RESUMO
AIMS: Vericiguat has been used to treat patients with heart failure with reduced ejection fraction (HFrEF) who demonstrated worsening heart failure despite treatment with other guideline-directed medical therapies. The haemodynamic effects of vericiguat remain unclear. METHODS AND RESULTS: This study enrolled 12 patients (median age, 63 [quartiles 53.5, 70] years; 16.7%(N=2) women) with symptomatic HFrEF (New York Heart Association functional class II-IV) who demonstrated worsening heart failure despite treatment with the four foundational guideline-recommended therapies between March and December 2022, with follow-ups completed in June 2023. A balloon-tipped pulmonary artery thermodilution catheter was placed in the right internal jugular vein to perform right heart catheterisation (RHC) on day 1. Haemodynamic data were acquired before and after vericiguat intake (2.5 mg) on days 2 and 3. The data on days 2 and 3 were averaged. RHC was repeated on day 105 (37, 168). Oral intake of vericiguat 2.5 mg decreased mean pulmonary artery pressure (19.3 [14.3, 26.8] mmHg) and pulmonary artery wedge pressure (PAWP) (11 [7.5, 15] mmHg) before the intake to mean pulmonary artery pressure (17.5 [12.5, 24] mmHg) and PAWP (9.3 [6.8, 14] mmHg) at 30 min after (both P < 0.05). Reduction in PAWP was also found from 14.5 [9.5, 19.5] mmHg on day 1 to 9.5 [6.5, 12.5] mmHg on day 105 (37, 168) (P < 0.05), when vericiguat was titrated to 2.5 mg 25% (N = 3), 5 mg 50% (N = 6), and 10 mg 25% (N = 3). CONCLUSIONS: The consistent reduction in PAWP underscores the well-tolerated nature of vericiguat and its potential to enhance cardiac performance in patients with HFrEF.
Assuntos
Insuficiência Cardíaca , Hemodinâmica , Pirimidinas , Volume Sistólico , Humanos , Feminino , Insuficiência Cardíaca/fisiopatologia , Insuficiência Cardíaca/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Volume Sistólico/fisiologia , Idoso , Pirimidinas/administração & dosagem , Hemodinâmica/efeitos dos fármacos , Hemodinâmica/fisiologia , Seguimentos , Cateterismo Cardíaco/métodos , Resultado do Tratamento , Pressão Propulsora Pulmonar/fisiologia , Pressão Propulsora Pulmonar/efeitos dos fármacos , Compostos Heterocíclicos com 2 AnéisAssuntos
Pressão Propulsora Pulmonar , Inibidores do Transportador 2 de Sódio-Glicose , Humanos , Inibidores do Transportador 2 de Sódio-Glicose/efeitos adversos , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Pressão Propulsora Pulmonar/efeitos dos fármacos , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Diabetes Mellitus Tipo 2/tratamento farmacológico , Glucosídeos/efeitos adversos , Glucosídeos/uso terapêutico , Compostos Benzidrílicos/uso terapêutico , Compostos Benzidrílicos/efeitos adversos , Hipertensão Pulmonar/tratamento farmacológico , Canagliflozina/efeitos adversos , Canagliflozina/uso terapêuticoAssuntos
Insuficiência Cardíaca/tratamento farmacológico , Hemodinâmica/efeitos dos fármacos , Fenilacetatos/farmacologia , Pressão Propulsora Pulmonar/efeitos dos fármacos , Idoso , Feminino , Insuficiência Cardíaca/etiologia , Hemodinâmica/fisiologia , Humanos , Masculino , Pessoa de Meia-Idade , Pressão Propulsora Pulmonar/fisiologia , Resultado do TratamentoAssuntos
Carvedilol/uso terapêutico , Hipertensão Arterial Pulmonar/complicações , Volume Sistólico/fisiologia , Disfunção Ventricular Direita/tratamento farmacológico , Função Ventricular Direita/fisiologia , Anti-Hipertensivos/uso terapêutico , Estudos de Viabilidade , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Hipertensão Arterial Pulmonar/tratamento farmacológico , Hipertensão Arterial Pulmonar/fisiopatologia , Pressão Propulsora Pulmonar/efeitos dos fármacos , Volume Sistólico/efeitos dos fármacos , Disfunção Ventricular Direita/etiologia , Disfunção Ventricular Direita/fisiopatologiaRESUMO
