RESUMO
Deceased diabetic kidneys are increasingly utilized in transplantation. The relationship of donor's history of diabetes to clinical and histological outcomes was examined. Forty-nine diabetic deceased donor kidneys (D-DM) were transplanted into 26 normal (R-N/D-DM) and 23 diabetic recipients (R-DM/D-DM) and compared to 211 diabetic recipients of normal kidneys(R-DM/D-N) and 466 normal recipients of normal kidneys (R-N/D-N). Patient survival at 5 years was 89.7% in R-N/D-N, 96.2% in R-N/D-DM, 80.1% in R-DM/D-N, and a 71.6% in R-DM/D-DM (P = .008). Death-censored graft survival at 5 years was 86.3% in R-N/D-N, 87.4% in R-N/D-DM, 93.5% in R-DM/D-N, and 87.5% in R-DM/D-DM (P = .24). Multivariable regression analysis showed that compared to non-diabetic recipients, diabetic recipients had a 2- to 3-fold increased risk of mortality. In this cohort, there was no impact on death-censored graft survival of diabetic donor status. Only 6 of 26 post-perfusion biopsies showed evidence of diabetic nephropathy (Assuntos
Diabetes Mellitus
, Transplante de Rim
, Sobrevivência de Enxerto
, Humanos
, Rim
, Doadores de Tecidos
, Resultado do Tratamento
RESUMO
BACKGROUND: Initial combination therapy with ambrisentan and tadalafil reduced the risk of clinical failure events for treatment-naïve participants with pulmonary arterial hypertension (PAH) as compared to monotherapy. Previous studies in PAH have demonstrated greater treatment benefits in more symptomatic participants. METHODS: AMBITION was an event-driven, double-blind study in which participants were randomized 2:1:1 to once-daily initial combination therapy with ambrisentan 10 mg plus tadalafil 40 mg, ambrisentan 10 mg plus placebo, or tadalafil 40 mg plus placebo. In this pre-specified subgroup analysis, we compared the efficacy data between those with functional class (FC) II vs. FC III symptoms at baseline. RESULTS: This analysis included 500 participants in the previously defined primary analysis set (n = 155 FC II, n = 345 FC III). Comparing combination therapy to pooled monotherapy, the risk of clinical failure events was reduced by 79% (hazard ratio, 0.21 [95% confidence interval: 0.071, 0.63]) for FC II patients and 42% (hazard ratio, 0.58 [95% confidence interval: 0.39, 0.86]) for FC III patients. In a post-hoc analysis, the risk of first hospitalization for worsening PAH was also reduced by combination therapy, particularly for FC II patients (0 combination vs. 11 [14%] pooled monotherapy). Adverse events were frequent but comparable between the subgroups. CONCLUSIONS: Treatment benefit from initial combination therapy appeared at least as great for FC II as for FC III participants. Hospitalizations for worsening PAH were not observed in FC II participants assigned to combination. The present data support an initial combination strategy for newly diagnosed patients even when symptoms are less severe. Funded by Gilead Sciences, Inc. and GlaxoSmithKline; AMBITION ClinicalTrials.gov number, NCT01178073.
Assuntos
Anti-Hipertensivos/administração & dosagem , Fenilpropionatos/administração & dosagem , Hipertensão Arterial Pulmonar/diagnóstico , Hipertensão Arterial Pulmonar/tratamento farmacológico , Piridazinas/administração & dosagem , Tadalafila/administração & dosagem , Vasodilatadores/administração & dosagem , Adulto , Idoso , Método Duplo-Cego , Quimioterapia Combinada , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
BACKGROUND: Data on the effect of initial combination therapy with ambrisentan and tadalafil on long-term outcomes in patients with pulmonary arterial hypertension are scarce. METHODS: In this event-driven, double-blind study, we randomly assigned, in a 2:1:1 ratio, participants with World Health Organization functional class II or III symptoms of pulmonary arterial hypertension who had not previously received treatment to receive initial combination therapy with 10 mg of ambrisentan plus 40 mg of tadalafil (combination-therapy group), 10 mg of ambrisentan plus placebo (ambrisentan-monotherapy group), or 40 mg of tadalafil plus placebo (tadalafil-monotherapy group), all administered once daily. The primary end point in a time-to-event analysis was the first event of clinical failure, which was defined as the first occurrence of a composite of death, hospitalization for worsening pulmonary arterial hypertension, disease progression, or unsatisfactory long-term clinical response. RESULTS: The primary analysis included 500 participants; 253 were assigned to the combination-therapy group, 126 to the ambrisentan-monotherapy group, and 121 to the tadalafil-monotherapy group. A primary end-point event occurred in 18%, 34%, and 28% of the participants in these groups, respectively, and in 31% of the pooled-monotherapy group (the two monotherapy groups combined). The hazard ratio for the primary end point in the combination-therapy group versus the pooled-monotherapy group was 0.50 (95% confidence interval [CI], 0.35 to 0.72; P<0.001). At week 24, the combination-therapy group had greater reductions from baseline in N-terminal pro-brain natriuretic peptide levels than did the pooled-monotherapy group (mean change, -67.2% vs. -50.4%; P<0.001), as well as a higher percentage of patients with a satisfactory clinical response (39% vs. 29%; odds ratio, 1.56 [95% CI, 1.05 to 2.32]; P=0.03) and a greater improvement in the 6-minute walk distance (median change from baseline, 48.98 m vs. 23.80 m; P<0.001). The adverse events that occurred more frequently in the combination-therapy group than in either monotherapy group included peripheral edema, headache, nasal congestion, and anemia. CONCLUSIONS: Among participants with pulmonary arterial hypertension who had not received previous treatment, initial combination therapy with ambrisentan and tadalafil resulted in a significantly lower risk of clinical-failure events than the risk with ambrisentan or tadalafil monotherapy. (Funded by Gilead Sciences and GlaxoSmithKline; AMBITION ClinicalTrials.gov number, NCT01178073.).
