Michelle Turner

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.

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.

Sex Differences in the Diagnosis, Treatment, and Outcome of Patients With Pulmonary Arterial Hypertension Enrolled in the Registry to Evaluate Early and Long-term Pulmonary Arterial Hypertension Disease Management

BACKGROUND Pulmonary arterial hypertension (PAH) is a life-threatening disease that affects more women than men. The reasons for the female preponderance are unclear, and there are limited data available for men with PAH. METHODS Data from the Registry to Evaluate Early and Long-term PAH Disease Management (REVEAL Registry) were analyzed to explore sex differences among patients with PAH with regard to 2-year survival from enrollment and 5-year survival from time of diagnosis. RESULTS The data set included 2,318 women and 651 men. More women had PAH associated with connective tissue disease (P < .001), and more men had portopulmonary hypertension (P < .001) and HIV-associated PAH (P < .001). More women had congenital heart disease-associated PAH (P = .017), thyroid disease (P < .001), and depression reported (P ≤ .001). At diagnosis, men had higher mean pulmonary artery pressure (53 ± 14 vs 51 ± 14.3 mm Hg; P = .013) and mean right atrial pressure (10 ± 6 vs 9 ± 6 mm Hg; P = .031). Women had better survival estimates for 2 years from enrollment and for 5 years from diagnosis. Stratifying by age showed that survival from enrollment was similar between men and women aged < 60 years at enrollment, whereas men aged ≥ 60 years have lower survival rates compared with women aged ≥ 60 years. CONCLUSIONS Our findings highlight similarities and differences between men and women with PAH, raising questions for future exploration regarding the role of hormones and sex in causation and survival in PAH. TRIAL REGISTRY ClinicalTrials.gov; No.: NCT00370214; URL: www.clinicaltrials.gov.

Comorbid Conditions and Outcomes in Patients With Pulmonary Arterial Hypertension: A REVEAL Registry Analysis

BACKGROUND Comorbidities can affect disease progression and/or response to treatment in various conditions. Comorbid conditions are prevalent in patients with pulmonary arterial hypertension (PAH); however, their effect on patient outcomes remains unknown. METHODS We evaluated the effect on functional class (FC), 6-min walk test distance (6MWD), and survival of the seven most common, comorbid conditions at enrollment in patients with PAH from the Registry to Evaluate Early and Long-term PAH Disease Management (REVEAL Registry): hypertension, clinical depression, type 2 diabetes mellitus (diabetes), obesity, COPD, sleep apnea, and thyroid disease. RESULTS Patients with COPD or diabetes had the shortest 6MWD at enrollment (304.5 and 304.6 m, respectively) vs other comorbidities. Adjusted linear regression for 6MWD at enrollment revealed significant reductions among patients who were hypertensive, obese, diabetic, or had COPD (P<.001). A larger proportion of patients who were obese or had COPD were FC III/IV vs FC I/II at enrollment (P<.001). There was a greater risk for death among patients with diabetes (hazard ratio [HR], 1.73; 95% CI, 1.40-2.13; P<.001) or COPD (HR, 1.59; 95% CI, 1.34-1.90; P<.001), but there was a reduced risk for death in patients who were obese (HR, 0.73; 95% CI, 0.61-0.86; P<.001). CONCLUSIONS Compared with other analyzed comorbidities in patients with PAH, hypertension, obesity, diabetes, and COPD were associated with significantly worse 6MWD; obesity and COPD were associated with worse FC; and diabetes and COPD were associated with increased risk for death. Further investigation of the effects of treating these comorbidities in patients with PAH is warranted. TRIAL REGISTRY ClinicalTrials.gov; Identifier: NCT00370214; URL: www.clinicaltrials.gov.

Functional Class Improvement and 3-Year Survival Outcomes in Patients With Pulmonary Arterial Hypertension in the REVEAL Registry

OBJECTIVE New York Heart Association/World Health Organization functional class (FC) is associated with outcomes in pulmonary arterial hypertension (PAH). We assessed whether patients with PAH who improve from FC III to FC I/II have improved survival vs patients who remain at FC III or worsen to FC IV. METHODS Patients aged ≥ 19 years with FC III PAH from the Registry to Evaluate Early and Long-Term PAH Disease Management (REVEAL Registry) (N = 982) were categorized as improved, unchanged, or worsened according to their change in FC from enrollment to first follow-up assessment within 1 year of enrollment. Kaplan-Meier estimates of 3-year survival from first follow-up and changes in 6-min walk distance (6MWD) from enrollment to first follow-up were determined. Subgroup analyses were conducted by cause (ie, idiopathic/familial, connective tissue disease [CTD], congenital heart disease) and time of diagnosis (ie, newly or previously diagnosed [diagnostic right-sided heart catheterization within or ≥3 months of enrollment, respectively]). RESULTS Overall, 27% of patients improved FC. Survival was better in patients whose FC improved (84%±2%, n=263) vs those who remained unchanged (66%±2%, n=645) or worsened (29%±6%, n=74) (all P<.001). Survival was also better in patient subgroups whose FC improved vs those who remained unchanged (idiopathic/familial [P<.001], CTD-associated PAH [P=.009], whether newly [P=.004] or previously diagnosed [P<.001]). 6MWD improvements were greater in patients whose FC improved vs those who remained unchanged in the overall (P<.001) and CTD (P=.028) cohorts. CONCLUSION Patients with PAH who improve from FC III to I/II, whether newly or previously diagnosed and regardless of PAH cause, have better survival vs patients who remain FC III. TRIAL REGISTRY ClinicalTrials.gov; No.: NCT00370214; URL: www.clinicaltrials.gov.

