Inhaled Treprostinil Improves Cardiac Output during Exertion in Interstitial Lung Disease

Introduction

Although inhaled treprostinil improves functional status in interstitial lung disease associated pulmonary hypertension(ILD-PH),(1,2) the mechanistic basis remains incompletely understood, with similar benefit not observed with oral vasodilators.(3–5) Only one study has evaluated hemodynamic response in ILD-PH, with reduction in resting pulmonary vascular resistance(PVR), and no impact on resting oxygenation.(6) However, resting measures imperfectly capture physiological abnormalities during exertion in ILD-PH, where hypoxemia worsens.(7) We hypothesized that inhaled treprostinil in ILD-PH would acutely improve cardiac output(CO) reserve during exertion without detrimental gas-exchange effects. To test this hypothesis, we conducted a paired exercise hemodynamic study with right heart catheterization(RHC), arterial line and gas-exchange monitoring in ILD-PH before and 30 minutes after acute administration of 32 mcg of inhaled treprostinil.

Methods

This was a prospective, single-arm, open-label interventional study of patients with suspected ILD-PH. The Mayo Clinic Institutional Review Board approved the study, all participants provided written informed consent, and the trial was registered (NCT05564637). Inclusion criteria required clinical diagnosis of ILD, and precapillary pulmonary arterial hypertension at rest.

Hemodynamic Assessment

Exercise RHC studies were performed as previously described.(8) For patients comfortable on room air, oxygen consumption (VO₂) and ventilatory parameters were continuously monitored to calculate CO using direct Fick. For patients who were O₂ dependent, CO was calculated using thermodilution, with arterial and PA blood gases were used to compute VO₂ as thermodilution CO*AVO₂diff.(9)

Following resting assessment, participants exercised on a supine cycle at a fixed 20-watt workload for 5 minutes at 60 rpm. Following exercise and a 5-minute waiting period, patients were given a single inhalation of 32 mcg of dry powdered treprostinil. After a 30-minute waiting period, repeat rest and 20-watt exercise hemodynamics were obtained.

Pressure tracings were measured offline at end-expiration with blinding to hemodynamic sequence and patient information during pressure waveform adjudication (YNR). As an alternate method of reporting pressures, we also report pressures averaged over 15 seconds during free breathing.(10) Measures of pulmonary vascular load, alveolar-to-arterial O₂ difference(A-a gradient) and physiological shunt fraction were calculated as previously described.(11)

Endpoints

The primary endpoint of the study was change in CO reserve with exercise (exercise CO-rest CO) with inhaled treprostinil compared to baseline. Secondary endpoints included V_E/VCO₂, rest and exercise PVR, pulmonary artery(PA) pressure and right atrial(RA) pressure. Changes in pulmonary capillary wedge pressure(PCWP) and gas exchange measures were exploratory endpoints. Changes from before to after inhaled treprostinil administration were compared by paired t-test or Wilcoxon signed rank test.

Results

Study population

Of 23 subjects enrolled, 1 patient had elevated resting PCWP, and did not receive inhaled treprostinil. The final study sample(n=22) had mean age 72±8 years, body mass index 30±8 kg/m², were 41% female and 95% White Race, with elevated NT-proBNP(median 177[IQR 83-452 pg/ml]) and impaired 6-minute walk distance (250±96m).The most common cause of ILD was idiopathic pulmonary fibrosis(63%) followed by connective tissue disease(23%) and hypersensitivity pneumonitis(9%). Patients had severe DL_CO impairment(median 35[IQR 31-42]%predicted) and restrictive physiology(TLC 66±13%predicted, FEV1/FVC 109±8%predicted).

Effect of inhaled treprostinil on resting hemodynamics

Inhaled treprostinil reduced resting RA pressure, with no change in PCWP(Table). There was a reduction in mean PA pressure from reduction in PVR, but no change in resting CO.

