Long-term Pulmonary Arterial Hypertension Research Articles

Comorbid Conditions and Outcomes in Patients With Pulmonary Arterial Hypertension

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. 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. 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). 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. ClinicalTrials.gov; Identifier: NCT00370214; URL: www.clinicaltrials.gov.

When to Initiate Intravenous Therapy and/or Refer

Intravenous (IV) prostacyclin (epoprostanol) and its analogs (iloprost and treprostinil) are effective in treating pulmonary artery hypertension (PAH). Although prostacyclins are available for inhaled and subcutaneous delivery, IV administration of prostacyclins, sometimes in combination with other agents, such as bosentan or sildenafil, is considered the most aggressive method to manage PAH. This report attempts to help clinicians determine when to initiate IV treatment of PAH and when to refer a patient with PAH to a center for treatment. IV prostacyclin therapy initiation is suggested when patients exhibit World Health Organization functional class IV symptoms. The Registry to EValuate Early And Long-term Pulmonary Arterial Hypertension disease management (REVEAL) risk calculator can help determine a patient's 1-year mortality with PAH and characterize the clinical course, treatment, and predictors of outcomes in patients with PAH. Referring physicians can screen their patients for PAH and refer even before the diagnosis has been confirmed so that the center can facilitate the diagnostic process and provide suggestions for initial therapy selection and provide other collaborative and supportive services. Alternatively, the physician can diagnose and initiate early therapy with a plan to involve the pulmonary hypertension center at the need for IV therapy or consideration for transplantation, working closely with the patient to ensure stability. Physicians and pulmonary centers must develop good methods of communication to ensure effective diagnosis and management.

BASELINE ESTIMATED RIGHT ATRIAL PRESSURE BY ECHOCARDIOGRAPHY PREDICTS MORTALITY IN IDIOPATHIC AND ASSOCIATED PULMONARY ARTERIAL HYPERTENSION

Elevated mean right atrial pressure (RAP) measured by cardiac catheterization is an independent risk factor for mortality in the REVEAL (Registry to Evaluate Early and Long-term Pulmonary Arterial Hypertension Disease Management) registry. This study was designed to assess the predictive value of

Demographics and Outcomes of Patients Diagnosed With Pulmonary Hypertension With Pulmonary Capillary Wedge Pressures 16 to 18 mm Hg: Insights From the REVEAL Registry

The Registry to Evaluate Early and Long-term Pulmonary Arterial Hypertension Disease Management (REVEAL Registry) is a multicenter, US-based, observational study of patients diagnosed with group 1 pulmonary hypertension enrolled consecutively from March 2006 to December 2009. Of 3,128 patients in this analysis, inclusion criteria permitted enrollment of 268 patients with mean pulmonary capillary wedge pressure (PCWP) 16 to 18 mm Hg at diagnostic right-sided heart catheterization (RHC) (above currently accepted pulmonary arterial hypertension [PAH] diagnostic criteria). This study compared the demographics and outcomes of those 268 patients with an elevated mean PCWP to patients with a mean PCWP ≤ 15 mm Hg. Demographic characteristics and outcomes were compared for patients with mean PCWP ≤ 12, 13 to 15, and 16 to 18 mm Hg at diagnostic and follow-up RHC. At diagnostic RHC, patients with PCWP 16 to 18 mm Hg were older, had more severe hemodynamic impairments, and were more likely to be obese and have other comorbidities than patients with PCWP ≤ 15 mm Hg. There were no clinically relevant differences in 5-year survival rates from diagnostic RHC regardless of PCWP at diagnosis (≤ 15 mm Hg vs 16-18 mm Hg, P = .07). Two-year survival rates of 108 patients with PAH whose PCWP increased to 19 mm Hg (regardless of PCWP at diagnosis) were significantly lower than that of patients with PAH with PCWP ≤ 18 mm Hg at subsequent RHC. Patients with PCWP 16 to 18 mm Hg who were diagnosed and treated for PAH were older, heavier, and more likely to have comorbidities associated with left ventricular diastolic dysfunction at diagnosis than those with PCWP ≤ 15 mm Hg. Five-year survival rates were similarly low for all PCWP subgroups. ClinicalTrials.gov; No.: NCT00370214; URL: www.clinicaltrials.gov