Assuntos
Carbolinas/uso terapêutico , Hipertensão Pulmonar/tratamento farmacológico , Fenilpropionatos/uso terapêutico , Piridazinas/uso terapêutico , Adulto , Idoso , Carbolinas/efeitos adversos , Progressão da Doença , Método Duplo-Cego , Quimioterapia Combinada , Feminino , Hospitalização , Humanos , Hipertensão Pulmonar/mortalidade , Hipertensão Pulmonar/fisiopatologia , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Peptídeo Natriurético Encefálico/sangue , Fragmentos de Peptídeos/sangue , Fenilpropionatos/efeitos adversos , Piridazinas/efeitos adversos , Fatores de Risco , TadalafilaRESUMO
BACKGROUND: Patients with connective tissue disease-associated pulmonary arterial hypertension (CTD-PAH), in particular systemic sclerosis (SSc), had an attenuated response compared with idiopathic PAH in most trials. Thus, there is uncertainty regarding the benefit of PAH-targeted therapy in some forms of CTD-PAH. OBJECTIVE: To explore the safety and efficacy of initial combination therapy with ambrisentan and tadalafil versus ambrisentan or tadalafil monotherapy in patients with CTD-PAH and SSc-PAH enrolled in the AMBITION trial. METHODS: This was a post hoc analysis of patients with CTD-PAH and SSc-PAH from AMBITION, an event-driven, double-blind trial in patients with WHO functional class II/III PAH. Treatment-naive patients were randomised 2:1:1 to once-daily initial combination therapy with ambrisentan plus tadalafil or monotherapy with ambrisentan or tadalafil, respectively. The primary endpoint was time to the first clinical failure event (first occurrence of death, hospitalisation for worsening PAH, disease progression or unsatisfactory long-term clinical response). RESULTS: In the primary analysis set (N=500), 187 patients had CTD-PAH, of whom 118 had SSc-PAH. Initial combination therapy reduced the risk of clinical failure versus pooled monotherapy in each subgroup: CTD-PAH (HR 0.43 (95% CI 0.24 to 0.77)) and SSc-PAH (0.44 (0.22 to 0.89)). The most common AE was peripheral oedema, which was reported more frequently with initial combination therapy than monotherapy in the two PAH subgroups. The relative frequency of adverse events between those on combination therapy versus monotherapy was similar across subgroups. CONCLUSIONS: This post hoc subgroup analysis provides evidence that CTD-PAH and SSc-PAH patients benefit from initial ambrisentan and tadalafil combination therapy. TRIAL REGISTRATION NUMBER: NCT01178073, post results.
Assuntos
Anti-Hipertensivos/uso terapêutico , Hipertensão Pulmonar/tratamento farmacológico , Fenilpropionatos/uso terapêutico , Inibidores da Fosfodiesterase 5/uso terapêutico , Piridazinas/uso terapêutico , Escleroderma Sistêmico/complicações , Tadalafila/uso terapêutico , Adulto , Idoso , Progressão da Doença , Método Duplo-Cego , Quimioterapia Combinada , Edema/induzido quimicamente , Feminino , Humanos , Hipertensão Pulmonar/etiologia , Lúpus Eritematoso Sistêmico/complicações , Masculino , Pessoa de Meia-Idade , Doença Mista do Tecido Conjuntivo/complicaçõesRESUMO
BACKGROUND: The natural history of de novo donor-specific antibodies (dnDSA) after lung transplantation is not well-described. We sought to determine the incidence and risk factors associated with dnDSA and compare outcomes between recipients with transient (or isolated) vs persistent dnDSA after transplantation. METHODS: A single-center review of all lung transplants from 1/2009-7/2013. DSAs were tested eight times in the first year and every 4 months thereafter. Outcomes examined included acute rejection and graft failure. RESULTS: Median follow-up was 18 months (range: 1-61 months), and 24.6% of 333 first-time lung-only transplant recipients developed a dnDSA. Ethnicity, HLA-DQ mismatches, post-transplantation platelet transfusion and Lung Allocation Score >60 were associated with dnDSA (P<.05). Overall graft survival was worse for dnDSA-positive vs negative recipients (P=.025). Of 323 recipients with 1-year follow-up, 72 (22.2%) developed dnDSA, and in 25 (34.7%), the dnDSA was transient and cleared. Recipients with transient dnDSA were less likely to develop acute rejection than those with persistent dnDSA (P=.007). CONCLUSIONS: Early post-lung transplantation, dnDSA occurred in 1/4 of recipients, was associated with peri-transplant risk factors and resulted in decreased survival. Spontaneous clearance of dnDSA, seen in one-third of recipients, was associated with a lower risk of acute rejection.
