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. 2024 Jan 10;14(1):e12310. doi: 10.1002/pul2.12310

Table 1.

Clinical trials targeting ILD with pulmonary vasodilators.

Lung disease Investigator Year Study design Pts Therapy Results Comments
ILD/IIP/IPF trials
IPF Collard et al. 63 2007 Open label 14 Sildenafil (N = 14)

57% improved 6MWT by

≥20%

 Median follow‐up of 91 days
IPF Zisman et al. 64 2010 RCT 180 Sildenafil (n = 89)

Failed to improve 6MWT by

≥20%

 Improved oxygen saturation and QOL
IPF Jackson et al. 65 2010 RCT 29 Sildenafil (n = 14) No difference in 6MWT or Borg score
IPF Gunther et al. 66 2007 Open label 12 Bosentan (n = 12) No worsening of gas exchange
IPF King et al. 67 2008 RCT 158 Bosentan (n = 74) Failed to improve 6MWT Trend to delayed death or disease progression
IPF King et al. 68 2011 RCT 610 Bosentan (n = 407) No effect on time to IPF worsening or death
IPF Raghu et al. 69 2013 RCT 492 Ambrisentan (n = 330) Terminated early for lack of efficacy in time to clinical worsening In 32 patients with PH—no change in time to disease progression
IPF Raghu et al. 70 2013 RCT 178 Macitentan (n = 178) Failed to alter primary endpoint of change in FVC
IPF Kolb et al. 71 2018 RCT 274

Nintedanib

 

+ Sildenafil (n = 137)

 Primary endpoint of change in SGRQ was not met Enriched for PH (DLCO ≤ 35%)

Fibrotic

ILD

 Nathan et al. 72 2020 RCT 45 iNO (n = 23) Improvement in moderate to vigorous activity and overall activity Enriched for PH (supplemental O2)
PH associated with ILD/IIP/IPF trials
PH‐ILD Faria‐Urbina et al. 73 2018 Retrospective 22

Treprostinil (inhaled)

(n = 22)

Improvement in FC

Improvement in 6MWD

No change in resting O2 requirements
PH‐PF Ghofrani et al. 74 2002 Open label 16

Sildenafil (n = 8)

Epoprostenol (n = 8)

 Sildenafil improved V/Q matching and oxygenation Epoprostenol worsened V/Q matching
PH‐IPF Krowka et al. 75 2007 RCT 51

Iloprost (inhaled)

(n = 26)

 No difference in 6MWT, NYHA FC, dyspnea score
PH‐ILD Chapman et al. 76 2009 Retrospective 5 Sildenafil (n = 5) Improved 6MWT Decreased mPAP 2–12 months after start of treatment
PH‐ILD Corte et al. 77 2010 Retrospective 15 Sildenafil (n = 15) Improved 6MWT and lower BNP
PH‐ILD Hoeper et al. 78 2013 Open label 22 Riociguat (n = 22) Improved CO and PVR but not mPAP Arterial saturation decreased but mixed‐venous saturation increased
PH‐ILD Zimmerman et al. 79 2014 Open‐label, observational 10

Sildenafil (n = 5)

Tadalafil (n = 5)

 Increased CO and decreased PVR No change in 6MWD or BNP
PH‐ILD Corte et al. 80 2014 RCT 60 Bosentan (n = 25) No effect on hemodynamics, symptoms, or functional capacity
PH‐ILD Saggar et al. 81 2014 Open label 15

Treprostinil (parenteral)

(n = 15)

 Improved hemodynamics without hypoxemia All had mPAP ≥ 35 mmHg
PH‐ILD (CPFE & ILD) Brewis et al. 82 2015 Retrospective 118

PDE‐5i (n = 31)

ERAs (n = 11)

Prostanoids (n = 1)

 Unchanged 6MWT, decreased BNP in ILD patients
PH‐IIP Nathan et al. 83 2019 RCT 147 Riociguat (n = 73) Terminated early for unfavorable risk/benefit profile
PH‐ILD Waxman et al. 22 2021 RCT 326

Treprostinil (inhaled)

(n = 163)

 Improved 6MWD, NT‐proBNP, clinical worsening, and FVC
PH‐ILD Dawes et al. 84 2022 Retrospective 60

PDE‐5i (n = 50)

ERAs (n = 10)

 Patients treated with sildenafil had longer survival No effect on V/Q mismatching

Abbreviations: 6MWT, 6‐min walk test; BNP, brain natriuretic peptide; CO, cardiac output; DLCO, diffusion capacity for carbon monoxide; ERA, endothelin receptor antagonist; FC, functional class; FVC, forced vital capacity; IIP, idiopathic interstitial pneumonia; ILD, interstitial lung disease; IPF, idiopathic pulmonary fibrosis; mPAP, mean pulmonary artery pressure; PDE‐5i, phosphodiesterase 5 inhibitor; PF, pulmonary fibrosis; PH, pulmonary hypertension; PVR, pulmonary vascular resistance; RCT, randomized controlled trial; RHC, right heart catheterization; SGRQ, St. George's Respiratory Quotient; QOL, quality of life; V/Q, Ventilation/Perfusion; WHO, World Health Organization.