Theodore G. Liou

Predicting Survival in Pulmonary Arterial Hypertension Insights From the Registry to Evaluate Early and Long-Term Pulmonary Arterial Hypertension Disease Management (REVEAL)

Background— Factors that determine survival in pulmonary arterial hypertension (PAH) drive clinical management. A quantitative survival prediction tool has not been established for research or clinical use. Methods and Results— Data from 2716 patients with PAH enrolled consecutively in the US Registry to Evaluate Early and Long-Term PAH Disease Management (REVEAL) were analyzed to assess predictors of 1-year survival. We identified independent prognosticators of survival and derived a multivariable, weighted risk formula for clinical use. One-year survival from the date of enrollment was 91.0% (95% confidence interval [CI], 89.9 to 92.1). In a multivariable analysis with Cox proportional hazards, variables independently associated with increased mortality included pulmonary vascular resistance >32 Wood units (hazard ratio [HR], 4.1; 95% CI, 2.0 to 8.3), PAH associated with portal hypertension (HR, 3.6; 95% CI, 2.4 to 5.4), modified New York Heart Association/World Health Organization functional class IV (HR, 3.1; 95% CI, 2.2 to 4.4), men >60 years of age (HR, 2.2; 95% CI, 1.6 to 3.0), and family history of PAH (HR, 2.2; 95% CI, 1.2 to 4.0). Renal insufficiency, PAH associated with connective tissue disease, functional class III, mean right atrial pressure, resting systolic blood pressure and heart rate, 6-minute walk distance, brain natriuretic peptide, percent predicted carbon monoxide diffusing capacity, and pericardial effusion on echocardiogram all predicted mortality. Based on these multivariable analyses, a prognostic equation was derived and validated by bootstrapping technique. Conclusions— We identified key predictors of survival based on the patients most recent evaluation and formulated a contemporary prognostic equation. Use of this tool may allow the individualization and optimization of therapeutic strategies. Serial follow-up and reassessment are warranted. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT00370214.

Pulmonary Arterial Hypertension : Baseline Characteristics From the REVEAL Registry

BACKGROUND The Registry to EValuate Early And Long-term pulmonary arterial hypertension disease management (REVEAL Registry) was established to provide updated characteristics of patients with pulmonary arterial hypertension (PAH) and to improve diagnosis, treatment, and management. METHODS Fifty-four US centers enrolled consecutively screened patients with World Health Organization group I PAH who met expanded hemodynamic criteria of mean pulmonary arterial pressure (PAP) > 25 mm Hg at rest (30 mm Hg with exercise), pulmonary capillary wedge pressure (PCWP) <or= 18 mm Hg, and pulmonary vascular resistance >or= 240 dynes x s x cm(-5). Patients meeting the traditional hemodynamic definition (PCWP <or= 15 mm Hg) were compared with those with a PCWP of 16 to 18 mm Hg. RESULTS Between March 2006 and September 2007, 2,967 patients enrolled. Among 2,525 adults meeting traditional hemodynamic criteria, the mean age was 53 +/- 14 years, and 2,007 (79.5%) were women. The mean duration between symptom onset and diagnostic catheterization was 2.8 years, and 1,008 (41.3%) patients were treated with more than one pulmonary vascular-targeted medication. Compared with patients meeting the traditional hemodynamic definition of PAH, patients with a PCWP of 16 to 18 mm Hg were older, more obese, had a lower 6-min walk distance, and had a higher incidence of systemic hypertension, sleep apnea, renal insufficiency, and diabetes. CONCLUSIONS Patients in the REVEAL Registry are older and more often female than in previous descriptions. Delays between symptom onset and diagnostic catheterization persist. Many treatment regimens are fundamentally empirical, and data will be required to determine outcomes, improve risk stratification, and develop and validate more precise prognostic tools. Patients with PCWP of 16 to 18 mm Hg differ in a number of important respects from those meeting the traditional hemodynamic definition of PAH.