Validation of the Registry to Evaluate Early and Long-Term Pulmonary Arterial Hypertension Disease Management (REVEAL) pulmonary hypertension prediction model in a unique population and utility in the prediction of long-term survival

The Registry to Evaluate Early and Long-Term Pulmonary Arterial (PAH) Hypertension Disease Management (REVEAL) model was designed to predict 1-year survival in patients with PAH. Multivariate prediction models need to be evaluated in cohorts distinct from the derivation set to determine external validity. In addition, limited data exist on the utility of this model in the prediction of long-term survival. REVEAL model performance was assessed to predict 1-year and 5-year outcomes, defined as survival or composite survival or freedom from lung transplant, in 140 patients with PAH. The validation cohort had a higher proportion of human immunodeficiency virus (7.9% vs 1.9%, p < 0.0001), methamphetamine use (19.3% vs 4.9%, p < 0.0001), and portal hypertension PAH (16.4% vs 5.1%, p < 0.0001) compared with the development cohort. The C-index of the model to predict survival was 0.765 at 1 year and 0.712 at 5 years of follow-up. The C-index of the model to predict composite survival or freedom from lung transplant was 0.805 and 0.724 at 1 and 5 years of follow-up, respectively. Prediction by the model, however, was weakest among patients with intermediate-risk predicted survival. The REVEAL model had adequate discrimination to predict 1-year survival in this small but clinically distinct validation cohort. Although the model also had predictive ability out to 5 years, prediction was limited among patients of intermediate risk, suggesting our prediction methods can still be improved.

Bloodstream Infections in Patients With Pulmonary Arterial Hypertension Treated With Intravenous Prostanoids: Insights From the REVEAL REGISTRY®

ObjectiveTo evaluate the rate of and potential risk factors for bloodstream infections (BSIs) using data from the REVEAL (Registry to Evaluate Early and Long-term Pulmonary Arterial Hypertension [PAH] Disease Management) REGISTRY®, which provides current information about patients with PAH. Patients and MethodsPatients were enrolled from March 30, 2006, through December 8, 2009, and data on reported BSIs were collected through the third quarter of 2010. Bloodstream infection rates were calculated per 1000 patient-days of risk. ResultsOf 3518 patients enrolled, 1146 patients received intravenous (IV) prostanoid therapy for more than 1 day (no BSI, n=1023; ≥1 BSI, n=123; total BSI episodes, n=166). Bloodstream infections rates were significantly increased in patients receiving IV treprostinil vs IV epoprostenol (0.36 vs 0.12 per 1000 treatment days; P<.001), primarily due to gram-negative organisms (0.20 vs 0.03 per 1000 treatment days; P<.001). Multivariate analysis adjusting for age, causes of PAH, and year of BSI found that treatment with IV treprostinil was associated with a 3.08-fold increase (95% confidence interval, 2.05-4.62; P<.001) in BSIs of any type and a 6.86-fold increase (95% confidence interval, 3.60-13.07; P<.001) in gram-negative BSIs compared with treatment with IV epoprostenol. ConclusionCompared with IV epoprostenol therapy, treatment with IV treprostinil is associated with a significantly higher rate of gram-negative BSIs; observed differences in BSI rate did not seem to be due to any other analyzed factors. Trial Registrationclinicaltrials.gov Identifier: NCT00370214

