**5. COPD and PH**

There is a growing body of evidence supporting different phenotypes among patients with COPD. These COPD phenotypes may be useful in defining patients who may benefit from particular therapies or interventions more than others. Potential phenotypes may be defined by symptoms, physiology, radiology and exacerbation history, although the relevant clinical outcomes have not been defined [33].

A PH phenotype in COPD is potentially defined by perceivable effects on functional perform‐ ance status and mortality [5]. PH is an independent prognostic factor in COPD [34-36]. The current accepted definition of PH in COPD is a mean PAP ≥ 25mmHg with underlying hypoxia. PH ideally should be measured by right heart catheterization, which may not be feasible in many cases. As an alternative, Doppler echocardiographic measurements have been used in a number of studies, although Doppler can be technically challenging due to body habitus and poor acoustic windows, precluding detection of a significant left heart pathology, which may also contribute to elevated pulmonary pressures [37]. Scharf et al. in a study of patients with severe COPD, reported over 60% of subjects had elevated pulmonary capillary wedge pressures [7]. The impact of PH on mortality in COPD is independent of age, lung function and blood gas derangements [5].

therapy (LTOT) and pulmonary rehabilitation [43]. Symptomatic (non-disease modifying) therapy for COPD-related PH includes LTOT, peripherally-acting calcium channel blockers and non-pharmacological interventions such as activity pacing and relaxation therapies.

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The only therapy that has demonstrated a survival advantage in people with COPD and coexistent PH is LTOT. Indications for LTOT include patients with severe hypoxemia or those with moderate hypoxemia and cor pulmonale [44-46], as it reduces pulmonary artery pressure

LTOT is, however, relatively cumbersome and intrusive, with variable patient adherence. Patients with the most severe COPD have the least reduction in PH with LTOT [44,46]. Patients will often be concerned about the imposition of being physically reliant on a machine [48]. LTOT is also expensive, and may be associated with a small number of very serious adverse events across the community, such as CO2 retention or burns, particularly where patients continue to smoke [49-51]. Actual adherence rates to LTOT are not precisely known and reports

PAH includes idiopathic disease and disease secondary to connective tissue disorders such as scleroderma and systemic lupus erythematosus. Current evidence points to the benefits of prostanoids, endothelin antagonists and phosphodiasterase-5 (PDE-5) inhibitors as disease

Given the evidence from PAH, it is plausible that in PH secondary to COPD pulmonary vasodilatation may improve the subjective sensation of dyspnoea and extend exercise endurance. Pulmonary vasodilator treatment (alone or as an adjunct to oxygen supplementa‐ tion) might be useful to reduce dyspnoea and improve quality of life (QOL) in people with COPD and secondary pulmonary hypertension. Potentially, if these interventions were of benefit, improved physical independence, symptomatic control of dyspnoea and potentially

Epoprostenol sodium is indicated for patients with idiopathic, heritable or connective tissue disease related PAH (Group 1) as a continuous infusion [54]. Iloprost is a prostacyclin analogue that can be administered orally, intravenously or as an aerosolised formulation [55]. These have been shown to improve exercise tolerance and haemodynamic parameters in patients

However, evidence for the use of prostacyclin analogues in COPD-related PH is very limited and current practice does not favour routine use of these medications. The primary concern in using pulmonary vasodilators is related to worsening gas exchange due to ventilation/

**6.1. Long-term home oxygen therapy**

vary between 45 - 70% [52,53].

modifying in these people [2].

**6.3. Prostanoids**

with PAH.

perfusion (V/Q) inequality [5].

even extended survival could be achieved.

**6.2. Evidence from pulmonary arterial hypertension**

[44,47].

PH has been associated with exercise limitation in patients with COPD. In a study of 362 pretransplant patients with COPD, PH (mean PAP ≥25mmHg) was associated with shorter 6 minute walking distance (6MWD) after adjustments for demographics and lung function [38]. In a large retrospective study of COPD patients studied with right heart catheterization, PAP had an inverse relationship with 6MWD [6]. A much smaller study of 29 COPD patients assessed with Doppler echocardiography could not detect statistically significant differences in cardiopulmonary exercise test parameters and 6MWD in patients with or without PH. However, the authors acknowledged that the small sample size and lack of invasive measures could restrict the generalisation of the results [39].

In patients with parenchymal lung disease PH is generally modest (mean PAP 25-35 mmHg). While PAP at rest varies from normal to moderately elevated, it increases significantly during exercise, sleep and acute infective exacerbations. Hilde et al. in a study of 98 patients with COPD undergoing right heart catheterization reported a 27% prevalence of PH. Hemodynamic response to exercise, including mean PAP, was abnormal and similar between the PH and non-PH COPD patients [40].

