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1.
J Am Coll Cardiol ; 84(9): 790-797, 2024 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-39168564

RESUMO

BACKGROUND: Olpasiran, a small interfering RNA (siRNA), blocks lipoprotein(a) (Lp(a)) production by preventing translation of apolipoprotein(a) mRNA. In phase 2, higher doses of olpasiran every 12 weeks (Q12W) reduced circulating Lp(a) by >95%. OBJECTIVES: This study sought to assess the timing of return of Lp(a) to baseline after discontinuation of olpasiran, as well as longer-term safety. METHODS: OCEAN(a)-DOSE (Olpasiran Trials of Cardiovascular Events And LipoproteiN[a] Reduction-DOSE Finding Study) was a phase 2, dose-finding trial that enrolled 281 participants with atherosclerotic cardiovascular disease and Lp(a) >150 nmol/L to 1 of 4 active doses of olpasiran vs placebo (10 mg, 75 mg, 225 mg Q12W, or an exploratory dose of 225 mg Q24W given subcutaneously). The last dose of olpasiran was administered at week 36; after week 48, there was an extended off-treatment follow-up period for a minimum of 24 weeks. RESULTS: A total of 276 (98.2%) participants entered the off-treatment follow-up period. The median study exposure (treatment combined with off-treatment phases) was 86 weeks (Q1-Q3: 79-99 weeks). For the 75 mg Q12W dose, the off-treatment placebo-adjusted mean percent change from baseline in Lp(a) was -76.2%, -53.0%, -44.0%, and -27.9% at 60, 72, 84, and 96 weeks, respectively (all P < 0.001). The respective off-treatment changes in Lp(a) for the 225 mg Q12W dose were -84.4%, -61.6%, -52.2%, and -36.4% (all P < 0.001). During the extension follow-up phase, no new safety concerns were identified. CONCLUSIONS: Olpasiran is a potent siRNA with prolonged effects on Lp(a) lowering. Participants receiving doses ≥75 mg Q12W sustained a ∼40% to 50% reduction in Lp(a) levels close to 1 year after the last dose. (Olpasiran Trials of Cardiovascular Events And LipoproteiN[a] Reduction-DOSE Finding Study [OCEAN(a)-DOSE]; NCT04270760).


Assuntos
Relação Dose-Resposta a Droga , Lipoproteína(a) , RNA Interferente Pequeno , Humanos , Lipoproteína(a)/sangue , Masculino , Feminino , Pessoa de Meia-Idade , RNA Interferente Pequeno/administração & dosagem , Idoso , Resultado do Tratamento , Método Duplo-Cego , Aterosclerose/tratamento farmacológico , Aterosclerose/sangue , Ácidos Dicarboxílicos , Ácidos Graxos
3.
NEJM Evid ; 3(5): EVIDoa2300349, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38815173

RESUMO

BACKGROUND: Accumulating preclinical and preliminary translational evidence shows that the hypothalamic peptide oxytocin reduces food intake, increases energy expenditure, and promotes weight loss. It is currently unknown whether oxytocin administration is effective in treating human obesity. METHODS: In this randomized, double-blind, placebo-controlled trial, we randomly assigned adults with obesity 1:1 (stratified by sex and obesity class) to receive intranasal oxytocin (24 IU) or placebo four times daily for 8 weeks. The primary end point was change in body weight (kg) from baseline to week 8. Key secondary end points included change in body composition (total fat mass [g], abdominal visceral adipose tissue [cm2], and liver fat fraction [proportion; range, 0 to 1; higher values indicate a higher proportion of fat]), and resting energy expenditure (kcal/day; adjusted for lean mass) from baseline to week 8 and caloric intake (kcal) at an experimental test meal from baseline to week 6. RESULTS: Sixty-one participants (54% women; mean age ± standard deviation, 33.6 ± 6.2 years; body-mass index [the weight in kilograms divided by the square of the height in meters], 36.9 ± 4.9) were randomly assigned. There was no difference in body weight change from baseline to week 8 between oxytocin and placebo groups (0.20 vs. 0.26 kg; P=0.934). Oxytocin (vs. placebo) was not associated with beneficial effects on body composition or resting energy expenditure from baseline to week 8 (total fat: difference [95% confidence interval], 196.0 g [-1036 to 1428]; visceral fat: 3.1 cm2 [-11.0 to 17.2]; liver fat: -0.01 [-0.03 to 0.01]; resting energy expenditure: -64.0 kcal/day [-129.3 to 1.4]). Oxytocin compared with placebo was associated with reduced caloric intake at the test meal (-31.4 vs. 120.6 kcal; difference [95% confidence interval], -152.0 kcal [-302.3 to -1.7]). There were no serious adverse events. Incidence and severity of adverse events did not differ between groups. CONCLUSIONS: In this randomized, placebo-controlled trial in adults with obesity, intranasal oxytocin administered four times daily for 8 weeks did not reduce body weight. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases and others; ClinicalTrials.gov number, NCT03043053.).


