Abstract
Rationale
Severe pulmonary hypertension (PH) is a rare clinically significant complication of COPD. The prognostic relevance of acute pulmonary vasoreactivity is well defined in pulmonary arterial hypertension (PAH) but remains poorly understood in PH-COPD.
Methods
We reported in a retrospective cohort study the clinical, functional and haemodynamic characteristics, the response to PAH-approved drugs, and the overall survival of patients with severe PH-COPD from the French PH National Referral Centre, according to acute pulmonary vasoreactivity testing. The acute vasodilator response was defined as the per cent decrease in pulmonary vascular resistance (PVR) during nitric oxide (NO) testing (ΔPVR post-NO).
Results
42 patients (female/male ratio 0.2, aged 65 (59–71) years) with severe PH-COPD (PVR 7.4 (6.2–9.3) WU, forced expiratory volume in 1 s 61 (50–84)%, diffusing capacity of the lung for carbon monoxide (DLCO) 24 (18–38)%) underwent NO testing at diagnosis. During NO testing, PVR decreased significantly from 7.4 (5.1–9.3) to 6.1 (5.0–8.5) WU (p<0.0001). An acute NO response (ΔPVR post-NO ≥19%) was associated with improved survival at 1, 3 and 5 years (93%, 70% and 61%) compared with patients with ΔPVR post-NO <19% (44%, 38% and 19%; p=0.01). Amongst 28 patients receiving PAH-approved drugs, ΔPVR post-NO correlated with PVR change at first reassessment.
Conclusion
In severe PH-COPD, acute pulmonary vasoreactivity is associated with improved long-term survival and a better response to PAH-approved therapies. Further studies are warranted to confirm that acute NO testing may help identify a specific PH-COPD subgroup likely to benefit from PAH-approved treatment.
Shareable abstract
Among patients with severe pulmonary hypertension associated with COPD, acute pulmonary vasoreactivity identified a subgroup with better haemodynamic response to approved PAH therapies and long-term survival https://bit.ly/4tt1y7h
Introduction
Pulmonary hypertension (PH) is a frequent complication of chronic respiratory diseases, particularly COPD, and is associated with a poor prognosis [1, 2]. PH associated with COPD (PH-COPD) belongs to group 3 of the current PH classification [3]. Most patients with PH-COPD have a mild precapillary PH with a moderate elevation of mean pulmonary artery pressure (mPAP) and pulmonary vascular resistance (PVR). Classically, the severity of PH in these patients has been considered to correlate with the severity of the underlying respiratory disease, but a distinct subgroup of patients develop severe PH, associated with worse survival and defined by the 2022 European Society of Cardiology (ESC)/European Respiratory Society (ERS) PH guidelines as PVR >5 WU [4–6]. The mechanisms underlying severe PH in COPD patients are multiple and remain incompletely understood. Chronic hypoxic pulmonary vasoconstriction appears to be one of the main initial mechanisms, and it has been shown in patients with severe PH that there is an increase in pulmonary arterial remodelling [7–9].
Optimal management strategies for PH-COPD are not yet established. Current recommendations emphasise optimal treatment of COPD and long-term oxygen therapy in cases of chronic hypoxaemia, which has long been known to reduce hypoxic pulmonary vasoconstriction [10]. Patients with severe PH should be referred to expert PH centres for inclusion in clinical trials and registries, as well as consideration for lung transplantation [2]. The use of drugs approved for pulmonary arterial hypertension (PAH) is not recommended in PH-COPD, given largely disappointing results from clinical trials [11, 12]. Nevertheless, it remains uncertain whether specific patient subgroups, particularly those with severe PH, may derive benefit from PAH-approved drugs [13].
In idiopathic PAH, the relative contribution of vascular tone in individual patients is assessed by acute administration of inhaled nitric oxide (NO), which has been labelled as a predictor of the response to calcium channel blockers and survival [14]. However, the prognostic impact of pulmonary vasoreactivity is unknown in severe PH-COPD. We hypothesise that the presence of acute vasoreactivity at diagnosis of severe PH-COPD is a prognostic factor and may influence response to treatment and survival.