Psychometric validation of the visual function questionnaire-25 in patients with diabetic macular edema

BackgroundDiabetic Macular Edema (DME) is a common cause of impaired vision and blindness amongst diabetics. If not detected and treated early, the resulting vision loss can lead to considerable health costs and decreased health-related quality of life (HRQoL). The aim of this study was to provide evidence of the psychometric properties of the National Eye Institute - Visual Functioning Questionnaire (VFQ-25) for use in a cohort of DME patients who participated in a clinical efficacy and safety trial of pegaptinib sodium (Macugen).MethodsA phase 2/3 randomised, double masked trial evaluated pegaptanib injection versus sham injection in patients with DME. The analysis was conducted using baseline HRQoL data of the VFQ-25 and the EQ-5D, on a modified intent-to-treat sample of 235 patients. These measures were administered by a trained interviewer by telephone in all but one of the study countries, where face-to-face interviews were conducted in the clinic. The measures were completed in the week prior to baseline, and after 54 weeks of treatment. Distance visual acuity, measured according to the Early Treatment Diabetic Retinopathy Study (ETDRS), was assessed at all time points. Psychometric properties of the VFQ-25 assessed included domain structure, reliability, concurrent and construct validity, responsiveness.ResultsThe VFQ-25 was found to consist of 11 domains slightly different than those proposed. Nevertheless, none of the eight established multi-item scales met the criterion for further splitting and the VFQ-25 was scored as in the developers’ instructions. Internal consistency reliability was demonstrated for six out of the eight original multi-item scales, with Cronbachs alpha ranging from 0.58 (Distance Activities) to 0.85 (Vision Specific: Dependency). The VFQ-25 domains generally showed a low to moderate correlation with EQ-5D visual analogue scale (range 0.16-0.43) and with the visual acuity score (range 0.10-0.41). Construct validity was upheld with higher VFQ-25 scores for patients who saw more letters according to the ETDRS. Almost all scales were shown to be responsive with Guyatts statistic ranging from 0.10 to 0.56 at 54 weeks.ConclusionsThe VFQ-25 has evidence to support its validity and reliability for measuring HRQoL in DME. However, some operating characteristics of the instrument need further consideration and discussion in the case of DME patients. Further research is therefore warranted in this indication.

Systemic BP and Heart Rate as Prognostic Indicators in Pulmonary Arterial Hypertension

BACKGROUND Heart rate (HR) and systolic BP (SBP) are significant multivariate predictors of survival in patients with pulmonary arterial hypertension (PAH) as part of a 19-element formula. To what extent HR and BP alone predict survival and future hospitalization in patients with PAH is unknown. METHODS We analyzed data from the Registry to Evaluate Early and Long-term PAH Disease Management (REVEAL Registry), a prospective, observational study of patients with PAH. Patients were analyzed by quintile (Q) according to values of HR, SBP, and SBP/HR. Kaplan-Meier curves were calculated by Q for survival and freedom from hospitalization. RESULTS For patients in the worst Q, 1-year survival after enrollment was 85% ± 2% for SBP, 86% ± 2% for HR, and 84% ± 2% for SBP/HR vs 91% ± 1% for the middle three Qs (P < .001). Hospitalization occurred more frequently than mortality but with a similar pattern among Qs. One-year survival after first follow-up of patients in the worst Q for change (Δ) in SBP since enrollment was 85% ± 2% (P = .004), 86% ± 2% for ΔHR (P = .12), and 84% ± 2% for ΔSBP/HR (P = .024) vs the middle three Qs (ΔSBP: 91% ± 1%; ΔHR: 90% ± 1%; ΔSBP/HR: 90% ± 1%). CONCLUSIONS Changes in vital signs from enrollment to first follow-up were less predictive of mortality than the values of vital-sign parameters at either enrollment or first follow-up. HR, SBP, and SBP/HR at enrollment identified high-risk groups with survival differences of 5% to 7% and freedom from hospitalization differences of 9% to 11% vs lower-risk groups. SBP/HR defines the highest-risk group, including most of the high-risk patients defined by HR and SBP separately. TRIAL REGISTRY ClinicalTrials.gov; No.: NCT00370214; URL: www.clinicaltrials.gov.