Assuntos
Administração Intranasal , Obesidade , Ocitocina , Humanos , Ocitocina/administração & dosagem , Ocitocina/farmacologia , Ocitocina/efeitos adversos , Feminino , Masculino , Adulto , Obesidade/tratamento farmacológico , Método Duplo-Cego , Metabolismo Energético/efeitos dos fármacos , Composição Corporal/efeitos dos fármacos , Ingestão de Energia/efeitos dos fármacos , Redução de Peso/efeitos dos fármacos
4.
Can J Cardiol ; 40(6): 1056-1068, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38593915

RESUMO

Cardiovascular disease has been the leading cause of death in the United States and Canada for decades. Although it affects millions of people across a multitude of backgrounds, notable disparities in cardiovascular health are observed among women and become more apparent when accounting for race and socioeconomic status. Although intrinsic sex-specific physiologic differences predispose women to poorer outcomes, social determinants of health (SDOH) and biases at both the individual provider and the larger health care system levels play an equal, if not greater, role. This review examines socioeconomic disparities in women compared with men regarding cardiovascular risk factors, treatments, and outcomes. Although various at-risk subpopulations exist, we highlight the impact of SDOH in specific populations, including patients with disabilities, transgender persons, and South Asian and Indigenous populations. These groups are underrepresented in studies and experience poorer health outcomes owing to structural barriers to care. These findings emphasise the significance of understanding the interplay of different socioeconomic factors and how their stacking can negatively affect women's cardiovascular health. To address these disparities, we propose a multipronged approach to augment culturally sensitive and patient-centred care. This includes increased cardiovascular workforce diversity, inclusion of underrepresented populations into analyses of cardiovascular metrics, and greater utilisation of technology and telemedicine to improve access to health care. Achieving this goal will necessitate active participation from patients, health care administrators, physicians, and policy makers, and is imperative in closing the cardiovascular health gap for women over the coming decades.


Assuntos
Doenças Cardiovasculares , Saúde da Mulher , Humanos , Canadá/epidemiologia , Feminino , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/etnologia , Doenças Cardiovasculares/terapia , Estados Unidos/epidemiologia , Fatores Socioeconômicos , Disparidades em Assistência à Saúde/estatística & dados numéricos , Disparidades em Assistência à Saúde/etnologia , Determinantes Sociais da Saúde , Disparidades nos Níveis de Saúde , Disparidades Socioeconômicas em Saúde
5.
Semin Thromb Hemost ; 50(5): 773-789, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38428841

RESUMO

Fibrinolytic agents catalyze the conversion of the inactive proenzyme plasminogen into the active protease plasmin, degrading fibrin within the thrombus and recanalizing occluded vessels. The history of these medications dates to the discovery of the first fibrinolytic compound, streptokinase, from bacterial cultures in 1933. Over time, researchers identified two other plasminogen activators in human samples, namely urokinase and tissue plasminogen activator (tPA). Subsequently, tPA was cloned using recombinant DNA methods to produce alteplase. Several additional derivatives of tPA, such as tenecteplase and reteplase, were developed to extend the plasma half-life of tPA. Over the past decades, fibrinolytic medications have been widely used to manage patients with venous and arterial thromboembolic events. Currently, alteplase is approved by the U.S. Food and Drug Administration (FDA) for use in patients with pulmonary embolism with hemodynamic compromise, ST-segment elevation myocardial infarction (STEMI), acute ischemic stroke, and central venous access device occlusion. Reteplase and tenecteplase have also received FDA approval for treating patients with STEMI. This review provides an overview of the historical background related to fibrinolytic agents and briefly summarizes their approved indications across various thromboembolic diseases.


