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2.
Am Heart J ; 220: 51-58, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31783279

RESUMO

BACKGROUND: Rates and predictors of major bleeding in patients with peripheral artery disease (PAD) treated with antiplatelets have not been well studied. This post hoc analysis of EUCLID aimed to determine the incidence of major/minor bleeding, predictors of major bleeding, and risk of major adverse cardiovascular events (MACE) following major bleeding events. METHODS: EUCLID, a multicenter randomized controlled trial of 13,885 patients with symptomatic PAD, compared ticagrelor with clopidogrel for the prevention of MACE. The primary safety end point was Thrombolysis in Myocardial Infarction (TIMI) major bleeding. Baseline characteristics were used to develop a multivariable model to determine factors associated with TIMI major bleeding. The occurrence and timing of MACE relative to a first major bleeding event were determined. RESULTS: TIMI major bleeding occurred in 2.3% of participants overall (0.94 event/100 patient-years). There was no significant difference in major bleeding rates by treatment assignment. Factors associated with TIMI major bleeding included older age, geographic region, Rutherford class, and ß-blocker use. Patients with TIMI major bleeding postrandomization had an increased risk of MACE (hazard ratio [HR] 4.46; 95% CI 3.40-5.84; P < .0001) compared with those without major bleeding; the association was strongest within 30 days after a bleeding event. CONCLUSIONS: In patients with symptomatic PAD, 0.94 major bleeding event/100 patient-years was observed and associated with older age, residing in North America, disease severity, and ß-blocker use. Patients who had a major bleeding event were significantly more likely to experience MACE, especially within the first 30 days, when compared with patients who did not have major bleeding.

3.
Am Heart J ; 220: 137-144, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31812755

RESUMO

BACKGROUND: Although spontaneous reperfusion (SR) prior to primary percutaneous coronary intervention (pPCI) is associated with improved outcomes, its pathophysiology remains unclear. The objective of the study was to explore associations between SR in ST-segment elevation myocardial infarction (STEMI) using a multimarker cardiovascular proteins strategy METHODS: We evaluated STEMI patients from the Assessment of Pexelizumab in Acute Myocardial Infarction trial treated with pPCI within 6 hours from symptom onset. SR was core laboratory-defined as pre-PCI Thrombolysis in Myocardial Infarction flow 2 or 3. Ninety-one cardiovascular disease-related serum biomarkers drawn prior to PCI were analyzed using a high-throughput "targeted discovery" panel. Expression levels for individual biomarkers were compared between patients with/without SR. A hierarchical clustering method of biomarkers identified clusters of biomarkers that differentiated the 2 groups. Associations between individual biomarkers and clusters with SR were further evaluated by multivariable logistic regression. RESULTS: Of 683 patients studied, 290 had spontaneous reperfusion; those with compared to without SR were more likely noninferior STEMI and had lower clinical acuity and lower baseline levels of troponin and creatine kinase. SR was associated with a lower occurrence of 90-day composite of death, heart failure, or cardiogenic shock. Fifty-two of 91 individual biomarkers were significantly univariably associated with SR. Forty-five remained significant with adjustment for false discovery rate. Using cluster analysis, 26 biomarkers clusters were identified, explaining 72% of total covariance, and 13 biomarker clusters were significantly associated with SR after multivariable adjustment. SR was associated with higher mean expression levels of proteins in all 13 clusters. The cluster most strongly associated with SR consisted of novel proteins across various distinct, yet interlinked, pathobiological processes (kallikrein-6, matrix extracellular phosphoglycoprotein, matrix mettaloproteinaise-3, and elafin). CONCLUSIONS: Spontaneous reperfusion prior to pPCI in STEMI was associated with a lower risk of adverse clinical events. These exploratory data from a targeted discovery proteomics platform identifies novel proteins across diverse, yet complementary, pathobiological axes that show promise in providing mechanistic insights into spontaneous reperfusion in STEMI. CONDENSED ABSTRACT: Spontaneous reperfusion has been established with improved STEMI outcomes, yet its pathobiology is unclear and appears to involve diverse physiological processes. Using a 91-biomarker high-throughput proteomics platform, we studied 683 STEMI patients in the APEX AMI trial (290 had core laboratory-adjudicated pre-PCI TIMI 2/3 flow) and identified 52 proteins that univariably associate with spontaneous reperfusion. Cluster analysis identified 26 biomarker clusters (explaining 72% of total variance), 13 of which, after multivariable adjustment, were significantly associated with spontaneous reperfusion. Four proteins (kallikrein-6, matrix extracellular phosphoglycoprotein, matrix mettaloproteinaise-3, and elafin) across diverse, yet complementary, pathways appear to be associated most strongly with spontaneous reperfusion.

