Abstract
Chronic obstructive pulmonary disease-associated pulmonary hypertension (COPD-PH) is an increasingly recognised condition which contributes to worsening dyspnoea and poor survival in COPD. It is uncertain whether specific treatment of COPD-PH, including use of medications approved for pulmonary arterial hypertension (PAH), improves clinical outcomes. This systematic review and meta-analysis assesses potential benefits and risks of therapeutic options for COPD-PH.
We searched Medline and Embase for relevant publications until September 2020. Articles were screened for studies on treatment of COPD-PH for at least 4 weeks in 10 or more patients. Screening, data extraction, and risk of bias assessment were performed independently in duplicate. When possible, relevant results were pooled using the random effects model.
Supplemental long-term oxygen therapy (LTOT) mildly reduced mean pulmonary artery pressure (PAP), slowed progression of PH, and reduced mortality, but other clinical or functional benefits were not assessed. Phosphodiesterase type 5 inhibitors significantly improved systolic PAP (pooled treatment effect −5.9 mmHg; 95% CI −10.3, −1.6), but had inconsistent clinical benefits. Calcium channel blockers and endothelin receptor antagonists had limited haemodynamic, clinical, or survival benefits. Statins had limited clinical benefits despite significantly lowering systolic PAP (pooled treatment effect −4.6 mmHg; 95% CI −6.3, −2.9).
This review supports guideline recommendations for LTOT in hypoxaemic COPD-PH patients as well as recommendations against treatment with PAH-targeted medications. Effective treatment of COPD-PH depends upon research into the pathobiology and future high-quality studies comprehensively assessing clinically relevant outcomes are needed.
Abstract
The presence of PH in COPD patients is associated with worsening morbidity and mortality. These findings support guideline recommendations for LTOT in hypoxaemic COPD-PH patients as well as recommendations against treatment using PAH-targeted medications. https://bit.ly/3Al4rLb
Introduction
Chronic obstructive pulmonary disease (COPD) is a progressive and incurable disease that represents one of the five leading causes of death worldwide [1, 2]. COPD is characterised by exertional dyspnoea, functional limitation, poor health-related quality of life (HRQoL), recurrent exacerbations and hospitalisations, as well as shortened survival [1, 2]. The presence of pulmonary hypertension (PH) in patients with COPD is increasingly recognised as an important contributing factor to its clinical manifestations and adverse clinical outcomes including increased mortality [3, 4]. For example, severe PH and resulting right ventricular (RV) failure are associated with more severe dyspnoea and limited exercise capacity [5, 6]. Indeed, the presence of PH has a stronger association with mortality in COPD than forced expiratory volume in 1 s (FEV1) or gas exchange variables [7, 8]. Moreover, enlarged pulmonary artery diameter on computed tomography scan is independently associated with a higher risk of acute COPD exacerbations and related hospitalisations [8, 9].
Estimates of the prevalence of PH in COPD (COPD-PH) vary widely (20–91%) [5, 10, 11], with increasing prevalence with greater severity of COPD [4]. For example, the most severe Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage IV COPD is associated with mild-moderate PH in up to 90% of patients [5]. PH in a patient with COPD could be due to a broad range of underlying conditions, such as left-heart disease [12], concomitant interstitial lung diseases or sleep disordered-breathing, or chronic thromboembolic PH. Management of associated cardiac and respiratory conditions can improve the clinical status and outcomes in COPD-PH patients [4, 13].
Specific medical treatment of COPD-PH may also offer clinical benefits, including improved dyspnoea, functional capacity, and long-term outcomes. Thus, we conducted a systematic review and meta-analysis for benefits and risks of treatment options for COPD-PH.
Methods
Search strategy and eligibility criteria
According to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, we searched MEDLINE and Embase databases from 1947 to 30 September 2020, using the search terms “pulmonary hypertension” AND “chronic obstructive airway disease or chronic obstructive pulmonary disease or COPD” AND “treatment or management”.