Methods
Patient selection
We conducted a retrospective cohort study including severe PH-COPD patients who were followed at the French Pulmonary Hypertension National Referral Centre (Department of Respiratory and Intensive Care Medicine, Hôpital Bicêtre, Le Kremlin-Bicêtre, France). Patients were naive to PAH-approved drugs and had undergone an acute vasodilator testing with NO during their initial haemodynamic evaluation. Clinical, functional and haemodynamic data and outcomes were extracted from the French PH Registry. This registry was set up in agreement with the French Bioethics Law and approved by the Commission Nationale de l'Informatique et des Libertés (CNIL, authorisation no. 842063). All patients provided informed consent prior to inclusion.
All participants met the Global Initiative for Chronic Obstructive Lung Disease (GOLD) diagnostic criteria for COPD [15]. Precapillary PH was confirmed by right heart catheterisation (RHC), according to the latest ESC/ERS guidelines [6]. Severe PH was defined by PVR >5 WU [6]. Patients with pulmonary artery wedge pressure (PAWP) exceeding 15 mmHg were excluded. Individuals with other underlying respiratory diseases or with a predominant cause of PH other than COPD were also excluded from the analysis.
Baseline assessment
We collected variables at time of diagnosis of severe PH confirmed by RHC, including clinical data (demographics, medical history) and dyspnoea assessed by New York Heart Association (NYHA) functional class. Exercise capacity was evaluated by the 6-min walk distance (6MWD). For patients in NYHA class IV unable to perform the test, a distance of 0 m was imputed. Pulmonary function tests included spirometry and diffusion capacity for carbon monoxide corrected for haemoglobin (DLCO). Arterial blood gases were analysed at rest. Brain natriuretic peptide (BNP) and N-terminal pro-brain natriuretic peptide (NT-proBNP) levels were recorded, with abnormal values defined as BNP >50 ng·L−1 or NT-proBNP >300 ng·L−1. Thoracic computed tomography performed at baseline was reviewed for all patients. Haemodynamic data obtained during RHC under the patients’ usual oxygen therapy, included mPAP, PAWP and right atrial pressure (RAP). Cardiac output (CO) was measured by the standard thermodilution technique, and the cardiac index (CI) was calculated as the CO divided by body surface area. PVR was calculated as ((mPAP − PAWP)/CO)).
Inhaled NO vasoreactivity testing
An acute vasoreactivity test with NO was performed during the first RHC (at the time of PH diagnosis) in all patients under the patients’ usual oxygen therapy. With the catheter in the pulmonary artery, patients inhaled 10 parts per million (ppm) of NO via a face mask under a constant air flow of 12 L·min−1 for 5 min associated if needed with usual oxygen level. Haemodynamic measurements were repeated under NO, which was maintained throughout the procedure, as previously described [16].
A positive vasoreactivity response was defined by a decrease in mPAP of at least 10 mmHg to a value <40 mmHg, with an unchanged or increased CO [14]. Relative changes in mPAP (ΔmPAP post-NO) and PVR (ΔPVR post-NO) were calculated as follows: ((mPAP under NO) − mPAP at baseline)/mPAP at baseline) and ((PVR under NO − PVR at baseline)/PVR at baseline) and expressed as percentages.
Follow-up and clinical outcomes
The time to death or lung transplantation was recorded for all patients. Decisions regarding the initiation of PAH-approved drugs, including endothelin receptor antagonists (ERA) and/or phosphodiesterase type 5 inhibitors (PDE5i), were made at the discretion of the treating physician. Follow-up clinical, functional and haemodynamic data were collected at the time of the second RHC (performed during reassessment). For patients treated with PAH-approved drugs who underwent follow-up assessment, relative changes in 6MWD, mPAP, CO, CI and PVR were calculated as (value at reassessment − baseline value)/baseline value.
Statistical analyses
Statistical analyses were performed with GraphPad Prism 9 (GraphPad Software Inc., La Jolla, CA, USA). Given the relatively small sample size, with subgroups of fewer than 30 patients, all variables were assumed to follow a nonparametric distribution. Continuous variables were presented as median (interquartile range, 25th–75th percentile), and categorical variables as counts and percentages.
Comparisons between independent continuous variables were assessed with the Mann–Whitney U-test, and categorical variables with Fisher's exact test. For paired analyses, changes in continuous variables before and after treatment were evaluated using the Wilcoxon signed-rank test, and changes in paired categorical variables with the McNemar test.
Correlations between acute vasoreactivity response (ΔPVR after NO inhalation) and changes in functional or haemodynamic parameters (6MWD, mPAP, CO, CI, PVR) in patients treated with PAH therapies and reassessed were examined using Spearman's rank correlation.
