Study | Design | Population | Intervention | Significant outcomes | Adverse effects |
Stolz 2008 [35] | RCT | n=30: bosentan (n=20) versus placebo (n=10) Inclusion criteria: COPD GOLD stage III–IV Age: 68±8.5 years (sd) Gender: 60% male FEV1: 39±13.3% 6MWD: 336.3±92.6 m SpO2: 92.6±3.3% Echo sPAP: 32 (median; IQR 29–38) versus 37 mmHg (20–42) in (n=14) bosentan versus (n=6) placebo | Bosentan 62.5 mg PO BID for 2 weeks then 125 mg PO BID for 12 weeks Note: (n=8 on LTOT) in bosentan versus (n=3) placebo | Outcomes in bosentan (n=14/20) versus placebo (n=9/10): No change in echo PVR versus increase (p=0.006) No difference in sPAP or cardiac index Improved SF-36 total and physical domain scores Decreased 6MWD 339±81 to 329±94 m (p=0.04) versus no change No change in BDI Decreased PaO2 (p=0.029) | Bosentan (n=6) versus placebo (n=1) withdrew (p=0.37) Bosentan (n=2) dose reduction (elevated liver enzymes) |
Valerio 2009 [34] | RCT (not blinded) | n=40: bosentan (n=20) versus placebo (n= 20) Inclusion criteria: RHC mPAP >20 mmHg and PAWP <15 mmHg Age: 65.5±9.5 years Gender: 78.1% male (n=32/40) FEV1: 38±18% 6MWD: 257±118 versus 270±150 m PaO2: 57±10 versus 58±9 mmHg mPAP: 37±5 mmHg (variance not defined) | Bosentan 125 mg PO BID versus placebo for 18 months Note: 40% of each group were on LTOT | Outcomes in bosentan (n=16/20) versus placebo (n=16/20): Decreased mPAP (37±5 to 31±6 mmHg; p=0.002) versus no change Decreased PVR (5.5±2.4 to 4.9±2.3 WU; p=0.012) versus no change Increased 6MWD (257±118 to 321±122 m; p=0.003) versus no change Decreased mNYHA FC (3.2±0.8 to 2.8±1.2; p=0.05) versus no change Decreased BODE index (6.6±2.8 to 5.5±3; p=0.002) versus no change No change in PaO2 | n=8 withdrew (noncompliance, other health problems) |
Rao 2011 [28] | RCT | n=37: sildenafil (n=17) versus placebo (n=20) Inclusion criteria: echo sPAP >40 mmHg Age: 62.3±7.5 years (sd) Gender: not specified FEV1: 32.5±11.1 versus 28.5±7.5% 6MWD: 268.9±139.9 versus 323.1±165.6 m Echo sPAP: 52.7±11.9 versus 47.8±13.4 mmHg | Sildenafil 20 mg PO TID versus placebo for 12 weeks Note: none of the study participants used LTOT | Outcomes in sildenafil (n=15/17) versus placebo (n=18/20): At 4 weeks: Increased mean 6MWD 150±123 versus 24±117 m (p<0.05) At 12 weeks: Increased mean 6MWD 191±127 versus 39±87 m (p<0.025) Decreased echo sPAP 53±12 to 41±8 mmHg (p<0.05) versus no change | Sildenafil n=2 (epigastric pain and lost to follow up) versus placebo n=2 (acute exacerbation and lost to follow up) |
Badesch 2012 [36] | Case series | n=24 (11%) with COPD-PH of n=224 with PH Inclusion criteria: FEV1 ≥50% RHC mPAP >35 mmHg and PVR > 3.5 mmHg·L−1·min−1 6MWD (150–450 m) Age: 68±11 years (sd) Gender: 71% male 6MWD:241±84 m BNP: 243±245 ng·L−1 mPAP: 45±10 mmHg | Ambrisentan 5 mg PO daily for 24 weeks Note: 52.2% receiving background PH therapy | Outcomes in COPD-PH: No change in 6MWD (−5 m; 95% CI −34, 24) Change in BNP (−38%; 95% CI −54, −17) Outcomes in all PH: 181 patients (81%) contributed to the primary endpoint, 34 patients (15%) discontinued prior to the week 24 visit Six patients died during the 24-week treatment period Improved mNYHA FC in 23%, worse in 7% (p<0.001). Change in BDI (−0.5; 95% CI −0.8, −0.3) | No specific data in COPD-PH |