The Estrogen Puzzle in Pulmonary Arterial Hypertension

> New Scientist: What do you think most about during the day? > > Stephen Hawking: Women. They are a complete mystery. > > —Stephen Hawking at 70 – exclusive interview at the New Scientist, Jan 4, 2012 The biology of pulmonary arterial hypertension (PAH) is full of mysteries, and one of its longer-standing ones has also intrigued and inspired both scientists and artists throughout history: the female sex. Although affecting patients of all ages and both sexes, PAH preferentially affects young women, suggesting that the female sex is a risk factor for PAH. Even in heritable PAH associated with autosomal dominant mutations in the gene encoding the bone morphogenetic protein receptor type 2 (BMPR2), women after puberty are ≈2.5 times more likely to develop PAH than males.1 In idiopathic PAH the female/male ratio ranges from 1.7:1 or 1.9:1 to 4.1:1 in 3 published PAH registries (the National Institutes of Health registry in the 80s,2 the French registry,3 and the Registry to Evaluate Early and Long-term PAH Disease Management (REVEAL),4 respectively). On the other hand, the disease can be more severe in men. Female animals with PAH tend to have lower pulmonary artery pressures and better outcomes compared with males,5 and similarly, male PAH patients have higher mortality than females.6 The basis for this apparent paradox remains unknown. Article see p 1087 Estrogens exert their effects through both genomic effects, by activating their cytosolic or membrane-bound receptors, and nongenomic effects, by activating membrane G protein–coupled estrogen receptors. For example, via the nongenomic effects, estrogens promote the release of both prostacyclin and nitric oxide while, via the genomic effects, they decrease the expression of endothelin 1 under hypoxia, all promoting vasoconstriction in the pulmonary circulation.5 Yet, the pathology of PAH is driven not by vasoconstriction, but rather by a proproliferative and antiapoptotic diathesis throughout the pulmonary arterial wall. The main circulating estrogen in …

An Evaluation of Long-term Survival From Time of Diagnosis in Pulmonary Arterial Hypertension From the REVEAL Registry

The Registry to Evaluate Early and Long-term Pulmonary Arterial Hypertension Disease Management (REVEAL Registry) was established to characterize the clinical course, treatment, and predictors of outcomes in patients with pulmonary arterial hypertension (PAH) in the United States. To date, estimated survival based on time of patient enrollment has been established and reported. To determine whether the survival of patients with PAH has improved over recent decades, we assessed survival from time of diagnosis for the REVEAL Registry cohort and compared these results to the estimated survival using the National Institutes of Health (NIH) prognostic equation. Newly or previously diagnosed patients (aged ≥ 3 months at diagnosis) with PAH enrolled from March 2006 to December 2009 at 55 US centers were included in the current analysis. A total of 2,635 patients qualified for this analysis. One-, 3-, 5-, and 7-year survival rates from time of diagnostic right-sided heart catheterization were 85%, 68%, 57%, and 49%, respectively. For patients with idiopathic/familial PAH, survival rates were 91% ± 2%, 74% ± 2%, 65% ± 3%, and 59% ± 3% compared with estimated survival rates of 68%, 47%, 36%, and 32%, respectively, using the NIH equation. Comprehensive analysis of survival from time of diagnosis in a large cohort of patients with PAH suggests considerable improvements in survival in the past 2 decades since the establishment of the NIH registry, the effects of which most likely reflect a combination of changes in treatments, improved patient support strategies, and possibly a PAH population at variance with other cohorts

Changing Demographics, Epidemiology, and Survival of Incident Pulmonary Arterial Hypertension

Incident pulmonary arterial hypertension was underrepresented in most pulmonary hypertension registries and may have a different disease profile to prevalent disease. To determine the characteristics and outcome of a purely incident, treatment-naive cohort of idiopathic, heritable, and anorexigen-associated pulmonary arterial hypertension and to determine the changes in presentations and survival over the past decade in the United Kingdom and Ireland. All consecutive newly diagnosed patients from 2001 to 2009 were identified prospectively. A total of 482 patients (93% idiopathic, 5% heritable, and 2% anorexigen-associated pulmonary arterial hypertension) were diagnosed, giving rise to an estimated incidence of 1.1 cases per million per year and prevalence of 6.6 cases per million in 2009. Younger patients (age ≤ 50 yrs) had shorter duration of symptoms, fewer comorbidities, better functional and exercise capacity, higher percent diffusing capacity of carbon monoxide, more severe hemodynamic impairment, but better survival compared with older patients. In comparison with the earlier cohorts, patients diagnosed in 2007-2009 were older, more obese, had lower percent diffusing capacity of carbon monoxide,(,) and more comorbidities, but better survival. Registry to Evaluate Early and Long-Term Pulmonary Arterial Hypertension Disease Management (REVEAL) equation, REVEAL risk score, and Pulmonary Hypertension Connection Registry survival equation accurately predicted survival of our incident cohort at 1 year. This study highlights the influence of age on phenotypes of incident pulmonary arterial hypertension and has shown the changes in demographics and epidemiology over the past decade in a national setting. The results suggest that there may be two subtypes of patients: the younger subtype with more severe hemodynamic impairment but better survival, compared with the older subtype who has more comorbidities.