BACKGROUND: Riociguat in Patients with Symptomatic Pulmonary Hypertension associated with Idiopathic Interstitial Pneumonias (RISE-IIP), a randomized, controlled, phase 2b trial of riociguat for pulmonary hypertension associated with idiopathic interstitial pneumonia, was terminated early due to increased mortality in riociguat-treated patients. Baseline characteristics of enrolled patients demonstrated a low diffusing capacity of the lung for carbon monoxide (DLCO) with preserved lung volumes at baseline, suggesting the presence of combined pulmonary fibrosis and emphysema (CPFE) in some patients. This post hoc analysis of RISE-IIP was undertaken to explore lung morphology, assessed by high-resolution computed tomography, and associated clinical outcomes. METHODS: Available baseline/pre-baseline high-resolution computed tomography scans were reviewed centrally by 2 radiologists. The extent of emphysema and fibrosis was retrospectively scored and combined to provide the total CPFE score. RESULTS: Data were available for 65/147 patients (44%), including 15/27 fatal cases (56%). Of these, 41/65 patients (63%) had CPFE. Mortality was higher in patients with CPFE (12/41; 29%) than those without (3/24; 13%). Fourteen patients with CPFE had emphysema > fibrosis (4 died). No relationship was observed between CPFE score, survival status, and treatment assignment. A low DLCO, short 6-min walking distance, and high forced vital capacity:DLCO ratio at baseline also appeared to be risk factors for mortality. CONCLUSIONS: High parenchymal lung disease burden and the presence of more emphysema than fibrosis might have predisposed patients with pulmonary hypertension associated with idiopathic interstitial pneumonia to poor outcomes in RISE-IIP. Future studies of therapy for group 3 pulmonary hypertension should include centrally adjudicated imaging for morphologic phenotyping and disease burden evaluation during screening.
Assuntos
Hipertensão Pulmonar/tratamento farmacológico , Pneumonias Intersticiais Idiopáticas/complicações , Pulmão/diagnóstico por imagem , Pressão Propulsora Pulmonar/fisiologia , Pirazóis/administração & dosagem , Pirimidinas/administração & dosagem , Idoso , Relação Dose-Resposta a Droga , Feminino , Volume Expiratório Forçado/fisiologia , Humanos , Hipertensão Pulmonar/etiologia , Hipertensão Pulmonar/fisiopatologia , Pneumonias Intersticiais Idiopáticas/diagnóstico , Pneumonias Intersticiais Idiopáticas/fisiopatologia , Pulmão/fisiopatologia , Masculino , Prognóstico , Pressão Propulsora Pulmonar/efeitos dos fármacos , Estudos Retrospectivos , Tomografia Computadorizada por Raios X/métodos , Capacidade Vital/fisiologiaRESUMO
BACKGROUND: Selexipag is a selective oral prostacyclin receptor agonist indicated for pulmonary arterial hypertension (PAH) treatment. SelexiPag: tHe usErs dRug rEgistry (SPHERE) (NCT03278002) is collecting data from selexipag-treated patients in real-world clinical practice to elucidate and describe the clinical characteristics, outcomes, and dosing/titration regimens of patients treated with selexipag in routine clinical practice. METHODS: SPHERE is a United States (US)-based, ongoing, multicenter, prospective observational study (target Nâ¯=â¯800). This study enrolls patients who are either newly initiated on selexipag (≤60 days before enrollment) or were previously receiving selexipag with documentation of dose titration at study enrollment. Data collection for the study occurs at routine clinic visits. In this paper, we report on the first 500 patients enrolled. RESULTS: Median follow-up was 17.8 months; 77.6% of patients completed the planned 18 months follow-up, and 22.4% discontinued early from the study. At diagnosis, 94.8% of patients had PAH (World Health Organization [WHO] Group 1), most commonly idiopathic (49.2%) and connective tissue disease associated (26.4%). Most patients (72.4%) initiated selexipag more than 60 days before enrollment. At initiation, 31.0% of patients had WHO functional class (FC) II disease, and 49.6% had WHO FC II or III disease. In addition, 55.0% of patients were receiving double therapy (most commonly an endothelin receptor antagonist plus phosphodiesterase type 5 inhibitor [42.3%]), whereas 30.6% were receiving monotherapy. Despite most patients already receiving PAH-specific therapy, at selexipag initiation, 67.2% (336 of 500) were at intermediate risk, and 9.6% (48 of 500) were at high risk of 1-year mortality. Risk scores remained stable in â¼55% of patients and improved in â¼20% at the end of the study. In total, 72.2% of patients had at least 1 adverse event (AE), and 37.6% reported a serious AE. The median selexipag maintenance dose was 1,200 µg twice daily (interquartile range: 800-1,600 µg twice daily). CONCLUSIONS: Real-world, US-based patients with PAH initiating selexipag typically have WHO FC II/III disease and are at intermediate risk, despite receiving PAH-specific treatment. Selexipag was prescribed as part of a combination regimen in most patients. The study identified no unexpected adverse effects.