We also reviewed bibliographies, identifying additional relevant studies. Titles and abstracts were screened, and full-text articles were reviewed independently and in duplicate (R. Arif and S. Mehta) in order to identify studies meeting the predefined inclusion and exclusion criteria (supplementary table S1): studies of 10 or more patients reporting the effects of at least 4 weeks of treatment on pulmonary haemodynamics, survival, or other clinical outcomes in patients with COPD-PH. Risk of bias was assessed using the Newcastle Ottawa Scale for observational studies and the Cochrane Collaboration tool for randomised controlled trials (RCTs). Disagreements were resolved by consensus.
Data collection
Data collection was performed independently by at least two authors (R. Arif, A. Pandey and Y. Zhao). The data extracted included: study characteristics, patients demographics and comorbidities, method of PH diagnosis, intervention type, dosage and frequency, duration of and loss to follow-up, as well as outcomes, including clinical outcomes (e.g. survival), cardiopulmonary haemodynamics (e.g. mean pulmonary artery pressure (mPAP)), pulmonary vascular resistance (PVR), cardiac output (CO), and others) as listed in supplementary table S1.
Data analysis
Subgroups based on the method of PH diagnosis were defined a priori and a sensitivity analysis performed; patients diagnosed using right-heart catheterisation (RHC)-determined mPAP versus those diagnosed using non-invasive echocardiography by estimating systolic PAP (sPAP) or calculating mPAP. During data analysis, another subset of COPD-PH patients was identified; those with more severe PH and RV failure, often in the setting of only mild to moderate COPD without resting hypoxaemia. This subgroup was analysed separately. Details of statistical analysis are given in the supplementary material.
Results
We retrieved and screened 4577 reports, and an additional 26 records were identified through other sources (figure 1). 4557 studies were excluded, leaving 46 studies reporting treatment of COPD-PH, including 23 RCTs (1159 patients) and 23 non-RCTs (1187 patients). Patients ranged from 35–85 years in age and were predominantly male in the majority of studies (range 32–100%). Lung function varied widely (FEV1 13–94% predicted), but most patients had moderate to severe COPD, many with hypoxaemia at rest.
We identified five categories of COPD-PH therapies, including supplemental oxygen (table 1), calcium-channel blockers (supplementary table S2), pulmonary arterial hypertension (PAH)-targeted therapy (table 2), statins (supplementary table S3), and miscellaneous therapies (supplementary table S4).
Long-term oxygen therapy
In COPD-PH patients, long-term oxygen therapy (LTOT) may have haemodynamic and clinical benefits. The evidence base consists of eight reports (n=596; 72–100% men), including one RCT [14], two randomised parallel group studies comparing LTOT versus nocturnal oxygen therapy (NOT), and four case series [15–18] (table 1). All patients underwent RHC which documented the presence and severity of baseline PH. Most studies report outcome data over longer than 1 year (range 2–6 years), but two studies were <8 weeks in duration [15, 19]. Most LTOT studies had an unclear or high risk of bias in at least one domain; only one study had a low risk of bias (supplementary tables S5 and S6) [20], which limits our confidence in the effects of LTOT in COPD-PH.
The haemodynamic benefit of LTOT varied, with small reductions (3–5 mmHg) in mPAP in four of eight studies [15, 16, 19, 21], and/or PVR in three [19–21], but no reported change in CO (three studies). Even in the absence of actual improvement in the severity of PH, LTOT may be associated with less progression of PH over time [14, 16]. For example, a progressive increase in mPAP in control patients was completely attenuated in LTOT patients in the Medical Research Council (MRC) trial [14].
No studies assessed clinical or functional patient outcomes other than mortality benefits of LTOT. Survival was assessed in four studies (n=480), of which three (n=408) reported improved survival [14, 20, 21], but one study found no effect [17]. Pulmonary haemodynamic improvement may be associated with greater survival [20, 21], but this was not consistently observed [22].
In summary, in COPD-PH patients with hypoxaemia, LTOT may mildly reduce severity of PH, slow PH progression over time, and reduce mortality, but without any other clinical or functional benefit (table 3). There are limited, conflicting data on NOT, with haemodynamic benefit in only one of two RCTs [22, 23], and no clinical benefits in either.
