[Show abstract][Hide abstract] ABSTRACT: Background
Clinical studies of pulmonary arterial hypertension have used change in 6-minute walk distance as a clinical endpoint; however, its association with survival outcomes has not been well established. In this analysis, we examined the prognostic value of baseline 6-minute walk distance, absolute thresholds of 6-minute walk distance, and change in 6-minute walk distance.
Patients in the Registry to Evaluate Early and Long-Term Pulmonary Arterial Hypertension Disease Management (REVEAL) with 6-minute walk distance at enrollment, with or without a follow-up assessment within the first year of observation, were included. Kaplan-Meier survival estimates were computed for subsets with baseline 6-minute walk distance that were above or below all possible thresholds, and for subsets with change in 6-minute walk distance 10 percentage points above or below all possible thresholds, including both improvement thresholds and worsening thresholds. Multivariable Cox regression models assessed the effect of both improvement and worsening in 6-minute walk distance on 1-year survival, adjusted for baseline factors.
One-year survival estimates were higher for patients with baseline 6-minute walk distance above versus below a threshold, although no specific threshold was more prognostic than others. In a model adjusted for baseline 6-minute walk distance and risk score, worsening of 6-minute walk distance over time significantly predicted decreased survival, but improvement in 6-minute walk distance did not affect survival.
No 6-minute walk distance improvement threshold carries particular prognostic value. Improvement in 6MWD was not associated with survival, but worsening of 6MWD was strongly and significantly associated with poor prognosis.
The Journal of Heart and Lung Transplantation 08/2014; · 5.11 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background:Patients with pulmonary arterial hypertension associated with systemic sclerosis (SSc-APAH) experience higher mortality rates than patients with idiopathic disease and those with other connective tissue diseases (CTD-APAH). We sought to identify unique predictors of mortality associated with SSc-APAH in the CTD-APAH population. Methods:The Registry to Evaluate Early and Long-Term PAH Management (REVEAL) is a multicenter, prospective US-based registry of patients with previously and newly diagnosed (enrollment within 90 days of diagnostic right heart catheterization) PAH. Cox regression models evaluated all previously identified candidate predictors of mortality in the overall REVEAL population to identify significant predictors of mortality in the SSc-APAH (n=500) versus non-SSc-CTD-APAH (n=304) populations. Results:Three-year survival in the previously diagnosed and newly diagnosed SSc-APAH group was 61.4±2.7% and 51.2±4.0%, respectively, compared with 80.9±2.7% and 76.4±4.6%, respectively, in the non-SSc-CTD-APAH group (P<.001). In multivariate analyses, males aged >60 years, systolic blood pressure (SBP) ≤110 mmHg, 6-minute walk distance (6MWD) <165 m, mean right atrial pressure (mRAP) >20 mmHg within 1 year, and pulmonary vascular resistance (PVR) >32 WU remained unique predictors of mortality in the SSc-APAH group; 6MWD ≥440 m was protective in the non-SSc-CTD-APAH group, but not the SSc-APAH group. Conclusions:Patients with SSc-APAH have higher mortality rates than non-SSc-CTD-APAH patients. Identifying SSc-APAH patients who are at particularly high risk of death, including elderly males and patients with low baseline SBP or 6MWD, or markedly elevated mRAP or PVR, will enable clinicians to identify patients who may benefit from closer monitoring and more aggressive treatment. Registered at:www.clinicaltrials.gov #NCT00370214.
[Show abstract][Hide abstract] ABSTRACT: Hospitalization is an important outcome in pulmonary arterial hypertension (PAH), shown previously to correlate with survival. Using the Registry to EValuate Early And Long-term PAH Disease Management (REVEAL), we sought to characterize first-time hospitalizations and their effect on subsequent hospitalization and survival in newly diagnosed patients.
[Show abstract][Hide abstract] ABSTRACT: In patients with pulmonary arterial hypertension (PAH) the relation of hemodynamic impairment experienced during daily activity and exercise test is not known.
Ten PAH patients received an implantable hemodynamic monitor that continuously recorded and stored right ventricular systolic (RVSP) and mean pulmonary artery pressure (MPAP). Before starting a new PAH treatment (baseline) and after 12-weeks on treatment (12W) a 6-min walk test (6MWT) and a maximal exercise test (MAXWT) were performed. Exercise pressure range was measured as the difference between rest before exercise and maximal pressure during 6MWT or MAXWT. Ambulatory range (AMB) was measured as the difference between the lowest (4th percentile) and highest (96th percentile) values recorded over 24-hours. One week of ambulatory ranges were averaged for each patient before each exercise test. Mean age was 54±18 years, 9 were female and all in WHO functional class 3. At baseline RVSP and MPAP increased 136±49% and 164±49% during AMB, 63±26% and 79±30% during MAXWT and 59±32% and 69±33% during 6MWT. There was no difference in pressure change at 12W.