Assuntos
Acetamidas/administração & dosagem , Hipertensão Arterial Pulmonar/tratamento farmacológico , Pressão Propulsora Pulmonar/efeitos dos fármacos , Pirazinas/administração & dosagem , Idoso , Anti-Hipertensivos/administração & dosagem , Relação Dose-Resposta a Droga , Feminino , Seguimentos , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Hipertensão Arterial Pulmonar/epidemiologia , Hipertensão Arterial Pulmonar/fisiopatologia , Receptores de Prostaglandina/agonistas , Resultado do Tratamento , Estados Unidos/epidemiologiaRESUMO
BACKGROUND: Early initiation of pulmonary arterial hypertension (PAH) therapies is associated with improved long-term outcomes, yet data on the early use of prostacyclin pathway agents are limited. In these post hoc analyses of the Prostacyclin (PGI2) Receptor Agonist In Pulmonary Arterial Hypertension (GRIPHON) study, the largest randomized controlled trial for PAH to date, the prognostic value of time from diagnosis and its impact on treatment response were examined. RESEARCH QUESTION: How does time from diagnosis impact morbidity/mortality events and response to selexipag treatment in patients with PAH? STUDY DESIGN AND METHODS: The GRIPHON study randomly assigned 1,156 patients with PAH to selexipag or placebo treatment. Patients were categorized post hoc into a time from diagnosis of ≤ 6 months and > 6 months at randomization. Hazard ratios (selexipag vs placebo) were calculated for the primary end point of morbidity/mortality by time from diagnosis using Cox proportional hazard models. RESULTS: Time from diagnosis was ≤ 6 months in 34.9% and > 6 months in 65.1% of patients. Time from diagnosis was prognostic of morbidity/mortality, with newly diagnosed patients having a poorer long-term outcome than patients diagnosed for longer. Compared with placebo, selexipag reduced the risk of morbidity/mortality in patients with a time from diagnosis of ≤ 6 months and > 6 months, with a more pronounced effect in newly diagnosed patients (hazard ratio, 0.45 [95% CI, 0.33-0.63] and 0.74 [95% CI, 0.57-0.96], respectively; P = .0219 for interaction). INTERPRETATION: In the GRIPHON study, newly diagnosed PAH patients had a worse prognosis than patients with a longer time from diagnosis. The benefit of selexipag treatment on disease progression was more pronounced in patients treated earlier than in patients treated later. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT01106014; URL: www.clinicaltrials.gov.
Assuntos
Acetamidas/uso terapêutico , Hipertensão Arterial Pulmonar/diagnóstico , Pressão Propulsora Pulmonar/fisiologia , Pirazinas/uso terapêutico , Adulto , Anti-Hipertensivos/uso terapêutico , Progressão da Doença , Método Duplo-Cego , Feminino , Seguimentos , Saúde Global , Humanos , Masculino , Pessoa de Meia-Idade , Morbidade/tendências , Prognóstico , Hipertensão Arterial Pulmonar/tratamento farmacológico , Hipertensão Arterial Pulmonar/epidemiologia , Pressão Propulsora Pulmonar/efeitos dos fármacos , Taxa de Sobrevida/tendênciasRESUMO
Phosgene (carbonyl dichloride) gas is an indispensable high-production-volume chemical intermediate used worldwide in numerous industrial processes. Published evidence of human exposures due to accidents and warfare (World War I) has been reported; however, these reports often lack specificity because of the uncharacterized exposure intensities of phosgene and/or related irritants. These may include liquid or solid congeners of phosgene, including di- and triphosgene and/or the respiratory tract irritant chlorine which are often collectively reported under the umbrella of phosgene exposure without any appreciation of their differences in causing acute lung injury (ALI). Among these irritants, phosgene gas is somewhat unique because of its poor water solubility. This prevents any appreciable retention of the gas in the upper airways and related trigeminal sensations of irritation. By contrast, in the pulmonary compartment, amphiphilic surfactant might scavenge this lipophilic gas. The interaction of phosgene and the surfactant may affect basic physiological functions controlled by Starling's and Laplace's laws, which can be followed by cardiogenic pulmonary edema. The phenotypic manifestations are dependent on the concentrationâ¯×â¯exposure duration (Câ¯×â¯t); the higher the Câ¯×â¯t is, the less time that is required for edema to appear. It is hypothesized that this type of edema is caused by cardiovascular and colloid osmotic imbalances to initial neurogenic events but not because of the injury itself. Thus, hemodynamic etiologies appear to cause imbalances in extravasated fluids and solute accumulation in the pulmonary interstitium, which is not drained away by the lymphatic channels of the lung. The most salient associated findings are hemoconcentration and hypoproteinemia. The involved intertwined pathophysiological processes coordinating pulmonary ventilation and cardiopulmonary perfusion under such conditions are complex. Pulmonary arterial catheter measurements on phosgene-exposed dogs provided evidence of 'cor pulmonale', a form of acute right heart failure produced by a sudden increase in resistance to blood flow in the pulmonary circulation about 20 h postexposure. The objective of this review is to critically analyze evidence from experimental inhalation studies in rats and dogs, and evidence from accidental human exposures to better understand the primary and secondary events causing cardiopulmonary dysfunction and an ensuing life-threatening lung edema. Mechanism-based diagnostic and therapeutic approaches are also considered for this form of cardiogenic edema.