In some patients with COPD PAP elevations can be more substantial (mean PAP ≥35mmHg). In patients with only moderate pulmonary mechanical impairment, this is considered "out-ofproportion" PH. A subset of COPD patients has been identified where progressive PH has prognostic implications. The term "PH out-of-proportion to COPD" has been applied to this group of patients. An unusual pattern of cardiopulmonary abnormalities has been described in the patients with more severe PH, including mild to moderate airway obstruction, severe hypoxemia, hypocapnia, and a very low diffusing capacity for carbon monoxide. The charac‐ teristics of this subset include the presence of obstructive airways disease and presence of fibrosis. A relative preservation of lung function and severe PH in COPD is believed to define this "vascular phenotype" [5]. Thabut et al. in a cluster analysis identified a subgroup of COPD patients with out-of-proportion PH associated with severe hypoxia [41]. Chaouat et al. also identified a similar cluster [42]. The challenge remains, however, to have uniformly applied definition of PH in COPD. As with PH out-of-proportion to left heart disease, large random‐ ized, controlled, studies of medications approved for PAH are not available for PH out-ofproportion for parenchymal lung disease.

## **6. Treatment of PH in COPD**

Although treatment of PH in COPD is conceptually appealing, there are no clear guidelines and no medications currently registered for the treatment of PH secondary to COPD. The primary focus of treatment, therefore, even in the vascular phenotype of COPD involves standard therapy with smoking cessation, bronchodilators, inhaled steroids, long-term oxygen therapy (LTOT) and pulmonary rehabilitation [43]. Symptomatic (non-disease modifying) therapy for COPD-related PH includes LTOT, peripherally-acting calcium channel blockers and non-pharmacological interventions such as activity pacing and relaxation therapies.

#### **6.1. Long-term home oxygen therapy**

also contribute to elevated pulmonary pressures [37]. Scharf et al. in a study of patients with severe COPD, reported over 60% of subjects had elevated pulmonary capillary wedge pressures [7]. The impact of PH on mortality in COPD is independent of age, lung function

PH has been associated with exercise limitation in patients with COPD. In a study of 362 pretransplant patients with COPD, PH (mean PAP ≥25mmHg) was associated with shorter 6 minute walking distance (6MWD) after adjustments for demographics and lung function [38]. In a large retrospective study of COPD patients studied with right heart catheterization, PAP had an inverse relationship with 6MWD [6]. A much smaller study of 29 COPD patients assessed with Doppler echocardiography could not detect statistically significant differences in cardiopulmonary exercise test parameters and 6MWD in patients with or without PH. However, the authors acknowledged that the small sample size and lack of invasive measures

In patients with parenchymal lung disease PH is generally modest (mean PAP 25-35 mmHg). While PAP at rest varies from normal to moderately elevated, it increases significantly during exercise, sleep and acute infective exacerbations. Hilde et al. in a study of 98 patients with COPD undergoing right heart catheterization reported a 27% prevalence of PH. Hemodynamic response to exercise, including mean PAP, was abnormal and similar between the PH and non-

In some patients with COPD PAP elevations can be more substantial (mean PAP ≥35mmHg). In patients with only moderate pulmonary mechanical impairment, this is considered "out-ofproportion" PH. A subset of COPD patients has been identified where progressive PH has prognostic implications. The term "PH out-of-proportion to COPD" has been applied to this group of patients. An unusual pattern of cardiopulmonary abnormalities has been described in the patients with more severe PH, including mild to moderate airway obstruction, severe hypoxemia, hypocapnia, and a very low diffusing capacity for carbon monoxide. The charac‐ teristics of this subset include the presence of obstructive airways disease and presence of fibrosis. A relative preservation of lung function and severe PH in COPD is believed to define this "vascular phenotype" [5]. Thabut et al. in a cluster analysis identified a subgroup of COPD patients with out-of-proportion PH associated with severe hypoxia [41]. Chaouat et al. also identified a similar cluster [42]. The challenge remains, however, to have uniformly applied definition of PH in COPD. As with PH out-of-proportion to left heart disease, large random‐ ized, controlled, studies of medications approved for PAH are not available for PH out-of-

Although treatment of PH in COPD is conceptually appealing, there are no clear guidelines and no medications currently registered for the treatment of PH secondary to COPD. The primary focus of treatment, therefore, even in the vascular phenotype of COPD involves standard therapy with smoking cessation, bronchodilators, inhaled steroids, long-term oxygen

and blood gas derangements [5].

26 Pulmonary Hypertension

PH COPD patients [40].

could restrict the generalisation of the results [39].

proportion for parenchymal lung disease.