Hurdman 2013 [39] | Retrospective non-randomised cohort analysis of prospective registry (ASPIRE) | n=59: PH-targeted therapy (n=43) versus no therapy (n=16) Inclusion criteria: Post-bronchodilator FEV1 ≤0.7 RHC mPAP ≥40 mmHg (“severe”) Age: 70±9 years (sd) Gender: 47% male (n=28/59) FEV1: 65±23% ISWD: 40 (Median:IQR 18–100) m PaO2: 45.8±11.3 mmHg mPAP: 49±8 mmHg | PDE-5i (n=31), ERA (n=10), SC treprostinil (n=1), Nebulised iloprost (n=1), Treatment for ≥3 months or until death Note: 85% received LTOT | Outcomes with PH-targeted therapy versus no therapy: No change in survival 72% versus 63%/1 year (p=0.67) PH-targeted therapy responder subgroup: n=8 (19%) objective response to PH therapy based on improved mNYHA FC or >20% fall in PVR Better survival versus non-responder (p<0.05) | No difference in SpO2 between groups; no discontinuation of medication (median 178 days) |
Blanco 2013 [29] | RCT | n=63: sildenafil per-protocol (n=32) versus placebo (n=31) Inclusion criteria: echo sPAP >34 or RHC mPAP ≥25 mmHg Age 65.5±8 years (n=60) Gender: 90% male (n=60) FEV1: 32±12% (sd) 6MWD: 392±81 versus 379±100 m (n=60) Echo sPAP: 42±10 or RHC mPAP mean 31±5 mmHg in 22% of patients | Sildenafil 20 mg TID versus placebo for 3 months All patients underwent pulmonary rehabilitation 3 times per week for 3 months Note: n=18 on LTOT | Primary outcome in sildenafil-treated (n=29/32) versus placebo (n=31) per protocol: No significant difference in improvement in cycle endurance time (p=0.77) Outcomes in sildenafil-treated (n=24/29) versus placebo (n=27/ 31) who completed study: No statistically significant differences in incremental exercise test, 6MWD, HRQoL | COPD exacerbation which occurred in about third of patients lead to 10% d/c and 8% hospitalisation with no difference between groups |
Goudie 2014 [33] | RCT | n=120: tadalafil (n=60) versus placebo (n=60) Inclusion criteria: Age 35–85 years Post-bronchodilator FEV1 <80% and FEV1/FVC <70% Echo sPAP >30 mmHg or PAAT ≤120 ms Age: 69±7.5 years (sd) Gender: 68.5% male FEV1: 40.5±16% 6MWD: 347.5±104.5 m SpO2: 95.4±2.9% Echo sPAP: 42±9.5 mmHg | Tadalafil 10 mg daily versus placebo for 12 weeks n=13 (11%) of patients were on LTOT | Outcomes in tadalafil (n=56/60) versus placebo (n=57/60): Primary end point: no difference in 6MWD (p=0.94) No significant changes in HRQoL (SF-36, SGRQ, MLHFQ), BNP Mean placebo-corrected decreased sPAP from baseline (12.3 mmHg; p=0.007; n=12 tadalafil versus n=13 placebo) Mean placebo-corrected decreased calculated mPAP from baseline (3.5 mmHg; p=0.025) | Expected tadalafil side-effects (e.g. dyspepsia, headache) more common than placebo No difference in SpO2 between groups |