Changes in RV and PA pressures during exercise tests were relatively small compared to the range seen during ambulatory conditions.
Journal of cardiac failure 05/2014; · 3.25 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Registries of patients with pulmonary arterial hypertension (PAH) have been instrumental in characterizing the presentation and natural history of the disease and provide a basis for prognostication. Since the initial accumulation of data conducted in the 1980s, subsequent registry databases have yielded information about the demographic factors, treatment, and survival of patients and have permitted comparisons between populations in different eras and environments. Inclusion of patients with all subtypes of PAH has also allowed comparisons of these subpopulations. We describe herein the basic methodology by which PAH registries have been conducted, review key insights provided by registries, summarize issues related to interpretation and comparison of the results, and discuss the utility of data to predict survival outcomes. Potential sources of bias, particularly related to the inclusion of incident and/or prevalent patients and missing data, are addressed. A fundamental observation of current registries is that survival in the modern treatment era has improved compared with that observed previously and that outcomes among PAH subpopulations vary substantially. Continuing systematic clinical surveillance of PAH will be important as treatment evolves and as understanding of mechanisms advance. Considerations for future directions of registry studies include enrollment of a broader population of patients with pulmonary hypertension of all clinical types and severity and continued globalization and collaboration of registry databases.
Journal of the American College of Cardiology 12/2013; 62(25 Suppl):D51-9. · 14.09 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The demands on a pulmonary arterial hypertension (PAH) treatment algorithm are multiple and in some ways conflicting. The treatment algorithm usually includes different types of recommendations with varying degrees of scientific evidence. In addition, the algorithm is required to be comprehensive but not too complex, informative yet simple and straightforward. The type of information in the treatment algorithm are heterogeneous including clinical, hemodynamic, medical, interventional, pharmacological and regulatory recommendations. Stakeholders (or users) including physicians from various specialties and with variable expertise in PAH, nurses, patients and patients' associations, healthcare providers, regulatory agencies and industry are often interested in the PAH treatment algorithm for different reasons. These are the considerable challenges faced when proposing appropriate updates to the current evidence-based treatment algorithm.The current treatment algorithm may be divided into 3 main areas: 1) general measures, supportive therapy, referral strategy, acute vasoreactivity testing and chronic treatment with calcium channel blockers; 2) initial therapy with approved PAH drugs; and 3) clinical response to the initial therapy, combination therapy, balloon atrial septostomy, and lung transplantation. All three sections will be revisited highlighting information newly available in the past 5 years and proposing updates where appropriate. The European Society of Cardiology grades of recommendation and levels of evidence will be adopted to rank the proposed treatments.
Journal of the American College of Cardiology 12/2013; 62(25 Suppl):D60-72. · 14.09 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Uncorrected congenital heart disease (CHD) frequently leads to pulmonary arterial hypertension (PAH), the most severe form of which is Eisenmenger syndrome (ES). We compared patients with idiopathic or heritable PAH (IPAH or HPAH; n = 1,626) against those with CHD-associated PAH (n = 353) who were enrolled in the Registry to Evaluate Early and Long-Term PAH Disease Management (REVEAL Registry). Of patients with CHD-associated PAH, 151 had ES. Compared with the IPAH or HPAH cohort, the ES cohort had greater systemic blood flow (2 ± 1 vs 3 ± 2 L/min/m(2), p <0.001), lower mean right atrial pressure (10 ± 6 vs 7 ± 4 mm Hg, p <0.001), higher mean pulmonary artery pressure (53 ± 14 vs 65 ± 17 mm Hg, p <0.001), higher pulmonary vascular resistance index (22 ± 12 vs 32 ± 31 Wood units × m(2), p <0.001), and lower systemic arterial oxygen saturation at rest (92 ± 11% vs 84 ± 13%, p <0.001). At 4 years from enrollment and 7 years from diagnosis, survival rate was similar between IPAH or HPAH and CHD-associated PAH cohorts. For the overall CHD-associated PAH cohort, longer 6-minute walk distance, lower mean right atrial pressure, brain natriuretic peptide level <50 pg/ml, and the presence of acute vasoreactivity were predictors of survival at 4 years from enrollment; younger age and lower mean right atrial pressure were predictors of survival at 7 years from diagnosis. In conclusion, these observations support predicted physiologic differences (e.g., hemodynamics) between patients with IPAH or HPAH and patients with CHD-associated PAH, with or without a systemic-pulmonary shunt. These differences, however, did not translate into significantly improved 4- and 7-year survival rates in patients with ES versus IPAH or HPAH and CHD-associated PAH.