Portopulmonary Hypertension: A Report From the US-Based REVEAL Registry

We evaluated survival and hospitalization rates in patients with group 1 portopulmonary hypertension (PoPH) in the Registry to Evaluate Early and Long-term Pulmonary Arterial Hypertension Disease Management (REVEAL Registry). The REVEAL Registry is a multicenter, observational, US-based study evaluating demographics and management of patients with pulmonary arterial hypertension (PAH). Outcomes were examined using Kaplan-Meier time-to-event estimates and compared with patients with idiopathic PAH (IPAH) or familial PAH (FPAH). One hundred seventy-four patients with PoPH were enrolled in the REVEAL Registry (IPAH/FPAH; n = 1,478) from March 2006 to December 2009. Mean age was 53 ± 10 years, 52% were female, 32% were newly diagnosed, and 6% were New York Heart Association/World Health Organization functional class IV. Outcome parameters were worse for PoPH vs IPAH/FPAH, respectively: 2-year survival from enrollment (67% vs 85%, P < .001), 5-year survival from time of diagnosis (40% vs 64%, P < .001), and 2-year freedom from all-cause hospitalization (49% vs 59%, P = .019). However, despite worse outcomes, hemodynamic parameters at diagnosis were better for PoPH vs IPAH/FPAH, respectively: mean pulmonary artery pressure (49 mm Hg vs 53 mm Hg, P < .001), mean right atrial pressure (9 mm Hg vs 10 mm Hg, P = .005), pulmonary vascular resistance (8 Wood units vs 12 Wood units, P < .001), and cardiac output (5 L/min vs 4 L/min, P < .001). Compared with patients with IPAH/FPAH, patients with PoPH were less likely to be on a PAH-specific therapy at enrollment (P < .001), suggesting potential delays in therapy for patients with PoPH. Patients with PoPH had significantly poorer survival and all-cause hospitalization rates compared with patients with IPAH/FPAH, despite having better hemodynamics at diagnosis. Further studies should investigate such outcomes and differences in treatment patterns. ClinicalTrials.gov; No.: NCT00370214; URL: www.clinicaltrials.gov.

Towards prognostic biomarkers in pulmonary arterial hypertension

The most reliable way to assess the clinical impact of a therapeutic intervention in pulmonary arterial hypertension (PAH) is through its effect on well-defined clinical end-points, such as mortality. However, this standard is often impractical because of the long period and large number of patients required to reach these clinical end-points, and substitutes, such as the 6-min walking distance, are often used. Biomarkers may also be reliable substitutes for clinical end-points, and are called surrogate end-points when they meet such requirements. According to the US National Institutes of Health Biomarkers Definitions Working Group, a biomarker is “a characteristic that is objectively measured and evaluated as an indicator of normal biological processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention” [1]. However, while this definition is used for drug discovery, another narrower definition is still commonly used: “disease-associated molecular changes in body tissue and fluids”, i.e. a biological marker [2]. Among the estimated 150,000 papers documenting thousands of biological markers, less than 100 biomarkers are routinely used in the clinic [2]. In the field of PAH, which is a rare disease, most biomarker studies examined less than 100 patients, and therefore lacked the statistical power needed to demonstrate a strong association between any biomarker and death. Registries such as the Registry to Evaluate Early And Long-term PAH Disease Management (REVEAL) [3] have the advantage of enabling the study of larger populations and, therefore, have much better statistical power. However, in most cases, registries are not designed to evaluate new biomarkers, as they do not reach the necessary quality of biological sampling with storage of samples in a biobank, and are often a mix of incident and prevalent patients. In addition, many studies have focused on just one biomarker, while there is increasing …