The changing picture of patients with pulmonary arterial hypertension in the United States: How REVEAL differs from historic and non-US contemporary registries

BACKGROUND REVEAL (The Registry to Evaluate Early and Long-term Pulmonary Arterial Hypertension Disease Management) provides current demographics of patients with group 1 pulmonary arterial hypertension (PAH) in the United States. METHODS A total of 2,967 patients with PAH diagnosed based on right-sided heart catheterization were enrolled in REVEAL between March 2006 and September 2007. Demographics from the REVEAL patient cohort and REVEAL subpopulations (matched by inclusion criteria to other registries) were compared with historic US registry data and other contemporary US and non-US national PAH registries by inclusion criteria, including the National Institutes of Health (NIH) PAH registry and the French PAH registry. RESULTS REVEAL patients matched to NIH registry patients were older at diagnosis (mean ± SE, 44.9 ± 0.6 years vs 36.4 ± 1.1 years; difference, 8.5 ± 1.4; P < .001) and more likely to be women (78.7 ± 1.2% vs 63.1 ± 3.5%; P < .001). REVEAL patients matched to French registry patients had similar age and severity at diagnosis, but REVEAL patients were more likely to be women (79.8 ± 0.8% vs 65.3 ± 1.8%; P < .001) and obese (BMI, ≥ 30 kg/m(2), 32.5 ± 1.0% vs 14.8 ± 1.4%; P < .001), whereas French patients were more likely to have HIV-associated PAH (6.2% vs 2.3%). The female preponderance is similar to that in other US-based contemporary registries. CONCLUSIONS At diagnosis, REVEAL patients were older than NIH registry patients and similar in age to patients enrolled in contemporary registries. Compared with NIH and contemporary European and UK registries, there was a striking preponderance of women, and REVEAL patients were more likely to be obese. These observations and the difference in HIV-associated PAH between REVEAL and other non-US contemporary registries warrant further investigation. TRIAL REGISTRY ClinicalTrials.gov; No.: NCT00370214; URL: clinicaltrials.gov.

Ivacaftor in subjects with cystic fibrosis who are homozygous for the F508del-CFTR mutation

BACKGROUND Ivacaftor (VX-770) is a cystic fibrosis transmembrane conductance regulator (CFTR) potentiator that was approved in the United States for the treatment of cystic fibrosis (CF) in patients ≥ 6 years of age who have a G551D mutation; however, the most prevalent disease-causing CFTR mutation, F508del, causes a different functional defect. The objectives of this study were to evaluate the safety of ivacaftor in a larger population and for a longer time period than tested previously and to assess the efficacy of ivacaftor in subjects with CF who are homozygous for F508del-CFTR. METHODS This was a phase 2 study with a 16-week randomized (4:1), double-blind, placebo-controlled period (part A) and an open-label extension (part B) for subjects who met prespecified criteria. RESULTS Part A: The safety profile of ivacaftor was comparable to that of the placebo. The overall adverse event frequency was similar in the ivacaftor (87.5%) and placebo (89.3%) groups through 16 weeks. The difference in the change of FEV₁ % predicted from baseline through week 16 (primary end point) between the ivacaftor and placebo groups was 1.7% (P = .15). Sweat chloride, a biomarker of CFTR activity, showed a small reduction in the ivacaftor vs placebo groups of -2.9 mmol/L (P = .04) from baseline through week 16. Part B: No new safety signals were identified. The changes in FEV₁ or sweat chloride in part A were not sustained with ivacaftor treatment from week 16 to week 40. CONCLUSIONS These results expand the safety information for ivacaftor and support its continued evaluation. Lack of a clinical effect suggests that a CFTR potentiator alone is not an effective therapeutic approach for patients who have CF and are homozygous for F508del-CFTR. TRIAL REGISTRY ClinicalTrials.gov; No.: NCT00953706; URL: www.clinicaltrials.gov.