**6. Treatment of PH in COPD**

The only therapy that has demonstrated a survival advantage in people with COPD and coexistent PH is LTOT. Indications for LTOT include patients with severe hypoxemia or those with moderate hypoxemia and cor pulmonale [44-46], as it reduces pulmonary artery pressure [44,47].

LTOT is, however, relatively cumbersome and intrusive, with variable patient adherence. Patients with the most severe COPD have the least reduction in PH with LTOT [44,46]. Patients will often be concerned about the imposition of being physically reliant on a machine [48]. LTOT is also expensive, and may be associated with a small number of very serious adverse events across the community, such as CO2 retention or burns, particularly where patients continue to smoke [49-51]. Actual adherence rates to LTOT are not precisely known and reports vary between 45 - 70% [52,53].

#### **6.2. Evidence from pulmonary arterial hypertension**

PAH includes idiopathic disease and disease secondary to connective tissue disorders such as scleroderma and systemic lupus erythematosus. Current evidence points to the benefits of prostanoids, endothelin antagonists and phosphodiasterase-5 (PDE-5) inhibitors as disease modifying in these people [2].

Given the evidence from PAH, it is plausible that in PH secondary to COPD pulmonary vasodilatation may improve the subjective sensation of dyspnoea and extend exercise endurance. Pulmonary vasodilator treatment (alone or as an adjunct to oxygen supplementa‐ tion) might be useful to reduce dyspnoea and improve quality of life (QOL) in people with COPD and secondary pulmonary hypertension. Potentially, if these interventions were of benefit, improved physical independence, symptomatic control of dyspnoea and potentially even extended survival could be achieved.

#### **6.3. Prostanoids**

Epoprostenol sodium is indicated for patients with idiopathic, heritable or connective tissue disease related PAH (Group 1) as a continuous infusion [54]. Iloprost is a prostacyclin analogue that can be administered orally, intravenously or as an aerosolised formulation [55]. These have been shown to improve exercise tolerance and haemodynamic parameters in patients with PAH.

However, evidence for the use of prostacyclin analogues in COPD-related PH is very limited and current practice does not favour routine use of these medications. The primary concern in using pulmonary vasodilators is related to worsening gas exchange due to ventilation/ perfusion (V/Q) inequality [5].

### **6.4. Endothelin receptor antagonists (ERA)**

Bosentan, an oral endothelin-1 receptor antagonist is registered for use in patients with PAH in World Health Organisation (WHO) functional classes (FC) II-IV. It has been shown to reduce pulmonary vascular resistance and moderately improve exercise tolerance in people with mildly symptomatic disease. Hepatotoxicity and teratogenicity are potential toxicities [56]. Ambrisentan has been approved for PAH in WHO FC II-IV and has been shown to delay disease progression and improve exercise tolerance in patients with PAH with lower levels of hepatotoxicity [57].

Reports of worsening ventilation / perfusion (V/Q) inequality [70,71], a lack of long-term effectiveness (or development of tolerance) [72,73] and the high incidence of side effects [73] have raised doubts about the benefits of a non-selective vasodilator treatment in COPD.

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29

Calcium channel blockers of the dihydropyridine group are the most extensively studied vasodilators in both PAH and PH secondary to COPD [70-85]. However, the non-selective vasodilator properties of these drugs give frequent systemic side effects (e.g. ankle oedema, headache, facial flushing), preventing their wider use in the COPD population. Their use is

In an earlier study by our group, felodipine, a non-selective dihydropyridine calcium channel blocker, significantly improved pulmonary haemodynamics in patients with COPD and PH [83]. Pulmonary vasodilatation in these patients was sustained for 3 months of treatment, without development of tolerance or deterioration in gas exchange, although a high incidence of vasodilator side effects was observed. A subsequent study by our group showed that amlodipine was as effective as felodipine in improving pulmonary haemodynamics in patients with COPD, with fewer side effects than felodipine [84]. One small randomised placebocontrolled trial in patients with COPD and PH reported significant improvement of the dyspnoea score and preserved cardiac output with nifedipine for one year, although there was no significant survival benefit [85]. This supports the hypothesis that pulmonary vasodilata‐ tion in patients with severe COPD and PH may improve their functional performance, dyspnoea and QOL, particularly if systemic vasodilatation side effects can be avoided.

An important practice point is that alternative causes of PH in patients with COPD, such as concomitant sleep disordered breathing or chronic thromboembolic disease should be actively

True prevalence of PH in OSA is unknown and ranges from 17 - 52% [86]. In our study of 27 patients with OSA 11 (41%) had mildly elevated PA pressures, mean PAP = 26 mmHg, in the

OSA patients maintain normal daytime oxygenation but experience episodic hypoxic events during sleep. Acute rises in PAP with sleep-disordered breathing have an inverse relationship with the degree of oxygen desaturation. Pulmonary artery pressure is influenced by an obstructive sleep apnoea cycle associated with changes to intra-thoracic pressure with the changes most marked in REM sleep [87]. Three main mechanisms have been proposed including hypoxia, mechanical factors and reflex mechanisms [16]. However, there are conflicting data to support these proposed mechanisms. It has been observed that changes in PA pressure were inversely correlated with the degree of arterial hypoxia [88, 89] while in

another study supplemental oxygen did not affect pulmonary artery pressures [90].