5.
JAMA Cardiol ; 4(7): 680-684, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-31141104

RESUMO

Importance: Physician behavior in response to knowledge of a patient's CYP2C19 clopidogrel metabolizer status is unknown. Objective: To investigate the association of mandatory reporting of CYP2C19 pharmacogenomic testing, provided to investigators with no direct recommendations on how to use these results, with changes in P2Y12 inhibitor use, particularly clopidogrel, in the Randomized Trial to Compare the Safety of Rivaroxaban vs Aspirin in Addition to Either Clopidogrel or Ticagrelor in Acute Coronary Syndrome (GEMINI-ACS-1) clinical trial. Design, Setting, and Participants: The GEMINI-ACS-1 trial compared rivaroxaban, 2.5 mg twice daily, with aspirin, 100 mg daily, plus open-label clopidogrel or ticagrelor (provided), in patients with recent acute coronary syndromes (ACS). The trial included 371 clinical centers in 21 countries and 3037 patients with ACS. Data were analyzed between May 2017 and February 2019. Interventions: Investigators were required to prestipulate their planned response to CYP2C19 metabolizer status. In response to a regulatory mandate, results for all patients were reported to investigators approximately 1 week after randomization. Main Outcomes and Measures: Reasons for switching P2Y12 inhibitors and occurrence of bleeding and ischemic events were collected. Results: Of 3037 patients enrolled (mean [SD] age, 62.8 [9.0] years; 2275 men [74.9%], and 2824 white race/ethnicity [93.0%]), investigators initially treated 1704 (56.1%) with ticagrelor and 1333 (43.9%) with clopidogrel. Investigators prestipulated that they would use CYP2C19 metabolizer status to change P2Y12 inhibitor in 48.5% of genotyped clopidogrel-treated patients (n = 642 of 1324) and 5.5% of genotyped ticagrelor-treated patients (n = 93 of 1692). P2Y12 inhibitor switching for any reason occurred in 197 patients and was more common in patients treated with ticagrelor (146 of 1704 [8.6%]) compared with clopidogrel (51 of 1333 [3.8%]). Of patients initially treated with ticagrelor, only 1 (0.1% overall; 0.7% of all who switched) was switched based on CYP2C19 status. Of patients initially treated with clopidogrel, 23 (1.7% overall,;45.1% of all who switched) were switched owing to metabolizer status. Of 48 patients (3.6%) with reduced metabolizer status treated initially with clopidogrel, 15 (31.3%) were switched based on metabolizer status, including 48.1% (13 of 27) in which switching was prestipulated. Conclusions and Relevance: Physicians were evenly split on how to respond to knowledge of CYP2C19 metabolizer status in clopidogrel-treated patients. Mandatory provision of this information rarely prompted P2Y12 inhibitor switching overall, including a minority of patients with reduced metabolizer status. These findings highlight the clinical equipoise among physicians regarding use of this information and the reluctance to use information from routine genotyping in the absence of definitive clinical trial data demonstrating the efficacy of this approach. Clinical Trial Registration: ClinicalTrials.gov identifier: NCT02293395.

6.
Lancet ; 393(10175): 1045-1055, 2019 Mar 09.
Artigo em Inglês | MEDLINE | ID: mdl-30860030

RESUMO

Heart failure is a common syndrome associated with substantial morbidity and mortality. The management of symptoms and the strategies for improving prognosis have largely been based on pharmacological treatments. The pathophysiology of heart failure is complex because of the multiple causes responsible for this syndrome. This Series paper presents some examples of advances in heart failure management, in which the treatment specifically targets the underlying pathophysiological mechanisms responsible for the symptoms. These treatments include treatment of electromechanical dyssynchrony and dysrhythmia by cardiac resynchronisation and implantable cardioverter-defibrillators; neurohumoral modification by baroreflex and vagal stimulation; prevention of adverse cardiac remodelling by interatrial shunts; and finally targeting the myocardium directly by cell therapy in an attempt to regenerate new myocardial cells.