Assuntos
Rejeição de Enxerto/imunologia , Sobrevivência de Enxerto/imunologia , Isoanticorpos/imunologia , Transplante de Pulmão , Adulto , Idoso , Estudos de Casos e Controles , Feminino , Seguimentos , Rejeição de Enxerto/epidemiologia , Rejeição de Enxerto/terapia , Antígenos HLA/imunologia , Humanos , Estimativa de Kaplan-Meier , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Avaliação de Resultados em Cuidados de Saúde , Estudos Retrospectivos , Fatores de Risco , Doadores de TecidosRESUMO
RATIONALE: Pulmonary arterial hypertension (PAH) is a progressive fatal disease. Variable response and tolerability to PAH therapeutics suggests that genetic differences may influence outcomes. The endothelin pathway is central to pulmonary vascular function, and several polymorphisms and/or mutations in the genes coding for endothelin (ET)-1 and its receptors correlate with the clinical manifestations of other diseases. OBJECTIVES: To examine the interaction of ET-1 pathway polymorphisms and treatment responses of patients with PAH treated with ET receptor antagonists (ERAs). METHODS: A total of 1,198 patients with PAH were prospectively enrolled from 45 U.S. and Canadian pulmonary hypertension centers or retrospectively from global sites participating in the STRIDE (Sitaxsentan To Relieve Impaired Exercise) trials. Comprehensive objective measures including a 6-minute-walk test, Borg dyspnea score, functional class, and laboratory studies were completed at baseline, before the initiation of ERAs, and repeated serially. Single-nucleotide polymorphisms from ET-1 pathway candidate genes were selected from a completed genome-wide association study performed on the study cohort. MEASUREMENTS AND MAIN RESULTS: Patient efficacy outcomes were analyzed for a relationship between ET-1 pathway polymorphisms and clinical efficacy using predefined, composite positive and negative outcome measures in 715 European descent samples. A single-nucleotide polymorphism (rs11157866) in the G-protein alpha and gamma subunits gene was significantly associated, accounting for multiple testing, with a combined improvement in functional class and 6-minute-walk distance at 12 and 18 months and marginally significant at 24 months. CONCLUSIONS: ET-1 pathway associated polymorphisms may influence the clinical efficacy of ERA therapy for PAH. Further prospective studies are needed.
Assuntos
Anti-Hipertensivos/uso terapêutico , Antagonistas dos Receptores de Endotelina/uso terapêutico , Endotelina-1/genética , Hipertensão Pulmonar/tratamento farmacológico , Hipertensão Pulmonar/genética , Polimorfismo de Nucleotídeo Único/genética , Teste de Esforço , Tolerância ao Exercício , Feminino , Seguimentos , Estudo de Associação Genômica Ampla , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Estudos Retrospectivos , Resultado do TratamentoRESUMO
The French Pulmonary Hypertension Network (FPHN) registry and the Registry to Evaluate Early And Long-term Pulmonary Arterial Hypertension Disease Management (REVEAL) have developed predictive models for survival in pulmonary arterial hypertension (PAH). In this collaboration, we assess the external validity (or generalisability) of the FPHN ItinérAIR-HTAP predictive equation and the REVEAL risk score calculator. Validation cohorts approximated the eligibility criteria defined for each model. The REVEAL cohort comprised 292 treatment-naïve, adult patients diagnosed <1â year prior to enrolment with idiopathic, familial or anorexigen-induced PAH. The FPHN cohort comprised 1737 patients with group 1 PAH. Application of FPHN parameters to REVEAL and REVEAL risk scores to FPHN demonstrated estimated hazard ratios that were consistent between studies and had high probabilities of concordance (hazard ratios of 0.72, 95% CI 0.64-0.80, and 0.73, 95% CI 0.70-0.77, respectively). The REVEAL risk score calculator and FPHN ItinérAIR-HTAP predictive equation showed good discrimination and calibration for prediction of survival in the FPHN and REVEAL cohorts, respectively, suggesting prognostic generalisability in geographically different PAH populations. Once prospectively validated, these may become valuable tools in clinical practice.