Calcium channel blockers
Four studies defining PH using mPAP threshold of 20 mmHg, including two RCTs (n=80) [24, 25] and two case series [26, 27], evaluated effects of calcium channel blockers (CCBs) over at least 8 weeks (supplementary table S2). All studies had an unclear or high risk of bias in at least one domain. Two small studies found no RHC-assessed haemodynamic benefit of nifedipine [25, 26], but felodipine decreased echo-calculated mPAP and total pulmonary resistance (TPR) as well as increased CO in a case-series [27]. Only one study assessed symptoms, reporting decreased dyspnoea scores, but found no difference in survival [24]. Another study reported no change in exercise capacity [27]. Side-effects of CCBs were common and many patients required dose reduction (50%) and/or withdrawal of therapy (7–27%).
In summary, based on limited evidence, CCBs may mildly improve haemodynamics with no evidence to suggest any clinical or survival benefits, and they are generally poorly tolerated (table 3).
PAH-targeted medications
Based on strong benefits in the treatment of PAH, 15 reports describe potential benefits of PAH-targeted therapies, including oral phosphodiesterase type 5 inhibitors (PDE-5i), oral endothelin receptors antagonists (ERAs), and prostanoids, in patients with COPD-PH (table 2).
PDE-5i
Six studies (n=459) assessed effects of PDE-5i, including sildenafil (5 studies) [28–32] and tadalafil [33]. In five studies, PH was echo-defined using variable thresholds (sPAP >30–40 mmHg) [28, 29, 31, 33], whereas a single study variably defined PH by RHC (mPAP >30–35 mmHg), depending on FEV1% predicted [30]. Three studies had a low risk of bias, one RCT was unclear [28], and two had a high risk of bias [31, 32]. All five studies assessing haemodynamics reported benefits of PDE-5i. Sildenafil improved echo-sPAP [28, 31], echo-calculated mPAP [32], and RHC-mPAP [30], and tadalafil improved both echo-sPAP and calculated mPAP [33]. Pooled analyses showed favourable effects on both sPAP and mPAP (figure 2).
Of six studies assessing functional capacity [28–33], sildenafil improved 6-min walk distance (6MWD) in two RCTs [28, 31] and one cohort study [32] but had no effect in two other RCTs [29, 30]. The one study of tadalafil showed a similar lack of benefit [33]. The pooled analysis of 6MWD showed no clear benefit with a trend towards improvement (figure 3). PDE-5i were generally well-tolerated with expected side-effects and did not worsen hypoxaemia.
There were inconsistent benefits in HRQoL in four RCTs using different measurement tools [29–31, 33]. Sildenafil improved mMRC dyspnoea [30, 31], 36-item Short Form survey (SF-36) score, and the multi-parameter COPD BODE index (body mass index, obstruction by FEV1, mMRC dyspnoea, and 6MWD) [30], but not HRQoL in an unspecified questionnaire [29]. Tadalafil had no effect using different scores (SF-36, SGRQ, MLHFQ) [33].
In summary, PDE-5i significantly improved haemodynamics in COPD-PH patients, but this did not translate to clinical, functional, or HRQoL benefits (table 3).
ERAs
Two placebo-controlled RCTs assessed the effects of bosentan in severe COPD. In a non-blinded study in RHC-diagnosed moderate to severe PH, bosentan had mild haemodynamic benefit associated with improved exercise capacity and limited symptomatic benefit [34]. In contrast, bosentan had inconsistent haemodynamic effects, uncertain clinical benefits (6MWD fell slightly, HRQoL improved), and reduced PaO2 in mild echo-defined PH [35]. Ambrisentan treatment in a case series (n=24) of RHC-diagnosed severe PH decreased brain natriuretic peptide (BNP) with no change in 6MWD [36]. Two studies had a high risk of bias and one RCT had a low risk of bias [35].
In summary, ERAs have limited haemodynamic and uncertain clinical benefits in COPD-PH patients.
