL-C was compared with the imputed baseline obtained within 18 months of the initiation of therapy. We compared the percent reduction in LDL-C on treatment from baseline with the published percent reductions. RESULTS: After eliminating individuals with missing data, nonstandard doses of statins, or medications other than statins or ezetimibe, we provide data on 951 patients. The mean ± SE baseline LDL-C was 243.0 (2.2) mg/dL [6.28 (0.06) mmol/L], and the mean ± SE imputed baseline LDL-C was 244.2 (2.6) mg/dL [6.31 (0.07) mmol/L] (P = 0.48). There was no difference in response according to the patient's sex or in percent reduction between observed and expected for individual doses or types of statin or ezetimibe. CONCLUSIONS: We provide a validated estimation of baseline LDL-C for patients with FH that may help clinicians in making a diagnosis.
Asunto(s)
Anticolesterolemiantes/uso terapéutico , LDL-Colesterol/sangre , Ezetimiba/uso terapéutico , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Hiperlipoproteinemia Tipo II/sangre , Hiperlipoproteinemia Tipo II/tratamiento farmacológico , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Algoritmos , Apolipoproteína B-100/genética , Niño , Estudios de Cohortes , Femenino , Humanos , Hiperlipoproteinemia Tipo II/genética , Masculino , Persona de Mediana Edad , Mutación , Proproteína Convertasa 9/genética , Receptores de LDL/genética , Adulto JovenRESUMEN
BACKGROUND: Automated office blood pressure (AOBP) measuring devices are increasingly recommended as preferred blood pressure (BP) diagnostic tools, but it is unclear how they compare and how clinical environments impact their performance. METHODS: This prospective randomized factorial parallel 4-group study compared BP estimates by BpTRU (VSM MedTech, Vancouver, BC, Canada) and Omron HEM 907 (Omron Healthcare, Kyoto, Japan) devices in closed vs open areas. Patients diagnosed with hypertension were recruited during office visits. After baseline open-room AOBP measurement with the BpTRU, patients had a second BP measurement with either the BpTRU or HEM 907 in either open or closed areas. Absolute BP levels and differences between the first and second measurements were compared. Diagnostic performance was also assessed. RESULTS: Two hundred fifty-eight patients were studied. Their mean age was 66.2 ± 12.0 years, and 62% were men. The mean of first AOBP estimates was 127.4/73.3 mm Hg. Analyses of subsequent measurements revealed no influence of open or closed areas on BP means and diagnostic performance. Conversely, the Omron HEM 907 exceeded BpTRU systolic BP measurements by 4.6 mm Hg (< 0.01) in closed areas and by 3.9 mm Hg (< 0.01) in open areas. The discrepancy between devices was amplified at lower BP levels. CONCLUSIONS: Although different areas did not influence BP estimates, the Omron HEM 907 significantly exceeded BpTRU measurements on average and especially at lower BP levels. These differences should be considered when interchanging devices and could have clinical decision impacts in a population of patients treated for hypertension. Our results support the constant use of only 1 device type in a given clinic.
Asunto(s)
Automatización , Determinación de la Presión Sanguínea/instrumentación , Presión Sanguínea/fisiología , Hipertensión/diagnóstico , Anciano , Diseño de Equipo , Femenino , Humanos , Hipertensión/fisiopatología , Masculino , Estudios Prospectivos , Reproducibilidad de los Resultados , EsfigmomanometrosRESUMEN
BACKGROUND: Familial hypercholesterolemia (FH) is a monogenic disease associated with elevated low-density lipoprotein (LDL) cholesterol and oxidized LDL (oxLDL) leading to premature cardiovascular disease. Lectin-like oxLDL receptor-1 (LOX1) is one of the major contributors of oxLDL uptake and degradation in macrophages, which leads to foam cell formation and the development of atherosclerosis. This study investigated the effect of the rs11053646 genotype of the oxidized low-density lipoprotein receptor 1 (OLR1) gene on coronary artery disease (CAD) risk in a cohort of FH patients. METHODS: A total of 665 genetically confirmed heterozygous adult patients with FH were included in the analysis. We evaluated the association between the rs11053646 genotype (GG vs GC) and CAD. RESULTS: The GC genotype (K167N carriers) represented 12.9% of the study cohort (n = 86), whereas 87.1% of the participants were noncarriers (GG genotype) (n = 579). A significantly higher proportion of GC carriers experienced a CAD event (40.7%) than did GG carriers (29.0%; P = 0.03). The presence of a C allele remained significantly associated with an increased CAD risk, even when the regression model was corrected for all traditional CAD risk factors (odds ratio, 3.05; 95% confidence interval, 1.63-5.70; P = 0.0005). The negative impact of carrying the C allele on CAD risk was similar in both sexes but was significantly more important in smokers as well as in younger patients with FH. CONCLUSIONS: Carrying the C allele of the rs11053646 variant of the OLR1 gene was associated with an increased risk of CAD in heterozygous adult patients with FH, and this risk could be even greater in smokers as well as in younger patients.