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1.
J Multimorb Comorb ; 13: 26335565231154447, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36762033

RESUMO

Background: Despite the great individual and societal burden associated with multimorbidity, little is known about how to effectively manage it. Objective: The aim of this multicenter randomized controlled trial (RCT) is to investigate the 12-month effects of a personalized exercise therapy and self-management support program in addition to usual care in people with multimorbidity. Design: This is a protocol for a pragmatic, parallel-group (1:1 ratio), superiority RCT conducted at five intervention sites (two hospitals, a private practice physiotherapy clinic and two municipal rehabilitation centers) in Region Zealand, Denmark. A total of 228 persons with multimorbidity aged 18 years or older, will be randomly allocated to one of two groups. Both groups will receive usual care, defined as routine care for multimorbidity at the discretion of the treating doctor, while the intervention group will also participate in a 12-week exercise therapy and self-management support program tailored to people with multimorbidity at one of the intervention sites. The primary outcome will be the between-group difference in change in EQ-5D-5L from baseline to the follow-up at 12 months. Secondary outcomes include objectively-measured physical function and physical activity, inflammatory markers, disease and treatment burden, anxiety, depression, stress, sleep, pain and other self-reported parameters. In parallel with the RCT, an observational cohort will follow persons aged ≥18 years with multimorbidity not adhering to all eligibility criteria, as well as people fulfilling all eligibility criteria, but unwilling to participate in the RCT. This study was approved by the Regional Committee on Health Research Ethics for Region Zealand (SJ-857) and results will be communicated in scientific papers, at relevant conferences and to a broader audience. Discussion: Exercise therapy and self-management support is safe and effective in people with single conditions. However, it is still unclear whether this holds true for individuals with multimorbidity. This pragmatic, multicenter RCT will provide high-quality evidence on the benefits and harms of exercise therapy and self-management support and, if the results support it, lead to the development of a plan for implementation in clinical practice.

2.
Clin Pharmacol Ther ; 108(5): 1067-1077, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32472697

RESUMO

Antiplatelet response to clopidogrel shows wide variation, and poor response is correlated with adverse clinical outcomes. CYP2C19 loss-of-function alleles play an important role in this response, but account for only a small proportion of variability in response to clopidogrel. An aim of the International Clopidogrel Pharmacogenomics Consortium (ICPC) is to identify other genetic determinants of clopidogrel pharmacodynamics and clinical response. A genomewide association study (GWAS) was performed using DNA from 2,750 European ancestry individuals, using adenosine diphosphate-induced platelet reactivity and major cardiovascular and cerebrovascular events as outcome parameters. GWAS for platelet reactivity revealed a strong signal for CYP2C19*2 (P value = 1.67e-33). After correction for CYP2C19*2 no other single-nucleotide polymorphism reached genomewide significance. GWAS for a combined clinical end point of cardiovascular death, myocardial infarction, or stroke (5.0% event rate), or a combined end point of cardiovascular death or myocardial infarction (4.7% event rate) showed no significant results, although in coronary artery disease, percutaneous coronary intervention, and acute coronary syndrome subgroups, mutations in SCOS5P1, CDC42BPA, and CTRAC1 showed genomewide significance (lowest P values: 1.07e-09, 4.53e-08, and 2.60e-10, respectively). CYP2C19*2 is the strongest genetic determinant of on-clopidogrel platelet reactivity. We identified three novel associations in clinical outcome subgroups, suggestive for each of these outcomes.


Assuntos
Plaquetas/efeitos dos fármacos , Doenças Cardiovasculares/prevenção & controle , Clopidogrel/uso terapêutico , Doença da Artéria Coronariana/terapia , Citocromo P-450 CYP2C19/genética , Intervenção Coronária Percutânea , Variantes Farmacogenômicos , Inibidores da Agregação Plaquetária/uso terapêutico , Polimorfismo de Nucleotídeo Único , Idoso , Plaquetas/metabolismo , Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/genética , Doenças Cardiovasculares/mortalidade , Clopidogrel/efeitos adversos , Doença da Artéria Coronariana/mortalidade , Citocromo P-450 CYP2C19/metabolismo , Feminino , Estudo de Associação Genômica Ampla , Humanos , Masculino , Pessoa de Meia-Idade , Intervenção Coronária Percutânea/efeitos adversos , Intervenção Coronária Percutânea/mortalidade , Farmacogenética , Inibidores da Agregação Plaquetária/efeitos adversos , Medição de Risco , Fatores de Risco , Resultado do Tratamento
3.
Eur Heart J Cardiovasc Pharmacother ; 6(4): 203-210, 2020 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-31504375