Assuntos
Fibrinolíticos , Tromboembolia , Humanos , Fibrinolíticos/uso terapêutico , Tromboembolia/tratamento farmacológico , História do Século XX
8.
JAMA Cardiol ; 9(4): 357-366, 2024 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-38416462

RESUMO

Importance: Polygenic risk scores (PRSs) have proven to be as strong as or stronger than established clinical risk factors for many cardiovascular phenotypes. Whether this is true for aortic stenosis remains unknown. Objective: To develop a novel aortic stenosis PRS and compare its aortic stenosis risk estimation to established clinical risk factors. Design, Setting, and Participants: This was a longitudinal cohort study using data from the Million Veteran Program (MVP; 2011-2020), UK Biobank (2006-2010), and 6 Thrombolysis in Myocardial Infarction (TIMI) trials, including DECLARE-TIMI 58 (2013-2018), FOURIER (TIMI 59; 2013-2017), PEGASUS-TIMI 54 (2010-2014), SAVOR-TIMI 53 (2010-2013), SOLID-TIMI 52 (2009-2014), and ENGAGE AF-TIMI 48 (2008-2013), which were a mix of population-based and randomized clinical trials. Individuals from UK Biobank and the MVP meeting a previously validated case/control definition for aortic stenosis were included. All individuals from TIMI trials were included unless they had a documented preexisting aortic valve replacement. Analysis took place from January 2022 to December 2023. Exposures: PRS for aortic stenosis (developed using data from MVP and validated in UK Biobank) and other previously validated cardiovascular PRSs, defined either as a continuous variable or as low (bottom 20%), intermediate, and high (top 20%), and clinical risk factors. Main Outcomes: Aortic stenosis (defined using International Classification of Diseases or Current Procedural Terminology codes in UK Biobank and MVP or safety event data in the TIMI trials). Results: The median (IQR) age in MVP was 67 (57-73) years, and 135 140 of 147 104 participants (92%) were male. The median (IQR) age in the TIMI trials was 66 (54-78) years, and 45 524 of 59 866 participants (71%) were male. The best aortic stenosis PRS incorporated 5 170 041 single-nucleotide variants and was associated with aortic stenosis in both the MVP testing sample (odds ratio, 1.41; 95% CI, 1.37-1.45 per 1 SD PRS; P = 4.6 × 10-116) and TIMI trials (hazard ratio, 1.44; 95% CI, 1.27-1.62 per 1 SD PRS; P = 3.2 × 10-9). Among genetic and clinical risk factors, the aortic stenosis PRS performed comparably to most risk factors besides age, and within a given age range, the combination of clinical and genetic risk factors was additive, providing a 3- to 4-fold increased gradient of risk of aortic stenosis. However, the addition of the aortic stenosis PRS to a model including clinical risk factors only improved risk discrimination of aortic stenosis by 0.01 to 0.02 (C index in MVP: 0.78 with clinical risk factors, 0.79 with risk factors and aortic stenosis PRS; C index in TIMI: 0.71 with clinical risk factors, 0.73 with risk factors and aortic stenosis PRS). Conclusions: This study developed and validated 1 of the first aortic stenosis PRSs. While aortic stenosis genetic risk was independent from clinical risk factors and performed comparably to all other risk factors besides age, genetic risk resulted in only a small improvement in overall aortic stenosis risk discrimination beyond age and clinical risk factors. This work sets the stage for further development of an aortic stenosis PRS.