In the absence of a standardised definition, the haemodynamic response to PAH-approved therapy was defined as a reduction of ≥20% in PVR at reassessment and the clinical response was defined as an improvement in 6MWD of ≥33 m and/or an improvement of at least one NYHA functional class (for example, from class III to class II) [17].
A receiver operating characteristic (ROC) curve was generated to determine the optimal ΔPVR after NO inhalation that best discriminated a favourable haemodynamic response to PAH therapy.
Survival was analysed with the Kaplan–Meier method, and survival curves were compared using the log-rank test. A two-sided p-value <0.05 was considered statistically significant.
Results
Clinical and functional characteristics at diagnosis
We identified 42 severe PH-COPD patients who underwent an NO vasoreactivity test at baseline. The cohort was predominantly male (female/male ratio 0.2) with a median age of 65 (59–71) years at diagnosis (table 1). All were current or former smokers. Patients had marked functional impairment, with 34 (81%) patients in NYHA functional class III or IV, and a median 6MWD of 311 (184–380) m.
TABLE 1.
Characteristics of patients with pulmonary hypertension and severe COPD at the time of diagnosis (n=42) and according to whether or not they had a decrease of 19% of pulmonary vascular resistance (PVR) during nitric oxide (NO) inhalation
| All | ΔPVR post-NO ≥19% | ΔPVR post-NO <19% | p-value | |
|---|---|---|---|---|
| Patients, n | 42 | 17 | 25 | |
| Demographic data | ||||
| Age at diagnosis, years | 65 (59–71) | 64 (59–72) | 66 (59–72) | 0.86 |
| Sex, F/M (ratio) | 7/35 (0.2) | 3/14 (0.21) | 4/21 (0.19) | 1 |
| BMI, kg·m−2 | 24.3 (19.2–28.1) | 25.24(21.6–30.3) | 24.2 (18.9–27.0) | 0.28 |
| Smoker or ex-smoker | 42 (100) | 17 (100) | 25 (100) | 1 |
| Pack-years | 40 (38–72) | 40 (40–72) | 40 (30–68) | 1 |
| Functional parameters | ||||
| NYHA functional class | 0.23 | |||
| I–II | 8 (19) | 5 (29) | 3 (12) | |
| III–IV | 34 (81) | 12 (71) | 22 (88) | |
| 6MWD#, m | 311 (184–380) | 283 (179–438) | 311 (160–367) | 0.54 |
| FEV1, % pred | 61 (50–84) | 58 (49–81) | 61 (54–84) | 0.55 |
| FEV1/FVC, % | 59 (44–65) | 46 (35–65) | 62 (56–65) | 0.02 |
| FVC¶, % pred | 97 (72–115) | 103 (75–116) | 88 (68–112) | 0.54 |
| TLC+, % pred | 95 (83–112) | 110 (93–122) | 84 (74–108) | 0.01 |
| DLCO¶, % pred | 24 (18–38) | 31 (19–39) | 23 (17–35) | 0.25 |
| KCO¶, % pred | 28 (22–44) | 33 (22–43) | 28 (21–45) | 0.34 |
| PaO2 on room air§, mmHg | 53 (44–63) | 57 (47–67) | 58 (46–63) | 0.66 |
| PaCO2 on room air§, mmHg | 34 (30–39) | 36 (34–41) | 33 (30–37) | 0.11 |
| Biologic tests | ||||
| Increased BNP/NT-proBNPƒ, % | 31 (84) | 11 (73) | 20 (91) | 0.20 |
| Haemodynamics | ||||
| mPAP, mmHg | 44 (37–51) | 40 (37–51) | 47 (40–53) | 0.16 |
| ΔmPAP post-NO, mmHg | 3 (1–6) | 5 (2–7) | 3 (3–1) | 0.054 |
| PAWP, mmHg | 9 (7–11) | 9 (8–11) | 9 (7–11) | 0.61 |
| RAP, mmHg | 8 (5–10) | 8 (6–11) | 7 (5–11) | 0.54 |
| CO, L·min−1 | 4.6 (3.8–5.3) | 4.5 (3.8–4.9) | 4.6 (3.9–5.5) | 0.37 |
| ΔCO post-NO, L·min−1 | 0.2 (0.01–0.4) | 0.3 (0.1–0.6) | 0.1 (0–0.4) | 0.02 |
| CI, L·min−1·m−2 | 2.5 (2.2–2.8) | 2.4 (2.2–2.7) | 2.6 (2.2–3.0) | 0.21 |
| PVR, WU | 7.4 (6.2–9.3) | 7.0 (6.4–8.7) | 7.8 (6.0–9.8) | 0.56 |
| ΔPVR post-NO, % | 16.2 (9.2–23.5) | 24.0 (22.7–31.2) | 11.5 (3.8–15.5) | |
