RESUMO
Sudden cardiac death in the young (SCDY) spans gender, race, ethnicity, and socioeconomic class. The loss of any pediatric patient is a matter of national and international public health concern, and focused efforts should be aimed at preventing these burdensome tragedies. Prepared by members of the Cardiac Safety Research Consortium, this White Paper summarizes and reports the dialogue at the second Think Tank related to the issues and the proposed solutions for the development of a national resource for screening and prevention of SCDY. This Think Tank, sponsored by the Cardiac Safety Research Consortium and the United States Food and Drug Administration, convened on February 18, 2016, in Miami, FL, to identify and resolve the barriers that prevent early identification of patients at risk for SCDY. All potential stakeholders including national and international experts from industry, medicine, academics, engineering, and community advocacy leaders had an opportunity to share ideas and collaborate.
Assuntos
Data Warehousing , Morte Súbita Cardíaca/prevenção & controle , Eletrocardiografia , Cardiopatias/diagnóstico , Programas de Rastreamento/normas , Criança , Consenso , Feminino , Humanos , Masculino , Valores de ReferênciaRESUMO
This White Paper, prepared by members of the Cardiac Safety Research Consortium, discusses important issues regarding sudden cardiac death in the young (SCDY), a problem that does not discriminate by gender, race, ethnicity, education, socioeconomic level, or athletic status. The occurrence of SCDY has devastating impact on families and communities. Sudden cardiac death in the young is a matter of national and international public health, and its prevention has generated deep interest from multiple stakeholders, including families who have lost children, advocacy groups, academicians, regulators, and the medical industry. To promote scientific and clinical discussion of SCDY prevention and to germinate future initiatives to move this field forward, a Cardiac Safety Research Consortium-sponsored Think Tank was held on February 21, 2015 at the US Food and Drug Administration's White Oak facilities, Silver Spring, MD. The ultimate goal of the Think Tank was to spark initiatives that lead to the development of a rational, reliable, and sustainable national health care resource focused on SCDY prevention. This article provides a detailed summary of discussions at the Think Tank and descriptions of related multistakeholder initiatives now underway: it does not represent regulatory guidance.
Assuntos
Morte Súbita Cardíaca/prevenção & controle , Recursos em Saúde/organização & administração , Vigilância da População/métodos , Pesquisa Qualitativa , Morte Súbita Cardíaca/epidemiologia , Humanos , Incidência , Estados Unidos/epidemiologia , Adulto JovemRESUMO
The Cardiac Safety Research Consortium (CSRC), a transparent, public-private partnership established in 2005 as a Critical Path Program and formalized in 2006 under a Memorandum of Understanding between the United States Food and Drug Administration and Duke University, is entering its second decade. Our continuing goal is to advance paradigms for more efficient regulatory science related to the cardiovascular safety of new therapeutics, both in the United States and globally, particularly where such safety questions add burden to innovative research and development. Operationally, CSRC brings together a broad base of stakeholders from academia, industry, and government agencies in a collaborative forum focused on identifying barriers and then creating novel solutions through shared data, expertise, and collaborative research. This white paper provides a brief overview of the Consortium's activities in its first decade and a context for some of our current activities and future directions. The growth and success of the CSRC have been primarily driven by members' active participation and the development of goodwill and trust throughout our membership, which have facilitated novel collaborations across traditionally competitive or contentious stakeholder boundaries. The continued expansion of our base of participating academicians, industry experts, and regulators will define the Consortium's success in our second decade. It is our hope that sharing our endeavors to date will stimulate additional participation in the CSRC and also provide a model for other groups starting to develop similar collaborative forums.