Assuntos
Lesão Pulmonar Aguda/induzido quimicamente , Substâncias para a Guerra Química/efeitos adversos , Substâncias para a Guerra Química/toxicidade , Fosgênio/administração & dosagem , Fosgênio/toxicidade , Lesão Pulmonar Aguda/metabolismo , Lesão Pulmonar Aguda/terapia , Administração por Inalação , Animais , Humanos , Pressão Propulsora Pulmonar/efeitos dos fármacos , Pressão Propulsora Pulmonar/fisiologia , Respiração Artificial/métodosRESUMO
OBJECTIVE: The role of inhaled nitric oxide in the treatment of shock remains controversial and further translational research is needed. Long-term observation studies using a model of endotoxin-induced shock to assess the effect of inhaled nitric oxide on platelet aggregation have not yet been reported. APPROACH AND RESULTS: The tests were carried out in an animal model of shock in two 10-h periods. During the first 10 h, endotoxin was infused and the inhibition of platelet aggregation was evaluated; following the termination of endotoxin infusion, the restoration of platelet aggregation was assessed for 10 h. A total of 30 pigs were used (NO group, N = 14; control, N = 16). In the NO group, nitric oxide inhalation (30 ppm) was started 3 h after endotoxin infusion and continued until the end of the study. Treatment with NO selectively decreased pulmonary artery pressure at 4 (p = 0.002) and 8 h (p = 0.05) of the experiment as compared to the control. Endotoxin significantly reduced platelet aggregation, as indicated by the decreased activity of platelet receptors: ASPI, ADP, collagen, and TRAP during the experiment (p < 0.001). Endotoxin had no significant effect on changes in the response of the receptor after ristocetin stimulation. After stopping endotoxin infusion, a significant restoration of receptor activity was observed for collagen and TRAP, while ASPI and ADP remained partially depressed. Inhaled nitric oxide did not cause additional inhibition of platelet aggregation, either during or after endotoxin challenge. CONCLUSIONS: A profound reduction in platelet aggregation was observed during endotoxic shock. After stopping endotoxin infusion a restoration of platelet receptor activity was seen. The inhibition of platelet aggregation induced by endotoxin infusion was not intensified by nitric oxide, indicating there was no harmful effect of inhaled nitric oxide on platelet aggregation.
Assuntos
Plaquetas/metabolismo , Óxido Nítrico/uso terapêutico , Agregação Plaquetária/efeitos dos fármacos , Choque Séptico/tratamento farmacológico , Administração por Inalação , Animais , Endotoxinas , Hidrocortisona/uso terapêutico , Óxido Nítrico/administração & dosagem , Pressão Propulsora Pulmonar/efeitos dos fármacos , Choque Séptico/induzido quimicamente , Choque Séptico/metabolismo , Suínos , Vasodilatadores/administração & dosagem , Vasodilatadores/uso terapêuticoRESUMO
BACKGROUND: Inhibition of the sodium-glucose cotransporter-2 (SGLT2i) improves outcomes in patients with heart failure (HF) and reduced ejection fraction (HFrEF), but the mechanism by which they improve outcomes remains unclear. OBJECTIVES: This study aimed to investigate the effects of sodium-glucose cotransporter-2 inhibitor empagliflozin on central hemodynamics in patients with HF and HFrEF. METHODS: This investigator-initiated, double-blinded, placebo-controlled, randomized trial enrolled 70 patients with HFrEF from March 6, 2018, to September 10, 2019. Patients were assigned to empagliflozin of 10 mg or matching placebo once daily on guideline-driven HF therapy for 12 weeks. The primary outcome was ratio of pulmonary capillary wedge pressure (PCWP) to cardiac index (CI) at peak exercise after 12 weeks. Patients underwent right-heart catheterization at rest and during exercise at baseline and 12-week follow-up. RESULTS: Patients with HFrEF, mean age of 57 years, mean left-ventricular ejection fraction, 26%, and 12 (17%) with type 2 diabetes mellitus were randomized. There was no significant treatment effect on peak PCWP/CI (-0.13 mm Hg/l/min/m2; 95% confidence interval: -1.60 to 1.34 mm Hg/l/min/m2; p = 0.86). Considering hemodynamics over the full range of exercise loads, PCWP was significantly reduced (-2.40 mm Hg; 95% confidence interval: -3.96 to -0.84 mm Hg; p = 0.003), but not CI (-0.09 l/min/m2; 95% confidence interval: -0.14 to 0.32 l/min/m2; p = 0.448) by empagliflozin. This was consistent among patients with and without type 2 diabetes. CONCLUSIONS: Among patients with stable HFrEF, empagliflozin for 12 weeks reduced PCWP compared with placebo. There was no significant improvement in neither CI nor PCWP/CI at rest or exercise.