Assuntos
Insuficiência Cardíaca/fisiopatologia , Insuficiência Cardíaca/terapia , Cateterismo Cardíaco , Terapia de Ressincronização Cardíaca , Desfibriladores Implantáveis , Regeneração Tecidual Guiada , Insuficiência Cardíaca/tratamento farmacológico , Humanos , Sistema Nervoso Simpático/fisiopatologia , Nervo Vago/fisiopatologia
7.
Circulation ; 139(7): 863-873, 2019 02 12.
Artigo em Inglês | MEDLINE | ID: mdl-30586739

RESUMO

BACKGROUND: Modern cardiometabolic clinical trials often include cardiovascular death as a component of a composite primary outcome, requiring central adjudication by a clinical events committee to classify cause of death. However, sometimes the cause of death cannot be determined from available data. The US Food and Drug Administration has indicated that this circumstance should occur only rarely, but its prevalence has not been formally assessed. METHODS: Data from 9 global clinical trials (2009-2017) with long-term follow-up and blinded, centrally adjudicated cause of death were used to calculate the proportion of deaths attributed to cardiovascular, noncardiovascular, or undetermined causes by therapeutic area (diabetes mellitus/pre-diabetes mellitus, stable atherosclerosis, atrial fibrillation, and acute coronary syndrome), region of patient enrollment, and year of trial manuscript publication. Patient- and trial-level variables associated with undetermined cause of death were identified using a logistic model. RESULTS: Across 127 049 enrolled participants from 9 trials, there were 9259 centrally adjudicated deaths: 5012 (54.1%) attributable to cardiovascular causes, 2800 (30.2%) attributable to noncardiovascular causes, and 1447 (15.6%) attributable to undetermined causes. There was variability in the proportion of deaths ascribed to undetermined causes by trial therapeutic area, region of enrollment, and year of trial manuscript publication. On multivariable analysis, acute coronary syndrome or atrial fibrillation trial (versus atherosclerotic vascular disease or diabetes mellitus/pre-diabetes mellitus), longer time from enrollment to death, more recent trial manuscript publication year, enrollment in North America (versus Western Europe), female sex, and older age were associated with greater likelihood of death of undetermined cause. CONCLUSIONS: In 9 cardiometabolic clinical trials with long-term follow-up, approximately 16% of deaths had undetermined causes. This provides a baseline for quality assessment of clinical trials and informs operational efforts to potentially reduce the frequency of undetermined deaths in future clinical research.


Assuntos
Doenças Cardiovasculares/mortalidade , Causas de Morte/tendências , Ensaios Clínicos como Assunto/métodos , Determinação de Ponto Final , Síndrome Metabólica/mortalidade , Projetos de Pesquisa , Idoso , Doenças Cardiovasculares/diagnóstico , Doenças Cardiovasculares/terapia , Comorbidade , Feminino , Nível de Saúde , Humanos , Masculino , Síndrome Metabólica/diagnóstico , Síndrome Metabólica/terapia , Pessoa de Meia-Idade , Características de Residência , Medição de Risco , Fatores de Risco , Fatores de Tempo , Resultado do Tratamento
8.
Circ Res ; 123(4): 495-505, 2018 08 03.
Artigo em Inglês | MEDLINE | ID: mdl-30355250

RESUMO

Although clinical trials of cell-based approaches to cardiovascular disease have yielded some promising results, no cell-based therapy has achieved regulatory approval for a cardiovascular indication. To broadly assess the challenges to regulatory approval and identify strategies to facilitate this goal, the Cardiac Safety Research Consortium sponsored a session during the Texas Heart Institute International Symposium on Cardiovascular Regenerative Medicine in September 2017. This session convened leaders in cardiovascular regenerative medicine, including participants from academia, the pharmaceutical industry, the US Food and Drug Administration, and the Cardiac Safety Research Consortium, with particular focus on treatments closest to regulatory approval. A goal of the session was to identify barriers to regulatory approval and potential pathways to overcome them. Barriers identified include manufacturing and therapeutic complexity, difficulties identifying an optimal comparator group, limited industry capacity for funding pivotal clinical trials, and challenges to demonstrating efficacy on clinical end points required for regulatory decisions. Strategies to overcome these barriers include precompetitive development of a cell therapy registry network to enable dual-purposing of clinical data as part of pragmatic clinical trial design, development of standardized terminology for product activity and end points to facilitate this registry, use of innovative statistical methods and quality of life or functional end points to supplement outcomes such as death or heart failure hospitalization and reduce sample size, involvement of patients in determining the research agenda, and use of the Food and Drug Administration's new Regenerative Medicine Advanced Therapy designation to facilitate early discussion with regulatory authorities when planning development pathways.