Assuntos
Pesquisa Biomédica , Fármacos Cardiovasculares , Procedimentos Cirúrgicos Cardiovasculares , Segurança de Equipamentos , Parcerias Público-Privadas , United States Food and Drug Administration , Universidades , Humanos , Segurança do Paciente , Estados UnidosRESUMO
OBJECTIVE: To identify clinical signs associated with and outcome of human exposure to Micotil 300 (tilmicosin injection). DESIGN: Retrospective case series. STUDY POPULATION: Reports of 3,168 human exposures to Micotil 300. PROCEDURES: Reports of human exposure to Micotil 300 submitted to the Elanco Animal Health Pharmacovigilance Unit between March 1992 and March 2005 were reviewed. RESULTS: At least 1 clinical sign was described in 1,404 (44%) reports, whereas the remaining 1,764 (56%) exposures were presumably asymptomatic. Eighty percent of exposures involved males; mean age was 38 years. Sixty-one percent of exposures were a result of accidental injection, with injection site pain, bleeding, swelling, or inflammation being the most common signs, followed by nausea, tachycardia, dizziness, anxiety, an abnormal taste, headache, lightheadedness, limb pain, paresthesia, chest pain, and soreness. Only 156 (5%) reports involved serious adverse effects (ie, tachycardia, bradycardia, hypertension, hypotension, heart disorder, chest pain, tachypnea, or death). There were reports of 13 deaths following tilmicosin exposure, but only 2 of those deaths were related to accidental exposure. Time to onset of clinical signs was < or = 60 minutes in 63 of the 156 (40%) reports involving serious adverse effects. CONCLUSIONS AND CLINICAL RELEVANCE: Results suggest that the overall risk of accidental human exposure to tilmicosin resulting in serious adverse effects is low (approx 2 people for every 1 million doses administered). Nevertheless, safe handling and proper use should be emphasized.
Assuntos
Acidentes de Trabalho , Antibacterianos/intoxicação , Macrolídeos/intoxicação , Ferimentos Penetrantes Produzidos por Agulha , Exposição Ocupacional , Tilosina/análogos & derivados , Drogas Veterinárias/intoxicação , Adulto , Dor no Peito/induzido quimicamente , Feminino , Humanos , Masculino , Estudos Retrospectivos , Taquicardia/induzido quimicamente , Tilosina/intoxicaçãoRESUMO
BACKGROUND: In chronic heart failure, sympathetic activation is increased. Moxonidine acts on central nervous system receptors to decrease sympathetic activation. We investigated the dose-response relationship of a new sustained-release (SR) preparation of moxonidine and the plasma concentration of norepinephrine in patients with chronic heart failure. METHODS AND RESULTS: A total of 268 patients with chronic heart failure in NYHA functional class II to IV on optimal standard therapy were randomized to placebo or 1 of 5 doses of moxonidine SR: 0.3, 0.6, 0.9, 1.2, or 1.5 mg BID. After a dose-titration phase (7 weeks), patients were followed up for another 12 weeks at their maximally tolerated dose. Blood samples for plasma norepinephrine were collected at baseline and weekly during the initial 7 weeks, at week 19, and at the end of the study. At baseline and 7 and 19 weeks, sampling was also done 4 hours after the dose. After the active phases of the study, plasma norepinephrine was evaluated for an additional 3 days. A marked, statistically significant dose-related decrease in plasma norepinephrine was observed for predose levels as well as 4 hours after the dose at week 19. At the highest dose (1.5 mg BID), the trough reduction in norepinephrine was 52%. These reductions were accompanied by a modest decrease in heart rate, a modest increase in left ventricular ejection fraction, and a dose-related increase in adverse events. CONCLUSIONS: Plasma norepinephrine was markedly reduced in a dose-related manner by moxonidine SR. This reduction was accompanied by evidence of reverse remodeling, but also by an increase in adverse events.
