Pulmonary arterial hypertension (PAH) is a chronic disease of the pulmonary vasculature characterized by progressive narrowing of the pulmonary arteries, which in turn leads to increased pulmonary vascular resistance, right heart failure, and death.¹ There has been a significant improvement in the available medical therapeutic options in this field that have impacted the short-term survival and morbidity in these patients.² However, the median survival post-diagnosis stays limited at 7 years.³ Physicians' ability to predict PAH disease progression allows them to determine the patient's prognosis, identify treatment goals, and monitor his or her response to therapy.⁴ If widely adopted, risk prediction can enhance the consistency of treatment approaches and improve the timeliness of referral for lung transplantation. This allows for an optimal, directed care that ultimately reduces morbidity and improves mortality in patients with PAH.

Important Factors for Risk Stratification

Like our patients with PAH, risk stratification should have a multifaceted approach that includes both objective and subjective variables that ultimately create an overall risk profile. These parameters should be statistically validated and evidence based. The following factors have been cited in literature in their implications for patient outcomes:

• Demographics. Within PAH, there are certain subtypes of patients that have a worse prognosis. These include age (>60 years), male gender, systemic connective tissue disease, and the bone morphogenetic protein receptor II mutation.^5-8
• Functional Class and Capacity. Functional class is an easily accessible risk parameter that can be obtained at every clinic visit. This self-reporting system of symptoms is a subjective but consistent and effective clinical tool, representing the continuum of disease. Patients who have a lower functional class (I or II) at baseline have a more favorable prognosis than those who are functional class III or IV. Although changes in 6-minute walk distance have not been shown to predict survival, improvement or deterioration of functional capacity is considered vital to decisions to initiate, maintain, or escalate therapy. A threshold of 440 meters is suggestive of a distinction between high-and low-risk patients in pulmonary hypertension guidelines.^6,8 Reduced exercise capacity noted on exercise testing also indicates a worse prognosis. Syncope, considered a marker of class IV symptoms, has additional prognostic relevance in PAH.
• Laboratory testing. Plasma brain natriuretic peptide (BNP) is secreted by the left and right ventricles when the cardiac muscle is under stress and is considered an independent predictor of mortality in patients with PAH.⁹ The degree of right ventricular dysfunction in patients with PAH correlates with increasing levels of BNP. A recently published evaluation of BNP demonstrated that an optimal BNP threshold of 340 pg/mL strongly predicts 5-year survival in patients with PAH (hazard ratio 3.6; 95% confidence interval, 3.0-4.2; p < 0.001).¹⁰ Additionally, elevated levels of creatinine, total bilirubin, uric acid, and troponin, along with decreased albumin and serum sodium, are all markers of worse outcomes in patients with PAH.⁴
• Imaging. An echocardiogram is a vital imaging tool in screening for pulmonary hypertension and assessing the right ventricular size and function in patients with PAH. A tricuspid annular plane systolic excursion of <1.8 cm, right atrial size >18 cm², and the presence of pericardial effusion are all known to suggest high-risk patients.¹ Cardiac magnetic resonance imaging is gaining ground in assessing these parameters due to better image quality, especially in reference to assessment of right ventricular size, morphology, and function.
• Hemodynamics. A right heart catheterization is vital for accurate diagnosis in PAH as well as providing prognostic information. Known prognostic parameters include high right atrial pressure (>14 mmHg), pulmonary vascular resistance (>5 WU), venous oxygen saturation <60%, and low cardiac index (<2 L/min/m²).⁸
• Hospitalizations. All-cause hospitalization, especially related to PAH events, within 6 months is associated with an increased risk of mortality and recurrent hospitalizations.¹⁰

Tools for Risk Stratification

There are various risk calculators that are available to risk stratify patients with PAH that all focus on different aspects of the disease process. The primary aim of these assessments is to project patient trajectory based on available information, allowing for informed and individualized decision-making. Ideally, these tools should be multifaceted, applicable along the continuum of disease, easy to use, and validated. Analysis of the Registry to Evaluate Early and Long-term PAH Disease Management data produced a versatile risk calculator based on over 2,500 PAH registry patients who were newly and previously diagnosed with PAH (Table 1).^6,10 Similarly, the European PAH registries (French Pulmonary Arterial Hypertension Network registry, Spanish Registry Of Pulmonary Arterial Hypertension, Swedish Pulmonary Arterial Hypertension Registry, and Comparative, Prospective Registry of Newly Initiated Therapies for Pulmonary Hypertension) have developed algorithms to stratify patients as low, intermediate, or high risk of death and are represented in the 2015 European Society of Cardiology and European Respiratory Society pulmonary hypertension guidelines (Table 2).^8,11,12 These registries and evaluations of clinical trial sets have provided important insights into the importance of both modifiable (e.g., 6-minute walk distance, functional class, and BNP) and nonmodifiable (e.g., age, gender, and PAH etiology) risk factors that predict survival.

Take-Home Points

When managing patients with PAH, risk assessment should play a vital role in the care delivered to the patient. To accurately prognosticate and provide evidence-based treatment plans to the patient should be of utmost importance. The various risk calculators, such as that from the Registry to Evaluate Early and Long-term PAH Disease Management, have been validated and are effective at providing the patient and physician with valuable information to predict mortality and prognosis and ultimately provide appropriate treatment.

