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OBJECTIVES: Skin improvement in diffuse cutaneous SSc (dcSSc), measured with modified Rodnan skin score (mRSS), is frequently used as a primary outcome in clinical trials, but it is uncertain whether mRSS changes reflect changes in other organ systems. This aim of this study was to explore if skin changes in early dcSSc over 1 and 2 years are associated with changes in severity of other organ involvement. METHODS: Canadian Scleroderma Research Group database patients with dcSSc, disease duration of ≤5 years, no evidence of initial end-stage organ damage and/or significant comorbidity who had 1 year (n = 154) and 2 years (n = 128) of follow-up data were included. mRSS changes of 25% and/or ≥5 points were considered significant. Organ involvement was assessed by Medsger Disease Severity Score and Canadian Scleroderma Research Group definitions using bivariate, chi-square, ANOVA, adjusted regression and longitudinal mixed effect model analyses. RESULTS: Improvement in mRSS was found in 41% of patients at 1 year and in 50% at 2 years. Improved patients showed less forced vital capacity decline (P = 0.012) and less frequent new cardiac involvement (P = 0.02) over 1 year, as well as better lung (by both Disease Severity Score, P = 0.006, and Δforced vital capacity%, P = 0.026), peripheral vascular (P = 0.006) and joint/tendon (P = 0.002) involvement over 2 years. mRSS worsening was consistently linked to less favourable lung outcomes at both 1- and 2-year follow-up visits, and more severe gastrointestinal disease at 2 years. CONCLUSION: Changes in lung function in early dcSSc closely parallel skin changes. mRSS improvement reflects better prognosis for visceral disease and may be a reliable outcome measure in clinical trials.
Assuntos
Coração/fisiopatologia , Pulmão/fisiopatologia , Esclerodermia Difusa/patologia , Pele/patologia , Corticosteroides/uso terapêutico , Adulto , Azatioprina/uso terapêutico , Progressão da Doença , Feminino , Humanos , Imunossupressores/uso terapêutico , Masculino , Metotrexato/uso terapêutico , Pessoa de Meia-Idade , Prognóstico , Sistema de Registros , Esclerodermia Difusa/diagnóstico , Esclerodermia Difusa/tratamento farmacológico , Esclerodermia Difusa/fisiopatologia , Índice de Gravidade de Doença , Pele/fisiopatologiaRESUMO
OBJECTIVE: To determine whether skin score changes are associated with changes in overall disease severity, function and quality of life in early dcSSc patients. METHODS: A total of 154 and 128 dcSSc patients from the Canadian Scleroderma Research Group database with 1 and 2 year follow-up and a disease duration ⩽5 years without end-stage organ damage and/or significant comorbidity at the initial visit were included. Skin was assessed using the modified Rodnan skin score (mRSS) and disease severity by the summed Medsger disease severity score (DSS) (without skin domain), physician and patient global assessments, function [HAQ disability index (HAQ-DI)] and quality of life [36-item Short Form Health Survey (SF-36) physical component summary (PCS)]. Analyses were repeated in patients with a disease duration ⩽3 years. RESULTS: At 2 years, 64 (50%) patients had improved skin (mRSS decrease of ⩾5 points and/or ⩾25%). Skin improvers had improved summed DSS (P = 0.002); better physician global assessments of disease activity, severity and damage (all P ⩽ 0.003); better HAQ-DI (P = 0.001) and SF-36 PCS (P = 0.005). Changes in the mRSS were positively correlated with changes in summed DSS (P = 0.006) and other disease outcomes. In the 26 (20.3%) patients with worsened skin (mRSS increase of ⩾5 points and/or ⩾25%), the summed DSS and physician global assessments were worse (P = 0.01 and P ⩽ 0.009, respectively). In the subgroup with a disease duration ⩽3 years, similar associations were found. CONCLUSION: At 1 and 2 years, overall disease improvement parallels skin improvement in early dcSSc. This is important for prognosis and reflects the value of mRSS as an outcome measure in trials with these patients.