Assuntos
Estenose da Valva Aórtica , Infarto do Miocárdio , Humanos , Masculino , Idoso , Feminino , Estratificação de Risco Genético , Estudos Longitudinais , Predisposição Genética para Doença , Fatores de Risco , Estenose da Valva Aórtica/genética
9.
Am J Speech Lang Pathol ; 33(3): 1337-1355, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38346137

RESUMO

PURPOSE: Qualitative engagement with stakeholders in the development of interventions can provide insight into strategies to maximize feasibility in real-life settings. We engaged stakeholders (autistic adults, early childhood educators, early childhood sector leaders and policy influencers, parents of autistic children, and speech-language pathologists) to inform the development of an educator-led peer-mediated intervention (PMI) for autistic preschoolers who use minimal speech that is feasible to implement in inclusive early childhood education and care (ECEC) settings. METHOD: A qualitative iterative intervention design process was utilized. Stakeholders (N = 15) attended an online workshop and completed a document review exploring the acceptability and feasibility of the proposed embedded PMI. A two-step analysis procedure using the Theoretical Domains Framework and template analysis was conducted to identify the barriers, enablers, and supports to the implementation of embedded PMI in early childhood settings. RESULTS: While embedded PMI was unanimously acceptable to stakeholders, several participants expressed concerns regarding feasibility. Barriers to the successful integration and implementation of PMI in inclusive preschool contexts included access to skills, knowledge, and resources. Participants identified strategies to overcome modifiable barriers and to enhance the existing enablers. These strategies are reflected in the following themes: build on the familiar, build capacity in augmentative and alternative communication, adopt a whole center approach, adapt to meet the needs of the ECEC setting, and engage in proactive implementation. CONCLUSION: To address barriers to the implementation of embedded PMI, action is needed at various levels: macro (national/policy), meso (organization/setting), and micro (individual). SUPPLEMENTAL MATERIAL: https://doi.org/10.23641/asha.25155770.


Assuntos
Estudos de Viabilidade , Grupo Associado , Pesquisa Qualitativa , Humanos , Pré-Escolar , Masculino , Feminino , Participação dos Interessados , Intervenção Educacional Precoce/métodos , Transtorno Autístico/terapia , Transtorno Autístico/psicologia , Transtorno do Espectro Autista/terapia , Transtorno do Espectro Autista/psicologia , Patologia da Fala e Linguagem/métodos , Adulto
10.
J Am Coll Cardiol ; 83(6): 652-664, 2024 02 13.
Artigo em Inglês | MEDLINE | ID: mdl-38325990

RESUMO

BACKGROUND: In FOURIER (Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk), during a median follow-up of 2.2 years, risk reduction for major adverse cardiovascular event with evolocumab was greater in patients with multivessel disease (MVD). The FOURIER Open-Label Extension (FOURIER-OLE) provides an additional median follow-up of 5 years. OBJECTIVES: The purpose of this study was to assess the long-term benefit of evolocumab in patients with and without MVD. METHODS: FOURIER randomized 27,564 patients to evolocumab vs placebo; 6,635 entered FOURIER-OLE. Patients with coronary artery disease were categorized based on the presence of MVD (≥40% stenosis in ≥2 large vessels). The primary endpoint was cardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina, or coronary revascularization; the key secondary endpoint was cardiovascular death, myocardial infarction, or stroke. RESULTS: Of 23,656 patients in FOURIER with coronary artery disease, 25.4% had MVD; 5,887 patients continued into FOURIER-OLE. The risk reduction with initial allocation to evolocumab tended to be greater in patients with MVD than in those without: 23% (HR: 0.77 [95% CI: 0.68-0.87]) vs 11% (HR: 0.89 [95% CI: 0.82-0.96]) for the primary and 31% (HR: 0.69 [95% CI: 0.59-0.81]) vs 15% (HR: 0.85 [95% CI: 0.77-0.94]) for the key secondary endpoints (Pinteraction = 0.062 and Pinteraction = 0.031, respectively). The magnitude of benefit tended to grow during the first several years, reaching 37% to 38% reductions in risk in patients with MVD and 23% to 28% reductions in risk in patients without MVD. CONCLUSIONS: Evolocumab reduced the rate of major adverse cardiovascular event in patients with and without MVD. The benefit tended to occur earlier and was larger in patients with MVD. However, the magnitude grew over time in both groups. These data support early initiation of intensive low-density lipoprotein cholesterol lowering both in patients with and without MVD.


