Francis Cordova

Macitentan for the treatment of idiopathic pulmonary fibrosis: the randomised controlled MUSIC trial

Idiopathic pulmonary fibrosis is a progressive, fatal disease. This prospective, randomised, double-blind, multicentre, parallel-group, placebo-controlled phase II trial (NCT00903331) investigated the efficacy and safety of the endothelin receptor antagonist macitentan in idiopathic pulmonary fibrosis. Eligible subjects were adults with idiopathic pulmonary fibrosis of <3 years duration and a histological pattern of usual interstitial pneumonia on surgical lung biopsy. The primary objective was to demonstrate that macitentan (10 mg once daily) positively affected forced vital capacity versus placebo. Using a centralised system, 178 subjects were randomised (2:1) to macitentan (n=119) or placebo (n=59). The median change from baseline up to month 12 in forced vital capacity was -0.20 L in the macitentan arm and -0.20 L in the placebo arm. Overall, no differences between treatments were observed in pulmonary function tests or time to disease worsening or death. Median exposures to macitentan and placebo were 14.5 months and 15.0 months, respectively. Alanine and/or aspartate aminotransferase elevations over three times upper limit of normal arose in 3.4% of macitentan-treated subjects and 5.1% of placebo recipients. In conclusion, the primary objective was not met. Long-term exposure to macitentan was well tolerated with a similar, low incidence of elevated hepatic aminotransferases in each treatment group. Long-term exposure to macitentan was well tolerated in IPF in a trial that did not meet its primary end-point http://ow.ly/p0RDL

The National Emphysema Treatment Trial (NETT): Part II: Lessons Learned about Lung Volume Reduction Surgery

Substantial information regarding the role of lung volume reduction surgery (LVRS) in severe emphysema emanates from the National Emphysema Treatment Trial (NETT). The NETT was not a crossover trial and therefore was able to examine the effects of optimal medical management and LVRS on short- and long-term survival,as well as lung function, exercise performance, and quality of life.The NETT generated multiple insights into the preoperative, perioperative,and postoperative management of patients undergoing thoracotomy; described pain control techniques that were safe and effective; and emphasized the need to address nonpulmonary issues to optimize surgical outcomes. After the NETT, newer investigation has focused on bronchoscopic endobronchial interventions and other techniques less invasive than LVRS to achieve lung reduction.In this review, we summarize what we currently know about the role of LVRS in the treatment of severe emphysema as a result of insights gained from the NETT and provide a brief review of the newer techniques of lung volume reduction.

Bosentan for Sarcoidosis-Associated Pulmonary Hypertension: A Double-Blind Placebo Controlled Randomized Trial

BACKGROUND Sarcoidosis-associated pulmonary hypertension (SAPH) is a common problem in patients with persistent dyspneic sarcoidosis. The objective of this study was to determine the effect of bosentan therapy on pulmonary arterial hemodynamics in patients with SAPH. METHODS This 16-week study was a double-blind, placebo-controlled trial of either bosentan or placebo in patients with SAPH confirmed by right-sided heart catheterization. Patients were enrolled from multiple academic centers specializing in sarcoidosis care. They were stable on sarcoidosis therapy and were receiving no therapy for pulmonary hypertension. The cohort was randomized two to one to receive bosentan at a maximal dose of 125 mg or placebo bid for 16 weeks. Pulmonary function studies, 6-min walk test, and right-sided heart hemodynamics, including pulmonary artery mean pressure and pulmonary vascular resistance (PVR), were performed before and after 16 weeks of therapy. RESULTS Thirty-five patients completed 16 weeks of therapy (23 treated with bosentan, 12 with placebo). For those treated with bosentan, repeat hemodynamic studies at 16 weeks demonstrated a significant mean±SD fall in PA mean pressure (-4±6.6 mm Hg, P=.0105) and PVR (-1.7±2.75 Wood units, P=.0104). For the patients treated with placebo, there was no significant change in either PA mean pressure (1±3.7 mm Hg, P>.05) or PVR (0.1±1.42 Wood units, P>.05). There was no significant change in 6-min walk distance for either group. Two patients treated with bosentan required an increase of supplemental oxygen by >2 L after 16 weeks of therapy. CONCLUSIONS This study demonstrated that bosentan significantly improved pulmonary hemodynamics in patients with SAPH. TRIAL REGISTRY ClinicalTrials.gov; No: NCT00581607; URL: www.clinicaltrials.gov.