Studies of multiple PAH-targeted therapies
Four retrospective cohort studies assessed the effects of multiple PAH-targeted therapies individually in RHC-defined COPD-PH [37–40], reporting haemodynamic improvement with no clinical or functional benefits [37, 38], or no effects at all [39, 40]. Three other retrospective cohort studies [41–43] reported no survival benefit of PAH-targeted therapies in various combinations in RHC-defined PH, but one found short-term clinical (improved New York Heart Association (NYHA) functional class) and functional (improved 6MWD) benefits up to 1 year which were not sustained at 2 years [41]. Three studies suggested greater improvements with PAH-targeted therapy in patients with more severe PH, including greater RHC-measured haemodynamic effects [37, 38, 41], and one showed clinical and functional benefits up to 1 year [41]. Risk of bias was high for six of seven studies of multiple PAH-targeted therapies, and unclear for one study, which limits confidence in the results.
In summary, combination PAH-targeted therapy does not improve survival but may offer some transient clinical and/or functional benefits. Patients with objective “response” to therapy, including improved mNYHA FC or PVR, may have improved survival [39].
Statins
Statins are widely used in COPD due to the prevalence of cardiovascular diseases and were used for treatment of COPD-PH in six studies (n=394; supplementary table S3), including five RCTs using echo-defined PH [44–48] and one RHC-defined PH cohort study [49]. Only one study had low risk of bias [44], but the other five studies had an unclear risk of bias.
Three RCTs showed statins decreased echo sPAP at rest [46–48] or during exercise [44], whereas another RCT showed no change [45]. Clinical and functional outcomes were infrequently assessed, and changes in dyspnoea, HRQoL, and functional capacity are inconsistent [44, 45, 47].
In summary, statins are well-tolerated, significantly reduced sPAP (figure 4) but had no clinical or functional benefits.
Other therapies
Single studies have reported on several miscellaneous, non-traditional potential therapies in patients with COPD-PH (supplementary table S4) [50–52]. Some therapies demonstrated improved pulmonary haemodynamics at rest (e.g. Dipyridamole [53], cicletanine [54], ACE inhibitors [55, 56], inhaled nitric oxide (iNO) [57]) or on exercise (e.g. Waon therapy [58]), reduced dyspnoea (e.g. Waon therapy [58]), and/or improved exercise capacity (e.g. iNO [57]), whereas many other therapies had no reported benefits. Combinations of such therapies may improve multiple parameters; for example, combination of azithromycin, simvastatin, and LTOT decreased RHC sPAP and increased 6MWD [59].
Discussion
Our systematic review focuses on the effect of various therapeutic options in COPD-PH. We identified studies that focused on treatment of COPD-PH for at least 4 weeks and captured haemodynamics and clinical outcomes including survival. Overall, many treatments improve PH haemodynamics and some may improve survival, but few are associated with improved symptoms, functional capacity, or HRQoL. For example, supplemental LTOT mildly reduces PH haemodynamic severity, may slow PH progression over time, and reduces mortality. However, other clinical and functional benefits of LTOT were not assessed. Similarly, PAH-targeted therapy using sildenafil improved PH haemodynamics, but had uncertain clinical and functional benefits. In contrast, other PAH-targeted medications, such as ERAs, had inconsistent effects, as did other therapies including CCBs and statins.
The presence and severity of PH in COPD patients is a significant contributor to clinical morbidity, including worse dyspnoea, functional capacity, and HRQoL [5, 6, 30], as well as being a prognostic marker for more frequent exacerbations and worse survival. However, there are no specific treatments for COPD-PH, and current guidelines for management of WHO group 3 PH, including COPD-PH, simply suggest LTOT for resting hypoxaemia and optimisation of underlying chronic cardiopulmonary conditions [4, 13].
COPD-PH is believed to be largely the result of hypoxaemia. As such, LTOT could be effective in the treatment of hypoxaemic COPD-PH. The data suggest mild improvements in severity of PH, some evidence for slowing progression of PH, and importantly, improved survival. However, oxygen did not normalise mPAP and there were no other symptomatic or functional clinical benefits reported. As for NOT, the limited available data shows no clear benefits in COPD-PH patients with either daytime or isolated nocturnal hypoxaemia. We did not find studies that assessed the long-term effect of supplemental oxygen in COPD-PH patients with exertional hypoxaemia.