Assuntos
Anticorpos Monoclonais Humanizados , Anticolesterolemiantes , Doença da Artéria Coronariana , Infarto do Miocárdio , Acidente Vascular Cerebral , Humanos , Doença da Artéria Coronariana/complicações , Doença da Artéria Coronariana/tratamento farmacológico , Doença da Artéria Coronariana/induzido quimicamente , Pró-Proteína Convertase 9 , Anticolesterolemiantes/uso terapêutico , Inibidores de PCSK9 , Resultado do Tratamento , Infarto do Miocárdio/tratamento farmacológico , Acidente Vascular Cerebral/tratamento farmacológico
12.
J Am Coll Cardiol ; 82(4): 336-349, 2023 07 25.
Artigo em Inglês | MEDLINE | ID: mdl-37468189

RESUMO

BACKGROUND: The relationship between omega-3 fatty acids and atrial fibrillation (AF) remains controversial. OBJECTIVES: This study aimed to determine the prospective associations of blood or adipose tissue levels of eicosapentaenoic acid (EPA), docosapentaenoic acid (DPA), and docosahexaenoic acid (DHA) with incident AF. METHODS: We used participant-level data from a global consortium of 17 prospective cohort studies, each with baseline data on blood or adipose tissue omega-3 fatty acid levels and AF outcomes. Each participating study conducted a de novo analyses using a prespecified analytical plan with harmonized definitions for exposures, outcome, covariates, and subgroups. Associations were pooled using inverse-variance weighted meta-analysis. RESULTS: Among 54,799 participants from 17 cohorts, 7,720 incident cases of AF were ascertained after a median 13.3 years of follow-up. In multivariable analysis, EPA levels were not associated with incident AF, HR per interquintile range (ie, the difference between the 90th and 10th percentiles) was 1.00 (95% CI: 0.95-1.05). HRs for higher levels of DPA, DHA, and EPA+DHA, were 0.89 (95% CI: 0.83-0.95), 0.90 (95% CI: 0.85-0.96), and 0.93 (95% CI: 0.87-0.99), respectively. CONCLUSIONS: In vivo levels of omega-3 fatty acids including EPA, DPA, DHA, and EPA+DHA were not associated with increased risk of incident AF. Our data suggest the safety of habitual dietary intakes of omega-3 fatty acids with respect to AF risk. Coupled with the known benefits of these fatty acids in the prevention of adverse coronary events, our study suggests that current dietary guidelines recommending fish/omega-3 fatty acid consumption can be maintained.


Assuntos
Fibrilação Atrial , Ácidos Graxos Ômega-3 , Humanos , Fibrilação Atrial/diagnóstico , Fibrilação Atrial/epidemiologia , Biomarcadores , Ácidos Docosa-Hexaenoicos , Ácido Eicosapentaenoico , Estudos Prospectivos , Fatores de Risco
13.
Circulation ; 147(25): 1933-1944, 2023 06 20.
Artigo em Inglês | MEDLINE | ID: mdl-37335828

RESUMO

Antiplatelet therapy is the mainstay of pharmacologic treatment to prevent thrombotic or ischemic events in patients with coronary artery disease treated with percutaneous coronary intervention and those treated medically for an acute coronary syndrome. The use of antiplatelet therapy comes at the expense of an increased risk of bleeding complications. Defining the optimal intensity of platelet inhibition according to the clinical presentation of atherosclerotic cardiovascular disease and individual patient factors is a clinical challenge. Modulation of antiplatelet therapy is a medical action that is frequently performed to balance the risk of thrombotic or ischemic events and the risk of bleeding. This aim may be achieved by reducing (ie, de-escalation) or increasing (ie, escalation) the intensity of platelet inhibition by changing the type, dose, or number of antiplatelet drugs. Because de-escalation or escalation can be achieved in different ways, with a number of emerging approaches, confusion arises with terminologies that are often used interchangeably. To address this issue, this Academic Research Consortium collaboration provides an overview and definitions of different strategies of antiplatelet therapy modulation for patients with coronary artery disease, including but not limited to those undergoing percutaneous coronary intervention, and consensus statements on standardized definitions.