| ΔPVR post-NO, WU | 1.3 (0.6–2.0) | 2 (1.6–2.7) | 0.8 (0.3–1.3) | |
| SVO2##, % | 61 (57–67) | 64 (58–69) | 60 (56–65) | 0.15 |
| Radiological characteristics on HRCT | ||||
| Emphysemaƒ | 29 (78) | 11 (79) | 18 (79) | 1 |
| Mediastinal lymph node enlargementƒ | 9 (24) | 2 (14) | 7 (30) | 0.43 |
Values are expressed as median (25th–75th percentile) or n (%) unless indicated otherwise. The p-values refer to a comparison between patients with or without a decrease of 19% of pulmonary vascular resistance (PVR) during NO inhalation. ΔPVR post-NO: difference in PVR before and after iNO test; BMI: body mass index; NYHA: New York Heart Association; 6MWD: 6-min walk distance; FEV1: forced expiratory volume in 1s; FVC: forced vital capacity; TLC: total lung capacity; DLCO: diffusing capacity for carbon monoxide corrected for haemoglobin level; KCO: transfer coefficient of the lung for carbon monoxide; PaO2: partial pressure of oxygen in arterial blood; PaCO2: partial pressure of carbon dioxide in arterial blood; BNP: brain natriuretic peptide; NT-proBNP: N-terminal prohormone of brain natriuretic peptide; mPAP: mean pulmonary artery pressure; ΔmPAP post-NO: difference in mPAP before and after iNO test; PAWP: pulmonary artery wedge pressure; RAP: right atrial pressure; CO: cardiac output; CI: cardiac index; SVO2: mixed venous oxygen saturation; HRCT: high-resolution computed tomography. #: n=35; ¶: n=41; +: n=34; §: n=40; ƒ: n=37; ##: n=36.
As per definition, all patients had obstructive ventilatory patterns, defined by a forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC) ratio <0.7. Airflow limitation was mild-to-moderate in 33 patients (FEV1 ≥50% predicted) and severe to very severe in nine patients (FEV1 <50% predicted). Lung volume measurements were normal or only mildly abnormal in most patients. Five patients had lung hyperinflation defined by total lung capacity (TLC) >120% predicted, and five had mild restriction (TLC >50% and <80% predicted). By contrast, diffusing capacity was decreased in all patients, with a median DLCO of 24 (18–38) % predicted. All but two patients were hypoxaemic, with a median partial pressure of oxygen in arterial blood of 53 (44–63) mmHg on room air. Emphysema on high-resolution computed tomography was present in 78% of patients. BNP or NT-proBNP levels were elevated in 83%.
Haemodynamic characteristics at diagnosis and acute vasoreactivity testing
RHC showed severe pre-capillary PH in all patients with a median mPAP of 44 (37–51) mmHg, PAWP 9 (7–11) mmHg, RAP 8 (5–10) mmHg, a CI of 2.5 (2.2–2.8)L·min−1·m−2 and a PVR of 7.4 (6.2–9.3) WU (table 1).
Of the 42 patients, only one fulfilled the classical positivity criteria for vasoreactivity. Overall, NO vasoreactivity test led to a significant reduction in mPAP (44 (37–51) to 42 (36–45) mmHg, −8% (−3% to −12%), p<0.0001, with a decrease in mPAP in 34 out of 42) and in PVR (7.4 (5.1–9.3) to 6.1 (5.0–8.5) WU, −16% (−9% to −23%), p<0.0001, with a decrease in PVR in 39 out of 42) (figure 1).
FIGURE 1.
Change in mean pulmonary artery pressure (mPAP) and pulmonary vascular resistance (PVR) during NO inhalation (NO) in patients with COPD with severe pulmonary hypertension at baseline (n=42). NO led to a reduction in mPAP from 44 (37–51) mmHg to 42 (36–45) mmHg (p<0.0001) and a reduction in PVR from 7.4 (5.1–9.3) WU to 6.1 (5.0–8.5) WU (p<0.0001). ****: p<0.0001.