Fossati 2014 [41] | Retrospective cohort | n=27/48 with COPD-PH, of n=463 attending PH clinic Inclusion criteria: FEV1/FVC <0.7 RHC mPAP ≥25 mmHg and PAWP ≤15 mmHg PH-targeted therapy for at least 3 months Age: 70 (Median:IQR 60–76) years Gender: 74% male FEV1: 60 (46–78) % 6MWD: 373 (236–452) m SpO2: 92 (86–94) % NT-proBNP: 653 (159–1194) ng·L−1 mPAP: 39 (32–44) mmHg | Sequential combination therapy; final: ERA (n=15), PDE-5i (n=25), prostanoids: inhaled (n=10), s/c (n=2), iv (n=3) Note: 60% of patients used supplemental oxygen at least during nights | Median follow-up 5.9 years: mNYHA FC improved at 3 and 6 months (p=0.02 and p=0.008, respectively), not significant at 1 and 2 years 6MWD increased significantly at 3, 6, and 12 months (p≤0.01 at each timepoint), not significant at 2 years No change in NT-proBNP and resting SpO2 Peak exercise SpO2 during 6MWD decreased at 3, 6, and 24 months (p<0.05 at each timepoint) No difference in transplant-free survival between PH-targeted therapies | None reported |
Lange 2014 [42] | Retrospective, non-randomised cohort | n=29 COPD-PH of n=72 WHO Group 3 PH Inclusion criteria: FEV1/FVC <0.7 FEV1 <70% or more than mild CT emphysema RHC mPAP >25 mmHg and PAWP ≤15 mmHg (n=72) Age: 67±9 years (sd) Gender: 68% male FEV1: 70±24% 6MWD: 300±100 m mPAP: 37.3±9.1 mmHg (n=12 severe mPAP ≥35 mmHg) | PDE-5i (n=29), ERA (n=11), Nebulised iloprost (n=6) Note: dual therapy (n=8), triple therapy (n=2) for median 25.5 months Note: PH-targeted therapy in 65% of severe PH and 25% of less severe PH | COPD-PH subgroup Outcomes with PH-targeted therapy (n=12) versus no therapy (n=17): reduced mortality (HR 0.235, p=0.075) Entire WHO group 3 PH cohort Outcomes with PH-targeted therapy (n=34; including n=26 severe PH) versus no therapy (n=38; including 14 severe PH): reduced mortality (HR 0.262, p=0.004) | Not reported |
Girard 2015 [37] | Retrospective non-randomised cohort analysis of prospective registry data | n=26 Inclusion criteria: Post-bronchodilator FEV1/FVC <0.7 Precapillary PH: RHC mPAP ≥25 and PAWP ≤15 mmHg Severe PH: mPAP >35 mmHg and/or cardiac index 2 L·min−1·m−2 Age: 66±11 years (sd) Gender: 96% male FEV1: 57±20% 6MWD: 212±104 m NT-proBNP: 3205±4250 ng·L−1 Nuclear RVEF: 22±6% mPAP: 48±9 mmHg | PDE-5i (n=11), ERA (n=11), CCB (n=1), prostanoids (n=2), dual therapy (n=3) for median 6±3 months Note all study participants were on optimal COPD treatment including LTOT | Outcomes with PH-targeted therapy: RHC (3–12 months post-treatment) mPAP decreased 48±9 to 42±10 mmHg (p=0.008) PVR decreased 8.5±3.0 to 6.6±2.0 WU (p=0.001) TD cardiac index improved 2.4±0.4 to 2.7±0.6 L·min−1·m−2 (p=0.015) Nuclear RVEF increased (p=0.03) No significant differences in mNYHA FC, 6MWD, echo parameters, or NT-proBNP levels | Decreased SpO2% in n=2 (ERA), leading to discontinuation of study treatment |
