Risk assessment in pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension

Abstract

Background: Current pulmonary hypertension treatment guidelines recommend use of a risk stratification model encompassing a range of parameters, allowing patients to be categorised as low, intermediate or high risk. Three abbreviated versions of this risk stratification model were previously evaluated in patients with pulmonary arterial hypertension (PAH) in the French, Swedish and COMPERA registries. Our objective was to investigate the three abbreviated risk stratification methods for patients with mostly prevalent PAH and chronic thromboembolic pulmonary hypertension (CTEPH), in patients from the PATENT-1/2 and CHEST-1/2 studies of riociguat.

Methods: Risk was assessed at baseline and at follow-up in PATENT-1 and CHEST-1. Survival and clinical worsening-free survival were assessed in patients in each risk group/strata.

Results: With all three methods, riociguat improved risk group/strata in patients with PAH after 12 weeks. The French non-invasive and Swedish/COMPERA methods discriminated prognosis for survival and clinical worsening-free survival at both baseline and follow-up. Furthermore, patients achieving one or more low-risk criteria or a low-risk stratum at follow-up had a significantly reduced risk of death and clinical worsening compared with patients achieving no low-risk criteria or an intermediate-risk stratum. Similar results were obtained in patients with inoperable or persistent/recurrent CTEPH.

Conclusions: This analysis confirms and extends the results of the registry analyses, supporting the value of goal-oriented treatment in PAH. Further assessment of these methods in patients with CTEPH is warranted.

FIGURE 1

Proportion of patients in each risk stratum at baseline and follow-up receiving a) riociguat and b) placebo in PATENT-1, and receiving c) riociguat and d) placebo in CHEST-1, according to the three abbreviated versions of the European Society of Cardiology (ESC)/European Respiratory Society (ERS) risk stratification model. Data may not add up to 100% due to rounding. Only patients who participated in PATENT-2 and CHEST-2 were included in the analysis. The analysis is based on observed data with no imputation. French registry invasive method: number of low-risk criteria fulfilled: 6-min walk distance (6MWD) >440 m, World Health Organization (WHO) functional class (FC) I/II, right atrial pressure (RAP) <8 mmHg and cardiac index ≥2.5 L·min⁻¹·m⁻². French registry non-invasive method: number of low-risk criteria fulfilled: 6MWD >440 m, WHO FC I/II and N-terminal pro-brain natriuretic peptide (NT-proBNP) <300 pg·mL⁻¹. Swedish/COMPERA method: mean of grades (1–3: low, intermediate, high) of six available criteria (6MWD, WHO FC, NT-proBNP, RAP, cardiac index and mixed venous oxygen saturation) as defined in the ESC/ERS 2015 treatment guidelines, rounded to the nearest integer.

FIGURE 2

Forest plots comparing survival in PATENT-2 expressed as hazard ratios (95% CI) for mortality comparing patients who achieved one or more low-risk criteria compared with those who achieved no low-risk criteria at a) baseline and b) follow-up in PATENT-1, and clinical worsening-free survival in PATENT-2 expressed as hazard ratios (95% CI) for clinical worsening comparing patients who achieved one or more low-risk criteria compared with those who achieved no low-risk criteria at c) baseline and d) follow-up in PATENT-1. Only patients receiving riociguat 2.5 mg three times daily maximum in PATENT-1 who participated in PATENT-2 were considered in this analysis. French registry invasive method: number of low-risk criteria fulfilled: 6-min walk distance (6MWD) >440 m, World Health Organization (WHO) functional class (FC) I/II, right atrial pressure (RAP) <8 mmHg and cardiac index ≥2.5 L·min⁻¹·m⁻². French registry non-invasive method: number of low-risk criteria fulfilled: 6MWD >440 m, WHO FC I/II and N-terminal pro-brain natriuretic peptide (NT-proBNP) <300 pg·mL⁻¹. Swedish/COMPERA method: mean of grades (1–3: low, intermediate, high) of six available criteria (6MWD, WHO FC, NT-proBNP, RAP, cardiac index and mixed venous oxygen saturation) as defined in the European Society of Cardiology/European Respiratory Society 2015 treatment guidelines, rounded to the nearest integer. ^#: due to the small number of patients in the high-risk category at baseline and follow-up according to the Swedish/COMPERA method, these patients were not included in this analysis. Due to no or few events in some risk groups/strata, hazards ratios could not be calculated in some cases.