Besides hypoxaemia, COPD-PH may also be driven through other potential mechanisms [60], including pathophysiologic features similar to PAH, including pulmonary micro-vessel rarefaction and endothelial dysfunction, for example decreased expression of endothelial nitric oxide synthetase (eNOS) [3, 4, 60]. Thus, PAH-targeted therapy may have a potential role in COPD-PH management. However, guidelines generally recommend against PAH-targeted therapy for mild to moderate WHO group 3 PH, including COPD-PH [13, 61].
In our systematic review, PAH-targeted therapy in patients with COPD-PH had inconsistent effects, including limited clinical benefits (for example, symptoms, functional capacity, HRQoL) but no assessment of hospitalisation or survival. Overall, our findings are similar to other analyses [4, 62, 63]. Some PAH-targeted medications may offer benefits, as PDE-5i (sildenafil and tadalafil) significantly improved pulmonary haemodynamics, and sildenafil improved mMRC [30, 31], BODE index, and SF-36 [30]. In our pooled analysis, 6MWD increased slightly but not significantly with PDE-5i treatment (+16 m; figure 3), which was less than the significant pooled effect of sildenafil on 6MWD (+29 m) in another review of COPD-PH [64]. Differences include our inclusion of a negative trial on tadalafil, possibly due to an ineffective small dose [33], and exclusion of several positive studies from China. Comparatively, there are fewer studies of other PAH-targeted therapies such as ERAs, but similar overall limited clinical benefits despite some haemodynamic effects. Combination PAH-targeted therapy is now standard of care in PAH [13, 61], but there are limited data in COPD-PH to suggest any benefit.
Interestingly, an objective “response” to PAH-targeted therapy (PDE-5i or ERA), as characterised by improved mNYHA FC or PVR (>20% fall), was predictive of better survival [39]. Furthermore, some COPD patients with more severe PH, generally defined as mPAP≥35 mmHg, may respond better to PAH-targeted therapy [37, 38, 41]. A subset of COPD patients with this severe precapillary PH and possibly RV failure, often in the setting of only mild to moderate COPD has been labelled, and may reflect a “vascular” phenotype [65] that may be at particularly high risk of long-term PH-related morbidity and mortality [5, 66]. This group of patients may have a genetic predisposition to PH, similar to heritable PAH, which may become manifest in the context of COPD, either driven by hypoxaemia, cigarette smoke, airway or systemic inflammation [60, 65], or simply due to concurrent COPD and unrelated PAH. This subset of COPD patients merits further study and may benefit clinically from referral to expert PH centres for further assessment and consideration of treatment [4, 13].
Concerns over potential risks of PAH-targeted therapies worsening ventilation/perfusion matching and hypoxaemia because of non-selective widespread pulmonary vasodilation are not supported by any evidence for any adverse effect on oxygenation [29–31, 33, 34]. Expected side-effects of PAH-targeted therapy were observed, for examplec flushing, headache, diarrhoea, but did not lead to high rates of medication discontinuation.
Among other treatment options, CCBs may mildly improve haemodynamics, but there is no evidence to suggest any clinical or survival benefits, and they are generally poorly tolerated. Statins reduced sPAP (mPAP in one study) but had limited clinical benefits. Although the statin effect in PH could be mediated through systemic vascular and/or left-ventricular effects rather than direct pulmonary vascular action, a multiple regression analysis suggested statins reduce mPAP independent of pulmonary artery wedge pressure [49]. Statins may also prevent COPD progression and improve PH by reducing C-reactive protein and other inflammatory factors [67]. Several other therapies (e.g. iNO, Waon, cicletanine) improved pulmonary haemodynamics with minimal clinical benefits.
