PULMONARY HYPERTENSION ASSOCIATED WITH CHRONIC OBSTRUCTIVE PULMONARY DISEASE

Pulmonary hypertension (PH) is a known complication of chronic parenchymal lung diseases, including chronic obstructive lung disease, interstitial lung diseases, and more rare parenchymal lung diseases. Together, these diseases encompass two of the five clinical classifications of PH: group 3 (chronic lung disease [CLD] and/or hypoxia) and group 5 (unclear and/or multifactorial mechanisms). The principal management strategy in PH associated with CLD is optimization of the underlying lung disease. There has been increasing interest in therapies that treat pulmonary arterial hypertension (group 1, PAH), and although some studies have explored the use of these oral PAH-targeted therapies to treat PH associated with CLD , there is currently no evidence to support their routine use; in fact, some studies suggest harm. Inhaled therapies that target the pulmonary vasculature may avoid certain problems observed with oral PAH therapies. Recent studies suggest a promising role for inhaled PAH therapies in group 3 PH, but this requires further study. The objective of this article is to review the current treatment strategies for group 3 and group 5 PH. METHODIST DEBAKEY CARDIOVASC J | 17 (2) 2021 REVIEW JOURNAL.HOUSTONMETHODIST. ORG 125 approach for managing COPD-associated PH.8 The pathophysiologic mechanisms of PH in COPD include airflow limitation, hyperinflation and compression of alveolar capillary vessels, alveolar hypoxia, vasoconstriction, and destruction or remodeling in the pulmonary vascular bed, which can all be present in varying degrees, ultimately leading to elevated PVR and mPAP.9-11 Supplemental oxygen therapy remains a key component of COPD management in patients with resting hypoxemia (PaO2 < 60 mm Hg or < 55 mm Hg in the presence of PH) because continuously administered oxygen for at least 18 hours per day has been shown to increase survival, improve PVR and cardiac function, and possibly slow the progressive increase in mPAP.12 Patients with right heart failure and edema may be managed with diuretics and sodium restriction. Due to the poor associated prognosis, moderate-to-severe PH in the setting of COPD is considered a criterion for lung transplantation in otherwise eligible patients.13 There is significant interest in the use of PAH therapies for PH in COPD, particularly in patients with severe PH, defined as mPAP ≥ 35 mm Hg or mPAP ≥ 25 mm Hg with a cardiac index < 2.0 L/min/m2.3,8 Severe PH is rare in COPD and often caused by concomitant left ventricular dysfunction or other pulmonary diseases; however, approximately 1% of cases have severe PH in the absence of another confounding factor. These patients may potentially have a “pulmonary vascular phenotype” of COPD and exhibit severe PH and a cardiovascular limitation to exercise without severe airflow obstruction.14,15 Therefore, pulmonary vasodilator therapies could be of interest in this subgroup population with severe hemodynamic impairment and lower concern for ventilation-perfusion mismatch and hypoxemia, although evidence to support the use of PAH therapies in this context is limited.14-16 Most randomized controlled trials (RCTs) evaluating PAH therapies in COPD-associated PH have tested phosphodiesterase-5 inhibitors (PDE5i), which have mostly demonstrated equivocal results, with no mortality or consistent functional benefit (Table 1). 17-23 An RCT conducted by Vitulo et al. compared sildenafil with placebo to determine the long-term hemodynamic effects of sildenafil in COPD patients with severe PH. They demonstrated a significant reduction in PVR as well as significant improvements in dyspnea and quality of life scores, both of which were secondary outcomes. However, there was no change in PaO2 or 6-minute walk distance (6MWD). 21 A recent meta-analysis by Hao et al. noted modest improvements in 6MWD in patients treated with sildenafil but no change in reported dyspnea or functional symptoms.22 Further studies of sildenafil or other PDE5i would be of interest in the specific subgroups of patients with mild COPD and severe PH. Treatment with endothelin receptor antagonists such as bosentan, ambrisentan, or macitentan is not supported by existing evidence.23,24 Similarly, while studies have been Figure 1. Differentiation between group 1 pulmonary hypertension (PH) and group 3 PH.1 Figure courtesy of authors. COPD: chronic obstructive pulmonary disease; FEV1: forced expiratory volume in 1 second; FVC: forced vital capacity; ILD: interstitial lung disease; PAH: pulmonary arterial hypertension; DLCO: carbon monoxide diffusing capacity test; CPET: cardiopulmonary exercise test 1 Moderate-to-severe PH defined as mean pulmonary arterial pressure ≥ 35 mm Hg, or ≥ 25 mm Hg with a cardiac index < 2.0 L/min/m2 2 Other risk factors include connective tissue disease, portal hypertension, human immunodeficiency virus infection, exposure to definite or probable medications that cause group 1 PH, genetic mutations, congenital heart disease 3 Features of circulatory limitation include preserved breathing reserve, low oxygen pulse, low cardiac output/VO2 slope, no change or decrease in PaCO2 during exercise. Features of ventilatory limitation include low breathing reserve, normal oxygen pulse, normal cardiac output/VO2 slope, increase in PaCO2 during exercise, dynamic hyperinflation. METHODIST DEBAKEY CARDIOVASC J | 17 (2) 2021 REVIEW JOURNAL.HOUSTONMETHODIST. ORG 126 conducted on calcium channel blockers, inhaled nitrous oxide, inhaled and intravenous prostacyclins, and guanylate cyclase stimulators in the context of COPD-associated PH, no studies support their routine use in these patients and they are not approved by regulatory bodies for this indication.3 Inhaled vasodilators have theoretical advantages in terms of avoiding worsening ventilation-perfusion mismatch, but the data are mixed. In patients with COPD and severe PH, inhaled nitric oxide (NO) may actually worsen gas exchange by inhibiting hypoxic vasoconstriction.25,26 Conversely, more recent studies suggest some benefit of NO inhalation on pulmonary vascular function in mild COPD without PH and in patients with PH.27,28 In nonrandomized studies of COPD patients with PH, inhaled iloprost (a prostacyclin analogue) improved hemodynamics and ventilatory efficiency without a detrimental effect on gas exchange.29,30 PULMONARY HYPERTENSION ASSOCIATED WITH INTERSTITIAL LUNG DISEASES As with COPD, the treatment of PH associated with interstitial lung diseases (ILD) consists of optimizing the underlying condition.3 ILD-related PH is most frequently seen in patients with idiopathic pulmonary fibrosis (IPF). The main mechanism of PH in ILD is due to parenchymal fibrosis and vascular bed destruction, although other concomitant factors can exist, including venous thromboembolism, sleep-disordered breathing, and left heart dysfunction with postcapillary PH.31-34 The only approved pharmacologic therapies for treating IPF are the antifibrotic agents pirfenidone and nintedanib, which slow the rate of disease progression but have shown no effect on the development or progression of pulmonary vascular disease. Table 1. Randomized trials of therapies proposed in the management of chronic obstructive pulmonary disease (COPD)-associated pulmonary hypertension (PH). Table courtesy of authors. PDE5: phosphodiesterase type-5; TID: three times a day; sPAP: systolic pulmonary artery pressure; 6MWD: 6-minute walk distance; VO2: oxygen uptake; QoL: quality of life; mPAP: mean pulmonary artery pressure; BNP: brain natriuretic peptide; PVR: pulmonary vascular resistance; WU: Wood units; BODE: body mass index, obstruction, dyspnea, exercise capacity index; CI: cardiac index; SF-36: Short Form 36; BID: twice daily AUTHOR REF N DRUG SEVERITY OF PH FOLLOW-UP PERIOD END POINT(S)