Rationale: Data from STEP-IPF in patients with IPF and DLco < 35% predicted suggested that sildenafil
may be associated with benefits on exercise capacity and health-related quality of
life (HRQL) versus placebo in patients with right ventricular systolic dysfunction
(RVSD) or right ventricular hypertrophy (RVH). In the INSTAGE trial, patients with
IPF and DLco ≤ 35% predicted received nintedanib plus sildenafil or nintedanib alone
for 24 weeks, stratified by the presence of echocardiographic signs of right heart
dysfunction (RHD) (defined as ≥ 1 of RVSD, RVH, right ventricular dilatation, paradoxical
septum motion, right atrium enlargement). Nintedanib plus sildenafil was not associated
with significant benefits on HRQL versus nintedanib alone; however, in an exploratory
analysis associated with stabilisation in brain natriuretic peptide (BNP) and reduced
FVC decline. We assessed whether the presence of RHD at baseline influenced the effects.
Methods: Changes from baseline in St Georgeʼs Respiratory Questionnaire (SGRQ) total score,
FVC at weeks 12 and 24, BNP at week 24; time to absolute FVC ≥ 5% predicted or death;
and time to relative FVC decline ≥ 10% predicted or death were assessed in patients
with and without signs of RHD at baseline.
Results: In total, 117 patients (nintedanib plus sildenafil 61; nintedanib 56) had signs of
RHD and 156 (76; 80) did not. In both subgroups, nintedanib plus sildenafil had a
numerically greater effect on change in SGRQ at week 24 and all endpoints related
to FVC versus nintedanib alone. There was a significant treatment-by-subgroup-by-time
(TST) interaction for change in BNP at week 24, indicating a significantly greater
effect of nintedanib plus sildenafil versus nintedanib alone in patients with RHD
at baseline ([Table 1]). Significant TST interactions were also observed for change in BNP at week 24 in
patients with versus without RVSD (n = 44 and n = 229), respectively) and with versus
without RVH (n = 53 and n = 219), respectively).
Table 1
|
|
Echocardiographic signs of right heart dysfunction
|
No echocardiographic signs of right heart dysfunction
|
Treatment-by-subgroup-by-time interaction p-value
|
|
|
Nintedanib + sildenafil
|
Nintedanib alone
|
|
Nintedanib + sildenafil
|
Nintedanib alone
|
|
|
|
Mean (SE) change from baseline
|
Mean (SE) change from baseline
|
Difference (95% CI)
|
Mean (SE) change from baseline
|
Mean (SE) change from baseline
|
Difference (95% CI)
|
|
* Rate of decline (slope) in FVC over the 24-week period. ** Data are n (%) of patients
with an event with between-group differences expressed as hazard ratios.
|
|
SGRQ total score
|
|
|
|
|
|
|
|
|
week 12
|
− 0.45 (.1.54)
|
− 0.45 (1.63)
|
− 0.01 (− 4.41, 4.40)
|
− 1.91 (1.35)
|
− 0.95 (1.30)
|
− 0.96 (− 4.65, 2.72)
|
0.7435
|
|
week 24
|
0.76 (1.79)
|
3.28 (1.91)
|
− 2.52 (− 7.67, 2.63)
|
− 0.16 (1.50)
|
1.93 (1.47)
|
− 2.10 (− 6.23, 2.04)
|
0.8999
|
|
BNP, ng/L, week 24
|
− 18.3 (18.3)
|
101.6 (18.9)
|
− 119.9 (− 171.3, − 68.5)
|
− 6.6 (15.9)
|
− 3.0 (15.5)
|
− 3.6 (− 47.2, 40.0)
|
0.0009
|
|
FVC, mL
|
|
|
|
|
|
|
|
|
week 12
|
35.4 (24.0)
|
− 12.3 (24.8)
|
47.7 (− 20.3, 115.6)
|
− 13.1 (21.2)
|
− 35.4 (20.3)
|
22.4 (− 35.5, 80.2)
|
0.5772
|
|
week 24
|
6.5 (29.9)
|
− 51.5 (31.4)
|
58.0 (− 27.5, 143.5)
|
− 39.9 (26.1)
|
− 64.4 (25.2)
|
24.5 (− 47.0, 96.0)
|
0.5541
|
|
Rate of FVC decline, mL/24 weeks*
|
22.9 (30.9)
|
− 63.3 (32.1)
|
86.2 (− 2.7, 175.0)
|
− 50.9 (25.5)
|
− 69.8 (24.4)
|
19.0 (− 51.0, 88.9)
|
0.2918
|
|
Absolute FVC decline ≥ 5% predicted or death**
|
22 (36.1)
|
27 (48.2)
|
0.72 (0.41, 1.27)
|
21 (27.6)
|
42 (52.5)
|
0.46 (0.27, 0.78)
|
0.2798
|
|
Relative FVC decline ≥ 10% predicted or death
|
17 (27.9)
|
22 (39.3)
|
0.71 (0.38, 1.34)
|
18 (23.7)
|
28 (35.0)
|
0.66 (0.36, 1.19)
|
0.8996
|
Conclusions: In patients with IPF and severely impaired gas exchange, nintedanib plus sildenafil
had a numerically greater effect on FVC decline than nintedanib alone in patients
with and without signs of RHD at baseline and the benefit on reducing BNP was more
pronounced in patients with RHD, or specifically with RVSD or RVH, at baseline.
* presented at ATS 2019