Assuntos
Compostos Benzidrílicos/uso terapêutico , Glucosídeos/uso terapêutico , Insuficiência Cardíaca/tratamento farmacológico , Insuficiência Cardíaca/fisiopatologia , Pressão Propulsora Pulmonar/efeitos dos fármacos , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Volume Sistólico/efeitos dos fármacos , Idoso , Dinamarca , Método Duplo-Cego , Teste de Esforço , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
Therapeutic strategies for pulmonary arterial hypertension (PAH) have made remarkable progress over the last two decades. Currently, 3 types of drugs can be used to treat PAH; prostacyclins, phosphodiesterase 5 inhibitors, and endothelin receptor antagonists (ERA). In Japan, the first generation ERA bosentan was reimbursed in 2005, following which the 2nd generation ERAs ambrisentan and macitentan were reimbursed in 2009 and 2015, respectively. The efficacy of each ERA on hemodynamics in PAH patients remains to be elucidated. The aims of this study were to evaluate the hemodynamic effects of ERAs and compare these effects among each generation of ERAs.We retrospectively examined the clinical parameters of 42 PAH patients who were prescribed an ERA (15 bosentan, 12 ambrisentan, and 15 macitentan) and who underwent a hemodynamic examination before and after ERA introduction at our institution from January 2007 to July 2019.In a total of 42 patients, mean pulmonary arterial pressure (mPAP) and pulmonary vascular resistance (PVR) were significantly decreased and cardiac index was significantly increased after ERA introduction (P < 0.001) and the World Health Organization-Functional class (WHO-Fc) was significantly improved after ERA introduction (P = 0.005). Next, in a comparison between 1st and 2nd generation ERAs, 2nd generation ERAs were found to have brought about greater improvements in hemodynamic parameters (mPAP and PVR. P < 0.01), heart rate, brain natriuretic peptide, arterial oxygen saturation, and mixed venous oxygen saturation than the 1st generation ERA bosentan.We conclude that all ERAs could successfully improve the hemodynamics of PAH patients and that the newer generation ERAs, ambrisentan and macitentan, seemed to be preferable to bosentan.
Assuntos
Bosentana/uso terapêutico , Antagonistas dos Receptores de Endotelina/uso terapêutico , Fenilpropionatos/uso terapêutico , Hipertensão Arterial Pulmonar/tratamento farmacológico , Piridazinas/uso terapêutico , Pirimidinas/uso terapêutico , Sulfonamidas/uso terapêutico , Administração Oral , Adulto , Idoso , Bosentana/administração & dosagem , Estudos de Casos e Controles , Antagonistas dos Receptores de Endotelina/administração & dosagem , Feminino , Hemodinâmica/efeitos dos fármacos , Humanos , Japão/epidemiologia , Masculino , Pessoa de Meia-Idade , Fenilpropionatos/administração & dosagem , Inibidores da Fosfodiesterase 5/uso terapêutico , Placebos/administração & dosagem , Prostaglandinas I/uso terapêutico , Hipertensão Arterial Pulmonar/fisiopatologia , Pressão Propulsora Pulmonar/efeitos dos fármacos , Piridazinas/administração & dosagem , Pirimidinas/administração & dosagem , Estudos Retrospectivos , Sulfonamidas/administração & dosagem , Resultado do Tratamento , Resistência Vascular/efeitos dos fármacosAssuntos
Acetamidas/uso terapêutico , Anemia Falciforme/complicações , Hipertensão Pulmonar/tratamento farmacológico , Pressão Propulsora Pulmonar/efeitos dos fármacos , Pirazinas/uso terapêutico , Anti-Hipertensivos/uso terapêutico , Criança , Feminino , Humanos , Hipertensão Pulmonar/etiologia , Hipertensão Pulmonar/fisiopatologia , Pró-FármacosAssuntos
Anti-Hipertensivos/efeitos adversos , Parada Cardíaca/induzido quimicamente , Insuficiência Cardíaca/complicações , Hipertensão Pulmonar/tratamento farmacológico , Artéria Pulmonar/efeitos dos fármacos , Pressão Propulsora Pulmonar/efeitos dos fármacos , Citrato de Sildenafila/efeitos adversos , Vasodilatadores/efeitos adversos , Feminino , Parada Cardíaca/diagnóstico , Parada Cardíaca/fisiopatologia , Insuficiência Cardíaca/diagnóstico , Insuficiência Cardíaca/fisiopatologia , Humanos , Hipertensão Pulmonar/diagnóstico , Hipertensão Pulmonar/etiologia , Hipertensão Pulmonar/fisiopatologia , Pessoa de Meia-Idade , Artéria Pulmonar/fisiopatologia , Fatores de Risco , Resultado do Tratamento , Função Ventricular Esquerda/efeitos dos fármacosRESUMO