Our understanding of the relationship between OSA and PH is evolving following recent studies. Twenty patients with OSA were treated for 4 months with CPAP and a decrease in

investigated, as there are important treatment alternatives in these patients.

**7. Sleep disordered breathing and PH**

absence of cardiac or pulmonary disease [14].

largely limited to patients who demonstrate acute vasoreactivity testing [73].

Trials with endothelin receptor antagonists in patients with COPD and PH have suffered from poor study design and the general trend was worsening gas exchange without improvement in functional capacity.

#### **6.5. Phosphodiesterase-5 (PDE-5) inhibitors**

Sildenafil is a selective inhibitor of PDE-5, an enzyme that is specific for both lung and penile vasculature. Although originally developed for treatment of erectile dysfunction, sildenafil is an effective pulmonary vasodilator [58-60]. PDE-5 is found throughout the muscularized pulmonary vascular tree, including in newly muscularized distal pulmonary arteries exposed to hypoxia.

Sildenafil may be preferred to other vasodilator agents, particularly in patients with severe COPD, PH and poor RV function, because hemodynamic effects are likely to be selective on the pulmonary circulation. PDE-5 inhibition with sildenafil attenuates the rise in PAP and vascular remodelling when given before chronic exposure to hypoxia and when administered as a treatment during ongoing hypoxia-induced PH [61].

Previous trials in patients with PAH (primary or associated with scleroderma) showed that sildenafil-induced pulmonary vasodilatation is well tolerated, increased exercise capacity, decreased Borg dyspnoea index and WHO functional class and improved haemodynamics [62,63]. Therefore, it has been proposed to consider the use of this medication in selected patients with COPD-related PH, although clinical trials in this group are limited.

A recent randomized trial in 20 patients with COPD-associated PH demonstrated that sildenafil improved pulmonary haemodynamics both at rest and during exercise, with mild to moderate worsening of gas exchange at rest due to worsening V/Q mismatch [64]. A longer duration of 3 months treatment with sildenafil did not significantly alter hemodynamic or functional capacity [65]. A more recent cross-over trial of sildenafil and placebo in COPDrelated PH showed significant worsening of gas exchange at rest and quality of life indices with no beneficial effect on exercise capacity [66].

#### **6.6. Calcium channel blockers**

Theadministrationofvasodilatordrugshasbeenproposedasanalternativeoradjuncttooxygen supplementationinthe treatmentofPHinCOPDforanumberofyears.However,there remains considerable controversy regarding the likely benefits of non-selective vasodilators [67-69]. Reports of worsening ventilation / perfusion (V/Q) inequality [70,71], a lack of long-term effectiveness (or development of tolerance) [72,73] and the high incidence of side effects [73] have raised doubts about the benefits of a non-selective vasodilator treatment in COPD.

Calcium channel blockers of the dihydropyridine group are the most extensively studied vasodilators in both PAH and PH secondary to COPD [70-85]. However, the non-selective vasodilator properties of these drugs give frequent systemic side effects (e.g. ankle oedema, headache, facial flushing), preventing their wider use in the COPD population. Their use is largely limited to patients who demonstrate acute vasoreactivity testing [73].

In an earlier study by our group, felodipine, a non-selective dihydropyridine calcium channel blocker, significantly improved pulmonary haemodynamics in patients with COPD and PH [83]. Pulmonary vasodilatation in these patients was sustained for 3 months of treatment, without development of tolerance or deterioration in gas exchange, although a high incidence of vasodilator side effects was observed. A subsequent study by our group showed that amlodipine was as effective as felodipine in improving pulmonary haemodynamics in patients with COPD, with fewer side effects than felodipine [84]. One small randomised placebocontrolled trial in patients with COPD and PH reported significant improvement of the dyspnoea score and preserved cardiac output with nifedipine for one year, although there was no significant survival benefit [85]. This supports the hypothesis that pulmonary vasodilata‐ tion in patients with severe COPD and PH may improve their functional performance, dyspnoea and QOL, particularly if systemic vasodilatation side effects can be avoided.

An important practice point is that alternative causes of PH in patients with COPD, such as concomitant sleep disordered breathing or chronic thromboembolic disease should be actively investigated, as there are important treatment alternatives in these patients.
