Patients' perceptions on clinical trials outcomes in pulmonary arterial hypertension therapy.

The value placed by patients and their caregivers on the components of composite outcomes in pulmonary arterial hypertension (PAH) remains unknown. We surveyed the importance of these outcomes from a patients' and caregivers' perspective, with participants (n=335, including 257 patients with PAH) rating individual components defining clinical worsening in PAH trials as of critical, major, mild-to-moderate or minor importance. Most outcomes were considered of major or mild-to-moderate importance to patients. Death was the only outcome considered of critical importance. Perceptions of clinical outcomes varied between patients and caregivers. Integrating patients' perception in the elaboration of clinical trials is essential.

Neutrophil-Lymphocyte Ratio as an Independent Predictor of Survival in Pulmonary Arterial Hypertension: An Exploratory Study.

Background: The blood neutrophil-to-lymphocyte ratio (NLR) has recently emerged as a powerful predictor of adverse outcomes in some cardiovascular and lung diseases. Pulmonary arterial hypertension (PAH) is a lethal vasculopathy associated with increased inflammation. Although PAH exhibits a higher prevalence among women, men have a poorer prognosis. We investigated the NLR as an independent predictor of transplant-free survival in PAH. Methods: We performed a retrospective analysis of 78 PAH patients from the Quebec PAHBiobank (71% female). We used univariate and multivariate (adjusted for age, sex, renal function, and disease severity) Cox regression analyses to assess the relationship between the NLR and transplant-free survival, in the whole sample, and according to sex. The NLR was categorized as high (≥ 4.8) or low (< 4.8) using receiver operating characteristic analysis. Unadjusted Kaplan-Meier analysis estimated survival per NLR category. Results: The NLR was higher in patients who died, compared to that in patients who had transplant-free survival (P < 0.05). The NLR was an independent predictor of event-free survival in PAH (unadjusted hazard ratio: 1.11, 95% confidence interval: 1.04-1.18, which remained significant after adjustment for covariates). The high-NLR group had lower 1-, 3-, and 5-year survival compared to those with a low NLR (P < 0.001). The NLR remains a predictor of survival in women. Conclusions: The NLR is an independent predictor of transplant-free survival in PAH. We report a potential sexual dimorphism in the ability of the NLR to predict mortality in PAH, emphasizing the importance of considering sex-related differences in the development of biomarkers in PAH.

Contexte: Le rapport neutrophiles/lymphocytes (RNL) s'est récemment imposé comme un puissant facteur prédictif de l'issue défavorable de certaines maladies cardiovasculaires et pulmonaires. L'hypertension artérielle pulmonaire (HTAP) est une vasculopathie mortelle associée à une inflammation accrue. Bien que sa prévalence soit plus élevée chez les femmes, son pronostic est plus défavorable chez les hommes. Nous avons étudié le RNL en tant que prédicteur indépendant de la survie sans greffe chez des sujets atteints d'HTAP. Méthodologie: Nous avons effectué une analyse rétrospective du matériel sur l'HTAP de la Biobanque du Québec se rapportant à 78 patients (71 % de femmes). Des analyses de régression de Cox univariées et multivariées (ajustées en fonction de l'âge, du sexe, de la fonction rénale et de la gravité de la maladie) nous ont permis d'évaluer la relation entre le RNL et la survie sans greffe dans l'ensemble de l'échantillon et selon le sexe. Le RNL a été classé comme élevé (≥ 4,8) ou faible (< 4,8) au terme d'une analyse des caractéristiques de fonctionnement du récepteur. Une analyse non ajustée effectuée selon la méthode de Kaplan-Meier a servi à estimer la survie par catégorie de RNL. Résultats: Le RNL était plus élevé chez les patients décédés que chez les patients ayant survécu sans greffe (p < 0,05). Le RNL était un prédicteur indépendant de la survie sans événement chez les patients atteints d'HTAP (rapport des risques instantanés non ajusté : 1,11, intervalle de confiance à 95 % : 1,04-1,18, demeuré significatif après ajustement en fonction des covariables). La survie à 1, 3 et 5 ans a été inférieure au sein du groupe présentant un RNL élevé comparativement au groupe présentant un RNL faible (p < 0,001). Le RNL demeure un prédicteur de la survie chez les femmes. Conclusions: Le RNL est un facteur prédictif indépendant de la survie sans greffe chez les sujets atteints d'HTAP. Selon nos observations, un dimorphisme sexuel potentiel le caractérise en tant que prédicteur de la mortalité chez les sujets atteints d'HTAP. Il importe donc de tenir compte des différences liées au sexe dans le développement des biomarqueurs de l'HTAP.