BACKGROUND: Approaches to risk assessment in pulmonary arterial hypertension (PAH) include the noninvasive French risk assessment approach (number of low-risk criteria based on the European Society of Cardiology and European Respiratory Society guidelines) and Registry to Evaluate Early and Long-term PAH Disease Management (REVEAL) 2.0 risk calculator. The prognostic and predictive value of these methods for morbidity/mortality was evaluated in the predominantly prevalent population of GRIPHON, the largest randomized controlled trial in PAH. METHODS: GRIPHON randomized 1,156 patients with PAH to selexipag or placebo. Post-hoc analyses were performed on the primary composite end-point of morbidity/mortality by the number of low-risk criteria (World Health Organization functional class I-II; 6-minute walk distance >440 m; N-terminal pro-brain natriuretic peptide <300 ng/liter) and REVEAL 2.0 risk category. Hazard ratios and 95% confidence intervals were calculated using Cox proportional hazard models. RESULTS: Both the number of low-risk criteria and the REVEAL 2.0 risk category were prognostic for morbidity/mortality at baseline and any time-point during the study. Patients with 3 low-risk criteria at baseline had a 94% reduced risk of morbidity/mortality compared to patients with 0 low-risk criteria and were all categorized as low-risk by REVEAL 2.0. The treatment effect of selexipag on morbidity/mortality was consistent irrespective of the number of low-risk criteria or the REVEAL 2.0 risk category at any time-point during the study. Selexipag-treated patients were more likely to increase their number of low-risk criteria from baseline to week 26 than placebo-treated patients (odds ratio 1.69, pâ¯=â¯0.0002); similar results were observed for REVEAL 2.0 risk score. CONCLUSIONS: These results support the association between risk profile and long-term outcome and suggest that selexipag treatment may improve risk profile.
Assuntos
Anti-Hipertensivos/administração & dosagem , Hipertensão Arterial Pulmonar/tratamento farmacológico , Pressão Propulsora Pulmonar/efeitos dos fármacos , Medição de Risco/métodos , Adolescente , Adulto , Idoso , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Morbidade/tendências , Prognóstico , Hipertensão Arterial Pulmonar/epidemiologia , Hipertensão Arterial Pulmonar/fisiopatologia , Estados Unidos/epidemiologia , Adulto JovemRESUMO
BACKGROUND: Ambrisentan has shown effectiveness in the treatment of Group 1 pulmonary arterial hypertension (PAH). Although portopulmonary hypertension (PoPH) is a subset of Group 1 PAH, few clinical trials have been testing PAH therapies in patients with PoPH. The objective of this study is to evaluate the efficacy and safety of ambrisentan in PoPH. METHODS: This study is a prospective, multicenter, open-label trial in which treatment-naive patients with PoPH with Child-Pugh class A/B were administered with ambrisentan for 24 weeks, followed by a long-term extension (24-28 weeks). The primary end-points were change in pulmonary vascular resistance (PVR) and 6-minutes walk distance (6MWD) at 24 weeks, whereas secondary end-points included safety, World Health Organization (WHO) functional class (FC) and echocardiographic assessments. RESULTS: Of the 31 patients, 23 finished 24 weeks of ambrisentan therapy and 19 finished the extension. PVR decreased significantly (mean ± SD) (7.1 ± 5 vs 3.8 ± 1.8 Wood units, p < 0.001), whereas 6MWD remained unchanged (314 ± 94 vs 336 ± 108 m). Other hemodynamic parameters such as right atrial pressure (13 ± 8 vs 9 ± 4 mm Hg, p < 0.05), mean pulmonary arterial pressure (46 ± 13 vs. 38 ± 8 mm Hg, p < 0.01), cardiac index (2.6 ± 0.6 vs. 3.5 ± 0.7 liter/min/m2, p < 0.001) showed improvement, whereas pulmonary capillary wedge pressure remained unchanged. Of the 22 patients with WHO FC assessments at baseline and 24 weeks, WHO FC improved significantly (pâ¯=â¯0.005). Most frequent drug-related adverse events were edema (38.7%) and headache (22.5%). One episode of leg edema resulted into the permanent discontinuation of ambrisentan. CONCLUSIONS: Ambrisentan monotherapy in PoPH improves hemodynamics and FC at 24 weeks; however, it did not show any improvement in 6MWD. These preliminary outcomes should be interpreted with caution (Clinicaltrials.Gov:NCT01224210).