Assuntos
Esclerodermia Difusa/diagnóstico , Pele/patologia , Adulto , Avaliação da Deficiência , Progressão da Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Esclerodermia Difusa/patologia , Índice de Gravidade de DoençaRESUMO
BACKGROUND: To understand the recent management status in Japan, we determined the low-density lipoprotein cholesterol (LDL-C) goal attainment (GA) rate of patients initiating statin monotherapy for dyslipidemia.MethodsâandâResults:Dyslipidemic patients undergoing either primary prevention with high cardiovascular risk or secondary prevention (defined by 2012 Japan Atherosclerosis Society Guidelines) were retrospectively analyzed from a hospital-based claims database. In both groups, the LDL-C levels and GA rates of patients treated with intensive or standard statin monotherapy for ≥4 weeks (January 2012-August 2016) were evaluated. Among 1,501,013 dyslipidemic patients, 11,695 and 9,642 were included in the primary and secondary prevention groups, respectively. A total of 94% of patients underwent statin monotherapy as the initial lipid-lowering therapy, of which most (≥80%) took intensive statins. The proportions of patients in the primary prevention group who achieved an LDL-C goal <120 mg/dL by intensive and standard statins were 81.1% and 61.2%, respectively, and the proportions of those who achieved a goal <100 mg/dL in the secondary prevention group were 73.3% and 48.1%, respectively. The GA rates were similar regardless of disease complications. CONCLUSIONS: Most patients (>70%) in both groups achieved LDL-C management goals using intensive statin monotherapy. Further treatment approaches are required for high-risk patients not achieving LDL-C goals by initial statin monotherapy. Continuous efforts are crucial for adherence and persistence of lipid-lowering therapies.
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Doenças Cardiovasculares/prevenção & controle , LDL-Colesterol/efeitos dos fármacos , Dislipidemias/tratamento farmacológico , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Doenças Cardiovasculares/tratamento farmacológico , Objetivos , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Japão , Prevenção Primária , Estudos Retrospectivos , Risco , Prevenção SecundáriaRESUMO
AIM: To conduct a systematic review and meta-analysis to determine the risk of cardiovascular events and all-cause mortality associated with sulphonylureas (SUs) vs other glucose lowering drugs in patients with T2DM (T2DM). MATERIALS AND METHODS: A systematic review of Medline, Embase, Cochrane and clinicaltrials.gov was conducted for studies comparing SUs with placebo or other antihyperglycaemic drugs in patients with T2DM. A cloglog model was used in the Bayesian framework to obtain comparative hazard ratios (HRs) for the different interventions. For the analysis of observational data, conventional fixed-effect pairwise meta-analyses were used. RESULTS: The systematic review identified 82 randomized controlled trials (RCTs) and 26 observational studies. Meta-analyses of RCT data showed an increased risk of all-cause mortality and cardiovascular-related mortality for SUs compared with all other treatments combined (HR 1.26, 95% confidence interval [CI] 1.10-1.44 and HR 1.46, 95% CI 1.21-1.77, respectively). The risk of myocardial infarction was significantly higher for SUs compared with dipeptidyl peptidase-4 (DPP-4) inhibitors and sodium-glucose co-transporter-2 inhibitors (HR 2.54, 95% CI 1.14-6.57 and HR 41.80, 95% CI 1.64-360.4, respectively). The risk of stroke was significantly higher for SUs than for DPP-4 inhibitors, glucagon-like peptide-1 agonists, thiazolidinediones and insulin. CONCLUSIONS: The present meta-analysis showed an association between SU therapy and a higher risk of major cardiovascular disease-related events compared with other glucose lowering drugs. Results of ongoing RCTs, which should be available in 2018, will provide definitive results on the risk of cardiovascular events and all-cause mortality associated with SUs vs other antihyperglycaemic drugs.
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Doenças Cardiovasculares/epidemiologia , Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/uso terapêutico , Mortalidade , Compostos de Sulfonilureia/uso terapêutico , Teorema de Bayes , Causas de Morte , Diabetes Mellitus Tipo 2/epidemiologia , Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Peptídeo 1 Semelhante ao Glucagon/agonistas , Humanos , Insulina/uso terapêutico , Infarto do Miocárdio/epidemiologia , Modelos de Riscos Proporcionais , Inibidores do Transportador 2 de Sódio-Glicose , Acidente Vascular Cerebral/epidemiologia , Taxa de Sobrevida , Tiazolidinedionas/uso terapêuticoRESUMO
Introduction: Chronic cough affects â¼10% of the population and adversely impacts quality of life. This retrospective observational cohort study aimed to identify the demographics, clinical characteristics and quality of life of the chronic cough population in a Dutch chronic cough clinic, at baseline and following treatment at 6â months. Patients were categorised based on the underlying phenotype and response to treatment. Methods: Retrospective data on 2397 patients who were diagnosed according to standard guidelines of the American College of Chest Physicians were analysed. Quality of life was captured via the Leicester Cough Questionnaire, the Cough Numeric Rating Scale and the Hospital Anxiety and Depression Scale. Results: Mean patient age was 59â years; 62.5% of the patients were female; and 69.1% had at least one underlying phenotype associated with chronic cough. Of the latter, 52.1% had bronchial hyperresponsiveness/airflow limitation, 33.3% had airway reflux and 20.1% had upper airway cough syndrome. 46% of patients with a phenotype, and 51% without, experienced no improvement in their quality of life or still had significant cough remaining after 6â months. Of patients with available quality-of-life data, 37.5% were categorised as having refractory chronic cough, and 9.5% were categorised as unexplained chronic cough. Discussion: This study highlights the poor quality-of-life outcomes in patients with chronic cough, despite interventions to treat underlying conditions, and indicates a need to manage chronic cough irrespective of phenotype.