Assuntos
Cardiologia/métodos , Congressos como Assunto , Cardiopatias/terapia , Medicina Regenerativa/métodos , Transplante de Células-Tronco/métodos , Animais , Humanos
10.
Eur Heart J ; 39(23): 2208-2216, 2018 06 14.
Artigo em Inglês | MEDLINE | ID: mdl-29315376

RESUMO

Aims: Autologous CD34+ (auto-CD34+) cells represent an attractive option for the treatment of refractory angina. Three double-blinded randomized trials (n = 304) compared intramyocardial (IM) auto-CD34+ cells with IM placebo injections to affect total exercise time (TET), angina frequency (AF), and major adverse cardiac events (MACE). Patient-level data were pooled from the Phase I, Phase II ACT-34, ACT-34 extension, and Phase III RENEW trials to determine the efficacy and safety of auto-CD34+ cells. Methods and results: Treatment effects for TET were analysed using an analysis of covariance mixed-effects model and for AF using Poisson regression in a log linear model with repeated measures. The Kaplan-Meier rate estimates for MACE were compared using the log-rank test. Autologous CD34+ cell therapy improved TET by 46.6 s [3 months, 95% confidence interval (CI) 13.0 s-80.3 s; P = 0.007], 49.5 s (6 months, 95% CI 9.3-89.7; P = 0.016), and 44.7 s (12 months, 95% CI - 2.7 s-92.1 s; P = 0.065). The relative frequency of angina was 0.78 (95% CI 0.63-0.98; P = 0.032), 0.66 (0.48-0.91; P = 0.012), and 0.58 (0.38-0.88; P = 0.011) at 3-, 6- and 12-months in auto-CD34+ compared with placebo patients. Results remained concordant when analysed by treatment received and when confined to the Phase III dose of 1 × 105 cells/kg. Autologous CD34 + cell therapy significantly decreased mortality (12.1% vs. 2.5%; P = 0.0025) and numerically reduced MACE (38.9% vs. 30.0; P = 0.14) at 24 months. Conclusion: Treatment with auto-CD34+ cells resulted in clinically meaningful durable improvements in TET and AF at 3-, 6- and 12-months, as well as a reduction in 24-month mortality in this patient-level meta-analysis.


Assuntos
Angina Pectoris/terapia , Tolerância ao Exercício , Mortalidade , Transplante de Células-Tronco/métodos , Idoso , Angina Pectoris/fisiopatologia , Antígenos CD34/metabolismo , Feminino , Humanos , Injeções Intramusculares , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Miocárdio , Ensaios Clínicos Controlados Aleatórios como Assunto , Transplante Autólogo
12.
Clin Pharmacol Ther ; 103(1): 77-87, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29044498

RESUMO

The treatment of atherosclerotic heart disease has improved remarkably over the last several decades; however, the outlook for patients with symptomatic congestive heart failure with reduced ejection fraction remains bleak. Current drug therapies target the neurohormonal activation that accompanies congestive heart failure, but do not address the fundamental pathology inherent in this condition-the loss of contractile capacity. Stem cell therapies offer the possibility of rectifying this deficiency and normalizing left ventricular dimensions and cardiac performance by regenerating novel contractile tissue, thereby reversing the negative remodeling that portends progressive left ventricular dysfunction, worsening symptoms, and ultimately cardiogenic shock. Here we review the promise of stem cell therapies in the treatment of heart failure with reduced ejection fraction, the current state of clinical developments, and briefly comment on the future of the field.


Assuntos
Insuficiência Cardíaca , Transplante de Células-Tronco/métodos , Disfunção Ventricular Esquerda , Progressão da Doença , Insuficiência Cardíaca/fisiopatologia , Insuficiência Cardíaca/terapia , Humanos , Contração Miocárdica , Resultado do Tratamento , Disfunção Ventricular Esquerda/fisiopatologia , Disfunção Ventricular Esquerda/terapia , Remodelação Ventricular
13.
Cardiovasc Drugs Ther ; 31(4): 445-458, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28735360

RESUMO

PURPOSE: The need for novel approaches to cardiovascular drug development served as the impetus to convene an open meeting of experts from the pharmaceutical industry and academia to assess the challenges and develop solutions for drug discovery in cardiovascular disease. METHODS: The Novel Cardiovascular Therapeutics Summit first reviewed recent examples of ongoing or recently completed programs translating basic science observations to targeted drug development, highlighting successes (protein convertase sutilisin/kexin type 9 [PCSK9] and neprilysin inhibition) and targets still under evaluation (cholesteryl ester transfer protein [CETP] inhibition), with the hope of gleaning key lessons to successful drug development in the current era. Participants then reviewed the use of innovative approaches being explored to facilitate rapid and more cost-efficient evaluations of drug candidates in a short timeframe. RESULTS: We summarize observations gleaned from this summit and offer insight into future cardiovascular drug development. CONCLUSIONS: The rapid development in genetic and high-throughput drug evaluation technologies, coupled with new approaches to rapidly evaluate potential cardiovascular therapies with in vitro techniques, offer opportunities to identify new drug targets for cardiovascular disease, study new therapies with better efficiency and higher throughput in the preclinical setting, and more rapidly bring the most promising therapies to human testing. However, there must be a critical interface between industry and academia to guide the future of cardiovascular drug development. The shared interest among academic institutions and pharmaceutical companies in developing promising therapies to address unmet clinical needs for patients with cardiovascular disease underlies and guides innovation and discovery platforms that are significantly altering the landscape of cardiovascular drug development.


