Figures
- FIGURE 1
The high co-incidence of interstitial lung disease and pulmonary hypertension can be explained by shared pathophysiology concerning parenchymal and vascular remodelling. ET: endothelin; ER: endothelin receptor; PGI2: prostaglandin I2 (prostacyclin); NO: nitric oxide; IP: prostacyclin; sGC: soluble guanylyl cyclase; PDE: phosphodiesterase; IL: interleukin; BMPR: bone morphogenetic protein receptor; TGF: transforming growth factor.
Tables
- TABLE 1
Findings suggestive for interstitial lung disease associated pulmonary hypertension
Clinical Bimalleolar oedema
Jugular venous distension
Signs of RV dysfunctionPulmonary function tests Disproportionately severe decrease in diffusing capacity of the lung, while lung volumes are normal or only modestly reduced 6-min walk test Lower than expected 6-min walk distance
Marked exertional desaturationLaboratory testing Elevated (NT-pro)BNP
Research: heart-type fatty acid binding protein, growth differentiation factor-15Chest imaging Increased pulmonary artery to ascending aorta ratio (>0.9)
Main pulmonary artery diameter >29 mm
RV enlargementEchocardiography Peak tricuspid regurgitation velocity ≥2.8 m·s−1
RV/LV basal diameter ratio >1.0
Flattening of the interventricular septum
RV outflow Doppler acceleration time <105 ms and/or midsystolic notching
Pulmonary artery diameter >25 mm
Inferior vena cava diameter >21 mm with decreased inspiratory collapse
Right atrial area >18 cm2RV: right ventricle; NT-proBNP: N-terminal pro-brain natriuretic peptide; LV: left ventricle.
- TABLE 2
Overview of double-blind, placebo-controlled, randomised clinical trials evaluating different classes of pulmonary arterial hypertension drugs in patients with idiopathic pulmonary fibrosis (IPF) and/or interstitial lung disease (ILD)
Trial Patient population Main inclusion criteria Intervention Primary end-point Results PDE-5 inhibitors STEP-IPF trial [32] 180:
89 sildenafil
91 placeboIPF at an advanced stage (DLCO <35% predicted) Sildenafil versus placebo for 12 weeks Proportion of patients with ≥20% increase on 6MWT ☒ 10% (sildenafil) versus 7% (placebo) (p=0.39) Soluble guanylate cyclase stimulators RISE-IIP trial
[33]147:
73 riociguat
74 placeboIIP
FVC >45%
6MWD 150–450 m
WHO functional classes II–IV
Pre-capillary PH confirmed by RHC
SBP >95 mmHg
No signs or symptoms of hypotensionRiociguat versus placebo for 26 weeks Change from baseline in 6MWT ☒ Study terminated early due to increased adverse events Endothelin receptor antagonists BPHIT trial [34] 60:
40 bosentan
20 placeboIIP
Pre-capillary PH confirmed by RHCBosentan versus placebo for 16 weeks Fall from baseline PVRI ≥20% ☒ 28.0% (bosentan) versus 28.6% (placebo) (p=0.97) ARTEMIS-IPF trial [35] 494:
330 ambrisentan
164 placeboPatients with IPF with minimal or no honeycombing on high-resolution computed tomography scan Ambrisentan versus placebo Time to IPF disease progression ☒ 27.4% (ambrisentan) versus 17.2% (placebo) (p=0.01); trial terminated early due to increased disease progression in intervention group MUSIC trial [36] 178:
119 macitentan
59 placeboIPF of <3 years’ duration
A histological pattern of usual interstitial pneumonia on surgical lung biopsyMacitentan versus placebo for 12 months Change from baseline in FVC ☒ −0.2 L (macitentan) versus −0.2 L (placebo) (p=1.00) Prostanoids INCREASE trial [37] 326:
163 inhaled treprostinil
163 placeboILD and pre-capillary PH confirmed by RHC
6MWT >100 mTreprostinil versus placebo for 16 weeks Change from baseline in distance on 6MWT ✓□☑ +21.1 m (treprostinil) versus −10.0 m (placebo) (p<0.001) PDE-5 inhibitors on top of approved IPF therapy INSTAGE trial [38] 273:
137 nintedanib+sildenafil
136 nintedanib+placeboIPF at an advanced stage (DLCO <35% predicted) Nintedanib+sildenafil versus nintedanib+placebo for 24 weeks Change from baseline in the total score on the SGRQ at week 12 ☒ −1.28 versus −0.77 points (p=0.72) Efficacy and safety of sildenafil added to pirfenidone in patients with advanced IPF and risk of PH [16] 177:
88 pirfenidone+sildenafil
89 pirfenidone+placeboIPF at an advanced stage (DLCO <40% predicted)
mPAP ≥20 mmHg with PAWP ≤15 mmHg on RHC
or
intermediate/high probability of group 3 PH on echocardiographyPirfenidone+sildenafil versus pirfenidone+placebo for 52 weeks Proportion of patients with disease progression ☒ 73% (sildenafil) versus 70% (placebo) (p=0.65) PDE: phosphodiesterase; DLCO: diffusing capacity of the lung for carbon monoxide; 6MWT: 6-min walk test; IIP: idiopathic interstitial pneumonia; FVC: forced vital capacity; 6MWD: 6-min walk distance; WHO: World Health Organization; PH: pulmonary hypertension; RHC: right heart catheterisation; SBP: systolic blood pressure; PVRI: pulmonary vascular resistance index; SGRQ: St George's Respiratory Questionnaire; mPAP: mean pulmonary artery pressure; PAWP: pulmonary artery wedge pressure; ☒: negative trial; ✓□☑: positive trial.