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The first example of an intramolecular asymmetric reductive amination of a dialkyl ketone with an aliphatic amine has been developed for the synthesis of Suvorexant (MK-4305), a potent dual Orexin antagonist under development for the treatment of sleep disorders. This challenging transformation is mediated by a novel Ru-based transfer hydrogenation catalyst that provides the desired diazepane ring in 97% yield and 94.5% ee. Mechanistic studies have revealed that CO(2), produced as a necessary byproduct of this transfer hydrogenation reaction, has pronounced effects on the efficiency of the Ru catalyst, the form of the amine product, and the kinetics of the transformation. A simple kinetic model explains how product inhibition by CO(2) leads to overall first-order kinetics, but yields an apparent zero-order dependence on initial substrate concentration. The deleterious effects of CO(2) on reaction rates and product isolation can be overcome by purging CO(2) from the system. Moreover, the rate of ketone hydrogenation can be greatly accelerated by purging of CO(2) or trapping with nucleophilic secondary amines.
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Azepinas/síntese química , Rutênio/química , Triazóis/síntese química , Aminação , Catálise , Hidrogenação , Peptídeos e Proteínas de Sinalização Intracelular/antagonistas & inibidores , Cinética , Neuropeptídeos/antagonistas & inibidores , Orexinas , EstereoisomerismoRESUMO
BACKGROUND: Patients with type 2 diabetes mellitus characteristically display an atherogenic lipid profile with high triglyceride concentrations, low high-density lipoprotein cholesterol (HDL-C) concentrations and low-density lipoprotein cholesterol (LDL-C) concentrations not always elevated. It is unclear if patients with diabetes who present with an acute coronary syndrome (ACS) receive different or more-potent lipid-lowering therapy (LLT). AIMS: To investigate lipid abnormalities in patients with and without type 2 diabetes hospitalised for an ACS, and use of LLT before admission and 4 months after the event. METHODS: Patients were included in the observational DYSIS II study if they were hospitalised for an ACS and had a full lipid profile. RESULTS: Of 3803 patients, diabetes was documented in 1344 (54.7%). Compared to patients without diabetes, those with diabetes had a lower mean LDL-C (101.2 vs. 112.0mg/dL; 2.6 vs. 2.9mmol/L; P<0.0001), with a greater proportion attaining concentrations<70mg/dL (1.8mmol/L) (23.9% vs. 16.0%; P<0.0001) and<55mg/dL (1.4mmol/L) (11.3% vs. 7.3%; P<0.0001), a higher mean triglyceride concentration (139.0 vs. 121.0mg/dL; 1.6 vs. 1.4mmol/L; P<0.0001) and a lower HDL-C concentration. LLT was more commonly given to patients with diabetes (77.5% vs. 58.8%; P<0.0001); there were no differences in types of therapy prescribed. Four months after hospitalisation, most patients from both groups were being treated with LLT (predominantly statin monotherapy). CONCLUSIONS: Despite the different lipid profiles, the type of LLT prescribed did not vary depending on the presence or absence of type 2 diabetes. There was no difference in LLT in patients with and without diabetes at 4-month follow-up, except for fibrates, which were used in 2% of patients with and 1% of patients without diabetes. Statin monotherapy of intermediate potency was the predominant treatment in both groups.
