Combination therapy with oral treprostinil for pulmonary arterial hypertension. A double-blind placebo-controlled clinical trial

Rationale: Oral treprostinil improves exercise capacity in patients with pulmonary arterial hypertension (PAH), but the effect on clinical outcomes was unknown. Objectives: To evaluate the effect of oral treprostinil compared with placebo on time to first adjudicated clinical worsening event in participants with PAH who recently began approved oral monotherapy. Methods: In this event-driven, double-blind study, we randomly allocated 690 participants (1:1 ratio) with PAH to receive placebo or oral treprostinil extended-release tablets three times daily. Eligible participants were using approved oral monotherapy for over 30 days before randomization and had a 6-minute-walk distance 150 m or greater. The primary endpoint was the time to first adjudicated clinical worsening event: death; hospitalization due to worsening PAH; initiation of inhaled or parenteral prostacyclin therapy; disease progression; or unsatisfactory long-term clinical response. Measurements and Main Results: Clinical worsening occurred in 26% of the oral treprostinil group compared with 36% of placebo participants (hazard ratio, 0.74; 95% confidence interval, 0.56–0.97; P = 0.028). Key measures of disease status, including functional class, Borg dyspnea score, and N-terminal pro–brain natriuretic peptide, all favored oral treprostinil treatment at Week 24 and beyond. A noninvasive risk stratification analysis demonstrated that oral treprostinil–assigned participants had a substantially higher mortality risk at baseline but achieved a lower risk profile from Study Weeks 12–60. The most common adverse events in the oral treprostinil group were headache, diarrhea, flushing, nausea, and vomiting. Conclusions: In participants with PAH, addition of oral treprostinil to approved oral monotherapy reduced the risk of clinical worsening. Clinical trial registered with www.clinicaltrials.gov (NCT01560624)

Rate and duration of hospitalisation for acute pulmonary embolism in the real-world clinical practice of different countries : Analysis from the RIETE registry

publishersversionPeer reviewe

Logistic regression analysis of potential prognostic factors for pulmonary thromboembolism

Objective: To identify potential prognostic factors for pulmonary thromboembolism (PTE), establishing a mathematical model to predict the risk for fatal PTE and nonfatal PTE.Method: the reports on 4,813 consecutive autopsies performed from 1979 to 1998 in a Brazilian tertiary referral medical school were reviewed for a retrospective study. From the medical records and autopsy reports of the 512 patients found with macroscopically and/or microscopically,documented PTE, data on demographics, underlying diseases, and probable PTE site of origin were gathered and studied by multiple logistic regression. Thereafter, the jackknife method, a statistical cross-validation technique that uses the original study patients to validate a clinical prediction rule, was performed.Results: the autopsy rate was 50.2%, and PTE prevalence was 10.6%. In 212 cases, PTE was the main cause of death (fatal PTE). The independent variables selected by the regression significance criteria that were more likely to be associated with fatal PTE were age (odds ratio [OR], 1.02; 95% confidence interval [CI], 1.00 to 1.03), trauma (OR, 8.5; 95% CI, 2.20 to 32.81), right-sided cardiac thrombi (OR, 1.96; 95% CI, 1.02 to 3.77), pelvic vein thrombi (OR, 3.46; 95% CI, 1.19 to 10.05); those most likely to be associated with nonfatal PTE were systemic arterial hypertension (OR, 0.51; 95% CI, 0.33 to 0.80), pneumonia (OR, 0.46; 95% CI, 0.30 to 0.71), and sepsis (OR, 0.16; 95% CI, 0.06 to 0.40). The results obtained from the application of the equation in the 512 cases studied using logistic regression analysis suggest the range in which logit p > 0.336 favors the occurrence of fatal PTE, logit p < - 1.142 favors nonfatal PTE, and logit P with intermediate values is not conclusive. The cross-validation prediction misclassification rate was 25.6%, meaning that the prediction equation correctly classified the majority of the cases (74.4%).Conclusions: Although the usefulness of this method in everyday medical practice needs to be confirmed by a prospective study, for the time being our results suggest that concerning prevention, diagnosis, and treatment of PTE, strict attention should be given to those patients presenting the variables that are significant in the logistic regression model

Phase 2 study of nilotinib in pediatric patients with Philadelphia chromosome-positive chronic myeloid leukemia

Chronic myeloid leukemia (CML) is rare in children and accounts for 5_15% of all myeloid leukemia cases. When we initiated this study with nilotinib, imatinib was the only tyrosine kinase inhibitor indicated for pediatric patients with Philadelphia chromosome - positive (Ph+) CML in chronic phase (CP); alternative treatment options were needed, particularly for patients who developed resistance or intolerance (R/I) to imatinib. This phase 2 study enrolled pediatric patients with either Ph+ CML-CP R/I to imatinib or dasatinib or newly diagnosed Ph+ CML-CP. Data presented are from analyses with minimum follow-up of up to 24 cycles (1 cycle is 28 days). Fifty-nine patients with Ph+ CML-CP were enrolled, and 58 were treated (R/I, n = 33; newly diagnosed, n = 25). Major molecular response (MMR) rate at cycle 6 in the R/I cohort was 39.4% (primary end point); 57.6% of patients achieved or maintained MMR and 81.8% achieved or maintained complete cytogenetic response (CCyR) by 24 cycles. In patients with newly diagnosed disease, rates of MMR by cycle 12 and CCyR at cycle 12 were 64.0% each (primary end points); by cycle 24, cumulative MMR and CCyR rates were 68.0% and 84.0%, respectively. The safety profile of nilotinib in pediatric patients was generally comparable with the known safety profile in adults, although cardiovascular events were not observed in this study, and hepatic laboratory abnormalities were more frequent; no new safety signals were identified. In summary, nilotinib demonstrated efficacy and a manageable safety profile in pediatric patients with Ph+ CML-CP

