Nintedanib plus sildenafil versus nintedanib alone in patients with IPF and severely impaired gas exchange: subgroup analysis by right heart dysfunction*

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