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Síndrome Coronariana Aguda/epidemiologia , Diabetes Mellitus Tipo 2/epidemiologia , Dislipidemias/tratamento farmacológico , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Lipídeos/sangue , Síndrome Coronariana Aguda/diagnóstico , Síndrome Coronariana Aguda/terapia , Idoso , Biomarcadores/sangue , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/terapia , Dislipidemias/sangue , Dislipidemias/diagnóstico , Dislipidemias/epidemiologia , Feminino , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Admissão do Paciente , Fatores de Risco , Resultado do TratamentoRESUMO
Previous syntheses of the biologically active 2-aminated benzoxazoles have relied on forcing thermal conditions to generate the products directly from the corresponding thiols. The resulting yields have ranged from moderate to poor. A mild and high-yielding alternative one-pot chlorination-amination procedure is described. Compounds with a variety of substitution patterns are reported and the methodology has been successfully extended to benzothiazoles. Palladium catalysis on suitably activated examples has been employed to generate the desired compounds of interest.
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Benzotiazóis/síntese química , Benzoxazóis/síntese química , Hidrocarbonetos Halogenados/química , Aminação , Benzotiazóis/química , Benzoxazóis/química , Catálise , Espectroscopia de Ressonância Magnética/métodos , Estrutura Molecular , Relação Estrutura-Atividade , Compostos de Sulfidrila/química , TemperaturaRESUMO
PURPOSE: While statins are used as first-line treatments for high-risk patients with hypercholesterolemia, statin monotherapy is often insufficient to achieve target low-density lipoprotein cholesterol (LDL-C) levels. Second-line treatment options include up-titration of statin dose, switching to a more potent statin, or combination therapy, e.g., with ezetimibe. The aim of this study was to evaluate the efficacy of adding ezetimibe to simvastatin, atorvastatin, or rosuvastatin monotherapy versus doubling the dosage or switching to a higher-potency statin in a population of patients with hypocholesterolemia at high risk of cardiovascular disease (CVD) and who had been previously treated with a statin. METHODS: A systematic literature search was performed and evidence bases were established for populations of atorvastatin-, simvastatin-, and rosuvastatin-experienced patients using eligible randomized controlled trials (RCTs). Based on the available data, we constructed networks of evidence and conducted a Bayesian network meta-analysis (NMA) within each statin population. The primary outcome of interest was percent change from baseline in LDL-C. Changes in total cholesterol were explored as a secondary outcome. FINDINGS: Across all patient populations, 35 RCTs were identified and included in the evidence base. Among patients on simvastatin therapy, the addition of ezetimibe resulted in a mean difference (MD) in LDL-C of - 13.62% (95% CrI - 19.99, - 6.91; see table below) compared to doubling the starting dose of simvastatin. In the population of patients on atorvastatin therapy, the addition of ezetimibe resulted in an MD in LDL-C of - 14.71% (95% CrI - 16.46, - 12.95) compared to doubling the starting dose of atorvastatin. The addition of ezetimibe to rosuvastatin resulted in an MD in LDL-C of - 14.96% (95% CrI - 17.79, - 12.11), compared to doubling the starting rosuvastatin dose. Similar trends were observed for changes in total cholesterol. IMPLICATIONS: Given the available data, the addition of ezetimibe to ongoing simvastatin, atorvastatin, or rosuvastatin monotherapy offers greater reduction in LDL-C among patients at high risk of CVD compared to doubling the initial statin dose.
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Doenças Cardiovasculares/prevenção & controle , Ezetimiba/uso terapêutico , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Hipercolesterolemia/tratamento farmacológico , Anticolesterolemiantes/uso terapêutico , Teorema de Bayes , Biomarcadores/sangue , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/etiologia , LDL-Colesterol/sangue , LDL-Colesterol/efeitos dos fármacos , Quimioterapia Combinada , Saúde Global , Humanos , Hipercolesterolemia/complicações , Incidência , Fatores de RiscoRESUMO
BACKGROUND: Careful management of lipid abnormalities in patients with coronary heart disease (CHD) or an acute coronary syndrome (ACS) can reduce the risk of recurrent cardiovascular events. The extent of hyperlipidemia in these very high-risk patients in the United Arab Emirates (UAE), along with the treatment strategies employed, is not clear. METHODS: The Dyslipidemia International Study II was a multinational observational analysis carried out from 2012 to 2014. Patients were enrolled if they had either stable CHD or an ACS. Patient characteristics, lipid levels, and use of lipid-lowering therapy (LLT) were recorded at enrollment. For the ACS patients, the LLT used during the 4 months' follow-up period was documented, as were any cardiovascular events. RESULTS: A total of 416 patients were recruited from two centers in the UAE, 216 with stable CHD and 200 hospitalized with an ACS. Comorbidities and cardiovascular risk factors were extremely common. A low-density lipoprotein cholesterol level of <70 mg/dl, recommended for patients at very high cardiovascular risk, was attained by 39.3% of the LLT-treated CHD patients and 33.3% of the LLT-treated ACS patients at enrollment. The mean atorvastatin-equivalent daily statin dose was 29 ± 15 mg for the CHD patients, with 13.7% additionally using ezetimibe. For the ACS patients, the daily dosage was 23 ± 13 mg at admission, rising to 39 ± 12 mg by the end of the 4-month follow-up. The use of nonstatin agents was extremely low in this group. CONCLUSIONS: Despite LLT being widely used, hyperlipidemia was found to be prevalent in ACS and CHD patients in the UAE. Treatment strategies need to be significantly improved to reduce the rate of cardiovascular events in these very high-risk patients.
