Risk Assessment in Pulmonary Arterial Hypertension

Pulmonary arterial hypertension (PAH) is characterized by elevation of both pulmonary artery pressure (PAP) and pulmonary vascular resistance, caused by vasoconstriction, pulmonary artery remodeling, and thrombosis. Only 30 years ago, PAH was a life-threatening disease and the mortality rate was very high. Now, PAH-targeted drugs are available and could improve hemodynamics, exercise capacity, and long-term survival. A risk assessment of PAH has been considered in guidelines, aimed firstly at evaluating the prognosis of PAH. The latest guideline’s risk assessment is also used for deciding on the treatment strategy.

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The factors for risk assessment are summarized in the Table. Risk assessment was first presented in 2009 by the American College of Cardiology Foundation and the American Heart Association Expert Consensus on pulmonary hypertension.¹ Clinical evidence of right ventricular (RV) failure, progression of symptoms, World Health Organization-functional class (WHO-FC), 6-min walk distance (6MWD), peak oxygen consumption, RV dysfunction by echocardiography, right atrial pressure (RAP), cardiac index (CI), and B-type natriuretic peptide (BNP) were the factors determining a low- or high-risk prognosis. The existence of RV failure, rapid progression, WHO-FC IV, short 6MWD, low maximal oxygen consumption, RAP >20 mmHg, CI <2.0 L/min/m², and high BNP were high-risk factors (=poor prognosis). This risk assessment had some problems. First, it was unclear whether this assessment evaluated short- or long-term prognosis. Second, a moderate-risk group exists in the real world. Based on these problems, a renewed risk assessment was presented in the 2015 guidelines for pulmonary hypertension of the European Society of Cardiology (ESC) and European Respiratory Society (ERS).² Clinical signs of right heart failure, progression of symptoms, syncope, WHO-FC, 6MWD, cardiopulmonary exercise testing (peak oxygen consumption, ventilatory equivalents for carbon dioxide slope), biomarker (BNP/NT-pro BNP), imaging (right atrial area and pericardial effusion) and hemodynamics (RAP, CI, mixed venous oxygen saturation) were factors in assessing the low, intermediate or high risk of 1-year death. Intermediate risk was established and the factors were detailed. However, low-, intermediate-, and high-risk factors can be mixed in the same patient. Additionally, risk assessment was not included in the treatment strategy.

Table.

Risk Assessment of Pulmonary Arterial Hypertension in Guidelines Over Time

Factors	ACCF/AHA 20091	ESC/ERS 20152	ESC/ERS 20223		Ishii et al5
		3-strata	3-strata	4-strata	Modified 3- or 4-strata
Clinical signs of right heart failure	○	○	○
Progression of symptoms	○	○	○
Syncope		○	○
WHO functional class	○	○	○	○	○
6-min walk distance	○	○	○	○	○
Cardiopulmonary exercise testing	○	○	○
Biomarker (BNP/NT-pro BNP)	○	○	○	○	○
Echocardiography		○	○		○ (TAPSE/PASP)
Cardiac MRI		○	○
Hemodynamics	○	○	○		○ (RAP, CI)

ACCF, American College of Cardiology Foundation; AHA, American Heart Association; BNP, B-type natriuretic peptide; CI, cardiac index; ERS, European Respiratory Society; ESC, European Society of Cardiology; NT-pro BNP, N-terminal pro-B-type natriuretic peptide; PASP, pulmonary artery systolic pressure; RAP, right atrial pressure; TAPSE, tricuspid annular plane systolic excursion; WHO, World Health Organization.

In the 2022 ESC/ERS guideline, risk assessment was revisited.³ A 3-strata model of risk assessment at diagnosis and a 4-strata model at follow-up were included in the treatment strategy. In the 3-strata model, each variable is graded from 1 to 3 where 1=‘Low risk’, 2=‘Intermediate risk’, and 3=‘High risk’. Dividing the sum of all grades by the number of available variables for each patient rendered a mean grade, which was rounded off to the nearest integer and used to define the patient’s risk group.⁴ Before the administration of PAH-targeted drugs, the patient is classified as low/intermediate risk or high risk (3-strata model). If low/intermediate risk, initial combination therapy with endothelin-receptor antagonists and phosphodiesterase 5 inhibitors is recommended. If high risk, initial combination therapy with endothelin-receptor antagonists, phosphodiesterase 5 inhibitors, and intravenous or subcutaneous prostacyclin is recommended. At follow-up after administration of PAH-targeted drugs, risk stratification is re-assessed with the 4-strata model (low, intermediate–low, intermediate–high, high risk) using WHO-FC, 6 MWD, and BNP/NT-pro BNP. In this model, each variable is graded from 1 to 4 where 1=‘Low risk’, 2=‘Intermediate–low risk’, 3=‘Intermediate–high risk’, and 4=‘High risk’. If low risk at follow-up, it is recommended to maintain the initial therapy. If intermediate–low, intermediate–high or high risk, addition or switching of other PAH-targeted drugs should be considered. Particularly, lung transplantation should be considered in cases of intermediate–high or high risk.