Assuntos
Hipertensão Pulmonar Primária Familiar/diagnóstico , Hipertensão Pulmonar Primária Familiar/mortalidade , Hipertensão Pulmonar/diagnóstico , Hipertensão Pulmonar/mortalidade , Modelos Teóricos , Adulto , Idoso , Algoritmos , Calibragem , Estudos de Coortes , Feminino , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Probabilidade , Modelos de Riscos Proporcionais , Sistema de Registros , Risco , Taxa de SobrevidaRESUMO
BACKGROUND: By its inhibitory effect on platelet-derived growth factor signaling, imatinib could be efficacious in treating patients with pulmonary arterial hypertension (PAH). METHODS AND RESULTS: Imatinib in Pulmonary Arterial Hypertension, a Randomized, Efficacy Study (IMPRES), a randomized, double-blind, placebo-controlled 24-week trial, evaluated imatinib in patients with pulmonary vascular resistance ≥ 800 dyne·s·cm(-5) symptomatic on ≥ 2 PAH therapies. The primary outcome was change in 6-minute walk distance. Secondary outcomes included changes in hemodynamics, functional class, serum levels of N-terminal brain natriuretic peptide, and time to clinical worsening. After completion of the core study, patients could enter an open-label long-term extension study. Of 202 patients enrolled, 41% patients received 3 PAH therapies, with the remainder on 2 therapies. After 24 weeks, the mean placebo-corrected treatment effect on 6-minute walk distance was 32 m (95% confidence interval, 12-52; P=0.002), an effect maintained in the extension study in patients remaining on imatinib. Pulmonary vascular resistance decreased by 379 dyne·s·cm(-5) (95% confidence interval, -502 to - 255; P<0.001, between-group difference). Functional class, time to clinical worsening, and mortality did not differ between treatments. Serious adverse events and discontinuations were more frequent with imatinib than placebo (44% versus 30% and 33% versus 18%, respectively). Subdural hematoma occurred in 8 patients (2 in the core study, 6 in the extension) receiving imatinib and anticoagulation. CONCLUSIONS: Imatinib improved exercise capacity and hemodynamics in patients with advanced PAH, but serious adverse events and study drug discontinuations were common. Further studies are needed to investigate the long-term safety and efficacy of imatinib in patients with PAH. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00902174 (core study); NCT01392495 (extension).
Assuntos
Hipertensão Pulmonar/tratamento farmacológico , Hipertensão Pulmonar/fisiopatologia , Piperazinas/administração & dosagem , Piperazinas/efeitos adversos , Pirimidinas/administração & dosagem , Pirimidinas/efeitos adversos , Adolescente , Adulto , Idoso , Benzamidas , Método Duplo-Cego , Tolerância ao Exercício/efeitos dos fármacos , Tolerância ao Exercício/fisiologia , Hipertensão Pulmonar Primária Familiar , Feminino , Hematoma Subdural/induzido quimicamente , Hematoma Subdural/enzimologia , Hematoma Subdural/fisiopatologia , Humanos , Hipertensão Pulmonar/enzimologia , Mesilato de Imatinib , Masculino , Pessoa de Meia-Idade , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/efeitos adversos , Adulto JovemRESUMO
BACKGROUND: Smoking prevalence and its association with pulmonary arterial hypertension (PAH) outcomes have not been described in patients in the United States. METHODS: Using the US-based Registry to Evaluate Early and Long-term PAH Disease Management (REVEAL), the prevalence, demographics, and outcomes in ever- versus never-smokers with PAH were determined. RESULTS: Ever-smoking status was more prevalent in males (61.7%) than in females (42.9%) enrolled in REVEAL. Ever-smokers were older than never-smokers at the time of PAH diagnosis and REVEAL enrollment. The time to first hospitalization, transplant-free survival, and survival did not differ between ever- and never-smokers overall; however, in newly diagnosed males, ever-smoking was associated with earlier death (hazard ratio [HR] 1.8, 95% confidence interval [CI] 1.1-3.0; p = 0.0199), the composite of transplant or death (HR 2.2, 95% CI 1.4-3.6; p = 0.0008), and first hospitalization (HR 1.8, 95% CI 1.2-2.7; p = 0.0063), though smoking exposure (pack-years) did not differ between newly and previously diagnosed males. CONCLUSIONS: REVEAL PAH data demonstrate that smoking prevalence in male PAH patients is disproportionate. The prevalence of cigarette smoking was significantly higher in males than females enrolled in REVEAL. Ever-smoking status was associated with increased age at PAH diagnosis and, in newly diagnosed male PAH patients, earlier time to hospitalization and shorter survival after PAH diagnosis.
Assuntos
Hipertensão Pulmonar , Hipertensão Arterial Pulmonar , Feminino , Humanos , Masculino , Estados Unidos/epidemiologia , Hipertensão Pulmonar Primária Familiar , Sistema de Registros , Prevalência , Fumar/efeitos adversos , Fumar/epidemiologiaRESUMO
BACKGROUND: Risk assessment is essential in pulmonary arterial hypertension (PAH) management. We investigated the effect of riociguat on REVEAL Lite 2 score, an abridged version of the REVEAL risk score, and its association with long-term outcomes in PATENT. METHODS: PATENT-1 was a randomized, double-blind study of riociguat vs placebo in patients with PAH. In the PATENT-2 open-label extension, all patients received riociguat up to 2.5 mg three times daily (n = 396). REVEAL Lite 2 scores were calculated at baseline, PATENT-1 Week 12, and PATENT-2 Week 12, with patients stratified as low- (1-5), intermediate- (6-7), or high-risk (≥8). Kaplan-Meier and Cox proportional hazards analyses assessed association of riociguat with survival and clinical worsening-free survival (CWFS). RESULTS: REVEAL Lite 2 score improved with riociguat 2.5 mg at PATENT-1 Week 12 (least-squares mean difference vs placebo: -0.8; p = 0.0004). More patients receiving riociguat 2.5 mg stabilized or improved risk stratum at PATENT-1 Week 12 vs placebo (p = 0.0005) and achieved low-risk status. REVEAL Lite 2 score at baseline and PATENT-1 Week 12 were associated with survival and CWFS (all p < 0.0001), as was change in score from baseline to Week 12 (p = 0.0002 and p < 0.0001, respectively). Survival and CWFS differed between risk strata at baseline (p < 0.0001) and PATENT-1 Week 12 (p < 0.0001). CONCLUSIONS: This analysis confirms the risk-reduction benefits of riociguat in patients with PAH and further contributes to the validation of REVEAL Lite 2 in facilitating PAH risk assessment.