Response to PAH-approved drugs and long-term outcomes
At the time of PH-COPD diagnosis, 19 (45%) patients were on long-term oxygen therapy, with a median oxygen flow rate of 3 (2–3) L·min−1. After diagnosis, oral PAH-approved drugs (ERA and/or PDE5i) were initiated in 28 patients: 25 received monotherapy and three combination dual therapy (figure 2 and supplementary Table S1). Among these patients, three patients died before reassessment (after 4, 4 and 10 months). Thus, 25 patients were reassessed after the initiation of PAH-approved drugs, with a median time interval of 4 (3–5) months. A significant improvement in haemodynamic parameters (mPAP, CO, CI, PVR) was observed (table 2). At the first reassessment, 15 (60%) had haemodynamic response to PAH-approved drugs and 12 (48%) had clinical response to treatment (two because of improvement of NYHA functional class, seven improvement of 6MWD ≥33 m and three both). There was no correlation between the decrease in PVR at first reassessment and the change in 6MWD (Spearman ρ −0.14 (−0.6–0.4), p=0.6), nor between the decrease in mPAP and the change in 6MWD (Spearman ρ −0.13 (−0.6–0.4), p=0.6).
FIGURE 2.
Flow chart of the study. NO: inhaled nitric oxide; PH-COPD: pulmonary hypertension associated with chronic obstructive pulmonary disease; PAH: pulmonary arterial hypertension.
TABLE 2.
Functional and haemodynamic parameters of patients treated with specific pulmonary arterial hypertension (PAH) treatment, at baseline and at first reassessment (n=25) after a period of 4 (3–5) months
| Baseline | First reassessment | p-value | |
|---|---|---|---|
| Patients, n | 25 | 25 | |
| Functional parameters | |||
| NYHA functional class | 0.26 | ||
| I–II | 3 (12) | 6 (24) | |
| III–IV | 22 (88) | 19 (76) | |
| 6MWD#, m | 311 (200–380) | 298 (180–427) | 0.52 |
| PaO2 on room air¶, mmHg | 51 (44–63) | 47 (45–62) | 0.61 |
| Haemodynamics | |||
| mPAP, mmHg | 48 (40–53) | 41 (34–49) | 0.004 |
| PAWP, mmHg | 9 (4–11) | 11 (7–12) | 0.28 |
| CO, L·min−1 | 4.6 (3.9–5.6) | 5.2 (4.4–6.8) | 0.004 |
| CI, L·min−1·m−2 | 2.5 (2.1–3.0) | 2.8 (2.4–3.5) | 0.01 |
| PVR, WU | 7.4 (6.2–10.6) | 5.6 (4.2–8.4) | 0.0001 |
| PAH-approved drugs | |||
| PDE5i | 15 (60) | ||
| ERA | 7 (28) | ||
| PDE5i+ERA | 3 (12) | ||
Values are expressed as median (25th–75th percentile) or n (%). The p-values refer to a comparison between baseline and the second evaluation. NYHA: New York Heart Association; 6MWD: 6-min walk distance; PaO2: partial pressure of oxygen in arterial blood; mPAP: mean pulmonary artery pressure; PAWP: pulmonary artery wedge pressure; CO: cardiac output; CI: cardiac index; PVR: pulmonary vascular resistance; PDE5i: phosphodiesterase type 5 inhibitors; ERA: endothelin receptor antagonist. #: n=19; ¶: n=16.
Overall prognosis of PH-COPD patients was poor. During follow-up, 36 (86%) patients died, with a median survival time of 27 (10–63) months after diagnosis. Survival rates at 1, 3 and 5 years were 76%, 50% and 33%, respectively. The cause of death was available for 18 patients: 13 due to right heart failure, two sudden deaths, two respiratory failure and one infection.