Original Research: Pulmonary Vascular DiseaseBosentan for Sarcoidosis-Associated Pulmonary Hypertension: A Double-Blind Placebo Controlled Randomized Trial

BACKGROUND Sarcoidosis-associated pulmonary hypertension (SAPH) is a common problem in patients with persistent dyspneic sarcoidosis. The objective of this study was to determine the effect of bosentan therapy on pulmonary arterial hemodynamics in patients with SAPH. METHODS This 16-week study was a double-blind, placebo-controlled trial of either bosentan or placebo in patients with SAPH confirmed by right-sided heart catheterization. Patients were enrolled from multiple academic centers specializing in sarcoidosis care. They were stable on sarcoidosis therapy and were receiving no therapy for pulmonary hypertension. The cohort was randomized two to one to receive bosentan at a maximal dose of 125 mg or placebo bid for 16 weeks. Pulmonary function studies, 6-min walk test, and right-sided heart hemodynamics, including pulmonary artery mean pressure and pulmonary vascular resistance (PVR), were performed before and after 16 weeks of therapy. RESULTS Thirty-five patients completed 16 weeks of therapy (23 treated with bosentan, 12 with placebo). For those treated with bosentan, repeat hemodynamic studies at 16 weeks demonstrated a significant mean±SD fall in PA mean pressure (-4±6.6 mm Hg, P=.0105) and PVR (-1.7±2.75 Wood units, P=.0104). For the patients treated with placebo, there was no significant change in either PA mean pressure (1±3.7 mm Hg, P>.05) or PVR (0.1±1.42 Wood units, P>.05). There was no significant change in 6-min walk distance for either group. Two patients treated with bosentan required an increase of supplemental oxygen by >2 L after 16 weeks of therapy. CONCLUSIONS This study demonstrated that bosentan significantly improved pulmonary hemodynamics in patients with SAPH. TRIAL REGISTRY ClinicalTrials.gov; No: NCT00581607; URL: www.clinicaltrials.gov.

The National Emphysema Treatment Trial (NETT): Part I: Lessons learned about emphysema.

The National Emphysema Treatment Trial (NETT) was a multicenter prospective randomized controlled trial that compared optimal medical treatment, including pulmonary rehabilitation, with optimal medical treatment plus lung volume reduction surgery (LVRS). It was the largest and most complete collection of patient demographic, clinical, physiological, and radiographic data ever compiled in severe emphysema. NETT investigated the effects of optimal medical management and LVRS on short- and long-term survival, as well as lung function, exercise performance, and quality of life. NETT also provided much information regarding the evaluation and prognosis of severe emphysema; specifically the important negative influences that hyperinflation and small airway disease have on survival. NETT emphasized the importance of addressing nonpulmonary issues such as nutrition, cardiac disease, anxiety, and depression in emphysema. NETT demonstrated that physiological, genomic, and radiographic phenotype can predict patient survival as well as response to treatment. Because the major purpose of NETT was to compare bilateral LVRS with optimal medical treatment in emphysema, patients enrolled into NETT were comprehensively characterized and selected to have a specific window of airflow obstruction and hyperinflation and to lack significant comorbidities. The NETT patient population’s restrictive features offer distinct advantages (well-characterized predominant emphysematous phenotype) and disadvantages (lack of comorbidities and significant chronic bronchitis) that must be considered when interpreting the implications of these results. Herein, we provide a summary of the major NETT findings that provide insight into the evaluation and medical treatment of emphysema.

Double-Lung Transplantation Can Be Safely Performed Using Donors With Heavy Smoking History