Table:

Effect of inhaled treprostinil on resting and exercise hemodynamics and gas exchange

	REST			EXERCISE
	Baseline mean (SD)	Post treprostinil mean (SD)	Paired T test p value	Baseline mean (SD)	Post treprostinil mean (SD)	Paired T test p value
Ventricular Filling pressures
PCWP, mmHg	11.3 (4.2)	10.8 (5.2)	0.46	18.6 (5.3)	22.4 (9.6)	0.03
PCWP v wave, mmHg	11.7 (5.2)	11.2 (5.2)	0.40	19.3 (5.6)	26.0 (13.2)	0.01
PCWPresp, mmHg	7.5 (3.3)	6.7 (3.5)	0.12	13.3 (5.7)	15.7 (7.8)	0.08
RA, mmHg	7.9 (3.4)	6.2 (3.1)	0.003	16.1 (6.3)	12.9 (6.0)	0.005
RAresp, mmHg	5.0 (3.5)	2.9 (2.9)	0.0004	12.1 (5.1)	8.0 (4.9)	<0.0001
Pulmonary Vascular Function
PA mean, mmHg	36.0 (7.3)	25.1 (5.2)	<0.0001	50.4 (9.3)	40.6 (9.0)	<0.0001
PA meanresp, mmHg	32.0 (6.6)	22.0 (4.8)	<0.0001	48.4 (8.7)	39.0 (9.6)	<0.0001
PVR, Wood units	5.4 (2.1)	3.1 (1.4)	<0.0001	4.3 (2.1)	2.2 (1.2)	<0.0001
PA compliance, ml/mmHg	2.2 (0.9)	3.6 (1.6)	<0.0001	2.1 (1.0)	3.1 (1.2)	<0.0001
PA-PCWP diastolic gradient	12.9 (4.7)	7.1 (3.4)	<0.0001	18.7 (6.6)	9.7 (6.0)	<0.0001
Integrated Indices
Heart Rate, bpm	76 (13)	76 (12)	0.93	102 (11)	100 (13)	0.14
Stroke volume, ml	65 (20)	66 (20)	0.64	79 (20)	87 (17)	0.04
Cardiac output, L/min	4.9 (1.4)	5.0 (1.3)	0.60	8.2 (2.3)	8.7 (2.2)	0.03*
VO2, ml/min	219 (57)	226 (53)	0.39	616 (198)	665 (223)	0.045
O2 delivery, ml/min	750 (226)	747 (212)	0.89	1159 (336)	1194 (342)	0.38
AVO2diff, ml/dl	4.6 (0.8)	4.6 (0.8)	0.43	7.7 (2.2)	7.6 (1.7)	0.73
Gas Exchange
A-a gradient, mm Hg (n=15)	38.0 (11.6)	41.7 (12.5)	0.01	59.6 (11.4)	63.4 (10.6)	0.038
Physiologic shunt fraction, %	27.9 (10.1)	28.9 (10.6)	0.47	32.5 (12.1)	35.0 (13.3)	0.0003
Minute ventilation, L/min (n=16)	9.2 (2.7)	9.7 (2.4)	0.38	32.1 (10.7)	33.5 (13.2)	0.27
VE/VCO2 (n=16)	56.3 (12.2)	55.7 (10.2)	0.75	50.4 (10.6)	51.2 (11.2)	0.57
Arterial O2 content, ml/dl (n=22)	15.4 (1.9)	15.1 (1.8)	0.009	14.3 (1.8)	13.7 (1.7)	0.005
Arterial pO2, mmHg (n=21)	61.3 (14.8)	57.8 (15.1)	0.12	47.9 (12.8)	43.8 (8.6)	0.003*
Arterial O2 saturation, % (n=22)	88.9 (5.1)	87.5 (5.3)	0.054	80.0 (8.6)	76.8 (9.3)	0.003

^*by Wilcoxon signed rank test. PCWP-pulmonary capillary wedge pressure, RA-right atrial pressure, PA-pulmonary artery, resp-respiratory averaged pressure, VO₂-oxygen consumption, AVO2diff-arterial venous O₂ content difference, V_E/VCO₂ -minute ventilation/CO₂ production

Effect of inhaled treprostinil on exercise hemodynamics

Inhaled treprostinil increased exercise CO reserve [median +0.77 L/min(IQR −0.15 to +1.29),p=0.018], absolute peak CO [median +0.9 L/min[IQR −0.1 to +1.6],p=0.03], and CO relative to VO₂ [median +0.81(IQR −0.00 to +2.12),p=0.043].(Table). There was a reduction in exercise PA pressure, along with improved PVR and RA pressure.

