2021 Volume 85 Issue 4 Pages 343-344
Pulmonary hypertension (PH) is characterized by an increase in pulmonary arterial pressure (PAP) and pulmonary vascular resistance, which causes right ventricular failure and poor outcomes.1 The clinical classification of PH has been updated as follows: Group 1, pulmonary arterial hypertension (PAH); Group 2, PH due to left heart disease; Group 3, PH due to lung diseases and/or hypoxia; Group 4, PH due to pulmonary arterial obstruction, mainly chronic thromboembolic PH (CTEPH); and Group 5, PH with unclear and/or multifactorial mechanisms.2 Lung transplant-free survival in patients has improved significantly in the past decade, especially in Japan.3 This improvement has been attributed, in large part, to pulmonary vasodilator therapy, more specifically the development of PAH-targeted drugs. PAH-targeted therapy consists of several forms of prostanoids, a phosphodiesterase-5 (PDE5) inhibitor or guanylate cyclase stimulator (riociguat) as activators of the nitric oxide-cGMP system, and endothelin receptor antagonists (ERA).3,4 The effect of PAH-targeted therapy in Group 1 PAH patients has been confirmed in terms of improvements in pulmonary hemodynamics, exercise capacity, quality of life, and survival period.3
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Meanwhile, according to the Assessing the Spectrum of Pulmonary hypertension Identified at a REferral centre (ASPIRE) registry, the prognosis of patients with PH due to lung diseases and/or hypoxia (PH with respiratory disease [R-PH]), classified as Group 3 PH, remains poor compared with other forms of PH, especially PAH and CTEPH, although PAH-targeted therapy was introduced to only approximately 47% of the R-PH group in that registry.5 In the R-PH group, the prognosis of patients with interstitial lung disease (ILD) and chronic obstructive pulmonary disease (COPD) was poorer than that of patients with sleep apnea syndrome or alveolar hypoventilation syndrome.5 In several double-blind studies or large trials, exercise capacity or survival in R-PH patients, especially those with ILD, were not improved by PAH-targeted therapies.6 A few studies have demonstrated that PDE5 inhibitors or an ERA improved functional parameters in those with both PH and COPD.7 Nevertheless, the improvement in outcomes in R-PH patients remains one of the most significant unmet needs in the treatment of PH.
PAH-targeted therapy used for R-PH patients is not as effective as that used for PAH, and there are various reasons for this. First, exercise capacity and prognosis in R-PH patients often depend on the severity of background lung disease, including ILD, COPD, combined pulmonary emphysema and fibrosis (CPFE), or other lung parenchymal disease. Second, pulmonary vasodilators may dilate pulmonary arterioles evenly in both lower and higher ventilated alveoli, which, in turn, may lead to increased ventilation-perfusion mismatch.8 This causes worsened systemic arterial hypoxemia, which can lead to poorer final outcomes. One PDE5 inhibitor, namely sildenafil, did not cause ventilation-perfusion mismatch compared with prostaglandin I2 in patients with idiopathic pulmonary fibrosis.8 However, exercise capacity and prognosis of those with ILD (with or without PH) were not improved with sildenafil or riociguat and 2 types of ERAs in large clinical trials.9–12 Therefore, is it futile to use PAH-targeted therapies for R-PH patients?
In this issue of the Journal, Tanabe et al report data from their registry in Japan, a multicenter, prospective study of patients with R-PH that examined real-world characteristics of responders by evaluating demographics, treatment background, and prognosis.13 In this registry, 68% of study subjects underwent PAH-targeted therapies (mainly PDE5 inhibitors). In the mild ventilatory impairment group, which had a forced vital capacity (FVC) >70% predicted and forced expiratory volume in 1 s (FEV1) >60% predicted, survival was better among patients who were initially treated with PAH-targeted therapies than those who were not. Meanwhile, in the severe ventilatory impairment group (FVC <70% predicted or FEV1 <60% predicted), there was no significant difference in survival between those who did and did not undergo initial PAH-targeted therapy. In treatment-naïve R-PH patients with normal pulmonary artery wedge pressure, there was no significant difference in survival between the severe form of PH (mean PAP [mPAP] ≥35 mmHg or cardiac index [CI] <2.5 L/min/m2) and the mild form of PH (mPAP <35 mmHg or CI ≥2.5 L/min/m2). The rates of initial PAH-targeted therapy, survival, and causes of death differed among the 4 patient groups categorized according to the 4 major underlying lung diseases, namely COPD, interstitial pneumonia (IP), IP with connective tissue disease (CTD-IP), and CPFE.13
It remains contentious whether patients with severe PH and mild ventilatory impairment should be categorized as “unproportional” PH due to chronic lung disease or as PAH with coexisting mild lung disease (PAH phenotype).14 Regardless, at the present stage, PAH-targeted therapies for R-PH patients should be carefully considered as limited to those patients with mild ventilatory impairment and lung parenchymal abnormalities on radiological assessment and with relatively severe PH, because those with mild R-PH should first be treated with the management of background lung disease and oxygen supply or ventilation support (more specifically, continuous positive airway pressure or non-invasive positive-pressure ventilation; Table).15
| Mild to moderate PH (mPAP <35 mmHg and CI ≥2.5 L/min/m2) |
Severe PH (mPAP ≥35 mmHg or CI <2.5 L/min/m2) |
|
|---|---|---|
| Mild ventilatory impairment (FVC >70% predicted and FEV1 >60% predicted) and minimal lung parenchymal change on CT |
PAH-targeted therapy may not be recommended, but can be considered under careful follow-up |
PAH-targeted therapy can be carefully considered (as PAH phenotype?) |
| Severe ventilatory impairment (FVC ≤70% predicted or FEV1 ≤60% predicted) or extensive lung parenchymal change on CT |
PAH-targeted therapy may not be recommended |
PAH-targeted therapy may not be recommended, but may be considered in a referral center for both PAH and lung diseases |
| Focus on treating background lung disease and hypoxia |
As the next stage, randomized placebo-controlled studies in each lung disease are needed to assess the efficacy of PAH-targeted therapy for patients with severe PH and mild ventilatory impairment. Similarly, the consideration of managing R-PH patients with severe ventilatory impairment or severe lung parenchymal disease (i.e., CPFE) should be continued by PH and lung disease specialists, and consist of PAH therapy combined with new drugs for refractory lung disease, including antifibrotic agents, bronchodilators, and/or immune modulators. These trials must be performed at referral centers for both PH and lung disease, although it may be difficult to collect the required sample sizes to support statistical power when trials are performed for each main lung disease, including COPD, ILD, CTD-ILD, and CPFE.
The authors declare no conflicts of interest in association with the present article.