Impact of acute vasoreactivity testing on outcomes and response to PAH-approved drugs
Baseline ΔPVR post-NO was significantly greater in patients with haemodynamic response to PAH-approved drugs at first reassessment compared with patients without haemodynamic response (–22.6% (–24.0% to −14.3%) versus −11.5% (–17.15 to −1.0%), p=0.01), whereas baseline ΔmPAP post-NO was not (figure 3). In addition, baseline ΔPVR post-NO correlated with the improvement in PVR at first reassessment on PAH-approved drugs (table 3, figure 4). ROC analysis identified a threshold of ΔPVR post-NO of 19%, corresponding to a decrease of 1.4 (1.2–1.8) WU, as the level with the greatest area under the curve to identify a haemodynamic response to PAH drug (sensitivity of 90% and specificity of 60% with an area of 0.79) (supplementary figure S1). ΔmPAP and ΔPVR post-NO were not correlated either with the improvement in 6MWD at reassessment on PAH-approved drugs (table 3). ΔPVR post-NO and ΔmPAP post-NO were not significantly different either in patients with clinical response to PAH-approved drugs (figure 3).
FIGURE 3.
Box plot of change in mean pulmonary artery pressure (mPAP) and pulmonary vascular resistance (PVR) during nitric oxide inhalation (iNO) at baseline in patients with COPD with severe pulmonary hypertension who were then treated with pulmonary arterial hypertension (PAH)-approved drugs and had a reassessment. a) According to haemodynamic response to PAH drug defined by a decrease of 20% in PVR at reassessment (n=25; 15 responders and 10 nonresponders). b) According to clinical response to PAH drug defined by an improvement in 6-min walk distance of ≥33 m and/or an improvement of at least one New York Heart Association functional class (n=25; 12 responders and 13 nonresponders). ∗: p<0.05.
TABLE 3.
Correlations between the decrease of pulmonary vascular resistance (PVR) during NO inhalation (ΔPVR post-NO) at baseline and the evolution at the first reassessment of functional and haemodynamic parameters in the treated patients with PAH-approved drugs (n=25)
| Spearman's ρ (95% confidence interval) | p-value | |
|---|---|---|
| Functional parameters | ||
| Change in 6MWD, % | −0.10 (−0.58–0.43) | 0.7 |
| Haemodynamics | ||
| Change in mPAP, % | 0.08 (−0.35–0.48) | 0.7 |
| Change in CI, % | −0.41 (−0.73–0.05) | 0.07 |
| Change in PVR, % | 0.42 (0.02–0.71) | 0.036 |
6MWD: 6-min walk distance; mPAP: mean pulmonary artery pressure; CI: cardiac index; PVR: pulmonary vascular resistance.
FIGURE 4.
Spearman correlation between ΔPVR post-NO and ΔPVR post-treatment. Scatter plot showing the Spearman correlation between the change in pulmonary vascular resistance (ΔPVR) after nitric oxide inhalation (post-NO) and the change in ΔPVR after treatment by pulmonary arterial hypertension (PAH)-approved drugs at first reassessment (n=25). Each point represents an individual patient. The Spearman ρ was 0.42 (0.02–0.71), p=0.036. NO: inhaled nitric oxide.
Baseline characteristics were largely similar between patients above and below this ΔPVR threshold, except for a higher prevalence of lung hyperinflation among those with ΔPVR ≥19% (table 1).
Among the 28 patients treated with PAH-approved drugs, survival was significantly better in those with ΔPVR post-NO ≥19% compared to those with ΔPVR <19%: 1-, 3- and 5-year survival of 90%, 70% and 50% versus 72%, 50% and 22%, respectively (p=0.04) (figure 5a). In the whole cohort, patients with ΔPVR post-NO ≥19% also had improved survival: 1-, 3- and 5-year survival was 88%, 59% and 47% versus 68%, 44% and 24% for those with ΔPVR <19% (p=0.018) (figure 5b).
FIGURE 5.
Kaplan–Meier survival curves in a) patients treated with specific pulmonary arterial hypertension (PAH)-approved drugs (n=28) and b) the whole population (n=42) whether or not they had a decrease of ≥19% of pulmonary vascular resistance (PVR) during nitric oxide (NO) inhalation.
Discussion
In this study, we showed that the NO vasoreactivity test at baseline led to a significant decrease in PVR in patients with severe PH-COPD and that there was a significant correlation between the ΔPVR post-NO and the improvement in PVR in patients treated with PAH-approved drugs and a better survival in patients with ΔPVR post-NO superior to the threshold of 19%.