RESUMO

AIMS: Clopidogrel is prescribed for the prevention of atherothrombotic events. While investigations have identified genetic determinants of inter-individual variability in on-treatment platelet inhibition (e.g. CYP2C19*2), evidence that these variants have clinical utility to predict major adverse cardiovascular events (CVEs) remains controversial. METHODS AND RESULTS: We assessed the impact of 31 candidate gene polymorphisms on adenosine diphosphate (ADP)-stimulated platelet reactivity in 3391 clopidogrel-treated coronary artery disease patients of the International Clopidogrel Pharmacogenomics Consortium (ICPC). The influence of these polymorphisms on CVEs was tested in 2134 ICPC patients (N = 129 events) in whom clinical event data were available. Several variants were associated with on-treatment ADP-stimulated platelet reactivity (CYP2C19*2, P = 8.8 × 10-54; CES1 G143E, P = 1.3 × 10-16; CYP2C19*17, P = 9.5 × 10-10; CYP2B6 1294 + 53 C > T, P = 3.0 × 10-4; CYP2B6 516 G > T, P = 1.0 × 10-3; CYP2C9*2, P = 1.2 × 10-3; and CYP2C9*3, P = 1.5 × 10-3). While no individual variant was associated with CVEs, generation of a pharmacogenomic polygenic response score (PgxRS) revealed that patients who carried a greater number of alleles that associated with increased on-treatment platelet reactivity were more likely to experience CVEs (ß = 0.17, SE 0.06, P = 0.01) and cardiovascular-related death (ß = 0.43, SE 0.16, P = 0.007). Patients who carried eight or more risk alleles were significantly more likely to experience CVEs [odds ratio (OR) = 1.78, 95% confidence interval (CI) 1.14-2.76, P = 0.01] and cardiovascular death (OR = 4.39, 95% CI 1.35-14.27, P = 0.01) compared to patients who carried six or fewer of these alleles. CONCLUSION: Several polymorphisms impact clopidogrel response and PgxRS is a predictor of cardiovascular outcomes. Additional investigations that identify novel determinants of clopidogrel response and validating polygenic models may facilitate future precision medicine strategies.


Assuntos
Clopidogrel/uso terapêutico , Doença da Artéria Coronariana/terapia , Técnicas de Apoio para a Decisão , Intervenção Coronária Percutânea , Variantes Farmacogenômicos , Inibidores da Agregação Plaquetária/uso terapêutico , Agregação Plaquetária/efeitos dos fármacos , Polimorfismo de Nucleotídeo Único , Idoso , Isquemia Encefálica/mortalidade , Isquemia Encefálica/prevenção & controle , Clopidogrel/efeitos adversos , Doença da Artéria Coronariana/sangue , Doença da Artéria Coronariana/diagnóstico , Doença da Artéria Coronariana/mortalidade , Trombose Coronária/mortalidade , Trombose Coronária/prevenção & controle , Europa (Continente) , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/mortalidade , Infarto do Miocárdio/prevenção & controle , Intervenção Coronária Percutânea/efeitos adversos , Intervenção Coronária Percutânea/instrumentação , Intervenção Coronária Percutânea/mortalidade , Agregação Plaquetária/genética , Inibidores da Agregação Plaquetária/efeitos adversos , Valor Preditivo dos Testes , Medição de Risco , Fatores de Risco , Stents , Acidente Vascular Cerebral/mortalidade , Acidente Vascular Cerebral/prevenção & controle , Resultado do Tratamento
4.
Am Heart J ; 198: 152-159, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29653637