Assuntos
Hipertensão Pulmonar/tratamento farmacológico , Fenilpropionatos/uso terapêutico , Piridazinas/uso terapêutico , Resistência Vascular/efeitos dos fármacos , Anti-Hipertensivos/uso terapêutico , Ecocardiografia , Feminino , Seguimentos , Humanos , Hipertensão Pulmonar/diagnóstico , Hipertensão Pulmonar/fisiopatologia , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Pressão Propulsora Pulmonar/efeitos dos fármacos , Resultado do TratamentoRESUMO
Evidence linking cocaine to the risk of pulmonary hypertension (PH) is limited and inconsistent. We examined whether cocaine use, in the absence of other known causes of PH, was associated with elevated systolic pulmonary artery pressure (sPAP) and increased probability of PH. We compared patients with documented cocaine use to a randomly selected age, sex, and race-matched control group without history of cocaine use. All participants had no known causes of PH and underwent echocardiography for noninvasive estimation of sPAP. We used routinely reported echocardiographic parameters and contemporary guidelines to grade the probability of PH. In 88 patients with documented cocaine use (mean age ± standard deviation 51.7 ± 9.5 years), 33% were women and 89% were of Black race. The commonest route of cocaine use was smoking (74%). Cocaine users compared with the control group had significantly higher sPAP (mean ± standard deviation, 30.1 ± 13.1 vs 22.0 ± 9.8 mm Hg, p <0.001) and greater likelihood of PH (25% vs 10%, pâ¯=â¯0.012). In multivariable analyses adjusted for potential confounders including left ventricular diastolic dysfunction, cocaine use conferred a fivefold greater odds of echocardiographic PH (pâ¯=â¯0.006). Additionally, a stepwise increase in the likelihood of PH was noted across cocaine users with negative or no drug screen on the day of echocardiography to cocaine users with a positive drug screen (multivariable p for trendâ¯=â¯0.008). In conclusion, cocaine use was associated with a higher sPAP and an increased likelihood of echocardiographic PH with a probable acute-on-chronic effect.
Assuntos
Transtornos Relacionados ao Uso de Cocaína/complicações , Cocaína/efeitos adversos , Ecocardiografia Doppler/métodos , Ventrículos do Coração/diagnóstico por imagem , Hipertensão Pulmonar/etiologia , Artéria Pulmonar/diagnóstico por imagem , Pressão Propulsora Pulmonar/efeitos dos fármacos , Cateterismo Cardíaco , Inibidores da Captação de Dopamina/efeitos adversos , Feminino , Seguimentos , Ventrículos do Coração/efeitos dos fármacos , Ventrículos do Coração/fisiopatologia , Humanos , Hipertensão Pulmonar/diagnóstico , Hipertensão Pulmonar/fisiopatologia , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , SístoleRESUMO
A 73-year-old woman with chronic myeloid leukemia developed severe pulmonary arterial hypertension (PAH) and pleural effusions after treatment with dasatinib. During workup, partial anomalous pulmonary venous connection and a sinus venosus atrial septal defect were found; these anomalies may have predisposed her to developing this rare and life-threatening condition. Fortunately, her PAH was completely reversible by discontinuation of dasatinib. This case highlights dasatinib's ability to cause PAH in patients predisposed to pulmonary vascular disease.