Assuntos
Fármacos Cardiovasculares/uso terapêutico , Doenças Cardiovasculares/tratamento farmacológico , Desenho de Drogas , Animais , Fármacos Cardiovasculares/farmacologia , Doenças Cardiovasculares/fisiopatologia , Descoberta de Drogas/métodos , Avaliação Pré-Clínica de Medicamentos/métodos , Indústria Farmacêutica , Humanos
14.
Eur J Heart Fail ; 19(11): 1520-1529, 2017 11.
Artigo em Inglês | MEDLINE | ID: mdl-28560782

RESUMO

AIMS: Left ventricular (LV) reverse remodelling is an important marker of improved outcomes in patients with advanced heart failure (HF). We examined the impact of the intramyocardial administration of bone-marrow-derived, lineage-directed, autologous cardiopoietic mesenchymal stem cells (C3BS-CQR-1) on LV remodelling in patients with advanced HF enrolled in the CHART-1 study. METHODS AND RESULTS: Patients (n=351) with symptomatic advanced HF secondary to ischaemic heart disease, and reduced LV ejection fraction (LVEF <35%) were randomized to receive C3BS-CQR-1 or a sham procedure. In a post hoc analysis we examined the effect of C3BS-CQR-1 on LV reverse remodelling within 1 year of the procedure and the influence of C3BS-CQR-1 dosing in the 271 patients treated as randomized. Delivery of C3BS-CQR-1 was associated with a progressive decrease in both LV end-diastolic volume (LVEDV) and end-systolic volume (LVESV) within 52 weeks after treatment. At 1 year, the LVEDV and LVESV of treated patients decreased by 17.0 mL and 12.8 mL greater than controls (P=0.006 and P=0.017, respectively). The effect on LVEDV was maintained after multivariable adjustment for baseline age, systolic blood pressure, LVEDV, LVEF and history of myocardial infarction. The largest reverse remodelling was evident in the patients receiving a moderate number of injections (<20). CONCLUSION: In CHART-1, intramyocardial administration of cardiopoietic stem cells led to reverse remodelling as evidenced by significant progressive decreases in LVEDV and LVESV through the 52 weeks of follow-up. Further studies are needed to explore the dose response with regard to cell number and injected volume, and reverse remodelling.


Assuntos
Terapia Genética/métodos , Insuficiência Cardíaca/terapia , Transplante de Células-Tronco Mesenquimais/métodos , Volume Sistólico/fisiologia , Função Ventricular Esquerda/fisiologia , Remodelação Ventricular/fisiologia , Feminino , Insuficiência Cardíaca/fisiopatologia , Humanos , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento
15.
Cardiovasc Revasc Med ; 18(8): 588-591, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-28529095

RESUMO

OBJECTIVES: We sought to characterize how the perceived risk of early dual antiplatelet therapy (DAPT) discontinuation is incorporated into operator decision-making regarding stent choice, using a simple pre-procedure survey screening for clinical variables that may lead to early DAPT discontinuation. BACKGROUND: Understanding which factors influence operator decision-making regarding stent choice during percutaneous coronary intervention (PCI) could help identify areas for quality improvement. METHODS: We retrospectively identified 1202 patients who underwent PCI from July 2008 to January 2013 at the Durham Veterans Affairs Medical Center. We excluded patients without a complete pre-procedure survey within 14days of PCI, repeat procedures on the same patient and those who received both drug-eluting stents (DES) and bare-metal stents (BMS) or no stent during PCI, leaving 864 patients. The primary outcome was the independent association of "yes" responses to survey items with the odds of DES use during PCI. RESULTS: Of 864 patients, 661 received DES and 203 received BMS. A "yes" response to "planned major surgery or dental work in the next year" (OR 0.20, 95% CI 0.11-0.36, p<0.001), "recent bleeding event or bleeding diathesis" (OR 0.31, 95% CI 0.14-0.68, p=0.003) or "currently taking Coumadin" (OR 0.39, 95% CI 0.19-0.78, p=0.007) was independently associated with lower odds of DES use. CONCLUSIONS: Responses to 3 items on a simple pre-procedure survey screening for clinical variables that may lead to early DAPT discontinuation were independently associated with stent type used during PCI, suggesting the importance of these factors in an operator's stent choice.