The American journal of cardiology 10/2013; · 3.58 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Current guidelines recommend intravenous prostacyclin as first-line therapy for patients with pulmonary arterial hypertension (PAH) in New York Heart Association/World Health Organization functional class (FC) IV, or combination therapy for patients in any FC who do not respond to monotherapy. We investigated the aggressiveness of therapy in patients enrolled in the REVEAL (Registry to Evaluate Early and Long-Term PAH Disease Management) Registry who deteriorated to FC IV or died.
Among 3,515 patients (age ≥ 18 years) in REVEAL with a mean pulmonary artery pressure ≥ 25 mm Hg and pulmonary capillary wedge pressure ≤ 15 mm Hg, we examined three sub-sets: the 487 patients who had a PAH-related death, the larger set of 908 patients who died from any cause (PAH-related, not PAH-related, or unknown), and the 294 patients who were FC I, II, or III at enrollment and later assessed as FC IV.
Among patients who died, 56% (n = 272 of 487) and 43% (n = 391 of 908) were receiving intravenous prostacyclin before death in the PAH-related death and all-cause death cohorts, respectively. In the PAH-related death cohort, 60% and 16% of patients were most recently assessed as FC III and IV, respectively; among those assessed as FC IV within 6 months of death, 57.7% (n = 15 of 26) had received intravenous prostacyclin. Because many patients died without an observed assessment of worsening to FC IV, we also evaluated medication use among the cohort of patients who worsened to FC IV during the study. One day before worsening to FC IV, 150 of 294 patients were not receiving intravenous prostacyclin and 70 were receiving only PAH-specific monotherapy; of these, 61% and 67%, respectively, received no additional therapy 90 days later.
Intravenous prostacyclin and combination therapy are not consistently used in the most seriously ill patients enrolled in REVEAL after being assessed as FC IV or at the time of death.
The Journal of heart and lung transplantation: the official publication of the International Society for Heart Transplantation 09/2013; · 3.54 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The presence and size of a pericardial effusion in pulmonary arterial hypertension (PAH) and it's association with outcome remains unclear.
Single center cohort study of 577 patients with group 1 PAH seen between 1/1/1995 and 12/31/2005. All patients underwent transthoracic echocardiography and followed for ≥ five years. Echo-guided pericardiocentesis was performed as needed.
Pericardial effusions on index echocardiography occurred in 150 (26%) patients; 128 patients had small and 22 had ≥ moderate sized effusions. Most of the ≥ moderate or greater effusions occurred in patients who had connective tissue disease (82%). Mean right atrial pressure was 13.4 ± 4.4 mm Hg (no effusion), 15.1 ± 4.4 (small effusion), and 17.0 ± 4.0 (≥ moderate effusion) (p < 0.0001). Median survival for patients with ≥ moderate effusion, mild effusion, or no effusion was 11.3 months, 42.3 months, and 76.5 months respectively. Four of the 22 patients with ≥ moderate pericardial effusions eventually required echo-guided pericardiocentesis because of clinical and echocardiographic evidence of hemodynamic impact. When drained, the effusions were large (858 ± 469 mL) and generally serous. All pericardiocenteses were performed cautiously under echo-guidance by a vastly experienced echocardiologist with low immediate morbidity and mortality.
Pericardial effusions are relatively common but rarely of hemodynamic significance in patients with PAH. However, even modest degrees of pericardial fluid are associated with significant increase in mortality and appear to reflect the presence of associated collagen vascular disease and high right atrial pressure.
[Show abstract][Hide abstract] ABSTRACT: Time to clinical worsening has been proposed as a primary endpoint in clinical trials of pulmonary arterial hypertension (PAH); however, there are neither standardized nor validated definitions of clinical worsening across PAH trials. This study aims to evaluate a proposed definition of clinical worsening within a large prospective, observational registry of patients with PAH with respect to its value as a predictor of proximate (within 1 year) risk for subsequent major events (ie, death, transplantation, or atrial septostomy).
We assessed overall 2-year survival and survival free from major events to determine the relationship between clinical worsening and major events among adults (N=3,001) with hemodynamically defined PAH. Freedom from clinical worsening was defined as freedom from worsening functional class (FC), a ≥15% reduction in 6-minute walk distance (6MWD), all-cause hospitalization, or the introduction of a parenteral prostacyclin analogue therapy.