Severe PH-COPD patients are known to have a particular phenotype, characterised by a limited decrease in FEV1, a very low DLCO, marked hypoxaemia associated with normocapnia/hypocapnia and a poor prognosis [1, 18–20]. This particular phenotype has led to the hypothesis of a vascular phenotype in PH-COPD and to discuss PAH-approved drugs in some patients. Indeed, PH-COPD results from multiple mechanisms, and the disparity in PH severity between patients remains poorly understood. Hypoxia of lung tissue leads to pulmonary arterial vasoconstriction and gradually induces remodelling of small pulmonary arteries with an increase in muscularisation of the vascular wall that will lead to PH. In addition, chronic pulmonary hypoxia will cause an increase in haematocrit, increasing blood viscosity and the risk of thrombosis [21] as well as chronic pulmonary endothelial dysfunction with decreased endothelial production of vasodilators, and increased secretion of vasoconstrictors [22–24]. There is also the involvement of activation of the sympathetic nervous system, increased oxidative stress, metabolic changes and activation of inflammation [25]. As in PH associated with interstitial lung disease (ILD), a destruction of pulmonary vessels leading to a vascular pruning is also one possible cause of PH, especially in case of associated emphysema [26, 27]. Therefore, it could be a key point to identify these different mechanisms to better phenotype patients with severe PH-COPD.
Pulmonary vasoreactivity is known to participate in the development of PH in COPD and may represent a potential marker of hypoxic vasoconstriction and endothelial dysfunction. A positive NO vasoreactivity test is found in a small subgroup (around 10%) of patients with idiopathic, heritable or drugs-induced PAH, whose primary mechanism of PAH is excessive vasoconstriction, and it is a predictive factor for long-term response to calcium channel blockers, with a real impact on prognosis compared to nonresponders [14, 28–30]. Positive NO vasoreactivity test can sometimes be found in other forms of PH, but it does not predict calcium channel blocker efficiency in these patients and these treatments should not be used [31].
Nevertheless, it could be a valuable measure in the investigation of mechanisms of disease or prognosis in other forms of PH and may be of help in phenotyping patients. For instance, the vasoreactivity test has been realised in patients with chronic thromboembolic PH (CTEPH), and a decrease in mPAP >10.4% after NO was found to be a predictive factor for long-term survival in patients undergoing pulmonary endarterectomy [32]; further, a recent study in 325 patients with CTEPH with vasoreactivity test showed an association between vasoreactivity at baseline and 5-year survival [33]. In PH associated with ILD, one recent study showed that acute vasoreactivity with NO and oxygen was associated with clinical and haemodynamic improvement among 33 patients treated with inhaled treprostinil [34]. Two studies investigated vasoreactivity in patients with PH-COPD. The first one included 29 severe-COPD patients [35]. Unlike in our study, the acute vasoreactivity test was positive in 41%, but the authors did not study the change in PVR during the vasoreactivity test. In agreement with our study, they did not find any demographical, functional or haemodynamic differences between patients with and without vasoreactivity. However, this study did not assess the prognosis impact of acute vasoreactivity [35]. A more recent study included 48 consecutive patients with severe PH associated with lung disease including 19 patients with COPD. Patients were divided into the vasoreactive and nonvasoreactive groups based on the median PVR response (−15%) to NO testing. As in our study they found that among the 36 patients (75%) who initiated pulmonary vasodilators after NO testing, the vasoreactive group demonstrated a significant clinical and haemodynamical improvement at the first follow-up (median 4 months), and a correlation was observed between the change in PVR at NO testing and the change in PVR after initiation of pulmonary vasodilators (r=0.42, p=0.02) [36].
In our study, there was a significant correlation between the ΔPVR post-NO and the improvement in PVR at the first reassessment in patients treated with PAH-approved drugs, suggesting that acute response may be predictive of haemodynamic long-term response to PAH-approved drug. PDE5i and ERA have vasodilator properties and directly target endothelial dysfunction. The best threshold to identify a haemodynamic response with these drugs was a ΔPVR post NO of 19%. It is interesting to note that a decrease of ΔPVR post NO of 20% has been proposed in the past as the definition of response to acute vasoreactivity test in PAH [37]. One hypothesis could be a difference in the predominant mechanism in the development of PH in those with decreased PVR under NO with more vasoreactivity, whereas those without significant decrease of PVR under NO could have more vascular pruning and less vasoreactivity as there are less functional vessels. Although not significant, some differences between the groups treated and not treated by PAH-approved treatments, such as older age, lower transfer coefficient of the lung for carbon monoxide and higher partial pressure of carbon dioxide in arterial blood in the nontreated group, may also have influenced the responses to treatment.