Assuntos
Dasatinibe/efeitos adversos , Hipertensão Arterial Pulmonar/induzido quimicamente , Pressão Propulsora Pulmonar/efeitos dos fármacos , Adulto , Antineoplásicos/efeitos adversos , Antineoplásicos/uso terapêutico , Dasatinibe/uso terapêutico , Feminino , Seguimentos , Humanos , Imageamento Tridimensional , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Imagem Cinética por Ressonância Magnética , Hipertensão Arterial Pulmonar/diagnóstico , Hipertensão Arterial Pulmonar/fisiopatologia , Pressão Propulsora Pulmonar/fisiologia , Tomografia Computadorizada por Raios XRESUMO
BACKGROUND: The Fontan circulation is fragile, which is easily broken down. For now, there is no consensus on the drug treatment for the prevention of failure of the Fontan circulation. METHODS: Studies comparing pulmonary vasodilator and control in Fontan patients were identified by searching the PubMed, EMBASE, Clinical Trials, and the Cochrane Library databases until March 20, 2019. The assessed variables included the change of pulmonary resistance, heart function, exercise capacity, life of quality, mortality, and serials of adverse events before and after drug administration. A random-effect/fixed-effect model was used to summarize the estimates of the mean difference (MD)/risk ratio (RR) with 95% confidence interval (CI). Subgroup analysis stratified by drug was performed. RESULTS: This study will be submitted to a peer-reviewed journal for publication. CONCLUSION: This study will assess the efficacy and safety of pulmonary vasodilators for patients after Fontan procedure, and provide more evidence-based guidance in clinical practice. PROSPERO REGISTRATION NUMBER: CRD42019132135.
Assuntos
Técnica de Fontan/métodos , Cardiopatias Congênitas/cirurgia , Hipertensão Pulmonar/tratamento farmacológico , Circulação Pulmonar/efeitos dos fármacos , Pressão Propulsora Pulmonar/efeitos dos fármacos , Vasodilatadores/uso terapêutico , Cardiopatias Congênitas/fisiopatologia , Humanos , Hipertensão Pulmonar/fisiopatologia , Metanálise como AssuntoRESUMO
Selexipag is an enteral, selective prostacyclin IP receptor agonist approved for pulmonary hypertension in adults. There are few reports of its use in children and none in infants. We report the first transition of an infant (11.5 months, 8.6 kg) from intravenous treprostinil (40 ng/kg/minute) to enteral selexipag (400 mcg twice daily) with a good response and no adverse effects.
Assuntos
Acetamidas/administração & dosagem , Epoprostenol/análogos & derivados , Hipertensão Arterial Pulmonar/tratamento farmacológico , Pressão Propulsora Pulmonar/efeitos dos fármacos , Pirazinas/administração & dosagem , Administração Intravenosa , Administração Oral , Anti-Hipertensivos/administração & dosagem , Ecocardiografia , Nutrição Enteral , Epoprostenol/administração & dosagem , Humanos , Recém-Nascido , Infusões Intravenosas , Masculino , Hipertensão Arterial Pulmonar/diagnóstico , Hipertensão Arterial Pulmonar/fisiopatologia , Receptores de ProstaglandinaRESUMO
BACKGROUND AND OBJECTIVE: Rapid saline infusion and exercise has been proposed as methods to unmask cardiovascular disease. However, the normal hemodynamic response to rapid saline infusion has not been compared to exercise nor is it known whether the responses are age-dependent.We assessed the hemodynamic response to rapid saline infusion in healthy participants over a wide age-range and compared it to exercise in the same participants. METHODS AND RESULTS: Fifty healthy participants (young <40 years, nâ¯=â¯16, middle-aged 40-59 years, nâ¯=â¯15, elderly 60-80 years, nâ¯=â¯19) underwent right heart catheterization at rest, during semisupine ergometer exercise at three exercise levels (25%, 50%, and 75% of peak VO2) and after rapid saline infusion (10â¯ml/kg at a rate of 150â¯ml/min). Rapid saline infusion significantly increased pulmonary capillary wedge pressure (PCWP) similarly across all age groups (∆PCWP 6⯱â¯2; 7⯱â¯2; 6⯱â¯4â¯mmHg for the young, middle-aged and elderly respectively) with no correlation between age and ∆PCWP (râ¯=â¯0.05; pâ¯=â¯0.74). However, there was a negative correlation between age and ∆stroke volume (SV) as elderly participants had a lower increase in SV following rapid saline infusion (râ¯=â¯0.44; pâ¯=â¯0.002). On the contrary, exercise-induced significantly larger and age-dependent increases in PCWP (râ¯=â¯0.58; p < 0.0001). Exercise also caused a larger increase in SV compared with rapid fluid loading (pâ¯=â¯0.0003) CONCLUSION: Unlike exercise, rapid saline infusion caused an age-independent increase in PCWP in healthy adults. Suggesting that age-related impairments beyond passive stiffness have a greater impact on exercise-induced increase in PCWP. CLINICAL TRIAL REGISTRATION: https://clinicaltrials.gov/ct2/show/NCT01974557.