FIGURE 3

Kaplan–Meier curves for survival in patients based on risk stratification at PATENT-1 follow-up: a) French registry invasive method, b) French registry non-invasive method and c) Swedish/COMPERA method. Only patients receiving riociguat 2.5 mg three times daily maximum in PATENT-1 who participated in PATENT-2 were considered in this analysis. Data were based on observed cases with no imputation. Day 0=start of extension study. Only three patients were in the Swedish/COMPERA high-risk group at PATENT-1 follow-up and were therefore not included in the analysis for this method. French registry invasive method: number of low-risk criteria fulfilled: 6-min walk distance (6MWD) >440 m, World Health Organization (WHO) functional class (FC) I/II, right atrial pressure (RAP) <8 mmHg and cardiac index ≥2.5 L·min⁻¹·m⁻². French registry non-invasive method: number of low-risk criteria fulfilled: 6MWD >440 m, WHO FC I/II and N-terminal pro-brain natriuretic peptide (NT-proBNP) <300 pg·mL⁻¹. Swedish/COMPERA method: mean of grades (1–3: low, intermediate, high) of six available criteria (6MWD, WHO FC, NT-proBNP, RAP, cardiac index and mixed venous oxygen saturation) as defined in the European Society of Cardiology/European Respiratory Society 2015 treatment guidelines, rounded to the nearest integer. Log-rank test: invasive p=0.5595, non-invasive p=0.0126 and Swedish/COMPERA p=0.0099. LTE: long-term extension.

FIGURE 4

Kaplan–Meier curves for clinical worsening-free survival in patients based on risk stratification at PATENT-1 follow-up: a) French registry invasive method, b) French registry non-invasive method and c) Swedish/COMPERA method. Only patients receiving riociguat 2.5 mg three times daily maximum in PATENT-1 who participated in PATENT-2 were considered in this analysis. Data were based on observed cases with no imputation. Day 0=start of extension study. Only three patients were in the Swedish/COMPERA high-risk group at PATENT-1 follow-up and were therefore not included in the analysis for this method. French registry invasive method: number of low-risk criteria fulfilled: 6-min walk distance (6MWD) >440 m, World Health Organization (WHO) functional class (FC) I/II, right atrial pressure (RAP) <8 mmHg and cardiac index ≥2.5 L·min⁻¹·m⁻². French registry non-invasive method: number of low-risk criteria fulfilled: 6MWD >440 m, WHO FC I/II and N-terminal pro-brain natriuretic peptide (NT-proBNP) <300 pg·mL⁻¹. Swedish/COMPERA method: mean of grades (1–3: low, intermediate, high) of six available criteria (6MWD, WHO FC, NT-proBNP, RAP, cardiac index and mixed venous oxygen saturation) as defined in the European Society of Cardiology/European Respiratory Society 2015 treatment guidelines, rounded to the nearest integer. Log-rank test: invasive p=0.0078, non-invasive p=0.0001 and Swedish/COMPERA p=0.0023. LTE: long-term extension.