Assuntos
Hipertensão Arterial Pulmonar/tratamento farmacológico , Pirazóis/uso terapêutico , Pirimidinas/uso terapêutico , Método Duplo-Cego , Humanos , Fatores de Risco , Resultado do TratamentoRESUMO
The post 3 kidney transplant course of pretransplant echocardiographically-defined pulmonary hypertension (PH) was reviewed in 115 patients. Of these 61 patients (the largest cohort reported to date), underwent 160 "for indication" echocardiograms posttransplant (mean echocardiograms per patient: 2.6 ± 2.3). Patients undergoing posttransplant echocardiograms demonstrated greater risks for worse outcomes than those without posttransplant echocardiograms; however, there was no difference in mortality, death-censored graft failure or the composite of death or graft failure between these two groups. Of patients tested, 36 (59%) showed resolution of PH at a median of 37.5 months. Six patients (16.7%) in whom PH resolved (at a median of 29 months), experienced recurrence of PH after an interval of 48 months. No pretransplant demographic or echocardiographic characteristics distinguished those in whom PH persisted versus resolved. Though there was no difference in the risk for mortality or death-censored graft loss between the two groups at 3 and 5 years, there was a higher risk for the composite of mortality or graft loss at three but not at five years in the group with persistent PH. In conclusion, echocardiographically defined PH resolved in 59% of patients following kidney transplantation; but irrespective of resolution there was no clear association with worse outcome.
RESUMO
This study aimed to develop a definition of vasoplegia that reliably predicts clinical outcomes. Vasoplegia was evaluated using data from the electronic health record for each 15-minute interval for 72 hours following cardiopulmonary bypass. Standardized definitions considered clinical features (systemic vascular resistance [SVR], mean arterial pressure [MAP], cardiac index [CI], norepinephrine equivalents [NEE]), threshold strategy (criteria occurring in any versus all measurements in an interval), and duration (criteria occurring over multiple consecutive versus separated intervals). Minor vasoplegia was MAP < 60 mm Hg or SVR < 800 dynesâ secâ cm-5 with CI > 2.2 L/min/m2 and NEE ≥ 0.1 µg/kg/min. Major vasoplegia was MAP < 60 mm Hg or SVR < 700 dynesâ secâ cm-5 with CI > 2.5 L/min/m2 and NEE ≥ 0.2 µg/kg/min. The primary outcome was incidence of vasoplegia for eight definitions developed utilizing combinations of these criteria. Secondary outcomes were associations between vasoplegia definitions and three clinical outcomes: time to extubation, time to intensive care unit discharge, and nonfavorable discharge. Minor vasoplegia detected anytime within a 15-minute period (MINOR_ANY_15) predicted the highest incidence of vasoplegia (61%) and was associated with two of three clinical outcomes: 1 day delay to first extubation (95% CI: 0.2 to 2) and 7 day delay to first intensive care unit discharge (95% CI: 1 to 13). The MINOR_ANY_15 definition should be externally validated as an optimal definition of vasoplegia.
Assuntos
Coração Auxiliar , Vasoplegia , Ponte Cardiopulmonar , Coração Auxiliar/efeitos adversos , Humanos , Incidência , Estudos Retrospectivos , Vasoplegia/etiologiaRESUMO
BACKGROUND: Currently there are no risk assessment recommendations for chronic thromboembolic pulmonary hypertension (CTEPH). The Registry to Evaluate Early and Long-Term PAH Disease Management (REVEAL) risk score (RRS), developed for risk assessment in patients with pulmonary arterial hypertension, has previously predicted outcomes in CTEPH. RRS 2.0 was developed to refine the RRS. METHODS: This post hoc analysis of the CHEST study (n = 237), which assessed riociguat in patients with inoperable and persistent/recurrent CTEPH, evaluated RRS 2.0 and its relationship with survival and clinical worsening-free survival (CWFS). RESULTS: At CHEST-1 Week 16, RRS 2.0 significantly improved and more patients moved into the low-risk stratum with riociguat versus placebo; these improvements were maintained at CHEST-2 Week 12. RRS 2.0 at CHEST-1 baseline and Week 16, and change in RRS 2.0 from CHEST-1 baseline to Week 16 were significant predictors of survival and CWFS in CHEST-2. CONCLUSIONS: Our data suggest that RRS 2.0 may have utility in predicting outcomes and monitoring treatment response in patients with inoperable or persistent/recurrent CTEPH.