Table 1

Risk Stratification Groups	PAH Risk Score
World Health Organization (WHO) Group I (PAH) Subgroup Associated – Connective tissue disease Associated – Portopulmonary hypertension Familial PAH	+1 +2 +2
Demographics and comorbidities Renal insufficiency Males age >60 years old	+1 +2
New York Heart Association/WHO Functional Class I III IV	-2 +1 +2
Vital signs Systolic blood pressure <110 mmHg Heart rate >92 bpm	+1 +1
6-minute walk test >440 meters <165 meters	-1 +1
B-type natriuretic peptide (BNP) <50 pg/mL >180 pg/mL	-2 +1
Echocardiogram Pericardial effusion	+1
Pulmonary function test % predicted diffusing capacity of the lungs for carbon monoxide >80 % predicted diffusing capacity of the lungs for carbon monoxide <32	-1 +1
Right heart catheterization Mean right atrial pressure >20 mmHg within 1 year Pulmonary vascular resistance >32 Wood units	+1 +2
	Sum of the above score +6
	= PAH risk score

Table 2

Determinants of 1-Year Mortality	Low Risk (<5%)	Intermediate Risk (5-10%)	High Risk (>10%)
Clinical signs of right heart failure	-	-	+
Progression of symptoms	-	Slow	Rapid
Syncope	-	Occasional	Multiple
WHO Functional Class	I, II	III	IV
6-minute walk test distance (meters)	>440	165-440	<165
Cardiopulmonary exercise test Peak VO2 (ml/min/kg) % Predicted Minute ventilation/carbon dioxide production slope	>15 >65% <36	11-15 35-65% 36-44.9	<11 <35% >45
N-terminal proBNP plasma level BNP (ng/l) N-terminal proBNP (ng/l)	<50 <300	50-300 300-1400	>300 >1400
Echocardiographic imaging or cardiac magnetic resonance imaging Right atrial area (cm2) Pericardial effusion	<18 No	18-26 No or minimal	>26 Yes
Hemodynamics Right atrial pressure (mmHg) Cardiac index (l/min/m2) Venous oxygen saturation	<8 >2.5 >65%	8-14 2.0-2.4 60-65%	>14 <2.0 <60%

References

1. McLaughlin VV, Shah SJ, Souza R, Humbert M. Management of pulmonary arterial hypertension. J Am Coll Cardiol 2015;65:1976-97.
2. Kanwar MK, Thenappan T, Vachiéry JL. Update in treatment options in pulmonary hypertension. J Heart Lung Transplant 2016;35:695-703.
3. McLaughlin V. Managing pulmonary arterial hypertension and optimizing treatment options: prognosis of pulmonary artery hypertension. Am J Cardiol 2013;111(8 Suppl):10C-5C.
4. Benza RL, Lohmueller LC, Kraisangka J, Kanwar M. Risk Assessment in Pulmonary Arterial Hypertension Patients: The Long and Short of it. Advances in Pulmonary Hypertension 2018;16:125-35.
5. Humbert M, Sitbon O, Chaouat A, et al. Survival in patients with idiopathic, familial, and anorexigen-associated pulmonary arterial hypertension in the modern management era. Circulation 2010;122:156-63.
6. 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;122:164-72.
7. Evans JD, Girerd B, Montani D, et al. BMPR2 mutations and survival in pulmonary arterial hypertension: an individual participant data meta-analysis. Lancet Respir Med 2016;4:129-37.
8. Galiè N, Humbert M, Vachiery JL, et al. 2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension: The Joint Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS): Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC), International Society for Heart and Lung Transplantation (ISHLT). Eur Heart J 2016;37:67-119.
9. Nagaya N, Nishikimi T, Okano Y, et al. Plasma brain natriuretic peptide levels increase in proportion to the extent of right ventricular dysfunction in pulmonary hypertension. J Am Coll Cardiol 1998;31:202-8.
10. Benza RL, Elliott CG, Farber HW, et al. Updated Risk Score Calculator for Patients with Pulmonary Arterial Hypertension (PAH) in the Registry to Evaluate Early and Long-Term PAH Disease Management (REVEAL). Am J Respir Crit Care Med 2017;195:A6899-A.
11. Boucly A, Weatherald J, Savale L, et al. Risk assessment, prognosis and guideline implementation in pulmonary arterial hypertension. Eur Respir J 2017;50:1700889.
12. Hoeper MM, Kramer T, Pan Z, et al. Mortality in pulmonary arterial hypertension: prediction by the 2015 European pulmonary hypertension guidelines risk stratification model. Eur Respir J 2017;50:1700740.
13. Benza RL, Gomberg-Maitland M, Miller DP, et al. The REVEAL Registry risk score calculator in patients newly diagnosed with pulmonary arterial hypertension. Chest 2012;141:354-62.

Clinical Topics: Arrhythmias and Clinical EP, Diabetes and Cardiometabolic Disease, Heart Failure and Cardiomyopathies, Noninvasive Imaging, Pericardial Disease, Prevention, Pulmonary Hypertension and Venous Thromboembolism, Atrial Fibrillation/Supraventricular Arrhythmias, Acute Heart Failure, Heart Failure and Cardiac Biomarkers, Pulmonary Hypertension, Echocardiography/Ultrasound, Magnetic Resonance Imaging, Hypertension

Keywords: Hypertension, Pulmonary, Hypertension, Risk Factors, Prospective Studies, Risk Assessment, Registries, Decision Making, Disease Management, Algorithms, Bone Morphogenetic Protein Receptors, Type II, Ventricular Dysfunction, Right, Pulmonary Artery, Natriuretic Peptide, Brain, Troponin, Heart Ventricles, Pericardial Effusion, Atrial Fibrillation, Atrial Pressure, Echocardiography, Lung Transplantation, Syncope, Vascular Resistance, Heart Failure, Cardiac Catheterization, Disease Progression, Magnetic Resonance Imaging, Connective Tissue Diseases, Demography, Ambulatory Care

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