Assuntos
Comportamento de Escolha , Tomada de Decisão Clínica , Stents Farmacológicos , Metais , Intervenção Coronária Percutânea/instrumentação , Padrões de Prática Médica , Stents , Idoso , Anticoagulantes/efeitos adversos , Técnicas de Apoio para a Decisão , Odontologia/métodos , Esquema de Medicação , Quimioterapia Combinada , Feminino , Pesquisas sobre Serviços de Saúde , Conhecimentos, Atitudes e Prática em Saúde , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Razão de Chances , Intervenção Coronária Percutânea/efeitos adversos , Inibidores da Agregação de Plaquetas/administração & dosagem , Desenho de Prótese , Estudos Retrospectivos , Fatores de Risco , Procedimentos Cirúrgicos Operatórios/efeitos adversos , Fatores de Tempo , Resultado do Tratamento , Estados Unidos , United States Department of Veterans Affairs , Varfarina/efeitos adversos
16.
Lancet ; 389(10081): 1799-1808, 2017 May 06.
Artigo em Inglês | MEDLINE | ID: mdl-28325638

RESUMO

BACKGROUND: Dual antiplatelet therapy (DAPT), aspirin plus a P2Y12 inhibitor, is the standard antithrombotic treatment following acute coronary syndromes. The factor Xa inhibitor rivaroxaban reduced mortality and ischaemic events when added to DAPT, but caused increased bleeding. The safety of a dual pathway antithrombotic therapy approach combining low-dose rivaroxaban (in place of aspirin) with a P2Y12 inhibitor has not been assesssed in acute coronary syndromes. We aimed to assess rivaroxaban 2·5 mg twice daily versus aspirin 100 mg daily, in addition to clopidogrel or ticagrelor (chosen at investigator discretion before randomisation), for patients with acute coronary syndromes started within 10 days after presentation and continued for 6-12 months. METHODS: In this double-blind, multicentre, randomised trial (GEMINI-ACS-1) done at 371 clinical centres in 21 countries, eligible patients were older than 18 years with unstable angina, non-ST segment elevation myocardial infarction (NSTEMI) or ST segment elevation myocardial infarction (STEMI), with positive cardiac biomarkers and either ischaemic electrocardiographic changes or an atherosclerotic culprit lesion identified during angiography. Participants were randomly assigned (1:1) within 10 days after admission for the index acute coronary syndromes event to either aspirin or rivaroxaban based on a computer-generated randomisation schedule. Randomisation was balanced by using randomly permuted blocks with size of four and was stratified based on the background P2Y12 inhibitor (clopidogrel or ticagrelor) intended to be used at the time of randomisation. Investigators and patients were masked to treatment assignment. Patients received a minimum of 180 days of double-blind treatment with rivaroxaban 2·5 mg twice daily or aspirin 100 mg daily. The choice of clopidogrel or ticagrelor during trial conduct was not randomised and was based on investigator preference. The primary endpoint was thrombolysis in myocardial infarction (TIMI) clinically significant bleeding not related to coronary artery bypass grafting (CABG; major, minor, or requiring medical attention) up to day 390. Primary analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT02293395. FINDINGS: Between April 22, 2015, and Oct 14, 2016, 3037 patients with acute coronary syndromes were randomly assigned; 1518 to receive aspirin and 1519 to receive rivaroxaban. 1704 patients (56%) were in the ticagrelor and 1333 (44%) in the clopidogrel strata. Median duration of treatment was 291 days (IQR 239-354). TIMI non-CABG clinically significant bleeding was similar with rivaroxaban versus aspirin therapy (total 154 patients [5%]; 80 participants [5%] of 1519 vs 74 participants [5%] of 1518; HR 1·09 [95% CI 0·80-1·50]; p=0·5840). INTERPRETATION: A dual pathway antithrombotic therapy approach combining low-dose rivaroxaban with a P2Y12 inhibitor for the treatment of patients with acute coronary syndromes had similar risk of clinically significant bleeding as aspirin and a P2Y12 inhibitor. A larger, adequately powered trial would be required to definitively assess the efficacy and safety of this approach. FUNDING: Janssen Research & Development and Bayer AG.