Tanabe 2015 [43] | Multicentre, retrospective cohort study | n=18 COPD-PH of n=70 WHO Group 3 PH Inclusion criteria: RHC mPAP ≥35 mmHg and “normal” PAWP Age: 67±9 years (sd) Gender: 94% male FEV1: 58±33% 6MWD: 263±97 m BNP: 397±608 pg·mL−1 PaO2: 52±16 mmHg mPAP: 47±15 | 78% (n=14) treated with PH-targeted therapy: PDE-5i (n=14), ERA (n=8), beraprost (n=7) for mean 1.9±1.7 years Note: 96% (n=67) of study participants used LTOT | COPD-PH subgroup Cumulative survival 50%/3 years No change in survival with PDE-5i treatment: 53.6% versus 37.5%/ 3 years (p= 0.56) Entire WHO group 3 PH cohort Improved survival with PDE-5i treatment (multivariate analysis, p=0.01) | Not reported |
Brewis 2015 [40] | Retrospective cohort study | n=40: COPD-PH of n=118 WHO Group 3 PH Inclusion criteria: FEV1/FVC <0.7 either FEV1 <60% or emphysema on CT with FEV1 <80% RHC mPAP ≥35 mmHg and PAWP ≤ 15 mmHg Age: 64±10 years (sd) Gender: 55% male FEV1: 56±16% 6MWD: 216±110 m NT-proBNP: 2169 (median; IQR 769–3919) pg·mL−1 PaO2: 57±10.5 mmHg mPAP: 49±10 mmHg | Initial: ERA (n=10), PDE-5i (n=26), CCB (n=2), prostanoid (n=2) for ≥3 months Note: n=5 on LTOT | COPD-PH subgroup No change in 6MWD No change in mNYHA FC No change in NT-proBNP Entire WHO group 3 PH cohort No change in 6MWD No change in mNYHA FC NT-proBNP improved (p=0.015) No change in PaO2 | |
Calcaianu 2016 [38] | Single centre, retrospective cohort study | n=28/537 Inclusion criteria: FEV1/FVC <70% and FEV1 >50% RHC mPAP ≥35 mmHg PAWP <15 mmHg Age: 71.2±9.4 years (sd) Gender: 79% male FEV1: 69.3±13.8% 6MWD: 259±104 m BNP: 296±389 ng·L−1 PaO2: 49.6±9.5 mmHg mPAP: 44.2±8.7 mmHg | Initial: ERA (n=23), PDE-5i (n=1), prostanoid (n=1), CCB (n=1), combination therapy (n=2); for 6–12 months (median 3 years) Note: All study participants used LTOT | Outcomes with PH-targeted therapy at 6–12 months (n=16/28): PVR decreased 8.4±4.2 to 5.0±1.7 WU (p= 0.008) Cardiac index increased 2.5±0.7 to 3.2±0.6 L·min−1·m−2 (p=0.003) No change in mPAP No change in mNYHA FC (3 months) No change in 6MWD, PaO2 Cumulative survival 57.2% /3 years (sequential combination therapy in n=10) | No side-effects leading to withdrawal of study treatment |
Alkhayat 2016 [32] | Parallel group cohort study | n=139: sildenafil (n=69) versus placebo (n=70) Inclusion criteria: COPD diagnosis: unclear criteria. Echo calculated mPAP ≥25 mmHg 6MWD (100–450) m Age: 48±15.5 years (sd) Gender: 76% male 6MWD: 345.5±84.5 m Calculated mPAP: 45±13 versus 56±16 mmHg | Sildenafil 20 mg PO TID versus placebo for 12 weeks | Outcomes in sildenafil versus placebo: Mean placebo-corrected increase in 6MWD 51 m from baseline (p<0.001) Decreased mPAP from baseline 2.1 mmHg (-4.3, 0.0) versus increased 0.6 (-0.8, 2.0; p= 0.04) | Expected sildenafil side-effects (e.g. flushing, dyspepsia, and diarrhoea) |