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BACKGROUND: As mortality due to cardiovascular disease increases throughout the world, accurate data on risk factors such as hyperlipidemia are required. This is lacking in the Asia-Pacific region. DESIGN: The observational Dyslipidemia International Study (DYSIS) II was established to quantify the extent of hyperlipidemia in adults with acute and stable coronary heart disease globally. METHODS: Patients with stable coronary heart disease or hospitalised with an acute coronary syndrome were enrolled across nine Asia-Pacific countries from July 2013 to October 2014. Lipid-lowering therapy and low-density lipoprotein cholesterol target attainment (<70 mg/dL) were assessed. The acute coronary syndrome cohort was followed up 4 months post-discharge. RESULTS: Of the 4592 patients enrolled, 2794 had stable coronary heart disease and 1798 were admitted with an acute coronary syndrome. In the coronary heart disease cohort, the mean low-density lipoprotein cholesterol level was 86.9 mg/dL, with 91.7% using lipid-lowering therapy and 31% achieving low-density lipoprotein cholesterol of less than 70 mg/dL. In the acute coronary syndrome cohort at admission, the corresponding values were 103.2 mg/dL, 63.4% and 23.0%, respectively. Target attainment was significantly higher in lipid-lowering therapy-treated than non-treated patients in each cohort (32.6% vs. 12.9% and 31.1% vs. 9.0%, respectively). Mean atorvastatin-equivalent dosages were low (20 ± 15 and 22 ± 18 mg/day, respectively), with little use of non-statin adjuvants (13.0% and 6.8%, respectively). Low-density lipoprotein cholesterol target attainment had improved by follow-up for the acute coronary syndrome patients, but remained low (41.7%). CONCLUSIONS: Many patients in Asia at very high risk of recurrent cardiovascular events had a low-density lipoprotein cholesterol level above the recommended target. Although lipid-lowering therapy was common, it was not used to its full potential.
Assuntos
Síndrome Coronariana Aguda/etnologia , Anticolesterolemiantes/uso terapêutico , LDL-Colesterol/sangue , Doença das Coronárias/etnologia , Dislipidemias/tratamento farmacológico , Síndrome Coronariana Aguda/mortalidade , Síndrome Coronariana Aguda/terapia , Idoso , Ásia/epidemiologia , Biomarcadores/sangue , Doença das Coronárias/mortalidade , Doença das Coronárias/terapia , Estudos Transversais , Dislipidemias/sangue , Dislipidemias/etnologia , Dislipidemias/mortalidade , Feminino , Fidelidade a Diretrizes , Humanos , Masculino , Pessoa de Meia-Idade , Guias de Prática Clínica como Assunto , Padrões de Prática Médica , Recidiva , Fatores de Risco , Fatores de Tempo , Resultado do TratamentoRESUMO
OBJECTIVES: To provide an overview of the extent of hyperlipidemia in very high-risk patients, and how lipid-lowering therapy (LLT) is used in a real-world setting. Methods: In this multicenter observational study, data were collected from LLT-treated patients with stable CHD or an ACS in Saudi Arabia between 2013 and 2014. Individuals were included if they were greater than 18 years and had a full lipid profile available, recorded either prior to the baseline physician visit (CHD patients) or within 24-hours of admission to hospital (ACS patients). Results: A total of 737 patients were included in the study, 597 with stable CHD and 140 with ACS. Few patients in either group had an LDL-C level of greater than 70 mg/dl, which is advocated for very high-risk patients (24.3% and 11.4%, respectively). The median distances to this value were 19.0 mg/dl (CHD) and 25.0 mg/dl (ACS). Low doses of statins were being utilized (31 and 24 mg/day for CHD and ACS, respectively), with only minimal intensification for the ACS patients after hospital admission (41 mg/day at follow-up). Conclusions: Achievement of recommended LDL-C levels was poor for patients with stable CHD or an ACS. Statin intensity was low, indicating huge scope for intensifying the treatment of these very high-risk patients.