Limitations of this review include paucity of RHC diagnosed PH, as only some studies reported RHC-mPAP, whereas most studies only reported echo-estimated sPAP ± calculated mPAP. A systemic vascular effect of a putative treatment could result in apparent pulmonary haemodynamic benefit as assessed simply by echocardiogram, for example, a decrease in sPAP with statins. Moreover, studies used various thresholds for both RHC and echo measurements to define presence of PH. In addition, study populations exhibited marked heterogeneity, including severity of COPD and presence of hypoxaemia. There was also treatment heterogeneity, as studies used various doses and duration of therapy, and in some studies of combination PAH-targeted therapies, specific combinations were not clearly defined. Most importantly, very few studies provided a comprehensive assessment of the potential benefits of PAH-targeted therapies, including multi-parameter characterisation of haemodynamic, clinical, and functional benefits.
In conclusion, this systematic review identifies the large number of studies assessing multiple treatments for patients with COPD-PH and highlights the limited evidence base. This review supports recent guidelines which recommend LTOT in hypoxaemic COPD-PH patients but do not recommend other treatments for COPD-PH, including PAH-targeted medications. Development of future therapies depends upon new ideas on the pathobiology of COPD-PH, as well as higher-quality studies on more homogeneous populations, including patients with more severe PH or a “vascular” phenotype, using a standardised RHC diagnosis of PH and comprehensive assessment of outcomes.
PRISMA flow diagram of identification of relevant articles for inclusion in systematic review and quantitative analysis. PH: pulmonary hypertension.
The effect of treatment with phosphodiesterase type 5 inhibitors (PDE-5i) on mean pulmonary artery pressure (mPAP; upper panel) and systolic pulmonary artery pressure (sPAP; lower panel) in COPD-associated pulmonary hypertension. Note: mPAP was measured by right heart catheterisation (Vitulo 2017) or estimated from echo measurement of sPAP (Goudie 2014). IV: inverse variance.
The effect of treatment with phosphodiesterase type 5 inhibitors (PDE-5i) on 6-min walk distance in patients with COPD-associated pulmonary hypertension (PH). Note: PH was diagnosed either by right heart catheterisation (Vitulo 2017) or by echocardiogram in the other studies. IV: inverse variance.
The effect of treatment with atorvastatin on systolic pulmonary artery pressure in COPD-associated pulmonary hypertension (PH). Note: PH was diagnosed by echocardiogram in all studies. IV: inverse variance.
Effects of supplemental oxygen therapy including long-term oxygen therapy (LTOT) and nocturnal oxygen therapy (NOT) in patients with COPD-associated pulmonary hypertension (PH)
Effects of pulmonary arterial hypertension-targeted therapies in patients with COPD-associated pulmonary hypertension (COPD-PH)
Summary of outcomes in treatment of COPD-associated pulmonary hypertension (PH)
Footnotes
Provenance: Submitted article, peer reviewed.
This article has supplementary material available from openres.ersjournals.com
Conflict of interest: R. Arif has nothing to disclose.
Conflict of interest: A. Pandey has nothing to disclose.
Conflict of interest: Y. Zhao has nothing to disclose.
Conflict of interest: K. Arsenault-Mehta has nothing to disclose.
Conflict of interest: D. Khoujah has nothing to disclose.
Conflict of interest: S. Mehta reports grants or contracts from Altavant Pharmaceuticals, Eiger Pharmaceuticals, Ikaria Pharmaceuticals, Janssen Pharmaceuticals, Reata Pharmaceuticals, and United Therapeutics; consulting fees from Acceleron Pharmaceuticals, Janssen Pharmaceuticals and Natco Pharmaceuticals; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Bayer Pharmaceuticals, Janssen Pharmaceuticals, Natco Pharmaceuticals and SpecialtyRx Pharmacy; payment for expert testimony from Bergeron Clifford LLP, Lerner Law and St. Lawrence Barristers LLP; support for attending meetings and/or travel from Janssen Pharmaceuticals; participation on a data safety monitoring or advisory board for Ozmosis Research; board directorship for the Pulmonary Hypertension Association of Canada (unpaid position); and receipt of equipment, materials, drugs, medical writing, gifts or other services from Janssen Pharmaceuticals, all outside the submitted work.
- Received May 29, 2021.
- Accepted September 27, 2021.
- Copyright ©The authors 2022
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References
