Cherylanne Glassner

Validation of the Pulmonary Hypertension Connection Equation for Survival Prediction in Pulmonary Arterial Hypertension

OBJECTIVE The pulmonary hypertension connection (PHC) equation predicts contemporary survival in idiopathic, heritable, and anorexigen-associated pulmonary arterial hypertension (PAH). The aim of this study is to validate the PHC equation in a prospective PAH population cohort and compare its predictability with the French equation. METHODS We compared the rates of actual survival in patients prospectively followed for up to 3.5 years in four double-blind, randomized trials and their open-label extension studies with predicted survival calculated using the PHC equation [(P(t) = e((-A(x,y,z)t)), A(x,y,z) = e((-1.270-0.0148x + 0.0402y - 0.361z)), where P(t) is the probability of survival, t the time interval in years, x the mean pulmonary artery pressure, y the mean right atrial pressure, and z the cardiac index] and the French equation in patients with idiopathic, heritable, and anorexigen-associated PAH (n = 449). RESULTS Mean age was 44 ± 15 years, 77% were women, and 80% had World Health Organization (WHO) functional class III/IV symptoms. The mean 6-min walk distance (6MWD) was 354 ± 95 m. The baseline hemodynamics were as follows: mean right atrial pressure 10 ± 6 mm Hg, mean pulmonary artery pressure 59 ± 15 mm Hg, and cardiac output 4.1 ± 1.5 L/min. The 1-, 2-, and 3-year Kaplan-Meier survival rates were 89%, 80%, and 70%, respectively; the nonadjusted survival rates were 91%, 87%, and 84%, respectively. The expected survival predicted by both the PHC and the French equations was similar to the actual observed Kaplan-Meier survival and was within its 95% confidence limits. The PHC equation also performed well when used in patients with WHO functional class III/IV, cardiac output < 4 L/min, or 6MWD < 380 m. CONCLUSION Risk prediction equations (PHC and French) accurately predicted survival and may be useful for risk estimation in patients with idiopathic, heritable, and anorexigen-associated PAH in large cohort studies. Their use for survival prediction for individual patients needs further study.

The Effect of Diluent pH on Bloodstream Infection Rates in Patients Receiving IV Treprostinil for Pulmonary Arterial Hypertension

BACKGROUND Recent studies have reported an increase in catheter-related bloodstream infections (BSIs) and gram-negative BSIs among patients with pulmonary arterial hypertension treated with IV treprostinil. One possible explanation is the neutral pH of the treprostinil diluent compared with the basic pH of epoprostenol. We hypothesized that administering IV treprostinil with epoprostenol diluent will lower the rate of gram-negative BSI. METHODS We prospectively enrolled patients treated with IV treprostinil and changed the diluent from native diluent to epoprostenol diluent. We compared the incidence of BSI and gram-negative BSI between those receiving IV treprostinil with epoprostenol diluent (n = 25) and those actively receiving IV epoprostenol (n = 61), as well as with a cohort of patients who received IV treprostinil in native diluent (n = 34). Incidence rates of BSI were expressed as a fraction of 1,000 medicine treatment days. RESULTS There were similar rates of BSI in those treated with treprostinil with epoprostenol diluent and those treated with epoprostenol (0.32 of 1,000 vs 0.40 of 1,000; P = .79). Also, there were similar rates of gram-negative BSI in these two cohorts (0.08 of 1,000 vs 0.20 of 1,000; P = .46). BSI rates were not statistically different between those treated with treprostinil with epoprostenol diluent and those treated with treprostinil (0.32 of 1,000 vs 0.90 of 1,000; P = .06). However, gram-negative BSIs were significantly lower in patients treated with treprostinil with epoprostenol diluent than in those treated with treprostinil (0.08 of 1,000 vs 0.71 of 1,000, respectively; P = .01). CONCLUSIONS Patients treated with treprostinil with epoprostenol diluent have a lower incidence of gram-negative BSI than do those treated with treprostinil and a similar rate to those treated with epoprostenol. Changing the diluent of treprostinil to epoprostenol diluent, in combination with the use of water-tight seals throughout the delivery system, appears to be an effective safety measure.