BACKGROUND Lung transplantation using grafts from donors with a history of heavy smoking (>20 pack-years) is thought to confer worse prognosis. We attempt to determine if adult, double-lung transplantation can be safely performed with lungs from heavy-smoking donors (HSD). METHODS The United Network for Organ Sharing (UNOS) database was examined for adult, double-lung transplants from 2005 to 2011. RESULTS Of 5,900 double-lung transplants, 766 (13.0%) were from HSDs. The two groups were similar in recipient age (49.8 vs 50.5 years, p = 0.15), male sex (56.9% vs 56.5%, p = 0.87), and lung allocation score (45.8 vs 44.9, p = 0.18). Recipients of lungs from HSDs had lower forced expiratory volume in 1 second (FEV1; 34.3 vs 36.1% predicted, p = 0.04), longer ischemic time (5.75 vs 5.58 hours, p = 0.01), less human leukocyte antigen mismatch (4.51 vs 4.62, p = 0.01), and lower class I plasma reactive antigens (2.64 vs 3.69%, p = 0.001). HSDs were older (40.9 vs 32.6 years, p < 0.001) and less likely male (51.7 vs 59.7%, p < 0.001). Recipients of lungs from HSDs had longer median length of stay (18.0 vs 17.0 days, p < 0.001). Freedom from bronchiolitis obliterans syndrome (p = 0.09), decrement in FEV1 (p = 0.12), peak FEV1 (79.8% vs 79.0%, p = 0.51), and median survival (2,043 vs 1,928 days, p = 0.69) were not different. On multivariate analysis, HSD lungs were not associated with death (hazard ratio, 1.003; 95% confidence interval, 0.867 to 1.161, p = 0.96). Death was associated with donor age, ischemic time, race mismatch, mechanical ventilation, and extracorporeal membranous oxygenation before transplantation. CONCLUSIONS Double-lung transplantation can be safely performed with lungs from donors with a heavy smoking history.

Atrial arrhythmias after lung and heart-lung transplant: effects on short-term mortality and the influence of amiodarone.

BACKGROUND The incidence and effect of atrial fibrillation or flutter (AF) after lung transplant are variable. An effect of pharmacologic treatment on outcomes is undetermined. METHODS One hundred thirty-seven consecutive lung or heart-lung transplant patients were reviewed retrospectively. Uni- and multivariate analyses were performed to determine statistically significant risk factors for AF and short-term mortality. RESULTS AF occurred in 45.0% of patients within 26 days. By univariate analysis, male gender was predictive of AF (hazard ratio [HR] = 2.25, 95% confidence interval [CI] 1.21 to 4.20, p = 0.011). Mortality within 200 days occurred in 36 of 137 (22.6%) patients. Those with AF had higher mortality than those without AF (27 of 62 [43.5%] vs 9 of 75 [12%]; p < 0.0001). Twenty-four of the 38 (63.1%) patients treated with amiodarone died, whereas 3 of 26 (11.5%) patients treated without amiodarone died (p < 0.0001). Mortality was similar among patients without AF, and those with AF not receiving amiodarone (9 of 75 [12%] vs 3 of 26 [11.5%], p = 1.00). By multivariate analysis, chronic obstructive pulmonary disease (HR = 0.395, CI 0.175 to 0.892, p = 0.025), primary pulmonary hypertension (HR = 7.245, CI 1.89 to 27.84, p = 0.0039), and use of amiodarone (HR = 2.967, CI 1.187 to 7.415, p = 0.020) were associated with death. Amiodarone was shown to be a significant statistical moderator (p < 0.0001) and mediator (p < 0.001) of mortality in AF patients. CONCLUSIONS There was a high incidence of AF after lung or heart-lung transplant, and a significant increase in mortality in AF patients treated with amiodarone. In patients with severe lung pathology, amiodarone pulmonary toxicity may be more common than previously known, and may be a significant contributor to mortality. Amiodarone use should be restricted in the lung transplant patient population.

Impact of extracorporeal membrane oxygenation or mechanical ventilation as bridge to combined heart-lung transplantation on short-term and long-term survival.

Background Extracorporeal membrane oxygenation (ECMO) and mechanical ventilation (MV) can be used as a bridge to heart-lung transplantation (HLT). The goal of this study was to determine if pretransplantation ECMO or MV affects survival in HLT. Methods The United Network for Organ Sharing database was reviewed for all adult patients receiving HLT from 1995 to 2011. The primary outcome measured was risk-adjusted all cause mortality. Results There were 542 adult patients received HLT during the study period. Of these, 15 (2.8%) required ECMO and 22 (4.1%) required MV as a bridge to transplantation. The groups were evenly matched with regards to recipient age, recipient gender, ischemic time, donor age, and donor gender. The ECMO cohort had worse survival than the control group at 30 days (20.0% vs. 83.5%) and 5 years (20.0% vs. 47.4%; P<0.001). When compared with control, patients requiring MV had worse survival at 1 month (77.3% vs. 83.5%) and 5 years (26.5% vs. 47.4%; P<0.001). The use of ECMO (hazard ratio [HR]=3.820, 95% confidence interval [CI]=1.600–9.116; P=0.003) or MV (HR=2.011, 95% CI=1.069–3.784; P=0.030) as a bridge to transplantation was independently associated with mortality on multivariate analysis. Recipient female gender was associated with survival (HR=0.754, 95% CI=0.570–0.998; P=0.048). Conclusions HLT recipients bridged by MV or ECMO have increased short-term and long-term mortality. Further studies are needed to optimize survival in these high-risk patients.