Assuntos
Hipertensão Pulmonar , Hipertensão Arterial Pulmonar , Embolia Pulmonar , Doença Crônica , Humanos , Embolia Pulmonar/complicações , Embolia Pulmonar/tratamento farmacológico , Medição de Risco , Fatores de Risco , Resultado do TratamentoRESUMO
Kidney Disease: Improving Global Outcomes (KDIGO) acute kidney injury (AKI) definitions were evaluated for cases detected and their respective outcomes using expanded time windows to 168 h. AKI incidence and outcomes with expanded time intervals were identified in the electronic health records (EHRs) from 126,367 unique adult hospital admissions (2012-2014) and evaluated using multivariable logistic regression with bootstrap sampling. The incidence of AKI detected was 7.4% (n = 9357) using a 24-h time window for both serum creatinine (SCr) criterion 1a (≥0.30 mg/dL) and 1b (≥50%) increases from index SCr, with additional cases of AKI identified: 6963 from 24-48 h.; 2509 for criterion 1b from 48 h to 7 days; 3004 cases (expansion of criterion 1a and 1b from 48 to 168 h). Compared to patients without AKI, adjusted hospital days increased if AKI (criterion 1a and 1b) was observed using a 24-h observation window (5.5 days), 48-h expansion (3.4 days), 48-h to 7-day expansion (6.5 days), and 168-h expansion (3.9 days); all are p < 0.001. Similarly, the adjusted risk of in-hospital death increased if AKI was detected using a 24-h observation window (odds ratio (OR) = 16.9), 48-h expansion (OR = 5.5), 48-h to 7-day expansion (OR = 4.2), and 168-h expansion (OR = 1.6); all are p ≤ 0.01. Expanding the time windows for both AKI SCr criteria 1a and 1b standardizes and facilitates EHR AKI detection, while identifying additional clinically relevant cases of in-hospital AKI.
RESUMO
BACKGROUND: Regular risk assessment is recommended in pulmonary arterial hypertension (PAH) management to improve patient outcomes. The REVEAL risk score (RRS) predicts survival in patients with PAH, including those from the PATENT study, which assessed riociguat, a soluble guanylate cyclase stimulator approved for PAH treatment. An updated version, RRS 2.0, has been developed to further refine risk prediction. METHODS: This post hoc analysis of PATENT-1 and its open-label extension PATENT-2 (n = 396) assessed RRS 2.0 score and risk stratum and their association with survival and clinical worsening-free survival (CWFS). RESULTS: At PATENT-1 Week 12, riociguat improved RRS 2.0 versus placebo (least-squares mean difference versus placebo: -1.0 [95% confidence interval - 1.4 to -0.6; p < 0.0001]) and more patients improved risk stratum with riociguat (57%) versus placebo (42%). These improvements were maintained at PATENT-2 Week 12. RRS 2.0 score and risk strata at PATENT-1 baseline and Week 12 were significantly associated with survival and CWFS in PATENT-2 (p < 0.0001); change in RRS 2.0 score from PATENT-1 baseline to Week 12 was also significantly associated with outcomes. CONCLUSIONS: These data suggest that RRS 2.0 has clinical utility in predicting long-term outcomes and monitoring treatment response in patients with PAH.
Assuntos
Hipertensão Pulmonar , Humanos , Hipertensão Pulmonar/diagnóstico , Hipertensão Pulmonar/tratamento farmacológico , Medição de Risco , Fatores de Risco , Resultado do TratamentoRESUMO
BACKGROUND: The treatment, genotyping, and phenotyping of patients with World Health Organization Group 1 pulmonary arterial hypertension (PAH) have evolved dramatically in the last decade. RESEARCH QUESTION: The United States Pulmonary Hypertension Scientific Registry was established as the first US PAH patient registry to investigate genetic information, reproductive histories, and environmental exposure data in a contemporary patient population. STUDY DESIGN AND METHODS: Investigators at 15 US centers enrolled consecutively screened adults diagnosed with Group 1 PAH who had enrolled in the National Biological Sample and Data Repository for PAH (PAH Biobank) within 5 years of a cardiac catheterization demonstrating qualifying hemodynamic criteria. Exposure and reproductive histories were collected by using a structured interview and questionnaire. The biobank provided genetic data. RESULTS: Between 2015 and 2018, a total of 499 of 979 eligible patients with clinical diagnoses of idiopathic PAH (IPAH) or familial PAH (n = 240 [48%]), associated PAH (APAH; n = 256 [51%]), or pulmonary venoocclusive disease/pulmonary capillary hemangiomatosis (n = 3 [1%]) enrolled. The mean age was 55.8 years, average BMI was 29.2 kg/m2, and 79% were women. Mean duration between symptom onset and diagnostic catheterization was 1.9 years. Sixty-six percent of patients were treated with more than one PAH medication at enrollment. Past use of prescription weight loss drugs (16%), recreational drugs (27%), and oral contraceptive pills (77%) was common. Women often reported miscarriage (37%), although PAH was rarely diagnosed within 6 months of pregnancy (1.9%). Results of genetic testing identified pathogenic or suspected pathogenic variants in 13% of patients, reclassifying 18% of IPAH patients and 5% of APAH patients to heritable PAH. INTERPRETATION: Patients with Group 1 PAH remain predominately middle-aged women diagnosed with IPAH or APAH. Delays in diagnosis of PAH persist. Treatment with combinations of PAH-targeted medications is more common than in the past. Women often report pregnancy complications, as well as exposure to anorexigens, oral contraceptives, and/or recreational drugs. Results of genetic tests frequently identify unsuspected heritable PAH.