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Síndrome Coronariana Aguda/epidemiologia , Doença das Coronárias/epidemiologia , Hiperlipidemias/epidemiologia , Idoso , LDL-Colesterol/sangue , Feminino , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Hiperlipidemias/sangue , Hiperlipidemias/tratamento farmacológico , Hipolipemiantes/uso terapêutico , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Planejamento de Assistência ao Paciente , Prevalência , Arábia Saudita/epidemiologia , Resultado do TratamentoRESUMO
BACKGROUND: Guidelines recommend lifestyle modification and medications to control risk factors in coronary heart disease (CHD). Using data from the observational DYSIS II study, we sought to evaluate the use of guideline-recommended treatments at discharge for acute coronary syndromes (ACS) or in the chronic phase for CHD, and participation in rehabilitation/secondary prevention programs. METHODS AND RESULTS: Between 2013 and 2014, 10,661 patients (3867 with ACS, 6794 with stable CHD) were enrolled in 332 primary and secondary care centers in 18 countries (Asia, Europe, Middle East). Patients with incident ACS were younger and more likely to be smokers than patients with recurrent ACS or stable CHD (both pâ¯<â¯0.0001). Sedentary lifestyle was common (44.4% of ACS patients; 44.2% of stable CHD patients); 22.8% of ACS patients and 24.3% of stable CHD patients were obese. Prevalence of low high-density lipoprotein cholesterol (<40â¯mg/dL in men/50â¯mg/dL in women) was 46.9% in chronic CHD and 55.0% in ACS. Rates of secondary prevention medications were lower among CHD versus ACS (all pâ¯<â¯0.0001): antiplatelet 94.3% vs 98.0%, beta-blocker 72.0% vs 80.0%, lipid-lowering therapy 94.7 vs 97.5%, and angiotensin-converting enzyme inhibitors/angiotensin-receptor blockers 69.4% vs 73.7%, respectively. Attendance at cardiac rehabilitation (16.8% of patients with a first ACS, 10.8% with recurrent ACS) or a secondary prevention program (3.7% of ACS and 11.7% of stable CHD patients) was infrequent. CONCLUSIONS: The high prevalence of risk factors in all CHD patients and reduced rates of secondary prevention medications in stable CHD offer areas for improvement. TRANSLATIONAL ASPECTS: The findings of DYSIS II may reinforce the importance of adopting a healthy lifestyle and prescribing (by clinicians) and adhering (by patients) to evidence-based medications in the management of CHD, not only during the short term but also over the longer term after a cardiac ischemic event. The results may help to increase the proportion of ACS patients who are referred to cardiac rehabilitation centres.
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Doença das Coronárias/epidemiologia , Doença das Coronárias/terapia , Gerenciamento Clínico , Internacionalidade , Guias de Prática Clínica como Assunto/normas , Idoso , Estudos de Coortes , Doença das Coronárias/diagnóstico , Feminino , Estilo de Vida Saudável , Humanos , Masculino , Adesão à Medicação , Pessoa de Meia-IdadeRESUMO
BACKGROUND: Patients with coronary heart disease (CHD) and survivors of acute coronary syndrome (ACS) are at very high risk for adverse cardiovascular events. Lowering low-density lipoprotein cholesterol (LDL-C) can reduce the risk, with effective lipid-lowering therapy (LLT) readily available; however, dyslipidemia remains prevalent throughout Europe. DESIGN: The observational Dyslipidemia International Study II (DYSIS II) aimed to identify unmet treatment needs in adult ACS and CHD patients. Data for the seven participating European countries are presented herein. METHODS: The study was carried out from December 2012 to November 2014. Use of LLT and attainment of European-guideline-recommended LDL-C targets were assessed. For ACS patients, changes in lipid levels and LLT were evaluated 4 months post-hospitalization. RESULTS: Of the 4344 patients enrolled, 2946 were attending a physician visit for the assessment of stable CHD, while 1398 had been hospitalized for an ACS event. In both patient sets, mean LDL-C levels were high (89.5 and 112.5 mg/dl, respectively) and <70 mg/dl target attainment extremely poor. The mean daily statin dosage (normalized to atorvastatin potency) was 27 ± 20 mg for CHD and 22 ± 17 mg for ACS patients. Treatment was intensified slightly for ACS subjects after hospitalization, with the dosage reaching 35 ± 24 mg/day. LDL-C target attainment was higher by the end of the 4-month follow up (30.9% and 41.5% for patients on LLT and without LLT at baseline, respectively; p < 0.05). CONCLUSION: Elevated blood cholesterol levels are highly prevalent across Europe, with low numbers of coronary patients reaching their recommended LDL-C target. While use of LLT is widespread, there is significant scope for intensifying treatment.