RESUMO

RATIONALE: The P2Y12 receptor inhibitor clopidogrel is widely used in patients with acute coronary syndrome, percutaneous coronary intervention, or ischemic stroke. Platelet inhibition by clopidogrel shows wide interpatient variability, and high on-treatment platelet reactivity is a risk factor for atherothrombotic events, particularly in high-risk populations. CYP2C19 polymorphism plays an important role in this variability, but heritability estimates suggest that additional genetic variants remain unidentified. The aim of the International Clopidogrel Pharmacogenomics Consortium (ICPC) is to identify genetic determinants of clopidogrel pharmacodynamics and clinical response. STUDY DESIGN: Based on the data published on www.clinicaltrials.gov, clopidogrel intervention studies containing genetic and platelet function data were identified for participation. Lead investigators were invited to share DNA samples, platelet function test results, patient characteristics, and cardiovascular outcomes to perform candidate gene and genome-wide studies. RESULTS: In total, 17 study sites from 13 countries participate in the ICPC, contributing individual patient data from 8,829 patients. Available adenosine diphosphate-stimulated platelet function tests included vasodilator-stimulated phosphoprotein assay, light transmittance aggregometry, and the VerifyNow P2Y12 assay. A proof-of-principle analysis based on genotype data provided by each group showed a strong and consistent association between CYP2C19*2 and platelet reactivity (P value=5.1 × 10-40). CONCLUSION: The ICPC aims to identify new loci influencing clopidogrel efficacy by using state-of-the-art genetic approaches in a large cohort of clopidogrel-treated patients to better understand the genetic basis of on-treatment response variability.


Assuntos
Síndrome Coronariana Aguda/tratamento farmacológico , Clopidogrel/uso terapêutico , Estudo de Associação Genômica Ampla , Terapia de Alvo Molecular/métodos , Receptores Purinérgicos P2Y12/genética , Síndrome Coronariana Aguda/diagnóstico , Síndrome Coronariana Aguda/mortalidade , Idoso , Feminino , Estudos de Associação Genética , Humanos , Internacionalidade , Masculino , Pessoa de Meia-Idade , Farmacogenética , Prognóstico , Receptores Purinérgicos P2Y12/efeitos dos fármacos , Medição de Risco , Taxa de Sobrevida , Resultado do Tratamento
5.
EuroIntervention ; 12(14): 1782-1788, 2017 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-28216475

RESUMO

AIMS: Patients in a coma after cardiac arrest may have adversely affected drug absorption and metabolism. This study, the first of its kind, aimed to investigate the early pharmacokinetic and pharmacodynamic effects of ticagrelor administered through a nasogastric tube (NGT) to patients resuscitated after an out of hospital cardiac arrest (OHCA) and undergoing primary percutaneous coronary intervention (pPCI). METHODS AND RESULTS: Blood samples were drawn at baseline and at two, four, six, eight, 12, and 24 hours and then daily for up to five days after administration of a 180 mg ticagrelor loading dose (LD), followed by 90 mg twice daily in 44 patients. The primary endpoint was the occurrence of high platelet reactivity (HPR) 12 hours after the LD. Assessment by VerifyNow (VFN) showed 96 (15.25-140.5) platelet reactivity units (PRU), and five (12%) patients exhibited HPR. Multiplate analysis showed 19 (12-29) units (U) at twelve hours, and three patients (7%) had HPR. Ticagrelor and its main metabolite AR-C124910XX concentrations were 85.2 (37.2-178.5) and 18.3 (6.4-52.4) ng/mL. Median times to sufficient platelet inhibition below the HPR limit were 3 (2-6) hours (VFN) and 4 (2-8) hours (Multiplate). CONCLUSIONS: Ticagrelor, administered as crushed tablets through a nasogastric tube, leads to sufficient platelet inhibition after 12 hours, and in many cases earlier, in the vast majority of patients undergoing pPCI and subsequent intensive care management after an OHCA.