Assuntos
Hipertensão Pulmonar/epidemiologia , Sistema de Registros , Adolescente , Adulto , Idoso , Estudos de Coortes , Feminino , Hormônios Esteroides Gonadais/uso terapêutico , Humanos , Hipertensão Pulmonar/complicações , Hipertensão Pulmonar/diagnóstico , Masculino , Pessoa de Meia-Idade , Mutação , História Reprodutiva , Avaliação de Sintomas , Estados Unidos/epidemiologia , Adulto JovemRESUMO
BACKGROUND: Pulmonary hypertension (PH) has been well characterized in end-stage kidney disease and carries a grave prognosis. Its relationship to kidney transplantation outcomes is uncertain. The purpose of the present study was to characterize PH in kidney transplant candidates and to evaluate the relationship of PH to post-transplantation outcomes. METHODS: A retrospective review of medical records and echocardiographic findings in all patients listed and transplanted at a large urban academic medical center from 2010 to 2015 was undertaken. PH (defined as echocardiographic evidence of pulmonary artery systolic pressure ≥ 35 mm Hg) was assessed along with demographics, and comorbidities for its relationship to patient, and graft survival by univariable and multivariable analysis. RESULTS: Of 733 patients, 15.6% (115) had PH. PH in this population was primarily due to left ventricular (LV) diastolic dysfunction. Patient survival (78.3% vs 89.6%, P = .02) and the composite of patient and graft survival (70.7% vs 85.0%, P = .04) was reduced at 5 years in patients with PH as compared to patients with No PH, respectively. However, multivariable analysis suggested that age at presentation, race, and left ventricular systolic function but not PH were significantly associated with patient mortality or graft loss. CONCLUSION: Reduced patient and graft survival seen in patients with pulmonary hypertension appears to be related to risk factors other than the pulmonary hypertension itself; therefore, pretransplant PH should not be considered as a barrier to kidney transplantation.
Assuntos
Sobrevivência de Enxerto , Hipertensão Pulmonar/complicações , Falência Renal Crônica/complicações , Falência Renal Crônica/cirurgia , Transplante de Rim , Adulto , Feminino , Humanos , Transplante de Rim/mortalidade , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Fatores de RiscoRESUMO
BACKGROUND: Oral sildenafil and intravenous epoprostenol have independently been shown to be effective in patients with pulmonary arterial hypertension. OBJECTIVE: To investigate the effect of adding oral sildenafil to long-term intravenous epoprostenol in patients with pulmonary arterial hypertension. DESIGN: A 16-week, double-blind, placebo-controlled, parallel-group study. SETTING: Multinational study at 41 centers in 11 countries from 3 July 2003 to 27 January 2006. PATIENTS: 267 patients with pulmonary arterial hypertension (idiopathic, associated anorexigen use or connective tissue disease, or corrected congenital heart disease) who were receiving long-term intravenous epoprostenol therapy. INTERVENTION: Patients were randomly assigned to receive placebo or sildenafil, 20 mg three times daily, titrated to 40 mg and 80 mg three times daily, as tolerated, at 4-week intervals. Of 265 patients who received treatment, 256 (97%) patients (123 in the placebo group and 133 in the sildenafil group) completed the study. MEASUREMENTS: Change from baseline in exercise capacity measured by 6-minute walk distance (primary end point) and hemodynamic measurements, time to clinical worsening, and Borg dyspnea score (secondary end points). RESULTS: A placebo-adjusted increase of 28.8 meters (95% CI, 13.9 to 43.8 meters) in the 6-minute walk distance occurred in patients in the sildenafil group; these improvements were most prominent among patients with baseline distances of 325 meters or more. Relative to epoprostenol monotherapy, addition of sildenafil resulted in a greater change in mean pulmonary arterial pressure by -3.8 mm Hg (CI, -5.6 to -2.1 mm Hg); cardiac output by 0.9 L/min (CI, 0.5 to 1.2 L/min); and longer time to clinical worsening, with a smaller proportion of patients experiencing a worsening event in the sildenafil group (0.062) than in the placebo group (0.195) by week 16 (P = 0.002). Health-related quality of life also improved in patients who received combined therapy compared with those who received epoprostenol monotherapy. There was no effect on the Borg dyspnea score. Of the side effects generally associated with sildenafil treatment, the most commonly reported in the placebo and sildenafil groups, respectively, were headache (34% and 57%; difference, 23 percentage points [CI, 12 to 35 percentage points]), dyspepsia (2% and 16%; difference, 13 percentage points [CI, 7 to 20 percentage points]), pain in extremity (18% and 25%; difference, 8 percentage points [CI, -2 to 18 percentage points]), and nausea (18% and 25%; difference, 8 percentage points [CI, -2 to 18 percentage points]). LIMITATIONS: The study excluded patients with pulmonary arterial hypertension associated with other causes. There was an imbalance in missing data between groups, with 8 placebo recipients having no postbaseline walk assessment compared with 1 sildenafil recipient. These patients were excluded from the analysis. CONCLUSION: In some patients with pulmonary arterial hypertension, the addition of sildenafil to long-term intravenous epoprostenol therapy improves exercise capacity, hemodynamic measurements, time to clinical worsening, and quality of life, but not Borg dyspnea score. Increased rates of headache and dyspepsia occurred with the addition of sildenafil.