Risk assessment with the 3-strata model at diagnosis and the 4-strata model at follow-up was validated. However, can a treatment strategy incorporating 3- or 4-strata models be adopted in Japan where the insurance system differs from those in overseas countries? In particular, is it too late to consider lung transplantation when patients are determined to be intermediate–high or high risk, because the number of brain-dead donors is small in Japan and the waiting period is approximately 3 years?

In this issue of the Journal, Ishii et al⁵ investigate the predictive value of current risk assessment in a lung transplantation center. They retrospectively evaluated the validity of a 3-strata model derived from 6 factors (WHO-FC, 6MWD, BNP, tricuspid annular plane systolic excursion (TAPSE)/pulmonary artery systolic pressure (PASP), RAP, CI) and a 4-strata model derived from 3 factors (WHO-FC, 6MWD, BNP) in 52 PAH patients referred for lung transplantation. With the 3-strata model, there was no survival difference among the low-, intermediate-, and high-risk groups. With the 4-strata model, there was no survival difference between the intermediate–low and intermediate–high groups. Therefore, the authors modified the 4-strata risk model as follows; the intermediate-risk group in the 3-strata model of the study was divided into 2 groups based on the median proportion. As a result, the intermediate–high-risk and high-risk groups had worse survival than the low- and intermediate–low-risk groups. Intermediate–high and high risk by the modified risk assessment at referral were significantly associated with all-cause death. The authors conclude that intermediate–high- and high-risk patients by the modified risk model after treatment should be referred for lung transplantation. The difference between the modified 4-strata model and the ESC/ERS guideline’s 4-strata model is the number of factors. The guideline’s 4-strata model consists of WHO-FC, 6MWD, and BNP, which can be evaluated noninvasively and simply, but are not sufficient for risk assessment because of the lack of hemodynamic factors. Sugiyama et al⁶ evaluated whether the treatment strategy for lowering mean PAP is effective and improves survival, using the definition of achieving the therapeutic goal as mean PAP <40 mmHg at follow-up. That goal was achieved in 86%, and the survival rate of patients who achieved the therapeutic goal was significantly better than that of the patients who did not achieve the therapeutic goal. Additionally, their study showed that ESC/ERS risk assessment at baseline and follow-up were not associated with 5-year survival. The modified 4-strata model by Ishii et al includes hemodynamic factors, which contributed to the improved prediction of survival. Although further investigation is needed on assessing the risk of PAH, the modified 4-strata risk assessment of PAH would be useful in Japan where the number of brain-dead donors is small and the waiting period is longer than overseas.

Funding

None.

Disclosure

S.A. have no relationships relevant to the content of this paper to disclose.

References

• 1.   McLaughlin VV, Archer SL, Badesch DB, Barst RJ, Farber HW, Lindner JR, et al. ACCF/AHA 2009 expert consensus document on pulmonary hypertension a report of the American College of Cardiology Foundation Task Force on Expert Consensus Documents and the American Heart Association developed in collaboration with the American College of Chest Physicians; American Thoracic Society, Inc.; and the Pulmonary Hypertension Association. J Am Coll Cardiol 2009; 53: 1573–1619.
• 2.   Galie N, Humbert M, Vachiery JL, Gibbs S, Lang I, Torbicki A, 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.
• 3.   Humbert M, Kovacs G, Hoeper MM, Badagliacca R, Berger RMF, Brida M, et al. 2022 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension. Eur Respir J 2023; 61: 2200879.
• 4.   Kylhammar D, Kjellstrom B, Hjalmarsson C, Jansson K, Nisell M, Soderberg S, et al. A comprehensive risk stratification at early follow-up determines prognosis in pulmonary arterial hypertension. Eur Heart J 2018; 39: 4175–4181.
• 5.   Ishii S, Hatano M, Minatsuki S, Hirose K, Saito A, Yagi H, et al. Comprehensive risk assessment in patients with pulmonary arterial hypertension referred for lung transplantation. Circ J 2024, doi:10.1253/circj.CJ-23-0790.
• 6.   Sugiyama Y, Matsubara H, Shimokawahara H, Ogawa A. Outcome of mean pulmonary arterial pressure-based intensive treatment for patients with pulmonary arterial hypertension. J Cardiol 2022; 80: 432–440.