Assuntos
Adenosina/análogos & derivados , Intervenção Coronária Percutânea , Antagonistas do Receptor Purinérgico P2Y/uso terapêutico , Adenosina/administração & dosagem , Adenosina/uso terapêutico , Plaquetas/efeitos dos fármacos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/terapia , Intervenção Coronária Percutânea/métodos , Inibidores da Agregação Plaquetária/administração & dosagem , Inibidores da Agregação Plaquetária/uso terapêutico , Testes de Função Plaquetária , Antagonistas do Receptor Purinérgico P2Y/administração & dosagem , Ticagrelor
6.
Am J Cardiol ; 117(11): 1735-40, 2016 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-27062938

RESUMO

Some patients presenting with ST-segment elevation myocardial infarction (STEMI) have complete ST resolution in the electrocardiogram, which may be clinical useful in the triage of patients with STEMI. However, the importance of complete ST resolution in these patients remains uncertain. Thus, the purpose was to describe the prognosis of patients with complete ST resolution before primary percutaneous coronary intervention (PCI). Continuous ST monitoring from arrival until 90 minutes after PCI was performed in 933 patients with STEMI. Complete ST resolution was defined as no residual significant ST elevations before intervention. The patients were followed clinically for 5.5 years (range 0 to 6.8 years). Infarct size and myocardial salvage were assessed in a subgroup of patients (n = 221) by cardiovascular magnetic resonance. Complete ST resolution was observed in 24% of the patients, who had a higher incidence of Thrombolysis In Myocardial Infarction grade 2/3 flow before intervention (64% vs 24%), smaller infarct size (6% vs 11%), and higher myocardial salvage index (0.82 vs 0.69; all p <0.001) compared with patients with continuous ST elevations. Complete ST resolution was associated with a significantly lower rate of the composite end point of all-cause death and admission for heart failure (14% vs 22%; p = 0.006) although it only tended to be an independent predictor in a multivariate analysis (hazard ratio 0.69, 95% CI 0.49 to 1.06; p = 0.09). In conclusion, compared to patients without incomplete ST resolution, patients with STEMI and complete ST resolution before primary PCI have a higher incidence of normalized epicardial flow before PCI, a larger myocardial salvage and smaller infarct size after the procedure and presumably improved long-term outcome compared with incomplete ST resolution.


Assuntos
Eletrocardiografia , Intervenção Coronária Percutânea/métodos , Recuperação de Função Fisiológica , Infarto do Miocárdio com Supradesnível do Segmento ST/cirurgia , Angiografia Coronária , Feminino , Seguimentos , Humanos , Imagem Cinética por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Infarto do Miocárdio com Supradesnível do Segmento ST/diagnóstico , Infarto do Miocárdio com Supradesnível do Segmento ST/fisiopatologia , Fatores de Tempo , Resultado do Tratamento
7.
EuroIntervention ; 10(4): 466-74, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-25138184

RESUMO

AIMS: To evaluate the clinical importance of the ST peak phenomenon during primary percutaneous coronary intervention (PCI) in patients with ST-segment elevation myocardial infarction (STEMI). METHODS AND RESULTS: Continuous ST monitoring was performed in 942 STEMI patients from arrival until 90 minutes after revascularisation. ST peak was defined as ≥1 mm increase in the ST-segment during PCI compared with the ST elevation before intervention. ST peak was observed in 26.9% of patients. During median follow-up of 4.1 years, 20.7% of patients experienced a major adverse cardiac event (MACE). ST peak was associated with higher rates of mortality (13.4% versus 9.3%; p=0.044), admission for heart failure (10.6% versus 5.2%; p=0.002) and MACE (26.9% versus 18.2%; p=0.002), but not reinfarction (7.1% versus 5.2%; p=0.14). In two different Cox regression analyses, adjusting for predictors of MACE and ST peak including ST resolution and epicardial flow, ST peak remained significantly associated with MACE: adjusted hazard ratio (HR) 1.40 (95% confidence interval [CI] 1.01-1.95) and 1.41 (95% CI: 1.02-1.96). CONCLUSIONS: In the largest study hitherto evaluating the ST peak phenomenon during primary PCI, we demonstrated that ST peak is a strong predictor of adverse long-term outcome and provides independent prognostic information beyond that provided by ST resolution and epicardial flow.