In the 2 years of follow-up, 583 deaths occurred; a total of 426 patients died after a documented clinical worsening event including FC worsening (n=128), a ≥15% reduction in 6MWD (n=118), all-cause hospitalization (n=370), or introduction of a prostacyclin analogue (n=91). Patients who experienced clinical worsening had significantly poorer subsequent 1-year survival post-worsening than patients who did not worsen (P < .001).
Clinical worsening was highly predictive of subsequent proximate mortality in this analysis from an observational study. These results validate the use of clinical worsening as a meaningful prognostic tool in clinical practice and as a primary endpoint in clinical trial design.
[Show abstract][Hide abstract] ABSTRACT: BACKGROUND: -Pulmonary arterial hypertension (PAH) is characterized by pulmonary vascular remodeling and right heart failure. The right (RV) and left ventricles (LV) do not function in isolation, sharing a common pericardial sac and interventricular septum. We sought to define the clinical and prognostic significance of ventricular interdependence in PAH and its association with left ventricular filling patterns through speckle-tracking strain echocardiography. METHODS AND RESULTS: -Echocardiography was performed in 71 adults with a new diagnosis of PAH. To separately analyze LV and RV function, we measured peak systolic longitudinal and circumferential strain of the LV and RV. Survival was assessed over two years. Patients had dilated right-sided chambers (RA volume index 44±19 mL/m(2); RV end-diastolic area 34±9 cm(2)), and reduced RV function (RV fractional area change 28±12%). Speckle tracking echocardiography revealed significant reductions in RV free wall peak systolic strain (-15±3%). Despite normal LV size and normal conventional measures of LV systolic function (end-diastolic dimension 42±6 mm; ejection fraction 65±8%; cardiac index 2.6±0.8 L/min/m(2)), patients had reduced LV free wall systolic strain (-15±3%). Decreased LV free wall systolic strain was associated with a delayed relaxation mitral inflow Doppler pattern, p=0.0002. During 2 years follow-up, 19 patients (27%) died. LV strain was associated with increased mortality (unadjusted HR 2.40 per 5% decrease in LV free wall strain, 1.22-4.68), which remained significant when adjusted for age, sex, WHO functional class, and PAH etiology (HR 3.11, 1.38-7.20). CONCLUSIONS: -The pressure loading in PAH results in geometric alterations and functional decline of the RV, with marked reduction in RV systolic strain. Despite preservation of LVEF, LV systolic strain was also reduced and associated with early mortality, highlighting the significance of ventricular interdependence in PAH.
[Show abstract][Hide abstract] ABSTRACT: ABSTRACT 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 versus patients who remain at FC III or worsen to FC IV. METHODS: Patients aged ≥19 years with FC III PAH from the 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-minute walk distance (6MWD) from enrollment to first follow-up were determined. Subgroup analyses were conducted by etiology (ie, idiopathic/familial, connective tissue disease [CTD], congenital heart disease) and time of diagnosis (ie, newly and previously diagnosed [diagnostic right 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) versus 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 versus 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 versus 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 etiology, have better survival versus patients who remain FC III.ClinicalTrials.gov Registration Number: NCT00370214.
[Show abstract][Hide abstract] ABSTRACT: ABSTRACT 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-minute walk test distance (6MWD), and survival of the 7 most common comorbid conditions at enrollment in patients with PAH from the Registry to Evaluate Early and Long-Term PAH Disease Management (REVEAL): hypertension, clinical depression, type II diabetes mellitus (diabetes), obesity, chronic obstructive pulmonary disease (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) versus other comorbidities. Adjusted linear regression for 6MWD at enrollment revealed significant reductions among hypertensive, obese, diabetic, and COPD patients (P<.001). A larger proportion of obese or COPD patients were FC III/IV versus FC I/II at enrollment (P<.001). There was a greater risk of 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 a reduced risk in obese patients (HR, 0.73; 95% CI, 0.61-0.86; P<.001). CONCLUSIONS: Compared with other analyzed comorbidities in PAH patients, hypertension, obesity, diabetes, and COPD were associated with significantly worse 6MWD; obesity and COPD with worse FC; and diabetes and COPD with increased risk of death. Further investigation of the effects of treating these comorbidities in patients with PAH is warranted. CLINICALTRIALS.GOV IDENTIFIER: NCT00370214.
