Baseline and Serial Brain Natriuretic Peptide Level Predicts 5-Year Overall Survival in Patients With Pulmonary Arterial Hypertension: Data From the REVEAL Registry Raymond Benza, MD, FACC Professor of Medicine Program Director, Advanced Heart Failure, Transplant, MCS and Pulmonary Hypertension Allegheny Health Network Pittsburgh, PA

Background Largest registry of PAH patients is the multicenter, observational US-based Registry to Evaluate Early and Long-term Pulmonary Arterial Hypertension Disease Management (REVEAL)  REVEAL has enrolled >  3,000 patients with WHO group I PAH1  Overall survival rates of patients with PAH remain poor with 5-year overall survival at 65.4% for previously diagnosed patients and 61.2% for newly diagnosed patients2 Plasma BNP level has been shown to be an independent predictor of mortality in patients with PAH3   A previous analysis of REVEAL data indicated that plasma BNP > 180 pg/mL was predictive of increased mortality risk at 1-year post-enrollment compared to patients with plasma BNP < 180 pg/ml (HR 3.2)4 The present analysis of the REVEAL database of 3,515 patients followed over 5 years, represents the largest and longest BNP cohort to date5 McGoon MD, Krichman A, Farber HW, et al. Design of the REVEAL registry for US patients with pulmonary arterial hypertension. Mayo Clin Proc. 2008;83: 923-931 Farber HW, Miller DP, Poms AD, et al. Five-year outcomes of patients enrolled in the REVEAL Registry. Chest. 2015;148:1043-1054. Nagaya N, Nishikimi T, Uematsu M, et al. Plasma brain natriuretic peptide as a prognostic indicator in patients with primary pulmonary hypertension. Circulation. 2000;102:865-870 Benza RL, Miller DP, Gomberg- Maitland M, et al. Predicting survival in pulmonary arterial hypertension: insights from the Registry to Evaluate Early and Long-Term Pulmonary Arterial Hypertension Disease Management (REVEAL). Circulation. 2010;122:164- 172. Frantz RP, Farber HW, Badesch DB, et al.  Baseline and Serial Brain Natriuretic Peptide Level Predicts 5-Year Overall Survival in Patients With Pulmonary Arterial Hypertension: Data From the REVEAL Registry. CHEST, 2018; Published online: January 16, 2018

Methodology REVEAL study design has been described previously1 Analysis included patients who had a BNP measurement at enrollment, were > 18 years of age, had WHO group 1 PAH (confirmed by RHC), and had pulmonary arterial wedge pressure < 15 mm Hg measured at rest at time of diagnosis2 Optimal BNP thresholds for predicting over all survival (OS) over 5 years were identified via receiver operating characteristics analysis BNP values were categorized as high and low using these thresholds Changes in BNP were also examined, with patients categorized as: Low-low (low BNP at baseline and last assessment) Low-high (BNP increased from low at baseline to high at last assessment) High-low (BNP decreased from high at baseline to low at last assessment) High-high (high BNP at baseline and last assessment) HRs for OS and comparisons between groups based on the BNP threshold were calculated using Cox regression BNP scores were developed based on the change in HR from the Cox regression model McGoon MD, Krichman A, Farber HW, et al. Design of the REVEAL registry for US patients with pulmonary arterial hypertension. Mayo Clin Proc. 2008;83: 923-931 Frantz RP, Farber HW, Badesch DB, et al.  Baseline and Serial Brain Natriuretic Peptide Level Predicts 5-Year Overall Survival in Patients With Pulmonary Arterial Hypertension: Data From the REVEAL Registry. CHEST, 2018; Published online: January 16, 2018

Patient Characteristics (Select) At Enrollment (n = 1426) BNP < 340 pg/ml (n = 1051) BNP > 340 pg/ml (n = P Value Age, y 50.9 + 14.5 57.0 + 14.3 < 0.0001 Gender > 0.5 Male, N (%) 205 (19.5) 86 (22.9) Female, N (%) 846 (80.5) 289 (77.1) Newly Diagnosed, N (%) 211 (20.1) 129 (34.4) <0.0001 PAH Etiology Idiopathic, N (%) 520 (49.5 161 (42.9) Connective Tissue Disease, N (%) 246 (23.4) 138 (36.8) Congenital Heart Disease, N (%) 103 (9.8) 21 (5.6) NHYA/WHO Functional Class I, N (%) 78 (8.3) 5 (1.6) II, N (%) 375 (40.1) 72 (22.6) III, N (%) 445 (47.6) 193 (60.5) IV, N (%) 37 (4.0) 49 (15.4) Resting mPAP, mmHg 48.9 + 14.3 52.0 + 12.6 < 0.001 PVRI, Wood Units x m2 17.8 + 11.8 22.1 + 10.6 Resting PAWP, mmHg 9.7 + 4.0 9.8 + 4.0 > 0.05 Data presented as mean + SD or N (%) mPAP = mean pulmonary arterial pressure; NYHA = New York Heart Association; PAH = pulmonary arterial hypertension; PAWP = pulmonary arterial wedge pressure; PVRI= pulmonary vascular resistance index; WHO = World Health Organization Frantz RP, Farber HW, Badesch DB, et al.  Baseline and Serial Brain Natriuretic Peptide Level Predicts 5-Year Overall Survival in Patients With Pulmonary Arterial Hypertension: Data From the REVEAL Registry. CHEST, 2018; Published online: January 16, 2018