Assuntos
Anti-Hipertensivos/administração & dosagem , Epoprostenol/administração & dosagem , Hipertensão Pulmonar/tratamento farmacológico , Piperazinas/administração & dosagem , Sulfonas/administração & dosagem , Vasodilatadores/administração & dosagem , Administração Oral , Adolescente , Adulto , Idoso , Anti-Hipertensivos/efeitos adversos , Método Duplo-Cego , Quimioterapia Combinada , Dispepsia/induzido quimicamente , Epoprostenol/efeitos adversos , Feminino , Cefaleia/induzido quimicamente , Hemodinâmica/fisiologia , Humanos , Hipertensão Pulmonar/etiologia , Hipertensão Pulmonar/fisiopatologia , Injeções Intravenosas , Masculino , Pessoa de Meia-Idade , Piperazinas/efeitos adversos , Purinas/administração & dosagem , Purinas/efeitos adversos , Qualidade de Vida , Citrato de Sildenafila , Sulfonas/efeitos adversos , Fatores de Tempo , Vasodilatadores/efeitos adversos , Caminhada/fisiologiaRESUMO
BACKGROUND: Pulmonary arterial hypertension is a progressive, fatal disease. Published treatment guidelines recommend treatment escalation on the basis of regular patient assessment with the goal of achieving or maintaining low-risk status. Various strategies are available to determine risk status. This analysis describes an update of the Registry to Evaluate Early and Long-Term PAH Disease Management (REVEAL) risk calculator (REVEAL 2.0) and compares it with recently published European Society of Cardiology/Respiratory Society guideline-derived risk assessment strategies. METHODS: A subpopulation from the US-based registry REVEAL that survived ≥ 1 year postenrollment (baseline for this cohort) was analyzed. For REVEAL 2.0, point values and cutpoints were reassessed, and new variables were evaluated. The Kaplan-Meier method was used to estimate survival at 12 months postbaseline; discrimination was quantified using the c-statistic. Mortality estimates and discrimination were compared between REVEAL 2.0 and Comparative, Prospective Registry of Newly Initiated Therapies for Pulmonary Hypertension (COMPERA) and French Pulmonary Hypertension Registry (FPHR) risk assessment strategies. For this comparison, a three-category REVEAL 2.0 score was computed in which patients were classified as low-, intermediate-, or high-risk. RESULTS: REVEAL 2.0 demonstrated similar discrimination as the original calculator in this subpopulation (c-statistic = 0.76 vs 0.74), provided excellent separation of risk among the risk categories, and predicted clinical worsening as well as mortality in patients who were followed ≥ 1 year. The REVEAL 2.0 three-category score had greater discrimination (c-statistic = 0.73) than COMPERA (c-statistic = 0.62) or FPHR (c-statistic = 0.64). Compared with REVEAL 2.0, COMPERA and FPHR both underestimated and overestimated risk. CONCLUSIONS: REVEAL 2.0 demonstrates greater risk discrimination than the COMPERA and FPHR risk assessment strategies in patients enrolled in REVEAL. After external validation, the REVEAL 2.0 calculator can assist clinicians and patients in making informed treatment decisions on the basis of individual risk profiles. TRIAL REGISTRY: ClinicalTrials.gov; No. NCT00370214; URL: www.clinicaltrials.gov.
Assuntos
Hipertensão Arterial Pulmonar/mortalidade , Adulto , Idoso , Estudos de Coortes , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Sistema de Registros , Medição de Risco , Taxa de SobrevidaRESUMO
BACKGROUND: In the randomized, double-blind, event-driven AMBITION study, initial combination therapy with ambrisentan and tadalafil was associated with a 50% reduction in risk of clinical failure (first occurrence of all-cause death, hospitalization for worsening pulmonary arterial hypertension [PAH], disease progression, or unsatisfactory long-term clinical response) vs pooled monotherapy. These results were primarily driven by a reduction in PAH-related hospitalization in the combination therapy group, although a significant effect was not observed in a post-hoc analysis of all-cause hospitalization. METHODS: The effect of initial combination therapy with ambrisentan and tadalafil in AMBITION was further explored to study PAH-related hospitalization, which was not reported in the primary publication. RESULTS: Initial combination therapy was associated with a 63% reduction in risk of PAH-related hospitalization when compared with pooled monotherapy (hazard ratio [HR] 0.372, 95% confidence interval [CI] 0.217 to 0.639, pâ¯=â¯0.0002). For every 9 patients treated with combination therapy vs monotherapy, 1 PAH-related hospitalization could be prevented over a 1-year period. Serious adverse events leading to hospitalization, not necessarily PAH-related, occurred in 87 of 253 (34%) and 89 of 247 (36%) of patients on combination therapy and pooled monotherapy, respectively (post-hoc summary). CONCLUSIONS: Initial combination therapy with ambrisentan and tadalafil was found to reduce the risk of PAH-related hospitalization by 63% compared with pooled monotherapy.