Insulin Therapy to Improve BMI in Cystic Fibrosis–Related Diabetes Without Fasting Hyperglycemia: Results of the Cystic Fibrosis Related Diabetes Therapy Trial

OBJECTIVE Cystic fibrosis–related diabetes (CFRD) without fasting hyperglycemia (CFRD FH−) is not associated with microvascular or macrovascular complications, leading to controversy about the need for treatment. The Cystic Fibrosis Related Diabetes Therapy (CFRDT) Trial sought to determine whether diabetes therapy improves BMI in these patients. RESEARCH DESIGN AND METHODS A three-arm multicenter randomized trial compared 1 year of therapy with premeal insulin aspart, repaglinide, or oral placebo in subjects with cystic fibrosis who had abnormal glucose tolerance. RESULTS One hundred adult patients were enrolled. Eighty-one completed the study, including 61 with CFRD FH− and 20 with severly impaired glucose tolerance (IGT). During the year before therapy, BMI declined in all groups. Among the group with CFRD FH−, insulin-treated patients lost 0.30 ± 0.21 BMI units the year before therapy. After 1 year of insulin therapy, this pattern reversed, and they gained 0.39 ± 21 BMI units (P = 0.02). No significant change in the rate of BMI decline was seen in placebo-treated patients (P = 0.45). Repaglinide-treated patients had an initial significant BMI gain (0.53 ± 0.19 BMI units, P = 0.01), but this effect was not sustained. After 6 months of therapy they lost weight so that by 12 months there was no difference in the rate of BMI change during the study year compared with the year before (P = 0.33). Among patients with IGT, neither insulin nor repaglinide affected the rate of BMI decline. No significant differences were seen in the rate of lung function decline or the number of hospitalizations in any group. CONCLUSIONS Insulin therapy safely reversed chronic weight loss in patients with CFRD FH−.

Delay in recognition of pulmonary arterial hypertension: factors identified from the REVEAL Registry.

BACKGROUND Pulmonary arterial hypertension (PAH) is a progressive and fatal disorder. Despite the emergence of effective therapy, PAH is commonly at an advanced stage when recognized. Factors associated with a prolonged symptomatic period before the recognition of PAH have not been fully evaluated. METHODS The Registry to Evaluate Early and Long-term PAH Disease Management (REVEAL Registry) enrolled 2,967 US adult patients with PAH from March 2006 to September 2007. Patients were considered to have delayed disease recognition if > 2 years elapsed between symptom onset and the patient receiving a PAH diagnosis, starting on PAH-specific therapy, or receiving a diagnosis by right-sided heart catheterization. RESULTS In 21.1% of patients, symptoms were experienced for > 2 years before PAH was recognized. Patients with onset of PAH symptoms before age 36 years showed the highest likelihood of delayed disease recognition (OR, 3.07; 95% CI, 2.03-4.66). History of obstructive airways disease (OR, 1.93; 95% CI, 1.5-2.47) and sleep apnea (OR, 1.72; 95% CI, 1.33-2.22) were independently associated with delayed PAH recognition. Six-minute walk distance < 250 m (OR, 1.91; 95% CI, 1.16-3.13), right atrial pressure < 10 mm Hg (OR, 1.77; 95% CI, 1.26-2.48), and pulmonary vascular resistance < 10 Wood units (OR, 1.28; 95% CI, 1.02-1.60) were also associated with delayed disease recognition, but sex, race/ethnicity, and geographic region showed no association. CONCLUSIONS One in five patients in the REVEAL Registry who were diagnosed with PAH reported symptoms for > 2 years before their disease was recognized. Younger individuals and patients with histories of common respiratory disorders were most likely to experience delayed PAH recognition. TRIAL REGISTRY ClinicalTrials.gov; No.: NCT00370214; URL: www.clinicaltrials.gov.

Insulin Therapy to Improve BMI in Cystic Fibrosis Related Diabetes Without Fasting Hyperglycemia: Results of the CFRDT Trial