FIGURE 5

Kaplan–Meier curves for survival in patients based on risk stratification at CHEST-1 follow-up: a) French registry invasive method, b) French registry non-invasive method and c) Swedish/COMPERA method. Only patients receiving riociguat 2.5 mg three times daily maximum in CHEST-1 who participated in CHEST-2 were considered in this analysis. Data were based on observed cases with no imputation. Day 0=start of extension study. Only five patients were in the Swedish/COMPERA high-risk group at CHEST-1 follow-up and were therefore not included in the analysis for this method. French registry invasive method: number of low-risk criteria fulfilled: 6-min walk distance (6MWD) >440 m, World Health Organization (WHO) functional class (FC) I/II, right atrial pressure (RAP) <8 mmHg and cardiac index ≥2.5 L·min⁻¹·m⁻². French registry non-invasive method: number of low-risk criteria fulfilled: 6MWD >440 m, WHO FC I/II and N-terminal pro-brain natriuretic peptide (NT-proBNP) <300 pg·mL⁻¹. Swedish/COMPERA method: mean of grades (1–3: low, intermediate, high) of six available criteria (6MWD, WHO FC, NT-proBNP, RAP, cardiac index and mixed venous oxygen saturation) as defined in the European Society of Cardiology/European Respiratory Society 2015 treatment guidelines, rounded to the nearest integer. Log-rank test: invasive p<0.0001, non-invasive p=0.0231 and Swedish/COMPERA p<0.0001. LTE: long-term extension.

FIGURE 6

Kaplan–Meier curves for clinical worsening-free survival in patients based on risk stratification at CHEST-1 follow-up: a) French registry invasive method, b) French registry non-invasive method and c) Swedish/COMPERA method. Only patients receiving riociguat 2.5 mg three times daily maximum in CHEST-1 who participated in CHEST-2 were considered in this analysis. Data were based on observed cases with no imputation. Day 0=start of extension study. Only five patients were in the Swedish/COMPERA high-risk group at CHEST-1 follow-up and were therefore not included in the analysis for this method. French registry invasive method: number of low-risk criteria fulfilled: 6-min walk distance (6MWD) >440 m, World Health Organization (WHO) functional class (FC) I/II, right atrial pressure (RAP) <8 mmHg and cardiac index ≥2.5 L·min⁻¹·m⁻². French registry non-invasive method: number of low-risk criteria fulfilled: 6MWD >440 m, WHO FC I/II and N-terminal pro-brain natriuretic peptide (NT-proBNP) <300 pg·mL⁻¹. Swedish/COMPERA method: mean of grades (1–3: low, intermediate, high) of six available criteria (6MWD, WHO FC, NT-proBNP, RAP, cardiac index and mixed venous oxygen saturation) as defined in the European Society of Cardiology/European Respiratory Society 2015 treatment guidelines, rounded to the nearest integer. Log-rank test: invasive p<0.0001, non-invasive p<0.0001 and Swedish/COMPERA p<0.0001. LTE: long-term extension.

FIGURE 7

Forest plots comparing survival in CHEST-2 expressed as hazard ratios (95% CI) for mortality comparing patients who achieved one or more low-risk criteria compared with those who achieved no low-risk criteria at a) baseline and b) follow-up in CHEST-1, and clinical worsening-free survival in CHEST-2 expressed as hazard ratios (95% CI) for clinical worsening comparing patients who achieved one or more low-risk criteria compared with those who achieved no low-risk criteria at c) baseline and d) follow-up in CHEST-1. Only patients receiving riociguat 2.5 mg three times daily maximum in CHEST-1 who participated in CHEST-2 were considered in this analysis. French registry invasive method: number of low-risk criteria fulfilled: 6-min walk distance (6MWD) >440 m, World Health Organization (WHO) functional class (FC) I/II, right atrial pressure (RAP) <8 mmHg and cardiac index ≥2.5 L·min⁻¹·m⁻². French registry non-invasive method: number of low-risk criteria fulfilled: 6MWD >440 m, WHO FC I/II and N-terminal pro-brain natriuretic peptide (NT-proBNP) <300 pg·mL⁻¹. Swedish/COMPERA method: mean of grades (1–3: low, intermediate, high) of six available criteria (6MWD, WHO FC, NT-proBNP, RAP, cardiac index and mixed venous oxygen saturation) as defined in the European Society of Cardiology/European Respiratory Society 2015 treatment guidelines, rounded to the nearest integer. ^#: due to the small number of patients in the high-risk category at baseline and follow-up according to the Swedish/COMPERA method, these patients were not included in this analysis. Due to no or few events in some risk groups/strata, hazards ratios could not be calculated in some cases.