Single-lung transplantation can be performed with acceptable outcomes using selected donors with heavy smoking history.

BACKGROUND We attempt to determine if adult, single-lung transplantation could be performed with acceptable results in heavy-smoking donors (HSDs; > 20 pack-years). METHODS The United Network of Organ Sharing database was examined for adult single-lung transplantation from 2005 to 2011. RESULTS Of the 3,704 single-lung transplantations, 498 (13.4%) were from HSDs. The 2 groups were similar in recipient age (60.6 vs. 60.7 years, p = 0.20), male gender (61.3% vs. 59.8%, p = 0.54), ischemic time (4.1 vs. 4.2 hours, p = 0.11), and pre-transplant forced expiratory volume in 1 second (FEV1; 41.1% vs. 40.0% predicted). Recipients of HSDs had lower lung allocation score (39.7 vs. 38.0, p = 0.02), less human leukocyte antigen mismatches (4.6 vs. 4.5, p = 0.01), and higher class I panel reactive antibody (2.9% vs. 3.8%, p < 0.001). HSDs were older (33.0 vs. 41.3 years, p < 0.001) and less likely male (62.5 vs. 56.0%, p = 0.01). Recipients with HSDs had longer length of stay (20.5 vs. 23.0 days, p < 0.001) and lower peak FEV1 after single-lung transplantation (80.1% vs. 73.4%, p < 0.001). Freedom from bronchiolitis obliterans syndrome (p = 0.64), post-single-lung transplantation decrement in FEV1 (p = 0.07), and median survival (1,516 vs. 1,488 days, p = 0.10) were similar. Multivariable analysis found receiving lungs from actively smoking HSDs was associated with mortality (hazard ratio [HR], 1.23, 95% confidence interval [CI], 1.05-1.45; p = 0.01). Use of HSDs who were not actively smoking was not associated with mortality (HR, 0.84; 95% CI, 0.59-1.19; p = 0.33). Mortality was associated with recipient age, longer ischemic time, race mismatch, class I panel reactive antibody > 10%, mechanical ventilation, and extracorporeal membrane oxygenation as a bridge to transplantation. CONCLUSIONS Although single-lung transplantation with actively smoking HSDs results in worse results, outcomes are acceptable and should continue to be considered.

The Impact of Alemtuzumab and Basiliximab Induction on Patient Survival and Time to Bronchiolitis Obliterans Syndrome in Double Lung Transplantation Recipients

We examined the effect of alemtuzumab and basiliximab induction therapy on patient survival and freedom from bronchiolitis obliterans syndrome (BOS) in double lung transplantation. The United Network for Organ Sharing database was reviewed for adult double lung transplant recipients from 2006 to 2013. The primary outcome was risk‐adjusted all‐cause mortality. Secondary outcomes included time to BOS. There were 6117 patients were identified, of whom 738 received alemtuzumab, 2804 received basiliximab, and 2575 received no induction. Alemtuzumab recipients had higher lung allocation scores compared with basiliximab and no‐induction recipients (41.4 versus 37.9 versus 40.7, p < 0.001) and were more likely to require mechanical ventilation before to transplantation (21.7% versus 6.5% versus 6.2%, p < 0.001). Median survival was longer for alemtuzumab and basiliximab recipients compared with patients who received no induction (2321 versus 2352 versus 1967 days, p = 0.001). Alemtuzumab (hazard ratio 0.80, 95% confidence interval 0.67–0.95, p = 0.009) and basiliximab induction (0.88, 0.80–0.98, p = 0.015) were independently associated with survival on multivariate analysis. At 5 years, alemtuzumab recipients had a lower incidence of BOS (22.7% versus 55.4 versus 55.9%), and its use was independently associated with lower risk of developing BOS on multivariate analysis. While both induction therapies were associated with improved survival, patients who received alemtuzumab had greater median freedom from BOS.