Assuntos
Síndrome Coronariana Aguda , Doença da Artéria Coronariana , Intervenção Coronária Percutânea , Trombose , Humanos , Inibidores da Agregação Plaquetária/efeitos adversos , Doença da Artéria Coronariana/complicações , Hemorragia/etiologia , Plaquetas , Terapia Antiplaquetária Dupla/efeitos adversos , Síndrome Coronariana Aguda/terapia , Trombose/etiologia , Intervenção Coronária Percutânea/efeitos adversos , Resultado do Tratamento
15.
J Autism Dev Disord ; 2023 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-36859610

RESUMO

Peer mediated intervention (PMI) is an evidence-based approach to supporting social and communication development for children on the autism spectrum. For PMI to be integrated into everyday practice, it needs to be acceptable to stakeholders. This article engaged with autistic individuals, early childhood educators, parents, and speech and language pathologists on the prospective acceptability of implementing PMI with minimally speaking preschoolers in inclusive preschool settings. Focus groups and semi-structured interviews were conducted. The transcriptions were analyzed qualitatively using reflexive thematic analysis. Stakeholders described PMI as an acceptable intervention approach for this population and provided valuable insights to inform the development and implementation of PMIs. Attention needs to be paid to how to support preschools to adopt a PMI-friendly philosophy.

16.
Semin Thromb Hemost ; 49(7): 725-735, 2023 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-36868268

RESUMO

Sex-specific factors are implicated in pulmonary embolism (PE) presentation in young patients, as indicated by increased risk in pregnancy. Whether sex differences exist in PE presentation, comorbidities, and symptomatology in older adults, the age group in which most PEs occur, remains unknown. We identified older adults (aged ≥65 years) with PE in a large international PE registry replete with information about relevant clinical characteristics (RIETE registry, 2001-2021). To provide national data from the United States, we assessed sex differences in clinical characteristics and risk factors of Medicare beneficiaries with PE (2001-2019). The majority of older adults with PE in RIETE (19,294/33,462, 57.7%) and in the Medicare database (551,492/948,823, 58.7%) were women. Compared with men, women with PE less frequently had atherosclerotic diseases, lung disease, cancer, or unprovoked PE, but more frequently had varicose veins, depression, prolonged immobility, or history of hormonal therapy (p < 0.001 for all). Women less often presented with chest pain (37.3 vs. 40.6%) or hemoptysis (2.4 vs. 5.6%) but more often with dyspnea (84.6 vs. 80.9%) (p < 0.001 for all). Measures of clot burden, PE risk stratification, and use of imaging modalities were comparable between women and men. PE is more common in elderly women than in men. Cancer and cardiovascular disease are more common in men, whereas transient provoking factors including trauma, immobility, or hormone therapy are more common in elderly women with PE. Whether such differences correlate with disparities in treatment or differences in short- or long-term clinical outcomes warrants further investigation.


Assuntos
Neoplasias , Embolia Pulmonar , Humanos , Masculino , Idoso , Feminino , Estados Unidos/epidemiologia , Caracteres Sexuais , Medicare , Embolia Pulmonar/diagnóstico , Embolia Pulmonar/epidemiologia , Embolia Pulmonar/etiologia , Fatores de Risco , Neoplasias/complicações
17.
Circulation ; 147(16): 1192-1203, 2023 04 18.
Artigo em Inglês | MEDLINE | ID: mdl-36779348

