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AIMS: Objective methods to determine statin adherence are requested to improve lipid management. We have recently established a method to detect reduced adherence to atorvastatin therapy with cut-off values based on the sum of atorvastatin and its major metabolites in the blood. We aimed to validate this method in patients with and without cardiovascular disease, and optimize previous cut-off values. METHODS AND RESULTS: The pharmacokinetic study included 60 participants treated with atorvastatin 20 mg (N = 20), 40 mg (N = 20), and 80 mg (N = 20). Atorvastatin was then stopped and blood samples collected from day zero to day four. Quantification of the parent drug and its metabolites in blood plasma was performed with a liquid chromatography-tandem mass spectrometry assay. The cut-off values for reduced adherence were validated and optimized by calculating diagnostic sensitivity and specificity. Our candidate cut-off value of dose-normalized six-component sum of atorvastatin plus metabolites <0.10 nM/mg provided a sensitivity of 97% and a specificity of 93% for detecting ≥2 omitted doses. An optimized cut-off <0.062 nM/mg provided a sensitivity of 90% and a specificity of 100%. An alternative simplified two-component metabolite sum with a cut-off value <0.05 nM/mg provided a sensitivity of 98% and a specificity of 76%. An optimized cut-off <0.02 nM/mg provided a sensitivity of 97% and a specificity of 98%. CONCLUSION: This validation study confirms that our direct method discriminates reduced adherence from adherence to atorvastatin therapy with high diagnostic accuracy. The method may improve lipid management in clinical practice and serve as a useful tool in future studies.
Assuntos
Atorvastatina , Inibidores de Hidroximetilglutaril-CoA Redutases , Adesão à Medicação , Atorvastatina/farmacocinética , Atorvastatina/uso terapêutico , Atorvastatina/sangue , Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacocinética , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Inibidores de Hidroximetilglutaril-CoA Redutases/sangue , Inibidores de Hidroximetilglutaril-CoA Redutases/administração & dosagem , Idoso , Ácidos Heptanoicos/farmacocinética , Ácidos Heptanoicos/administração & dosagem , Ácidos Heptanoicos/sangue , Ácidos Heptanoicos/uso terapêutico , Pirróis/farmacocinética , Pirróis/sangue , Pirróis/administração & dosagem , Espectrometria de Massas em Tandem , Cromatografia Líquida , Doenças Cardiovasculares/tratamento farmacológico , Doenças Cardiovasculares/diagnóstico , Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/prevenção & controle , Reprodutibilidade dos Testes , Relação Dose-Resposta a DrogaRESUMO
BACKGROUND: Cardiac allograft vasculopathy is characterized by increased coronary intimal thickness and is a leading cause of death in heart transplant (HTx) recipients despite the routine use of statins. The experience with inhibitors of proprotein convertase subtilisin-kexin type 9 in HTx recipients is limited. Our hypothesis was that lowering cholesterol with the proprotein convertase subtilisin-kexin type 9inhibitor evolocumab would reduce coronary intimal thickness in these patients without compromising safety. OBJECTIVES: This double blind, randomized trial was conducted to test whether evolocumab reduces the burden of cardiac allograft vasculopathy. METHODS: Patients who had received a cardiac allograft at one of the Nordic transplant centers within the prior 4 to 8 weeks were randomized to monthly subcutaneous injections of evolocumab 420 mg or matching placebo. The primary endpoint was the baseline-adjusted maximal intimal thickness as measured by intracoronary ultrasound after 12 months' treatment. RESULTS: The trial enrolled 128 patients between June 2019 and May 2022. Matched pairs of coronary ultrasound images were available for 56 patients assigned to evolocumab and 54 patients assigned to placebo. At 12 months, the adjusted mean difference in the maximal intimal thickness between the 2 arms was 0.017 mm (95% CI: -0.006 to 0.040; P = 0.14). The mean reduction in low-density lipoprotein cholesterol with evolocumab compared with placebo was 1.11 mmol/L (95% CI: 0.86-1.37 mmol/L). The use of evolocumab was not associated with an increase in adverse events. CONCLUSIONS: Twelve months of treatment with evolocumab substantially reduced low-density lipoprotein cholesterol but did not reduce maximal coronary intimal thickness in HTx recipients. (Cholesterol Lowering With EVOLocumab to Prevent Cardiac Allograft Vasculopathy in De-novo Heart Transplant Recipients [EVOLVD]; NCT03734211).
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INTRODUCTION: It is unclear whether moderate-to-vigorous physical activity (MVPA) is associated with a lower mortality risk, over and above its contribution to total physical activity volume. METHODS: 46,682 adults (mean age: 64 years) were included in a meta-analysis of nine prospective cohort studies. Each cohort generated tertiles of accelerometry-measured physical activity volume and volume-adjusted MVPA. Hazard ratios (HR, with 95% confidence intervals) for mortality were estimated separately and in joint models combining volume and MVPA. Data was collected between 2001 and 2019 and analyzed in 2023. RESULTS: During a mean follow-up of 9 years, 4,666 deaths were recorded. Higher physical activity volume, and a greater contribution from volume-adjusted MVPA, were each associated with lower mortality hazard in multivariable-adjusted models. Compared to the least active tertile, higher physical activity volume was associated with a lower mortality (HRs: 0.62; 0.58, 0.67 and 0.50; 0.42, 0.60 for ascending tertiles). Similarly, a greater contribution from MVPA was associated with a lower mortality (HRs: 0.94; 0.85, 1.04 and 0.88; 0.79, 0.98). In joint analysis, a lower mortality from higher volume-adjusted MVPA was only observed for the middle tertile of physical activity volume. CONCLUSIONS: The total volume of physical activity was associated with a lower risk of mortality to a greater extent than the contribution of MVPA to physical activity volume. Integrating any intensity of physical activity into daily life may lower mortality risk in middle-aged and older adults, with a small added benefit if the same amount of activity is performed with a higher intensity.