Assuntos
Síndrome Coronariana Aguda/tratamento farmacológico , Aspirina/uso terapêutico , Hemorragia/induzido quimicamente , Antagonistas do Receptor Purinérgico P2Y/uso terapêutico , Rivaroxabana/uso terapêutico , Adenosina/administração & dosagem , Adenosina/análogos & derivados , Adenosina/uso terapêutico , Idoso , Aspirina/administração & dosagem , Clopidogrel , Angiografia Coronária/métodos , Método Duplo-Cego , Quimioterapia Combinada/métodos , Eletrocardiografia/métodos , Inibidores do Fator Xa/uso terapêutico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/diagnóstico por imagem , Infarto do Miocárdio/tratamento farmacológico , Infarto do Miocárdio/fisiopatologia , Inibidores da Agregação de Plaquetas/uso terapêutico , Antagonistas do Receptor Purinérgico P2Y/administração & dosagem , Rivaroxabana/administração & dosagem , Terapia Trombolítica/métodos , Ticagrelor , Ticlopidina/administração & dosagem , Ticlopidina/análogos & derivados , Ticlopidina/uso terapêutico , Resultado do Tratamento
18.
Catheter Cardiovasc Interv ; 89(2): 169-177, 2017 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-27148802

RESUMO

OBJECTIVE: To assess safety and feasibility of autologous adipose-derived regenerative cells (ADRCs), for treatment of chronic ischemic cardiomyopathy patients. BACKGROUND: Preclinical and early clinical trials suggest ADRCs have excellent potential for ischemic conditions. METHODS: The Athena program consisted of two parallel, prospective, randomized (2:1, active: placebo), double-blind trials assessing intramyocardial (IM) ADRC delivery [40-million, n = 28 (ATHENA) and 80-million (ATHENA II) cells, n = 3]). Patients with an EF ≥20% but ≤45%, multivessel coronary artery disease (CAD) not amenable to revascularization, inducible ischemia, and symptoms of either angina (CCS II-IV) or heart failure (NYHA Class II-III) on maximal medical therapy were enrolled. All patients underwent fat harvest procedure (≤450 mL adipose), on-site cell processing (Celution® System, Cytori Therapeutics), electromechanical mapping, and IM delivery of ADRCs or placebo. RESULTS: Enrollment was terminated prematurely due to non-ADRC-related adverse events and subsequent prolonged enrollment time. Thirty-one patients (17-ADRCs, 14-placebo) mean age 65 ± 8 years, baseline LVEF(%) 31.1 ± 8.7 (ADRC), 31.8 ± 7.7 (placebo) were enrolled. Change in V02 max favored ADRCs (+45.4 ± 222 vs. -9.5 ± 137 mL/min) but there was no difference in left ventricular function or volumes. At 12-months, heart failure hospitalizations occurred in 2/17 (11.7%) [ADRC] and 3/14 (21.4%) [placebo]. Differences in NYHA and CCS classes favored ADRCs at 12-months with significant improvement in MLHFQ (-21.6 + 13.9 vs. -5.5 + 23.8, P = 0.038). CONCLUSIONS: A small volume fat harvest, automated local processing, and IM delivery of autologous ADRCs is feasible with suggestion of benefit in "no option" CAD patients. Although the sample size is limited, the findings support feasibility and scalability for treatment of ischemic cardiomyopathy with ADRCs. © 2016 Wiley Periodicals, Inc.


Assuntos
Tecido Adiposo/citologia , Isquemia Miocárdica/cirurgia , Miocárdio/patologia , Regeneração , Transplante de Células-Tronco , Disfunção Ventricular Esquerda/cirurgia , Função Ventricular Esquerda , Idoso , Doença Crônica , Progressão da Doença , Método Duplo-Cego , Término Precoce de Ensaios Clínicos , Estudos de Viabilidade , Feminino , Insuficiência Cardíaca/etiologia , Insuficiência Cardíaca/fisiopatologia , Insuficiência Cardíaca/terapia , Humanos , Masculino , Pessoa de Meia-Idade , Isquemia Miocárdica/diagnóstico por imagem , Isquemia Miocárdica/patologia , Isquemia Miocárdica/fisiopatologia , Readmissão do Paciente , Estudos Prospectivos , Recuperação de Função Fisiológica , Transplante de Células-Tronco/efeitos adversos , Volume Sistólico , Fatores de Tempo , Transplante Autólogo , Resultado do Tratamento , Estados Unidos , Disfunção Ventricular Esquerda/diagnóstico por imagem , Disfunção Ventricular Esquerda/patologia , Disfunção Ventricular Esquerda/fisiopatologia
19.
Cell Transplant ; 26(2): 205-214, 2017 02 16.
Artigo em Inglês | MEDLINE | ID: mdl-27543900