Reliability of Home Nocturnal Oximetry in the Diagnosis of Overlap Syndrome in COPD.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) and sleep apnea are common conditions and often coexist. The proper diagnosis of sleep apnea may affect the management and outcome of patients with COPD. OBJECTIVE: To determine the accuracy of home nocturnal oximetry to distinguish between nocturnal oxygen desaturation related to COPD alone or to sleep apnea in patients with moderate-to-severe COPD who have significant nocturnal hypoxemia with cyclical changes in saturation. METHODS: This study involved a comparison of home nocturnal oximetry and laboratory-based polysomnography (PSG) in patients with moderate-to-severe COPD considered for inclusion in a trial of nocturnal oxygen therapy. All of the patients had significant nocturnal oxygen desaturation (defined as ≥30% of the recording time with a transcutaneous arterial oxygen saturation <90%) with cyclical changes in saturation suggestive of sleep apnea. RESULTS: PSG was obtained in 90 patients; 45 patients (mean age = 68 years, SD = 8; 71% men; mean forced expiratory volume in 1 s [FEV1] = 50.6% predicted value, SD = 18.6%; data from 41 patients) fulfilled the criteria for sleep apnea (mean apnea-hypopnea index = 32.6 events/h, SD = 19.9) and 45 patients (mean age = 69 years, SD = 8; 87% men; mean FEV1 predicted value 44.6%, SD = 15%) did not (mean apnea-hypopnea index = 5.5 events/h, SD = 3.8). None of the patients' characteristics (including demographic, anthropometric, and physiologic measures) predicted the diagnosis of sleep apnea according to PSG results. CONCLUSION: The diagnosis of sleep apnea in patients with moderate to severe COPD cannot rely on nocturnal oximetry alone, even when typical cyclical changes in saturation are seen on oximetry tracing. When suspecting an overlap syndrome, a full-night, in-laboratory PSG should be obtained.

Automatic versus Manual Oxygen Titration in Patients Requiring Supplemental Oxygen in the Hospital: A Systematic Review and Meta-Analysis.

BACKGROUND: Closed-loop oxygen titration devices have been developed to avoid periods of hypoxemia and hyperoxemia, both detrimental to patients hospitalized for respiratory failure and requiring supplemental oxygen. However, their clinical impact remains unknown. OBJECTIVE: To compare the effect of automatic versus manual oxygen titration on clinical outcomes in pediatric and adult patients requiring supplemental oxygen in the hospital. METHODS: We conducted a systematic review and meta-analysis of randomized controlled trials. We searched MEDLINE, EMBASE, and CENTRAL electronic databases (from inception to August 2018), and conference proceedings of major societies in respiratory medicine (2015-2018). Randomized controlled trials were included if they compared automatic to manual oxygen titration in hypoxemic inpatients and if they assessed at least one of the following: length of hospital stay (primary outcome), length of oxygen therapy, need and duration of mechanical ventilation, mortality, percentage of time within, above, and below the oxygen saturation target range, as well as the percentage of time spent in hypoxemia and hyperoxemia. RESULTS: We included 9 trials (354 patients, adults and preterm infants, with or without ventilatory assistance). Eight of these trials were at high risk of bias due to lack of blinding and selective reporting. Automatic titration was associated with a significant decrease in the length of hospital stay (mean difference: -2.2 days; 95% CI: -3.8 to -0.6; p = 0.009; I2 = 0%; n = 237, 2 trials), and a decrease in the length of oxygen therapy (mean difference: -1.6 days; 95% CI: -3.1 to 0.0; p = 0.05; I2 = 0%; n = 237; 2 trials). We did not observe a reduction in the need for ventilatory assistance or in mortality in the automatic titration period. An increase in the percentage of time spent within target (mean difference: 18.23%; 95% CI: 10.93-25.52; I2 = 81%; n = 351, 7 trials) and a significant reduction in the percentage of time spent in both hypoxemia and hyperoxemia with automatic compared to manual oxygen titration were, however, observed. CONCLUSIONS: In patients requiring supplemental oxygen in the hospital, automatic oxygen titration was associated with a reduction in length of both hospital stay and oxygen therapy, as well as a greater percentage of time spent within the saturation target range. However, it was not associated with a significant difference in the need for mechanical ventilation or in mortality. Results should be interpreted with caution due to the small number of included trials and their high risk of bias.