Assuntos
Insuficiência Cardíaca/diagnóstico , Coração/fisiopatologia , Infarto do Miocárdio/diagnóstico , Intervenção Coronária Percutânea , Idoso , Diagnóstico Precoce , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/fisiopatologia , Miocárdio/patologia , Intervenção Coronária Percutânea/métodos , Prognóstico , Resultado do Tratamento
8.
J Electrocardiol ; 45(6): 708-16, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22832151

RESUMO

BACKGROUND AND PURPOSE: One third of patients treated with primary percutaneous coronary intervention (PCI) for ST-elevation myocardial infarction develop a secondary increase in electrocardiographic ST segment (ST peak) during reperfusion. The purpose was to determine the clinical importance of ST peak during primary PCI. METHODS: A total of 363 patients with ST-elevation myocardial infarction were stratified to no ST peak or ST peak. Final infarct size and ejection fraction (EF) were assessed by cardiovascular magnetic resonance. RESULTS: Patients with ST peak had a larger infarct size (14% vs 10%; P = .003) and lower EF (53% vs 57%; P = .022). Rates of cardiac mortality (8% vs 3%; P = .047) and cardiac events (cardiac mortality and admission for heart failure; 19% vs 10%; P = .018) were higher among patients with ST peak, but not all-cause mortality (8% vs 5%; P = .46). In a multivariable Cox regression analysis, ST peak remained significantly associated with cardiac events (adjusted hazard ratio, 2.03 [1.08-3.82]). CONCLUSION: ST peak during primary PCI is related to larger final infarct size, a reduced EF, and adverse cardiac clinical outcome.


Assuntos
Eletrocardiografia/estatística & dados numéricos , Infarto do Miocárdio/mortalidade , Infarto do Miocárdio/cirurgia , Intervenção Coronária Percutânea/mortalidade , Disfunção Ventricular Esquerda/mortalidade , Disfunção Ventricular Esquerda/prevenção & controle , Comorbidade , Dinamarca/epidemiologia , Feminino , Humanos , Masculino , Infarto do Miocárdio/diagnóstico , Prevalência , Prognóstico , Reprodutibilidade dos Testes , Medição de Risco , Sensibilidade e Especificidade , Análise de Sobrevida , Taxa de Sobrevida , Resultado do Tratamento , Disfunção Ventricular Esquerda/diagnóstico
9.
Clin Appl Thromb Hemost ; 17(6): E211-7, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-21406416

RESUMO

The Multiplate, a whole blood (WB) platelet function test, has shown promising results identifying patients on antiplatelet therapy at increased risk of rethrombosis. In the present study, the influence of low platelet count on platelet aggregation was analyzed and compared with aggregation results in an artificial matrix, platelet-rich plasma (PRP). Heparinized and citrated blood was diluted with autologous plasma to platelet concentrations 200 to 25 × 10(9)/L in WB samples (n = 10) and 200 to 100 × 10(9)/L in PRP samples (n = 7). The platelet aggregation was investigated by the ADP-, ASPI-, COL-, and TRAP-test. The WB responses decreased at platelet concentration of ≤100 × 10(9)/L (all P < .03), except for heparin-TRAP (50 × 10(9)/L, P = .008) and citrate-ASPI (150 × 10(9)/L, P = .03). In general, WB samples demonstrated higher aggregation than PRP samples at platelet concentrations 200 to 100 × 10(9)/L (P < .05). In conclusion, platelet concentration of <150 × 10(9)/L may influence Multiplate which should be considered in clinical settings. Furthermore, the findings emphasize the importance of evaluating haemostasis in its natural matrix, WB.


Assuntos
Plaquetas/fisiologia , Agregação Plaquetária/fisiologia , Testes de Função Plaquetária/métodos , Feminino , Humanos , Masculino , Inibidores da Agregação Plaquetária/farmacologia , Contagem de Plaquetas
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