RESUMO

Autologous cardiosphere-derived cells (CDCs) were the first therapeutic modality to demonstrate myocardial regeneration with a decrease in scar size and an increase in viable, functional tissue. Widespread applicability of autologous CDC therapy is limited by the need for patient-specific myocardial biopsy, cell processing, and quality control, resulting in delays to therapy and inherent logistical and economic constraints. Preclinical data had demonstrated equivalent efficiency of allogeneic to autologous CDCs. The ALLogeneic Heart STem Cells to Achieve Myocardial Regeneration (ALLSTAR) trial is a multicenter randomized, double-blind, placebo-controlled phase 1/2 safety and efficacy trial of intracoronary delivery of allogeneic CDCs (CAP-1002) in patients with myocardial infarction (MI) and ischemic left ventricular dysfunction. The phase 1 safety cohort enrolled 14 patients in an open-label, nonrandomized, dose-escalation safety trial. The phase 2 trial is a double-blind, randomized, placebo-controlled trial that will compare intracoronary CDCs to placebo in a 2:1 allocation and will enroll up to 120 patients. The primary endpoint for both phases is safety at 1 month. For phase 2, the primary efficacy endpoint is relative change from baseline in infarct size at 12 months, as assessed by magnetic resonance imaging. The ALLSTAR trial employs a "seamless" WOVE 1 design that enables continuous enrollment from phase 1 to phase 2 and will evaluate the safety of intracoronary administration of allogeneic CDCs and its efficacy in decreasing infarct size in post-MI patients.


Assuntos
Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/terapia , Miócitos Cardíacos/citologia , Células-Tronco/citologia , Células Cultivadas , Método Duplo-Cego , Feminino , Humanos , Masculino , Miócitos Cardíacos/fisiologia , Medicina Regenerativa/métodos , Transplante de Células-Tronco , Células-Tronco/fisiologia , Transplante Autólogo , Disfunção Ventricular Esquerda/metabolismo , Disfunção Ventricular Esquerda/terapia
20.
Eur Heart J ; 38(9): 648-660, 2017 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-28025189

RESUMO

Aims: Cardiopoietic cells, produced through cardiogenic conditioning of patients' mesenchymal stem cells, have shown preliminary efficacy. The Congestive Heart Failure Cardiopoietic Regenerative Therapy (CHART-1) trial aimed to validate cardiopoiesis-based biotherapy in a larger heart failure cohort. Methods and results: This multinational, randomized, double-blind, sham-controlled study was conducted in 39 hospitals. Patients with symptomatic ischaemic heart failure on guideline-directed therapy (n = 484) were screened; n = 348 underwent bone marrow harvest and mesenchymal stem cell expansion. Those achieving > 24 million mesenchymal stem cells (n = 315) were randomized to cardiopoietic cells delivered endomyocardially with a retention-enhanced catheter (n = 157) or sham procedure (n = 158). Procedures were performed as randomized in 271 patients (n = 120 cardiopoietic cells, n = 151 sham). The primary efficacy endpoint was a Finkelstein-Schoenfeld hierarchical composite (all-cause mortality, worsening heart failure, Minnesota Living with Heart Failure Questionnaire score, 6-min walk distance, left ventricular end-systolic volume, and ejection fraction) at 39 weeks. The primary outcome was neutral (Mann-Whitney estimator 0.54, 95% confidence interval [CI] 0.47-0.61 [value > 0.5 favours cell treatment], P = 0.27). Exploratory analyses suggested a benefit of cell treatment on the primary composite in patients with baseline left ventricular end-diastolic volume 200-370 mL (60% of patients) (Mann-Whitney estimator 0.61, 95% CI 0.52-0.70, P = 0.015). No difference was observed in serious adverse events. One (0.9%) cardiopoietic cell patient and 9 (5.4%) sham patients experienced aborted or sudden cardiac death. Conclusion: The primary endpoint was neutral, with safety demonstrated across the cohort. Further evaluation of cardiopoietic cell therapy in patients with elevated end-diastolic volume is warranted.


Assuntos
Insuficiência Cardíaca/terapia , Transplante de Células-Tronco Mesenquimais/métodos , Isquemia Miocárdica/terapia , Adulto , Idoso , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Resultado do Tratamento , Adulto Jovem
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