At 5 Years, Group 1 PAH Survival Is Reduced In Patients With BNP >340 pg/ml 5-y Overall Survival For Patients With WHO Group1 Peripheral Arterial Hypertension: Stratified By Baseline + 1.0 0.8 0.6 0.4 0.2 0.0 + Survival Probability BNP level ≤340 pg/mL (n = 1,051, [events = 289]); mOS (95% CI) Not Estimable >340 pg/mL (n = 375, [events = 244]); mOS (95% CI) 37.5 mOS (29.8, 43.6) HR (95% CI): 3.555 (2.993-4.233) Log-Rank P value: > .0001 0.5 1 1.5 2 2.5 3 3.5 4 4.5 5 Years From Enrollment Frantz RP, Farber HW, Badesch DB, et al.  Baseline and Serial Brain Natriuretic Peptide Level Predicts 5-Year Overall Survival in Patients With Pulmonary Arterial Hypertension: Data From the REVEAL Registry. CHEST, 2018; Published online: January 16, 2018

Higher Baseline BNP Has Negative Influence On 5-Year Survival 1.0 0.8 0.6 0.4 0.2 0.0 0.5 1 1.5 2 2.5 3 3.5 4 4.5 5 Years From Enrollment Survival Probability + Baseline BNP value, pg/mL ≥1,100 500-<1,100 200-<500 80-<200 50-<80 <50 Frantz RP, Farber HW, Badesch DB, et al.  Baseline and Serial Brain Natriuretic Peptide Level Predicts 5-Year Overall Survival in Patients With Pulmonary Arterial Hypertension: Data From the REVEAL Registry. CHEST, 2018; Published online: January 16, 2018

Elevation In Plasma BNP At Any Time Confers Lower Survival Change in BNP from baseline to last assessment within 1 y post-enrollment 1.0 0.8 0.6 0.4 0.2 0.0 0.5 1 1.5 2 2.5 3 3.5 4 4.5 5 Years From Enrollment Survival Probability High-High (n=300, [events = 205]) + BNP level at baseline and at last assessment Low-Low (n=969, [events = 244]) Low-High (n=82, [events = 45]) High-Low (n=75, [events = 39]) Change in BNP from baseline to last assessment within 5 y of enrollment 1.0 0.8 0.6 0.4 0.2 0.0 0.5 1 1.5 2 2.5 3 3.5 4 4.5 5 Years From Enrollment Survival Probability BNP level at baseline and at last assessment Low-Low (n=908, [events = 198]) Low-High (n=143, [events = 91]) High-Low (n=103, [events = 38]) High-High (n=272, [events = 206]) + Frantz RP, Farber HW, Badesch DB, et al.  Baseline and Serial Brain Natriuretic Peptide Level Predicts 5-Year Overall Survival in Patients With Pulmonary Arterial Hypertension: Data From the REVEAL Registry. CHEST, 2018; Published online: January 16, 2018

Conclusions BNP level strongly predicts 5-year overall survival in patients with PAH 340 pg/mL is a predictive BNP threshold Patients who remained in the low BNP group had the lowest mortality risk, and those remaining in the high BNP group had the highest mortality risk Increased BNP was associated with a 3.2-fold increase in risk of mortality Use of two consecutive BNP assessments provided a reliable prediction of overall survival, especially for patients showing improvement: an important parameter in the updated REVEAL calculator Analyses confirm and expand on previous REVEAL results, showing high levels of BNP at enrollment were a strong indicator of increased mortality Frantz RP, Farber HW, Badesch DB, et al.  Baseline and Serial Brain Natriuretic Peptide Level Predicts 5-Year Overall Survival in Patients With Pulmonary Arterial Hypertension: Data From the REVEAL Registry. CHEST, 2018; Published online: January 16, 2018