Risk assessment in pulmonary hypertension associated with heart failure and preserved ejection fraction

BACKGROUND Pulmonary hypertension (PH) is common in patients with left heart failure (HF), especially those with HF and preserved ejection fraction (HFpEF). However, there is limited data on risk stratification in these patients. METHODS Baseline clinical and hemodynamic variables of 339 patients with World Health Organization (WHO) Group 2 PH, 90% of whom had HFpEF, were studied to derive a multivariate Cox proportional hazards model. A simplified prognostic risk score was created based on the outcome of all-cause mortality. Nine predictors, significant after stepwise multivariable regression (p < 0.05), were used to create the risk score. Components of the risk score were functional class, diastolic blood pressure, pulmonary artery saturation, interstitial lung disease, hypotension on initial presentation, right ventricular hypertrophy, diffusion capacity of the lung for carbon monoxide, and 2 serum creatinine variables (≤ 0.9 mg/dl and ≥ 1.4 mg/dl). RESULTS Overall 2-year survival was 73.8% ± 2.4% in the derivation cohort, and 87.5% ± 2.3%, 66.4% ± 4.9%, and 24.4% ± 6.7% for risk scores of 0 to 2, 3 to 4, and 5+, respectively (p < 0.0001 for the trend), with a C-index of 0.76 (95% confidence interval [CI], 0.71-0.81). The risk score was validated in 2 independent PH-HFpEF cohorts: 179 patients with a C-index of 0.68 (95% CI, 0.55-0.80) and 117 patients with a C-index of 0.68 (95% CI, 0.53-0.83). For the 3 cohorts combined (N = 635), the overall C-index was 0.72 (95% CI 0.68-0.76). In all 3 cohorts individually and in the 3 cohorts combined, the risk score predicted death (hazard ratio, 1.4-1.6; p < 0.01). CONCLUSIONS Several clinical factors independently predict death in PH-HFpEF confirmed by validation. A novel risk score composed of these factors can be used to determine prognosis and may be useful in making therapeutic decisions.

The management of pregnancy and pregnancy‐related medical conditions in pulmonary arterial hypertension patients

Pulmonary arterial hypertension (PAH) is a complex disorder in which pulmonary arterial obstruction leads to elevated pulmonary arterial resistance and right ventricular failure. Normal physiologic changes that occur during pregnancy and immediately postpartum may produce fatal consequence in PAH patients. Pregnancy in patients with PAH has a high maternal mortality, estimated at 30–56%. Contemporary estimates of mortality are better but still prohibitively high. Current guidelines recommend that pregnancy be avoided or terminated early in women with PAH. Some patients, despite counselling by their physician, choose to continue with their pregnancy. In addition, some women first present with PAH during pregnancy leading to complex management issues in a high‐risk patient. PAH‐specific therapies may allow patients to better tolerate pregnancy. These patients should be treated by experienced physicians at tertiary care centres. This review article will focus on the management of the pregnant PAH patient and the preventative options available for this high‐risk cohort.

Treadmill testing improves survival prediction models in pulmonary arterial hypertension

BACKGROUND Six-minute walk distance (6MWD) is used in the REVEAL equation to predict 1-year survival for patients with pulmonary arterial hypertension. We sought to determine whether exercise treadmill testing (ETT) could be used in its place. METHODS This was a single-center study in which 449 patients were enrolled. The variables predictive of survival in the REVEAL equation were evaluated and compared with survival predicted by the REVEAL equation without an exercise measure and a revised equation using ETT. RESULTS The addition of ETT to the equation improved the predictive ability of the REVEAL equation in the high- and low-risk patient groups. CONCLUSION The study findings suggest that the addition of ETT parameters to the REVEAL prognostic equation improves the predictive value of the equation when 6-minute walk distance is unavailable.

A Serial NT-proBNP Model to Improve Prognostication in Patients with Pulmonary Arterial Hypertension

Background: Baseline elevation in N-terminal pro-brain natriuretic peptide (NT-proBNP) in pulmonary arterial hypertension (PAH) patients is associated with worse outcomes. Serial measurement of commonly available biomarkers could improve the precision of prognostic estimates and our understanding of PAH pathophysiology. Methods: Included were 103 PAH patients with baseline elevated NT-proBNP prior to the initiation or escalation of therapy with at least two subsequent NT-proBNP measurements. Using patients’ serial measurements, a linear mixed-effects model extrapolated a baseline NT-proBNP (intercept) and evolution (slope). These model-determined values were then used in Cox proportional hazards analysis to determine predictors of survival. Time-dependent area under the curve (AUC) analysis compared survival discrimination of serial versus single measurements of NTproBNP. Results: Subjects were 50 ± 14 years; most had idiopathic PAH, congenital heart disease, or connective tissue disease. Survivors were younger than non-survivors 47 ± 14 versus 55 ± 12 years (p=0.002). A multivariable survival model using invasive and non-invasive covariates found NT-proBNP significantly predicted mortality. Timedependent AUC was significantly greater for modeled (intercept) versus measured NT-proBNP. Conclusions: Prognostic modeling utilizing serial NT-proBNP measurements better predict survival than a single baseline value. This evidence supports the conduct of future studies of serial measurement of NT-proBNP to further clarify its role in the clinical care of PAH patients.