Investigação da trombose venosa na gravidez Deep vein thrombosis during pregnancy work up

CONTEXTO: A trombose venosa profunda (TVP) na gravidez é fator determinante no aumento da morbidade e da mortalidade maternofetal. Pode ocorrer na presença de trombofilias, por compressão da veia cava inferior, estase venosa ou alterações hormonais. OBJETIVOS: Analisar pacientes grávidas e no pós-parto imediato portadoras de TVP em membros inferiores, pesquisar as possíveis causas de trombofilia e realizar revisão de literatura. MÉTODOS: Foram analisadas gestantes e puérperas encaminhadas por ginecologistas e obstetras com quadro clínico suspeito de TVP, de janeiro de 2004 a novembro de 2006, período em que foram realizados 24.437 partos no Hospital e Maternidade São Luiz (HMSL), sendo 89% cesarianas, 7,5% partos normais e 3,5% fórceps. Do total de pacientes encaminhadas com quadro clínico sugestivo, foram realizados 42 diagnósticos clínicos de TVP em gestantes com idade entre 21 e 39 anos, confirmados por duplex scan venoso. Imediatamente antes da introdução da terapia anticoagulante, foram colhidos exames para pesquisa de trombofilia, os quais foram repetidos após o período de tratamento. RESULTADOS: Das 42 pacientes portadoras de TVP, 32 eram primigestas (três gemelares sem alterações trombofílicas, duas por fecundação in vitro), oito secundigestas e duas tercigestas. Em quatro pacientes, a TVP ocorreu no primeiro trimestre da gestação (9,5%); em 11, no segundo trimestre (26,2%); em 27, no terceiro trimestre (64,3%). Dos 42 casos de diagnóstico de TVP, 18 (42,8%) ocorreram nas veias infrapatelares. Houve um caso de tromboembolismo pulmonar (TEP) em paciente de 37 anos que havia realizado fecundação in vitro, com gestação gemelar, e TVP (ausência de trombofilia) diagnosticada após a cesariana. Das 42 pacientes, 16 (38,1%) tiveram a causa da TVP estabelecida, com prevalência de mutação heterozigótica do fator V de Leiden (FVL) em seis pacientes (14,2%), seguida pela síndrome antifosfolípide e outras. A maioria das pacientes foi tratada com heparina de baixo peso molecular. CONCLUSÃO: A TVP na gravidez, apesar de sua baixa freqüência, aumenta consideravelmente a morbidade maternofetal. A pesquisa de trombofilia deve ser realizada em casos selecionados, tais como antecedentes pessoais ou familiares de fenômenos trombóticos e/ou trombofilia. A gestação gemelar, a cesariana e a inseminação artificial também foram fatores predisponentes para a ocorrência de TVP.<br>BACKGROUND: Deep venous thrombosis (DVT) during pregnancy is a determining factor that contributes to increased maternal-fetal morbidity and mortality. It may occur when there is thrombophilia, due to compression of the inferior vena cava, venous stasis or hormonal changes. OBJECTIVES: To assess patients who are pregnant or have just given birth and who have a DVT condition in the lower limbs, to search for possible causes of thrombophilia and to perform a review of the literature. METHODS: Pregnant and puerperal patients were assessed by gynecologists and obstetricians when there was suspicion of DVT, from January 2004 through November 2006, during which time there were 24,437 childbirths at Hospital e Maternidade São Luiz; of these, 89% were cesarean, 7.5% were normal births and 3.5% were forceps deliveries. Of the total number of patients referred with a clinical status suggesting DVT, 42 cases were clinically diagnosed as DVT, in pregnant women aged between 21-39 years, confirmed by venous duplex scan. Right before the introduction of anticoagulant therapy, samples were collected to investigate thrombophilia, which were repeated after the treatment. RESULTS: Of the 42 patients with DVT, 32 were primigravid (three twin pregnancies with no thrombophilic changes, two resulting from in vitro fecundation), eight were mothers at second birth and two were at third birth. In four patients, DVT occurred in the first trimester of pregnancy (9.5%), in 11 patients DVT was present in the second trimester (26.2%) and in 27 patients the disease developed in the third trimester of pregnancy (64.3%). Of the 42 patients diagnosed with DVT, 18 (42.8%) occurred in infrapatellar veins. There was a case of pulmonary thromboembolism in a 37-year-old patient, who had been submitted to in vitro fecundation, with twin pregnancy and a diagnostic of DVT (no thrombophilia) after a cesarean section. Of the 42 patients, 16 (38.1%) had the cause of their DVT determined, with a prevalence of heterozygous mutation of factor V Leiden in six patients (14.2%), followed by phospholipid syndrome and other causes. Most patients were treated with low-molecular-weight heparin. CONCLUSION: DVT during pregnancy, despite having low frequency, is a major cause of increased maternal-fetal morbidity. Investigation of thrombophilia should be conducted in selected cases, such as personal or family history of thrombotic phenomena and/or thrombophilia. Twin pregnancy, cesarean birth and artificial insemination were also found as factors leading to DVT