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Síndrome Coronariana Aguda/epidemiologia , Anticolesterolemiantes/uso terapêutico , LDL-Colesterol/sangue , Doença das Coronárias/epidemiologia , Dislipidemias/tratamento farmacológico , Síndrome Coronariana Aguda/terapia , Idoso , Biomarcadores/sangue , Doença das Coronárias/terapia , Dislipidemias/sangue , Dislipidemias/epidemiologia , Europa (Continente)/epidemiologia , Feminino , Fidelidade a Diretrizes , Humanos , Masculino , Pessoa de Meia-Idade , Guias de Prática Clínica como Assunto , Padrões de Prática Médica , Prevalência , Fatores de Risco , Fatores de Tempo , Resultado do TratamentoRESUMO
DYSIS II ACS was a longitudinal, observational study in 3867 patients from 18 countries. They were being hospitalized after suffering an acute coronary syndrome. Evaluations were performed at the time of admission and again 120±15 days following the date of admission (the follow-up time point). 2521 patients were on active lipid lowering treatment (LLT) at admission. Mean atorvastatin dose was 22 mg per day and 2.7% received ezetimibe in combination with a statin. At discharge from hospital, 3767 patients received LLT expressed as a mean atorvastatin dose of 36 mg per day with 4.8% receiving ezetimibe on top of a statin. After 120 days, intensity in lipid lowering treatment was reduced to 32 mg per day with 4.9% of the patients receiving ezetimibe and a statin. Of note, during this 4-month follow up period, only 32% of all patients received laboratory lipid testing. 37% attained the low density lipoprotein cholesterol (LDL-C) target value of <70 mg/dl after 120 days. There are differences in the therapy administered as well as in the switch strategies when comparing the data from the respective countries studied. CONCLUSIONS: Only one in three patients achieved the LDL-C target value following only marginal improvements in atorvastatin dose or combination therapy after an ACS event.
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DYSIS II CHD was a longitudinal, observational study in 6794 patients from 18 countries. They were attending an outpatient physician appointment for coronary heart disease (CHD). 6370 patients (93.8%) were on active lipid lowering therapy (LLT). The mean atorvastatin dose equivalent was 25â¯mg per day and 10.5% received ezetimibe in combination with a statin. The mean low-density lipoprotein cholesterol (LDL-C) level was 88â¯mg/dL, with 29.4% of patients displaying a level below the 70â¯mg/dL target for very high-risk subjects. CONCLUSION: While more than 90% of patients with CHD were on lipid lowering drugs, only three out of ten patients achieved their LDL-C target value.
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A novel method is presented using N-N ylides (prepared by in situ amination of a tertiary amine) for the aziridination of a range of enone systems. The amine may be used sub-stoichiometrically, and promising levels of enantioselectivity are observed with quinine as promoter. [reaction: see text].
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Aminas/química , Aziridinas/síntese química , Cetonas/química , Aziridinas/química , Catálise , Estrutura Molecular , EstereoisomerismoRESUMO
A comparative study of chiral Mo- and Ru-based catalysts to promote enantioselective synthesis of 2,6-disubstituted pyrans and piperidines through asymmetric ring-opening/cross-metathesis (AROM/CM) reactions is presented. These studies demonstrate the critical complementarity that exists between the two classes of chiral catalysts.