OBJECTIVE Cystic fibrosis–related diabetes (CFRD) without fasting hyperglycemia (CFRD FH−) is not associated with microvascular or macrovascular complications, leading to controversy about the need for treatment. The Cystic Fibrosis Related Diabetes Therapy (CFRDT) Trial sought to determine whether diabetes therapy improves BMI in these patients. RESEARCH DESIGN AND METHODS A three-arm multicenter randomized trial compared 1 year of therapy with premeal insulin aspart, repaglinide, or oral placebo in subjects with cystic fibrosis who had abnormal glucose tolerance. RESULTS One hundred adult patients were enrolled. Eighty-one completed the study, including 61 with CFRD FH− and 20 with severly impaired glucose tolerance (IGT). During the year before therapy, BMI declined in all groups. Among the group with CFRD FH−, insulin-treated patients lost 0.30 ± 0.21 BMI units the year before therapy. After 1 year of insulin therapy, this pattern reversed, and they gained 0.39 ± 21 BMI units (P = 0.02). No significant change in the rate of BMI decline was seen in placebo-treated patients (P = 0.45). Repaglinide-treated patients had an initial significant BMI gain (0.53 ± 0.19 BMI units, P = 0.01), but this effect was not sustained. After 6 months of therapy they lost weight so that by 12 months there was no difference in the rate of BMI change during the study year compared with the year before (P = 0.33). Among patients with IGT, neither insulin nor repaglinide affected the rate of BMI decline. No significant differences were seen in the rate of lung function decline or the number of hospitalizations in any group. CONCLUSIONS Insulin therapy safely reversed chronic weight loss in patients with CFRD FH−.

Design of the REVEAL Registry for US Patients With Pulmonary Arterial Hypertension

The Registry to Evaluate Early and Long-term PAH Disease Management (REVEAL) has been designed to meet the need for current information about patients with pulmonary arterial hypertension (PAH). The main objectives of REVEAL are to better define and understand PAH and to assess the consequences of treatment strategies. REVEAL is collecting clinically relevant data from 3500 consecutively enrolled patients with confirmed PAH diagnoses. Outcomes will be evaluated longitudinally and compared according to the baseline classification of PAH. The primary outcome for group comparisons will be survival. Collected data include World Health Organization functional class, 6-minute walk distance, cardiopulmonary exercise testing, pulmonary function test results, hemodynamic measurements, functional status, hospitalizations, and death. REVEAL will be the richest source of data on patients with World Health Organization group I PAH.

Year-to-year changes in lung function in individuals with cystic fibrosis

BACKGROUND We examined the year-to-year change in FEV(1) for individuals and the overall cystic fibrosis population to better understand how individual trends may differ from population trends. METHODS We calculated individual yearly changes using the largest annual FEV(1) percent predicted (FEV(1)%) measurement in 20,644 patients (6-45years old) included in the Epidemiologic Study of Cystic Fibrosis. We calculated yearly population changes using age-specific medians. RESULTS FEV(1)% predicted decreased 1-3 points per year for individuals, with maximal decreases in 14-15year olds. Population changes agreed with individual changes up to age 15; however after age 30, yearly population change approximated zero while individual FEV(1)% predicted decreases were 1-2 points per year. CONCLUSIONS Adolescents have the greatest FEV(1)% predicted decreases; however, loss of FEV(1) is a persistent risk in 6-45year old CF patients. Recognizing individual year-to-year changes may improve patient-specific care and may suggest new methods for measuring program quality.

Lung Transplantation for Cystic Fibrosis

Lung transplantation is a complex, high-risk, potentially life-saving therapy for the end-stage lung disease of cystic fibrosis (CF). The decision to pursue transplantation involves comparing the likelihood of survival with and without transplantation as well as assessing the effect of wait-listing and transplantation on the patients quality of life. Although recent population-based analyses of the US lung allocation system for the CF population have raised controversies about the survival benefits of transplantation, studies from the United Kingdom and Canada have suggested a definite survival advantage for those receiving transplants. In response to these and other controversies, leaders in transplantation and CF met together in Lansdowne, Virginia, to consider the state of the art in lung transplantation for CF in an international context, focusing on advances in surgical technique, measurement of outcomes, use of prognostic criteria, variations in local control over listing, and prioritization among the United States, Canada, the United Kingdom, and The Netherlands, patient adherence before and after transplantation and other issues in the broader context of lung transplantation. Finally, the conference members carefully considered how efforts to improve outcomes for lung transplantation for CF lung disease might best be studied. This Roundtable seeks to communicate the substance of our discussions.