Vitulo 2016 [30] | Multicentre, RCT | n=28: sildenafil (n=18) versus placebo (n=10) Inclusion criteria: RHC mPAP ≥30 mmHg for FEV1 >30% post-bronchodilator or RHC mPAP ≥35 mmHg if FEV1 <30% post-bronchodilator PAWP ≤15 mmHg LTOT ≤6 L·min−1 PaCO2 ≤55 mmHg No decrease in PaO2 ≤55 mmHg after first dose of blinded study medication Age: 67.9±8.1 years (sd) Gender: 75% male FEV1: 52.3±23.4% 6MWD: 229.2±101.4 versus 308.5±99.6 m PaO2: 74.3±14.5 mmHg mPAP: 39.2±9.35 mmHg | Sildenafil 20 mg TID versus placebo for 16 weeks | Outcomes in sildenafil (n=15/18) versus placebo (n=10): PVR decreased 1.4 WU (p=0.04) Cardiac index increased 0.4 L·min−1·m−2 (p=0.004) Secondary end points: BODE index improved 0.40 units (p=0.02) mMRC dyspnoea improved (0.6 units; p=0.03) No change in 6MWD | Expected sildenafil side-effects (e.g. (headache, flushing, myalgia) mild-moderate in n=5; no interruption of study treatment; no difference in SpO2 between groups |
Shrestha 2017 [31] | Non-placebo RCT | n=72: sildenafil (n=36) versus standard medical therapy (n=36) Inclusion criteria: echo sPAP >36 mmHg Age: 64.2±5 years Gender: not specified FEV1: 46.1±12.8% 6MWD: 183±78 m mPAP: 71.3±14.7 mmHg (variance not defined) | Sildenafil 25 mg PO TID versus standard medical therapy for 4 weeks Note: LTOT permitted | Outcomes in sildenafil (n=30) versus standard medical therapy (n=31): Decreased sPAP 9.9±7.8 versus 5.9±7.4 mmHg (p=0.048) Increased 6MWD 48±26 versus 33±33 m (p=0.047) Secondary outcomes: Decreased mMRC (p=0.037) No difference in mNYHA FC, BDI | Expected sildenafil side-effects (e.g. flushing, diarrhoea, syncope), no interruption of study treatment No difference in SpO2 between groups |
Data are mean±sem unless otherwise specified. 6MWD: 6-min walk distance (m); BDI: Borg dyspnoea index; BID: twice daily; BNP: brain natriuretic peptide; BODE index: Body mass index, Obstruction by FEV1, Dyspnoea by mMRC grade, and Exercise capacity by 6MWD; CCB: calcium channel blocker; CT: computed tomography; ERA: endothelin receptor antagonist; FEV1: forced expiratory volume in 1 s; FVC: forced vital capacity; GOLD: Global Initiative for Chronic Obstructive Lung Disease; HR: hazard ratio; HRQoL: health-related quality of life; IQR: interquartile range; ISWD: incremental shuttle walk distance; LTOT: long-term oxygen therapy; mMRC: modified Medical Research Council; mNYHA FC: modified New York Heart Association functional class; mPAP: mean pulmonary artery pressure; NT-proBNP: N-terminal propeptide of brain natriuretic peptide; PAAT: pulmonary artery acceleration time; PaCO2: partial pressure of carbon dioxide in arterial blood; PaO2: partial pressure of oxygen in arterial blood; PAWP: pulmonary arterial wedge pressure; PDE-5i: phosphodiesterase type 5 inhibitors; PH: pulmonary hypertension; PO: by mouth; PVR: pulmonary vascular resistance; RCT: randomised controlled trial; RHC: right heart catheterisation; RVEF: right ventricular ejection fraction; SGRQ: St George's Respiratory Questionnaire; SC: subcutaneous; sPAP: systolic pulmonary arterial pressure (mmHg); SpO2: transcutaneous pulse oximetry oxygen saturation (%); TID: three times a day; WHO: World Health Organization; WU: Wood unit (mmHg·L−1·min−1).