The pooled evidence in our systematic review showed a statistically significant increase in exercise capacity with PH-specific treatment in COPD patients with confirmed PH by right heart catheterization or echocardiography. There was no significant hypoxemia associated with PH-specific treatment that gave us pause to prescribe PH specific agents for COPD patients having PH. However, in all severe COPD patients, regardless of PH there was a question as to whether they could improve their exercise capacity.
There were some difference between PH due to COPD and other types PH. In COPD, peripheral edema may not be a sign of RV failure, because it may result from the effects of hypoxemia and hypercapnia on the renin-angiotensin-aldosterone system (17
). Furthermore, concomitant left heart disease, which is commonly associated with chronic respiratory diseases, may also contribute to raise pulmonary arterial pressure (5
). The diagnostic threshold for mean pulmonary arterial pressure used to diagnose PH in WHO Group 3 are perhaps reflective of the fact that these definitions were established by expert consensus rather than by objective right heart catheterization data to support an optimal diagnostic threshold (18
). Previous studies have used mean pulmonary artery pressures exceeding 20 mmHg to define PH in some conditions such as COPD. The definition for PH in COPD has been debatable. Thirty five percent of all patients with severe COPD have a pulmonary artery pressure >20 mmHg at rest (19
). Pulmonary pressures during exercise are greater than predicted by the PVR equation in COPD, suggesting active pulmonary vasoconstriction on exertion (9
). Hence, of those patients without PH at rest, a further 52% are estimated to develop PH during exercise (4
). Like idiopathic PAH, pulmonary arteries in patients with COPD show evidence of fibromuscular intimal thickening with a diffuse increase in smooth muscle cells within the intima (20
). In severe COPD, the occasional application of PH specific treatment has been used to improve RV function and exercise capacity. However, in this meta-analysis on COPD, PH-specific treatment was only effective in cases of confirmed PH at rest. It had no salience in terms of PH-specific treatment as the improvement of exercise capacity in the absence of proven PH at rest by right heart catheterization.
Concerns about worsening Ventilation/perfusion (V/Q) mismatching and hypoxia arise (21
) when considering PH-specific treatment in COPD patients (22
). Pulmonary vasodilators may attenuate hypoxic vasoconstriction in poorly ventilated units (23
). In this meta-analysis for the secondary outcome, no worsening in oxygenation occurred significantly with PH-specific treatment, suggesting that any adverse impact on V/Q matching is minimal. In patients who have COPD, in whom hypoxemia is primarily caused by V/Q imbalance, PH-specific treatment can worsen arterial PaO2
as a result of increased perfusion to poorly ventilated units (23
). This effect can be prevented by concomitant use of supplemental oxygen.
Under the treatment guideline for PH, there is a limitation for the treatment that patients with disproportion PH due to lung diseases should be enrolled in RCTs targeting PAH-specific drugs (24
). Published experience with specific PAH drug therapy is scarce and consists of the assessment of acute effects and uncontrolled studies in small series. This meta-analysis indicated that small number of randomized controlled trial is unavoidable.
Our meta-analysis was hampered by heterogeneity. We could not help converting the unit from the final value of 6 minute walking distance to the change value. We requested the additional data from the authors; some responded and others did not. Almost all patients included in meta-analysis had an optimal bronchodilator therapy except for domiciliary oxygen. There were different kind of vasodilator and diagnostic tool for PH. The meta-analysis for observational study was working together to compensate the defect. The result of meta-analysis of RCTs for the observational studies showed a similar trend of improvement of the exercise capacity.
In conclusion, PH specific treatments have significant effect in improving the exercise capacity in COPD patients with overt PH at rest. However, our systematic review did not show a statistically significant increase in exercise capacity with PH-specific treatment in COPD patients regardless of PH at rest. From the results of this systematic review, we suggest PH-specific treatments in COPD patients with PH at rest might be as beneficial as other PH group. Future studies will be needed to determine the exact indications and risk-benefit balance of PH-specific therapy in the setting of COPD with PH at rest.