Assuntos
Alcenos/química , Compostos Bicíclicos com Pontes/química , Molibdênio/química , Rutênio/química , Catálise , EstereoisomerismoRESUMO
AIMS: This study assessed the cost-effectiveness of ezetimibe with statin therapy vs statin monotherapy from a US payer perspective, assuming the impending patent expiration of ezetimibe. METHODS: A Markov-like economic model consisting of 28 distinct health states was used. Model population data were obtained from US linked claims and electronic medical records, with inclusion criteria based on diagnostic guidelines. Inputs came from recent clinical trials, meta-analyses, and cost-effectiveness analyses. The base-case scenario was used to evaluate the cost-effectiveness of adding ezetimibe 10 mg to statin in patients aged 35-74 years with a history of coronary heart disease (CHD) and/or stroke, and with low-density lipoprotein cholesterol (LDL-C) levels ≥70 mg/dL over a lifetime horizon, assuming a 90% price reduction of ezetimibe after 1 year to take into account the impending patent expiration in the second quarter of 2017. Sub-group analyses included patients with LDL-C levels ≥100 mg/dL and patients with diabetes with LDL-C levels ≥70 mg/dL. RESULTS: The lifetime discounted incremental cost-effectiveness ratio (ICER) for ezetimibe added to statin was $9,149 per quality-adjusted life year (QALY) for the base-case scenario. For patients with LDL-C levels ≥100 mg/dL, the ICER was $839/QALY; for those with diabetes and LDL-C levels ≥70 mg/dL, it was $560/QALY. One-way sensitivity analyses showed that the model was sensitive to changes in cost of ezetimibe, rate reduction of non-fatal CHD, and utility weight for non-fatal CHD in the base-case and sub-group analyses. LIMITATIONS: Indirect costs or treatment discontinuation estimation were not included. CONCLUSIONS: Compared with statin monotherapy, ezetimibe with statin therapy was cost-effective for secondary prevention of CHD and stroke and for primary prevention of these conditions in patients whose LDL-C levels are ≥100 mg/dL and in patients with diabetes, taking into account a 90% cost reduction for ezetimibe.
Assuntos
Anticolesterolemiantes/economia , Doença das Coronárias/tratamento farmacológico , Ezetimiba/economia , Inibidores de Hidroximetilglutaril-CoA Redutases/economia , Acidente Vascular Cerebral/tratamento farmacológico , Adulto , Idoso , Anticolesterolemiantes/uso terapêutico , LDL-Colesterol/sangue , Doença das Coronárias/epidemiologia , Análise Custo-Benefício , Diabetes Mellitus/tratamento farmacológico , Diabetes Mellitus/epidemiologia , Quimioterapia Combinada , Ezetimiba/uso terapêutico , Honorários Farmacêuticos , Feminino , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Masculino , Cadeias de Markov , Pessoa de Meia-Idade , Modelos Econômicos , Anos de Vida Ajustados por Qualidade de Vida , Acidente Vascular Cerebral/epidemiologia , Estados UnidosRESUMO
BACKGROUND: The 2008 Ezetimibe and Simvastatin in Hypercholesterolemia Enhances Atherosclerosis Regression (ENHANCE) study demonstrated ezetimibe + simvastatin vs simvastatin alone had a neutral effect on the surrogate endpoint of carotid intima-media thickness. Subsequent media portrayal of the study prompted ezetimibe discontinuation in many patients. OBJECTIVE: The objective of the study was to assess the impact of ENHANCE reporting on ezetimibe discontinuation, low-density lipoprotein cholesterol (LDL-C) changes, and potential cardiovascular disease (CVD) risk. METHODS: This analysis used claims data in a retrospective, observational study of patients receiving ezetimibe + statin and compared LDL-C for patients who discontinued ezetimibe (n = 970) vs those who continued ezetimibe + statins (n = 3706) after ENHANCE results disclosure. Change in relative CVD risk was estimated from the absolute LDL-C difference between groups per the Cholesterol Treatment Trialists' meta-analysis of statin trials. RESULTS: The rate of ezetimibe discontinuation was 2% in the 6 months before and 21% in the 6 months after reporting of ENHANCE results. Among patients who ultimately discontinued vs continued ezetimibe, respective mean LDL-C levels were 79.8 and 78.3 mg/dL 6 months before reporting of the ENHANCE results and 93.5 and 78.1 mg/dL 6 months after reporting of ENHANCE. Predictive application of the Cholesterol Treatment Trialists' meta-analysis suggested the 13.9 mg/dL increase in mean LDL-C translated to a 9.4% increase in relative CVD risk for those who discontinued ezetimibe. CONCLUSION: After reporting of the neutral ENHANCE results, ezetimibe discontinuation rate increased, LDL-C levels increased, and predicted CVD risk increased among those who discontinued ezetimibe. Characterization of clinical outcomes regarding lipid-altering agents based on surrogate biomarker studies not designed to assess CVD outcomes may be misleading, potentially placing patients at increased CVD risk.