The fifth world symposium on pulmonary hypertension will REVEAL the impact of registries

One of the meanings of “reveal” is “to disclose through prophets”. In the world of pulmonary arterial hypertension (PAH), REVEAL refers more modestly to the Registry to EValuate Early and Long-term PAH Disease Management [1–3]. In the current issue of the European Respiratory Review , two of the key contributors to this modern era registry have elegantly summarised their recent findings and future research plans [4]. The ability to identify and evaluate factors that affect survival in patients with PAH is of critical interest to clinicians. The first of several registries (Patient Registry for the Characterization of Primary Pulmonary Hypertension), supported by the National Institutes of Health (NIH) and the National Heart, Lung, and Blood Institute, was initiated in 1981 [5, 6 …

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

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. 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. 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. 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. ClinicalTrials.gov; No.: NCT00370214; URL: www.clinicaltrials.gov.

The REVEAL Registry Risk Score Calculator in Patients Newly Diagnosed With Pulmonary Arterial Hypertension

In pulmonary arterial hypertension (PAH), survival predictions can be important for optimization of therapeutic strategies. The present study aimed to validate a quantitative algorithm for predicting survival derived from the Registry to Evaluate Early and Long-term PAH Disease Management (REVEAL Registry) and develop a simplified calculator for everyday clinical use. Prospectively collected data from patients with newly diagnosed (< 3 months) World Health Organization group I pulmonary hypertension enrolled in the REVEAL Registry were used to validate a predictive algorithm for 1-year survival. Model calibration was evaluated by comparing algorithm-predicted survival with observed Kaplan-Meier estimates for the overall validation cohort and for five risk groups. Similarly, the risk discriminators for the simplified calculator were compared with those of the quantitative algorithm. The validation cohort comprised 504 individuals with mean ± SD 6-min walk distance 308 ± 128 m, and 61.5% were functional class III. The proportion of patients surviving 1 year fell within the range predicted by the model (95.1%, 91.5%, 84.6%, 76.3%, and 58.2%, respectively) among patients in the low (predicted survival ≥ 95%), average (90% to < 95%), moderate (85% to < 90%), high (70% to < 85%), and very high (< 70%) risk strata. Predicted and observed 1-year survival were similar across risk stratum, and the c-index indicated good discrimination for both the full equation (0.726) and the simplified risk calculator (0.724). The REVEAL Registry predictive algorithm and simplified risk score calculator are well calibrated and demonstrate good discriminatory ability in patients with newly or previously diagnosed PAH. ClinicalTrials.gov; No.: NCT00370214; URL: www.clinicaltrials.gov.

Survival in Childhood Pulmonary Arterial Hypertension

Background— Pulmonary arterial hypertension (PAH) is a rare but important cause of morbidity and mortality in children. Methods and Results— We analyzed data from 216 patients ≤18 years of age at diagnosis who were enrolled in the Registry to Evaluate Early and Long-Term PAH Disease Management (REVEAL). Median age at diagnosis and enrollment was 7 and 15 years, respectively. The most frequent presenting symptom was dyspnea (idiopathic/familial PAH, 53%; PAH associated with congenital heart disease, 30%). Presyncope/syncope was more frequent in patients with idiopathic PAH/familial PAH (36%) than in those with PAH associated with congenital heart disease (4%). At diagnosis, mean pulmonary artery pressure and pulmonary vascular resistance index were 56 mm Hg and 17 Wood units · m 2 , respectively. Five-year survival from diagnosis for the overall cohort was 74±6%, with no significant difference between the idiopathic PAH/familial PAH (n=122, 75±7%) and PAH associated with congenital heart disease (n=77, 71±13%) cohorts ( P =0.53). Older age at diagnosis was the only variable significantly associated with decreased survival from diagnosis. Variables at enrollment that were significantly associated with decreased survival from enrollment included higher pulmonary vascular resistance index, lower-weight z scores, and familial PAH. Additional variables at enrollment, identified in a secondary analysis, that were marginally associated with increased survival from enrollment included acute vasoreactivity (adaptation of conventional pediatric definition; P =0.087) and lower brain natriuretic peptide ( P =0.060). None of the 22 patients who were acute responders treated with high-dose calcium channel blockade as monotherapy or combination therapy died within 5 years of diagnosis. Conclusion— Using REVEAL, we identified key predictors of survival in childhood PAH. Refining these prognostic parameters should help clinicians improve outcomes. Clinical Trial Registration— URL: www.clinicaltrials.gov . Unique identifier: NCT00370214.