RESUMO

BACKGROUND: Low-density lipoprotein cholesterol (LDL-C) is a well-established risk factor for atherosclerotic cardiovascular disease. However, the optimal achieved LDL-C level with regard to efficacy and safety in the long term remains unknown. METHODS: In FOURIER (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk), 27 564 patients with stable atherosclerotic cardiovascular disease were randomized to evolocumab versus placebo, with a median follow-up of 2.2 years. In the open-label extension (FOURIER-OLE), 6635 of these patients were transitioned to open-label evolocumab regardless of initial treatment allocation in the parent trial and were followed for an additional median of 5 years. In this prespecified analysis, we examined the relationship between achieved LDL-C levels (an average of the first 2 LDL-C levels measured) in FOURIER-OLE (available in 6559 patients) and the incidence of subsequent cardiovascular and safety outcomes. We also performed sensitivity analyses evaluating cardiovascular and safety outcomes in the entire FOURIER and FOURIER-OLE patient population. Multivariable modeling was used to adjust for baseline factors associated with achieved LDL-C levels. RESULTS: In FOURIER-OLE, 1604 (24%), 2627 (40%), 1031 (16%), 486 (7%), and 811 (12%) patients achieved LDL-C levels of <20, 20 to <40, 40 to <55, 55 to <70, and ≥70 mg/dL, respectively. There was a monotonic relationship between lower achieved LDL-C levels-down to very low levels <20 mg/dL-and a lower risk of the primary efficacy end point (composite of cardiovascular death, myocardial infarction, stroke, hospital admission for unstable angina or coronary revascularization) and the key secondary efficacy end point (composite of cardiovascular death, myocardial infarction, or stroke) that persisted after multivariable adjustment (adjusted Ptrend<0.0001 for each end points). No statistically significant associations existed in the primary analyses between lower achieved LDL-C levels and increased risk of the safety outcomes (serious adverse events, new or recurrent cancer, cataract-related adverse events, hemorrhagic stroke, new-onset diabetes, neurocognitive adverse events, muscle-related events, or noncardiovascular death). Similar findings were noted in the entire FOURIER and FOURIER-OLE cohort up to a maximum follow-up of 8.6 years. CONCLUSIONS: In patients with atherosclerotic cardiovascular disease, long-term achievement of lower LDL-C levels, down to <20 mg/dL (<0.5 mmol/L), was associated with a lower risk of cardiovascular outcomes with no significant safety concerns. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT01764633.


Assuntos
Anticolesterolemiantes , Aterosclerose , Doenças Cardiovasculares , Inibidores de Hidroximetilglutaril-CoA Redutases , Infarto do Miocárdio , Acidente Vascular Cerebral , Humanos , Pró-Proteína Convertase 9 , Anticolesterolemiantes/efeitos adversos , LDL-Colesterol , Inibidores de PCSK9 , Doenças Cardiovasculares/tratamento farmacológico , Resultado do Tratamento , Aterosclerose/tratamento farmacológico , Infarto do Miocárdio/epidemiologia , Acidente Vascular Cerebral/epidemiologia , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico
18.
Eur Heart J ; 44(4): 293-300, 2023 01 21.
Artigo em Inglês | MEDLINE | ID: mdl-36303404

RESUMO

AIMS: Levels of growth differentiation factor 15 (GDF-15), a cytokine secreted in response to cellular stress and inflammation, have been associated with multiple types of cardiovascular (CV) events. However, its comparative prognostic performance across different presentations of atherosclerotic cardiovascular disease (ASCVD) remains unknown. METHODS AND RESULTS: An individual patient meta-analysis was performed using data pooled from eight trials including 53 486 patients. Baseline GDF-15 concentration was analyzed as a continuous variable and using established cutpoints (<1200 ng/L, 1200-1800 ng/L, > 1800 ng/L) to evaluate its prognostic performance for CV death/hospitalization for heart failure (HHF), major adverse cardiovascular events (MACE), and their components using Cox models adjusted for clinical variables and established CV biomarkers. Analyses were further stratified on ASCVD status: acute coronary syndrome (ACS), stabilized after recent ACS, and stable ASCVD. Overall, higher GDF-15 concentration was significantly and independently associated with an increased rate of CV death/HHF and MACE (P < 0.001 for each). However, while GDF-15 showed a robust and consistent independent association with CV death and HHF across all presentations of ASCVD, its prognostic association with future myocardial infarction (MI) and stroke only remained significant in patients stabilized after recent ACS or with stable ASCVD [hazard ratio (HR): 1.24, 95% confidence interval (CI): 1.17-1.31 and HR: 1.16, 95% CI: 1.05-1.28 for MI and stroke, respectively] and not in ACS (HR: 0.98, 95% CI: 0.90-1.06 and HR: 0.87, 95% CI: 0.39-1.92, respectively). CONCLUSION: Growth differentiation factor 15 consistently adds prognostic information for CV death and HHF across the spectrum of ASCVD. GDF-15 also adds prognostic information for MI and stroke beyond clinical risk factors and cardiac biomarkers but not in the setting of ACS.