[Show abstract][Hide abstract] ABSTRACT: The aim of this study was to assess whether serial quantitative assessment of right ventricular (RV) function by speckle-based strain imaging is affected by pulmonary hypertension-specific therapies and whether there is a correlation between serial changes in RV strain and clinical status. RV longitudinal systolic function was assessed using speckle-tracking echocardiography in 50 patients with pulmonary arterial hypertension (PAH) before and after the initiation of therapy. The mean interval to follow-up was 6 ± 2 months. Subsequent survival was assessed over 4 years. Patients demonstrated a mean increase in RV systolic strain from -15 ± 5 before to -20 ± 7% (p = 0.0001) after PAH treatment. Persistence of or progression to a severe reduction in free wall systolic strain (<-12.5%) at 6 months was associated with greater disease severity (100% were in functional class III or IV vs 42%, p = 0.005), greater diuretic use (86% vs 40%, p = 0.02), higher mean pulmonary artery pressure (67 ± 20 vs 46 ± 17 mm Hg, p = 0.006), and poorer survival (4-year mortality 43% vs 23%, p = 0.002). After adjusting for age, functional class, and RV strain at baseline, patients with ≥5% improvement in RV free wall systolic strain had a greater than sevenfold lower mortality risk at 4 years (hazard ratio 0.13, 95% confidence interval 0.03 to 0.50, p = 0.003). In conclusion, serial echocardiographic assessment of RV longitudinal systolic function by quantitative strain imaging independently predicts clinical deterioration and mortality in patients with PAH after the institution of medical therapy.
The American journal of cardiology 10/2012; · 3.58 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Pulmonary arterial hypertension (PAH) is a complex disease with variable clinical manifestations; nevertheless, morbidity and mortality associated with PAH are considerable. This study examined quality of life (QOL) in PAH patients and assessed use of palliative care (PC) for addressing QOL issues and what barriers might exist regarding early PC implementation for patients with PAH.
An Internet-based survey was distributed to Pulmonary Hypertension Association patient-related listservs. Symptom burden and QOL were assessed using Linear Analog Self Assessment (LASA) QOL items and the Cambridge Pulmonary Hypertension Outcome Review (CAMPHOR).
Of 774 eligible patients with active e-mail addresses, 315 returned surveys (41% overall response), and 276 (88%) contained analyzable responses. Responders (mean age, 48.9 years ± 16.0) were predominantly white (85%), female (86%), and with idiopathic PAH (42%). Profound deficiency in overall QOL (40%), fatigue (57%), physical well-being (56%), social activity (49%), emotional well-being (49%), and pain (38%) were reported. Most patients believed their PAH physician had excellent understanding of PAH progression/plan of care (92%), but less were satisfied with care regarding QOL management (77%). Few patients considered PC (8%), or had pain management (4%) or PC involved (1%). Most common reasons were beliefs that patients were doing well/not sick (63%) or that PC had not been suggested (22%).
PAH may result in symptoms or QOL impairment persisting despite optimal PAH therapy. However, PC awareness or use by PAH patients and providers is low. Opportunities may exist to integrate PC into care for PAH patients.
The Journal of heart and lung transplantation: the official publication of the International Society for Heart Transplantation 10/2012; 31(10):1102-8. · 3.54 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Pulmonary arterial hypertension (PAH) is characterised by increased pressure in the pulmonary arteries leading to right-sided ventricular failure, and death. Identification of factors that affect patient survival is important to improve patient management and outcomes. The first registry to evaluate survival and develop a prognostic model was the National Institutes of Health (NIH) registry in 1981. Importantly this prognostic model is based on data collected prior to availability of PAH-targeted therapies and does not reflect survival rates for treated patients. Since the 1980s , however, four modern registries of PAH now exist which compensate for the NIH equations shortcomings and include the French National registry, Pulmonary Hypertension Connection registry, the Mayo registry, and the Registry to Evaluate Early and Long-Term PAH Disease Management (REVEAL). The similarities and difference in these registries are highlighted in this review and although similar in many respects, the four registries vary in patient population, including the numbers of newly and previously diagnosed patients, as well as the era of observation, period of survival, and timing of assessment of potential predictive factors. Despite this, the predictive factors identified in each registry and described in detail within the body of this manuscript share surprising homology in that disease aetiology, patient gender and factors reflective of right heart failure are integral in depicting survival. Future modifications of modern prognostic equations should be an ongoing goal of the PAH community in order to provide increased accuracy with identification of novel risk factors and prediction of disease course.
Thrombosis and Haemostasis 09/2012; 108(6). · 5.76 Impact Factor