Combination therapy in pulmonary arterial hypertension: recent accomplishments and future challenges.

Pulmonary arterial hypertension (PAH) is a life-threatening disease characterized by a progressive increase in pulmonary vascular resistance, ultimately leading to right heart failure and death. Throughout the past 20 years, numerous specific pharmacologic agents, including phosphodiesterase-5 inhibitors, endothelin receptor antagonists, prostaglandins, and more recently, soluble guanylate cyclase stimulators and selective IP prostacyclin receptor agonist, have emerged for the treatment of PAH. Early clinical trials were typically of short-term duration, comparing the effects of PAH-targeted therapies versus placebo and using exercise tolerance as the primary endpoint in most trials. A meta-analysis of these trials documented a reduction in short-term mortality of ∼40% with monotherapy. More recently, we have witnessed a progressive shift in PAH study designs using longer event-driven trials comparing the effects of upfront and sequential combination therapy on clinical worsening that is perceived as a more clinically relevant outcome measure. Recent meta-analyses also documented that combination therapy significantly reduced the risk of clinical worsening by ∼35% compared with monotherapy alone. In this review article, we will discuss the evolution of treatments and clinical trial design in the field of PAH over the past decades with a special focus on combination therapy and its current role in the management of PAH. We will also detail unresolved questions regarding the future of PAH patients' care and the challenges of future clinical trials.

Combination therapy versus monotherapy for pulmonary arterial hypertension: a meta-analysis.

BACKGROUND: Several randomised controlled studies and a previous meta-analysis have reported conflicting results regarding the effect of combined targeted therapy compared with monotherapy for pulmonary arterial hypertension (PAH). We did a systematic review and meta-analysis to assess the effects of a combination of PAH-specific therapies compared with monotherapy on predefined clinical worsening in PAH. METHODS: We searched MEDLINE, Embase, and the Cochrane Library for reports published from Jan 1, 1990, to May 31, 2015, of prospective randomised controlled trials of at least 12 weeks that assessed a combination of PAH-specific therapies (upfront and sequential add-on) compared with background PAH-specific monotherapy in patients older than 12 years. We extracted data from the reports, and assessed the primary outcome of risk of clinical worsening, as defined a priori in each trial, using the Mantel-Haenszel method based on a fixed-effects model. FINDINGS: Of 2017 studies that we identified from our search, we included 17 (4095 patients) in our analysis. 15 studies assessed clinical worsening and were included in the primary analysis. Combined therapy was associated with significant risk reduction for clinical worsening compared with monotherapy (combined therapy 17% [332 of 1940 patients] vs monotherapy 28% [517 of 1862 patients], risk ratio [RR] 0·65 [95% CI 0·58-0·72], p<0·00001). We noted no heterogeneity between the studies (I(2)=18%, phomogeneity=0·25). A publication bias was suggested by the results of an Egger test (t=-2·3982, p=0·031), but when we excluded the four studies with the highest SEs, the RR for clinical worsening was identical (0·65 [95% CI 0·58-0·73], p<0·00001). INTERPRETATION: In our analysis, combined therapy for PAH was associated with a significant reduction in clinical worsening compared with monotherapy. However, our study was limited by the variable definition of clinical worsening among the trials and possible publication bias. Because many patients still had clinical worsening with combination therapy, identification of innovative therapeutic targets for PAH is thus urgently needed. FUNDING: None.