Assuntos
Insuficiência Cardíaca/tratamento farmacológico , Imidazóis/administração & dosagem , Norepinefrina/sangue , Simpatolíticos/administração & dosagem , Pressão Sanguínea/efeitos dos fármacos , Doença Crônica , Preparações de Ação Retardada , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Insuficiência Cardíaca/sangue , Insuficiência Cardíaca/fisiopatologia , Frequência Cardíaca/efeitos dos fármacos , Humanos , Imidazóis/efeitos adversos , Imidazóis/uso terapêutico , Masculino , Pessoa de Meia-Idade , Simpatolíticos/efeitos adversos , Simpatolíticos/uso terapêutico , Disfunção Ventricular Esquerda/tratamento farmacológicoRESUMO
STUDY OBJECTIVE: To gather additional 28-day all-cause mortality and safety data among adult patients with severe sepsis who were treated with drotrecogin alfa (activated). DESIGN: Prospective, single-arm, multicenter clinical trial. SETTING: Eighty-five study sites in the United States and two in Puerto Rico. PARTICIPANTS: Adult patients (273 patients) with a diagnosis of severe sepsis, which was defined as a systemic inflammatory response due to acute infection and one or more sepsis-induced organ dysfunctions present for = 48 h, as in the recombinant human activated Protein C Worldwide Evaluation in Severe Sepsis (PROWESS) trial. INTERVENTIONS: Drotrecogin alfa (activated) [Xigris; Eli Lilly and Company; Indianapolis, IN], 24 micro g/kg/h, as a continuous IV infusion for a duration of 96 +/- 1 h. MEASUREMENTS AND RESULTS: The primary end point was all-cause mortality, which was assessed 28 days after the start of the infusion of drotrecogin alfa (activated). Serious bleeding was monitored to day 28. Comparisons of mortality were made to treatment groups from two double-blind, placebo-controlled clinical trials (PROWESS United States and the Secretory Phospholipase A2 Inhibitor [sPLA2I] in Severe Sepsis trial) that used similarly defined patient populations from the United States. For the 273 adult patients enrolled in this study, the 28-day all-cause mortality rate was 26.4%. This mortality rate was 6% lower than that observed in the placebo groups in the PROWESS US trial (32.9%) and the sPLA2I trial (33.2%), and was similar to that of the group treated with drotrecogin alfa (activated) in the PROWESS US trial (24.4%). One nonfatal intracranial hemorrhage was reported in the Extended Evaluation of Recombinant Human Activated Protein C United States trial (ENHANCE US) [0.35%]. Serious bleeding events during the infusion period occurred in 11 patients (4.0%) compared to 10 patients (2.8%) in the PROWESS US drotrecogin alfa (activated) treatment group. CONCLUSIONS: Despite the limitations associated with comparisons across trials, this study provides confirmatory evidence of the efficacy and safety of drotrecogin alfa (activated) documented in the PROWESS trial.
Assuntos
Causas de Morte , Proteína C/administração & dosagem , Proteínas Recombinantes/administração & dosagem , Sepse/tratamento farmacológico , Sepse/mortalidade , APACHE , Adulto , Fatores Etários , Idoso , Intervalos de Confiança , Estado Terminal , Relação Dose-Resposta a Droga , Esquema de Medicação , Feminino , Seguimentos , Hemorragia/induzido quimicamente , Hemorragia/epidemiologia , Humanos , Infusões Intravenosas , Masculino , Pessoa de Meia-Idade , Probabilidade , Estudos Prospectivos , Proteína C/efeitos adversos , Proteínas Recombinantes/efeitos adversos , Valores de Referência , Medição de Risco , Sepse/diagnóstico , Índice de Gravidade de Doença , Fatores Sexuais , Método Simples-Cego , Análise de Sobrevida , Resultado do Tratamento , Estados UnidosRESUMO
BACKGROUND: The association between sympathetic activation and mortality in chronic heart failure and the favorable effect of beta blocking drugs has raised the possibility of therapeutic efficacy for central sympathetic inhibition with sustained-release (SR) moxonidine, an imidazoline receptor agonist. METHODS: A randomized double-blind, placebo-controlled trial was initiated in 425 centers in 17 countries with a plan to enter 4533 patients with New York Heart Association class II-IV heart failure and a reduced ejection fraction. Moxonidine SR or matching placebo was titrated to a target dose of 1.5 mg BID. The trial was powered to detect a 20% reduction in mortality, which required a total of 724 deaths. FINDINGS: An early increase in death rate and adverse events in the moxonidine SR group led to premature termination of the trial because of safety concerns after 1934 patients were entered. Final analysis revealed 54 deaths (5.5%) in the moxonidine SR group and 32 deaths (3.4%) in the placebo group during the active treatment phase. Survival curves revealed a significantly (P=0.012) worse outcome in the moxonidine SR group. Hospitalization for heart failure, acute myocardial infarction and adverse events were also more frequent in the moxonidine SR group. Plasma norepinephrine was significantly decreased by moxonidine SR (-18.8% from baseline) vs. placebo (+6.9%). INTERPRETATION: Early termination of the trial limited conclusions regarding the long-term effects of central sympathetic inhibition. Nonetheless, the excess early mortality and morbidity suggest the likelihood of an adverse effect of moxonidine SR and raise concerns regarding the efficacy of generalized sympathetic inhibition in heart failure.