Use of Parenteral Prostanoids at Time of Death in Patients With Pulmonary Arterial Hypertension Enrolled in REVEAL

PURPOSE: A primary objective of the Registry to EValuate Early And Long-term Pulmonary Arterial Hypertension (PAH) Disease Management (REVEAL) is to determine outcomes in patients with PAH. Analysis of PAH-specific therapy at time of death could provide information on the aggressiveness of therapy and the adherence to recommended treatment guidelines in patients with the most severe disease. In this study, we compared functional class assessments prior to death and parenteral prostanoid administration at time of death to determine whether PAH patients were treated according to recommendations.

Hepatic Transaminase Abnormalities in Pulmonary Arterial Hypertension: A Report From the REVEAL Registry

PURPOSE: The Registry to EValuate Early And Long-term Pulmonary Arterial Hypertension (PAH) Disease Management (REVEAL), a 55-center observational, US study, examines current clinical practice in patients with PAH. We assessed aspartate transaminase/alanine transaminase (AST/ALT) elevation frequencies in patients by PAH-specific medication class, and by specific endothelin receptor antagonist (ERA) due to ERAs’ association with AST/ALT abnormalities.

Four-Year Outcomes of Patients With Pulmonary Arterial Hypertension: Risk, Prognosis, and the Disease Duration Continuum

PURPOSE: The Registry to EValuate Early And Long-term Pulmonary Arterial Hypertension (PAH) Disease Management (REVEAL) provides information about demographics, clinical course, and management of PAH patients. The compositions of incident and prevalent cohorts are known to differ; however, sample size restraints have previously limited our ability to describe a continuum of risk profiles from recently diagnosed patients to long-term survivors.

Delay in Recognition of Pulmonary Arterial Hypertension: Factors Identified From the REVEAL Registry

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. 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. 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. 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. ClinicalTrials.gov; No.: NCT00370214; URL: www.clinicaltrials.gov.

Integration of Clinical and Hemodynamic Parameters in the Prediction of Long-term Survival in Patients With Pulmonary Arterial Hypertension

Current management guidelines for pulmonary arterial hypertension (PAH) recommend a treatment choice based primarily on World Health Organization (WHO) functional class. This study was designed to assess how the incorporation of readily obtained clinical and test-based information may significantly improve the prediction of outcomes over functional class alone. Clinical and hemodynamic variables were assessed in 484 consecutive patients presenting with WHO group 1 PAH. The primary outcome measure was time to all-cause mortality over 5 years from the index presentation (data available in all). Follow-up was censored at the time of lung or heart/lung transplant in 21 patients or at 5 years. Predictors of mortality were assessed sequentially using Cox models, with the step-wise incorporation of clinical variables, echocardiographic, and catheterization findings. Results were further compared with the REVEAL (Registry to Evaluate Early and Long-term Pulmonary Arterial Hypertension Disease Management) prediction score. Overall median survival was 237 weeks (95% CI, 196-266), corresponding to 1-year, 3-year, and 5-year survival rates of 81.1% (77.0, 84.7), 61.1% (56.5, 65.3), and 47.9% (43.2, 52.4), respectively. The prediction of mortality was improved incrementally by incorporating clinical and echocardiographic measures with a concordance index (c-index) of 0.84 compared with that of 0.60 with functional class alone. The REVEAL prediction score was validated independently in this cohort to predict both 1-year and 5-year mortality. It had a prediction c-index of 0.71. The integration of routine PAH clinical (predominantly noninvasive) parameters predicts long-term outcome better than functional class and, hence, should be incorporated into medical management decisions.