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Achieving low-risk status key to management of pulmonary arterial hypertension

11 May 2020

Management of pulmonary arterial hypertension (PAH) requires regular multidimensional assessments with the aim of achieving a low-risk status, defined as one of the main treatment goals by the joint guideline of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS). The PAH risk assessment tool has been validated and simplified, allowing accurate and streamlined diagnosis and monitoring to improve patient outcomes.

ESC/ERS guideline recommendation

Management of PAH requires multidisciplinary effort involving experts in cardiology, respiratory medicine and imaging, as reflected by the composition of the task force for the ESC/ERS guideline for pulmonary hypertension. [Eur Respir J 2015;46:903-975]

The guideline recommends regular follow-up assessments of PAH severity every 36 months in stable patients. Multidimensional risk assessment is strongly recommended as there is no single variable that can provide sufficient diagnostic and prognostic information to guide therapeutic decisions. WHO functional class, 6-minute walking distance (6MWD), brain natriuretic peptide (BNP) or N-terminal pro-BNP (NT-proBNP) level, and haemodynamic parameters, such as right atrial pressure and cardiac index, are some of the most commonly used variables to assess PAH risk.

The treatment goal of PAH is to achieve or maintain a low-risk profile, which is usually associated with good exercise capacity, good quality of life, good right ventricular function, and a low risk of mortality.

Notably, the guideline recommends the upfront use of combination therapy even in low- or intermediate-risk patients.

Validating ESC/ERS guideline recommendations: Swedish registry

The ESC/ERS guideline-recommended strategy of comprehensive risk assessment and the aim of reaching a low-risk profile were validated in a Swedish real-world observational study. [Eur Heart J 2018;39:4175-4181]

The study included 530 patients from the Swedish PAH Register, who were followed up for a median of 27 months. WHO functional class, 6MWD, and at least one measure of right ventricular function (NT-proBNP level, echocardiography and/or right heart catheterization) were available in 79 percent of patients at baseline and 80 percent at follow-up. The median time from baseline to first follow-up was 4 months.

Among these patients, 23 percent, 67 percent and 10 percent were classified as having a low, intermediate and high risk at baseline, respectively. During follow-up, 29 percent of the patients were classified as being at low risk, while 60 percent and 11 percent were in the intermediate- and high-risk groups, respectively. Low-risk patients were significantly younger than those in the intermediate- and high-risk groups both at baseline and during follow-up.

Overall, survival was significantly longer in patients with a higher proportion of low-risk variables during follow-up. Importantly, the 1-, 3- and 5-year survival rates were significantly different between the baseline risk groups as well as follow-up risk groups. Results also demonstrated a survival advantage associated with achieving a low-risk profile, as patients who remained at or improved to low-risk status had significantly longer survival than those who remained at or worsened to intermediate- or high-risk status. (Figure 1)

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In univariate analysis, patients who were at low risk during follow-up were found to have significant survival benefits vs intermediate- or high-risk patients (hazard ratio [HR], 0.1; 95 percent confidence interval [CI], 0.1 to 0.3; p<0.001). The benefits remained significant (HR, 0.2; 95 percent CI, 0.1 to 0.4; p<0.001) after adjusting for age, gender and PAH subsets in multivariate analysis.

These results support the use of comprehensive risk assessments and the goal-oriented treatment approach of targeting a low-risk profile in PAH, as recommended by the ESC/ERS guidelines.

Simple quantification of low-risk criteria predicts survival

A retrospective study showed that simple quantification of four low-risk criteria (ie, WHO/New York Heart Association [NYHA] functional class III, 6MWD >440 m, right atrial pressure <8 mm Hg, cardiac index ≥2.5 L/min/m2) at diagnosis and after treatment initiation accurately predicted survival in patients with PAH. [Eur Respir J 2017;50:1700889]

The study included 1,017 PAH patients from the French Registry, who were followed up for a median of 34 months and had baseline and re-evaluation WHO/NYHA functional class, 6MWD, right atrial pressure and cardiac index available for analysis.

At diagnosis, 25.5 percent, 36.5 percent, 21 percent, 11 percent and 6 percent of patients fulfilled no, one, two, three and four low-risk criteria, respectively.

At the first re-evaluation after a median of 4.4 months from baseline, larger proportions of patients attained two (27 percent), three (24.5 percent) or four low-risk criteria (17 percent) vs no (9.5 percent) or one low-risk criterion (22 percent). Patients attaining three or four low-risk criteria at follow-up had significantly better long-term prognosis than those attaining only one or two low-risk criteria.

In univariate and multivariate analyses, all low-risk criteria were significantly and independently associated with a reduction in mortality or lung transplantation. Transplant-free survival was significantly different between all low-risk criteria groups at baseline and first re-evaluation.

Notably, patients who had fewer than three low-risk criteria at baseline but improved to three or four low-risk criteria at the time of re-evaluation had similar outcomes compared with those who maintained three or four low-risk criteria from diagnosis to first re-evaluation, while those who had fewer than three low-risk criteria at baseline and follow-up had the worst outcomes.

In a subgroup analysis of 603 patients with BNP or NT-proBNP levels available, the three noninvasive low-risk criteria (ie, BNP level <50 ng/L or NT-proBNP level <300 ng/mL, WHO/NYHA functional class III, 6MWD >440 m) were found to be predictive of transplant-free survival in univariate and multivariate analyses. The haemodynamic variables were no longer significant in multivariate analysis in this subset. (Table) Patients with more of the three noninvasive low-risk criteria had better long-term survival. (Figure 2) Those who had all three noninvasive low-risk criteria had 2-, 3- and 5-year survival rates of 100 percent, 99 percent and 97 percent, respectively.

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 The results suggested that the use of simplified multidimensional risk assessment and an ambitious treatment target of maximizing the number of low-risk criteria could improve long-term prognosis in newly diagnosed PAH patients. The use of noninvasive variables, which would be especially valuable in case of serial follow-up assessments, enabled the identification of patients at very low risk of death or lung transplantation and may obviate the need for routine invasive haemodynamic follow-up assessments in selected patients.

Conclusion

The ESC/ERS guideline recommends multidimensional risk assessment every 36 months in patients with PAH, with achievement of a low-risk status as the treatment goal.

The comprehensive risk assessment and goal-oriented treatment approach were validated in a Swedish real-world study, which showed a survival advantage in patients who had a low-risk profile.

A simplified risk assessment tool comprising four low-risk criteria was shown to be accurate in predicting long-term prognosis in PAH patients. Assessment using three noninvasive variables, which included BNP/NT-proBNP measurements, may provide a reasonable alternative to four-variable assessment in evaluating PAH treatment response in selected patients.

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