Assuntos
Síndrome Coronariana Aguda , Aterosclerose , Doenças Cardiovasculares , Insuficiência Cardíaca , Infarto do Miocárdio , Acidente Vascular Cerebral , Humanos , Doenças Cardiovasculares/complicações , Fator 15 de Diferenciação de Crescimento , Fatores de Risco , Infarto do Miocárdio/etiologia , Síndrome Coronariana Aguda/complicações , Biomarcadores , Insuficiência Cardíaca/complicações , Acidente Vascular Cerebral/complicações , Fatores de Risco de Doenças Cardíacas , Aterosclerose/complicações
19.
Eur Heart J ; 44(3): 221-231, 2023 01 14.
Artigo em Inglês | MEDLINE | ID: mdl-35980763

RESUMO

AIMS: Interest in targeted screening programmes for atrial fibrillation (AF) has increased, yet the role of genetics in identifying patients at highest risk of developing AF is unclear. METHODS AND RESULTS: A total of 36,662 subjects without prior AF were analyzed from four TIMI trials. Subjects were divided into quintiles using a validated polygenic risk score (PRS) for AF. Clinical risk for AF was calculated using the CHARGE-AF model. Kaplan-Meier event rates, adjusted hazard ratios (HRs), C-indices, and net reclassification improvement were used to determine if the addition of the PRS improved prediction compared with clinical risk and N-terminal pro-B-type natriuretic peptide (NT-proBNP). Over 2.3 years, 1018 new AF cases developed. AF PRS predicted a significant risk gradient for AF with a 40% increased risk per 1-SD increase in PRS [HR: 1.40 (1.32-1.49); P < 0.001]. Those with high AF PRS (top 20%) were more than two-fold more likely to develop AF [HR 2.45 (1.99-3.03), P < 0.001] compared with low PRS (bottom 20%). Furthermore, PRS provided an additional gradient of risk stratification on top of the CHARGE-AF clinical risk score, ranging from a 3-year incidence of 1.3% in patients with low clinical and genetic risk to 8.7% in patients with high clinical and genetic risk. The subgroup of patients with high clinical risk, high PRS, and elevated NT-proBNP had an AF risk of 16.7% over 3 years. The C-index with the CHARGE-AF clinical risk score alone was 0.65, which improved to 0.67 (P < 0.001) with the addition of NT-proBNP, and increased further to 0.70 (P < 0.001) with the addition of the PRS. CONCLUSION: In patients with cardiovascular conditions, AF PRS is a strong independent predictor of incident AF that provides complementary predictive value when added to a validated clinical risk score and NT-proBNP.


Assuntos
Fibrilação Atrial , Doenças Cardiovasculares , Humanos , Fibrilação Atrial/complicações , Fibrilação Atrial/genética , Fibrilação Atrial/epidemiologia , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/genética , Prognóstico , Biomarcadores , Fatores de Risco , Peptídeo Natriurético Encefálico , Fragmentos de Peptídeos
20.
Am Heart J Plus ; 27: 100267, 2023 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38511090

RESUMO

Cardiovascular disease (CVD) is a major health threat to women worldwide. In addition to traditional CVD risk factors, autoimmune conditions are increasingly being recognized as contributors to adverse CVD consequences in women. Chronic systemic autoimmune and inflammatory disorders can trigger premature and accelerated atherosclerosis, microvascular dysfunction, and thrombosis. The presence of comorbid conditions, duration of the autoimmune condition, disease severity, and treatment of underlying inflammation are all factors that impact CVD risk and progression. Early identification and screening of CVD risk factors in those with underlying autoimmune conditions may attenuate CVD in this population. Treatment with non-steroidal anti-inflammatory drugs, corticosteroids, disease modifying agents and biologics may influence CVD risk factors and overall risk. Multi-disciplinary and team-based care, clinical trials, and collaborative team-science studies focusing on systemic autoimmune conditions will be beneficial to advance care for women.

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