This study has some limitations. First, its retrospective design limits the ability to establish causality, and prospective validation would be required to confirm the prognostic value of ΔPVR post-NO as a predictor of treatment response and survival. Second, the relatively small sample size limited the statistical power of the study. Nevertheless, the cohort was well characterised, and 25 of the 28 treated patients had a complete follow-up with haemodynamic reassessment. Third, although we identified a significant correlation between ΔPVR post-NO and the haemodynamic response following PAH-targeted therapy, defined as a ≥20% reduction in PVR, the clinical relevance of this haemodynamic improvement remains uncertain, and there was no correlation between the haemodynamic improvement and the clinical response. There is also a lack of reliable criteria for defining clinical response.
In conclusion, acute pulmonary vasoreactivity (ΔPVR post-NO ≥19%) identified a subgroup with better haemodynamic response to PAH-approved drugs and long-term survival despite limited changes in clinical end-points. Prospective studies are now required to validate the ΔPVR post-NO threshold and to determine whether an early treatment strategy guided by vasoreactivity improves patient-centred outcomes and risk profiles.
Acknowledgements
We thank all the physicians and members of the French Pulmonary Hypertension Network. We thank Laurence Rottat (Assistance Publique – Hôpitaux de Paris, Department of Respiratory and Intensive Care Medicine, Pulmonary Hypertension National Referral Centre, FHU André Cournand, ERN-LUNG, Bicêtre Hospital, Le Kremlin-Bicêtre, France) for help with data collection.
Footnotes
Provenance: Submitted article, peer reviewed.
Conflict of interest: E-M. Jutant reports grants from Agence Nationale de la Recherche; payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing or educational events from Boehringer, Chiesi, GSK, Merck MSD and AstraZeneca; and support for attending meetings from Janssen and MSD. B. Delarche reports payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing or educational events from Chiesi. M. Croquette reports receiving support for attending meetings from MSD. F. Caron reports payment or honoraria for lectures’, presentations, speakers bureaus, manuscript writing or educational events from GSK, Chiesi, AstraZeneca, CSL-Behring and ADS. M. Riou reports consultancy fees from Ferrer, MSD France and Boehringer Ingelheim; and payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing or educational events from MSD France and Menarini. A. Boucly reports grants from Acceleron, Janssen and MSD; payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing or educational events from Janssen, Merck, AOP Orphan, Ferrer, Gossamer, AstraZeneca and United Therapeutics; and support for attending meetings and/or travel from Janssen, MSD, Ferrer and AOP Orphan. X. Jaïs reports grants from Janssen, Bayer HealthCare; consultancy fees from MSD; and payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing or educational events from MSD. L. Savale reports grants from Acceleron, Janssen and MSD; payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing or educational events Janssen and Merck; and support for attending meetings from Janssen and MSD. O. Sitbon reports grants from AOP Orphan, Ferrer, Gossamer Bio, Janssen and MSD; consultancy fees from AOP Orphan, Ferrer, Gossamer Bio, Janssen, Liquidia, MSD, Pulmovant, Respira Therapeutics and United Therapeutics; payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing or educational events from Aerovate, AOP Orphan, Janssen, Ferrer and MSD; and participation on a data safety monitoring or advisory board for Altavant/Enzyvant, Gossamer Bio and Respira Therapeutics. L. Bertoletti reports grants from Bayer and MSD; consultancy fees from BMS/Pfizer, MSD and Leo-Pharma; payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing or educational events from BMS/Pfizer, MSD and Leo-Pharma; support for attending meetings from BMS/Pfizer, MSD and Leo-Pharma; and participation on a data safety monitoring or advisory board for Bayer. M. Humbert reports grants from Merck and Gossamer; consultancy fees from 35 Pharma, AllRock, AOP Orphan, Chiesi, Ferrer, Gossamer, Inhibikase, Johnson & Johnson, Keros, Liquidia, Merck, Novartis, Regeneron, Respira, Pfizer, Pulmovant and United Therapeutics; payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing or educational events from Merck; participation on a data safety monitoring or advisory board for 35 Pharma, Aerovate, Janssen, Inhibikase, Keros, Merck, Novartis and United Therapeutics. D. Montani is an associate editor of this journal. The remaining authors have nothing to disclose.
Support statement: No funding declared.
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01606-2025.SUPPLEMENT
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