PAH is a progressive disease1

PAH is a rare, progressive disease that results in increased pulmonary vascular resistance and right heart dysfunction.1,2 PAH is unrelenting and may lead to right heart failure.

PAH causes progressive blood flow restriction and RV dysfunction1,2

PAH disease progression chart. PAH causes progressive blood flow restriction and right ventricle dysfunction.

CO=cardiac output; LV=left ventricle; PA=pulmonary arterial; PAH=pulmonary arterial hypertension; PVR=pulmonary vascular resistance; RV=right ventricle.

Figure reproduced with permission from Champion HC et al. Circulation. 2009;120(11):992-1007.

Right heart dysfunction and failure may be an inevitable outcome of increasing cardiopulmonary pressures3

Progression of PAH and right heart dysfunction and failure may be an outcome of increasing cardiopulmonary pressures.

Although patients may not be experiencing symptoms, PAH may still be progressing.1

mPAP=mean pulmonary arterial pressure; RAP=right atrial pressure.

Figure reproduced with permission from Klinger JR. J Respir Dis. 2009;30:1-11.

Illustration of the hemodynamic changes associated with disease progression in patients with PAH. PAP and PVR rise while patients are asymptomatic. Further elevation in resistance causes symptoms of exercise limitation, but CO at rest is maintained. In the final stages, PAP may fall even as PVR increases as a result of declining right-sided heart function. The fall in right ventricular systolic function and CO is often heralded by a rise in right ventricular end-diastolic pressure and RAP.3

Are your patients stable? And is stability enough?

Is there any evidence of clinical deterioration? Does your patient meet low-risk criteria?4

In treating PAH, identify risk status and make low risk the goal4

Assessing risk criteria can help determine whether a patient has a good long-term prognosis or if treatment escalation should be considered to reach low-risk status.4

Prognostic evaluation and risk assessment from the 2015 ESC/ERS PAH guidelines4

Determinants of Prognosis*

(Estimated 1-Year Mortality)
Low Risk
(<5%)
Intermediate Risk (5%-10%) High Risk
(>10%)
Clinical signs of right heart failure Absent Absent Present
Progression of symptoms No Slow Rapid
Syncope No Occasional syncope Repeated syncope
WHO FC I, II III IV ESC/ERS risk stratification parameters independently supported by PAH registries4-8
6MWD >440 m 165-440 m <165 m
NT-proBNP plasma levels NT-proBNP <300 ng/L BNP <50 ng/L NT-proBNP 300-1400 ng/L BNP 50-300 ng/L NT-proBNP >1400 ng/L BNP >300 ng/L
Hemodynamics RAP <8 mm Hg Cl ≥2.5 L/min/m2 SvO2 >65% RAP 8-14 mm Hg Cl 2.0-2.4 L/min/m2 SvO2 60%-65% RAP >14 mm Hg Cl <2.0 L/min/m2 SvO2 <60%
Imaging (echocardiography, CMR imaging) RA area <18 cm2
No pericardial effusion
RA area 18-26 cm2
No or minimal pericardial effusion
RA area >26 cm2
Pericardial effusion
  • *Most of the proposed variables and cut-off values are based on expert opinion. They may provide prognostic information and may be used to guide therapeutic decisions, but application to individual patients must be done carefully. One must also note that most of these variables have been validated mostly for idiopathic PAH, and the cut-off levels used above may not necessarily apply to other forms of PAH. Furthermore, the use of approved therapies and their influence on the variables should be considered in the evaluation of the risk.4
  • Occasional syncope during brisk or heavy exercise, or occasional orthostatic syncope in an otherwise stable patient.4
  • Repeated episodes of syncope, even with little or regular physical activity.4

6MWD=6-minute walk distance; BNP=brain natriuretic peptide; CI=cardiac index; CMR=cardiac magnetic resonance; EqCO2=ventilatory equivalent for CO2; ERS=European Respiratory Society; ESC=European Society of Cardiology; FC=functional class; NT-proBNP=N-Terminal pro-brain natriuretic peptide; RA=right atrial; SvO2=mixed venous oxygen saturation; VO2=oxygen consumption; WHO=World Health Organization.

The 2015 ESC/ERS PAH guidelines recommend achieving a low-risk status. Low-risk status is associated with improved prognosis.4

Variables for consideration in PAH risk assessment6,8

1

6MWD

  • Widely used as a primary or secondary endpoint in randomized controlled trials for PAH9
  • Considered an integral tool for patient prognosis and determining therapeutic response4,10
  • 2015 ESC/ERS PAH guidelines recommend targeting a 6MWD threshold of >440 m4
2

Functional Class4

  • Widely used measure of patient functional status
  • 2015 ESC/ERS PAH guidelines recommend targeting FC I/II as a treatment goal
3

CI and RAP4

  • Important indicators of RV function and prognosis in PAH
  • Hemodynamic assessment helps guide therapeutic decisions
  • 2015 ESC/ERS PAH guidelines recommend CI ≥2.5 L/min/m2 and RAP <8 mm Hg
4

NT-proBNP or BNP

  • Indicator of RV function in PAH11
  • A predictor of prognosis in select clinical studies and PAH registries6,8,11
  • 2015 ESC/ERS PAH guidelines recommend NT-proBNP plasma levels of <300 ng/L and BNP of <50 ng/L4

3 observational European PAH registries support the prognostic utility of risk stratification6-8

Parameter SPAHR7 COMPERA6 French PAH Registry8
Overview Swedish observational study (2008-2016)
N=530
European* prospective observational study (2009-2016) N=1588 French retrospective analysis (2006-2016) N=1017
Variables WHO FC, 6MWD, RA area, NT-proBNP, RAP, pericardial effusion, CI, SvO2 WHO FC, 6MWD, NT-proBNP or BNP, RAP, CI, SvO2 WHO/NYHA FC, 6MWD, RAP, CI 6MWD was the most predictive parameter for long-term outcomes6,8
Observed analysis
(Kaplan–Meier)
Overall survival Transplant-free survival
Median follow-up duration 27 months
(range, 11-51)
3 months to
2 years
34 months
(range, 16-56)
  • *European countries included Austria, Belgium, Germany (~80%), Greece, Hungary, Italy, Netherlands, Switzerland, and United Kingdom.6
  • NT-proBNP or BNP and SvO2 were included as an exploratory analysis when data were available.8
  • Follow-up was the first visit with hemodynamics (35%) or, if no hemodynamics were available, the investigators chose the follow-up visit with the most variables recorded.6

COMPERA=Comparative, Prospective Registry of Newly Initiated Therapies for Pulmonary Hypertension; NYHA=New York Heart Association; SPAHR=Swedish PAH Register.

Registry limitations6-8

  • Risk stratification did not account for all variables in 2015 ESC/ERS PAH guidelines
  • Baseline and follow-up assessments were not standardized; therefore, missing follow-up data may have an increased risk of selection bias
  • Enrolled patient populations differed between registries
  • Prospective studies are needed to validate the tested risk parameter panels

Understanding the variables considered in risk assessment and PAH registries may help address disease progression in PAH patients.

Identify risk status and make low-risk the goal.