Inhaled treprostinil increased exercise PCWP(+3.7 mmHg[+0.4 to +7.1], p=0.03) . Prior to inhaled treprostinil, only 1 patient(4.5%) had an exercise PCWP≥25 mm Hg, but 8 additional patients [9/22 patients](40.9%) had exercise PCWP≥25 mm Hg following inhaled treprostinil(McNemar p=0.005).

Effect of inhaled treprostinil on ventilatory parameters and gas exchange

There was no effect of inhaled treprostinil on ventilation or arterial pO₂ during rest.(Table). During exercise, there was an increase in A-a gradient and physiological shunt fraction with a reduction in exercise arterial pO₂ and O₂ content. The reduction in exercise arterial pO₂ was related to the increase in exercise physiological shunt fraction (r=0.94, p<0.0001), and to the increase in exercise PCWP (r=0.57, p=0.006).

Clinical response to inhaled treprostinil

All 22 participants initiated inhaled treprostinil, of whom 13(59%) reported either improved or stable symptoms in follow up and 9 participants reported worsening symptoms(41%). Out of these 9 participants with clinical worsening, 8 discontinued therapy due to intolerance and worsening symptoms. An acute increase in exercise PCWP with treprostinil compared to baseline was associated with subsequent worsening symptoms(OR 1.20 [95% CI 1.03-1.49] per mm Hg, AUC 0.80, p=0.01).

Discussion

This is the first study to test the effects of inhaled treprostinil on the O₂ transport cascade during exercise in ILD-PH. Following a single dose of inhaled treprostinil, there was a reduction in resting PVR without observable effect on resting CO or oxygenation. An improvement in CO reserve was only apparent during exertion, in tandem with modest worsening of arterial O₂ content, in the setting of greater physiological shunting, and an increase in exercise PCWP. The favorable effects on RV-PA coupling from vascular unloading were offset by decreases in arterial O₂ content and increasing PCWP, with no net effect on systemic O₂ delivery. These findings provide new insights into the complex and competing interplay between hydraulic and gas exchange limitations in ILD-PH.

The rapid onset of action of inhaled treprostinil without ventilatory effects emphasizes the predominant hemodynamic mechanisms of benefit. The observation that longer term treatment with inhaled treprostinil in ILD-PH improves functional status(1) even among those with comorbidities(12) indicates that on average the favorable pulmonary vascular effects to improve exercise CO outweigh the modest deleterious effects on arterial oxygenation and left heart filling pressures. It is notable that the therapeutic effects of treprostinil were underestimated from resting measurements, with augmentation in CO, elevation in PCWP and decline in arterial saturation observed only during exertion emphasizing the value of functional exercise testing to understand individual response to therapy. The unexpected increase in exercise PCWP and its association with worsening hypoxia and symptoms in a subset of patients following inhaled treprostinil may reflect occult left heart abnormalities(13) with potential implications for optimal patient selection for pulmonary vasodilation in the setting of lung disease. Whether similar changes in exercise PCWP may have contributed to the unexpected clinical worsening in patients with chronic obstructive pulmonary disease treated with inhaled treprostinil requires further study.(14)

Limitations

The non-randomized, non-placebo controlled nature of the study introduces potential for bias, including possibility of carryover effects from the first bout of exercise. However, we have previously shown that such salutary effects from repeat 20 watt exercise in the setting of placebo did not change exercise PVR, and were associated with a decrease in exercise PCWP (whereas we observed the opposite with an increase in exercise PCWP).(15) To minimize bias, we utilized blinded pressure interpretation at end-expiration, and in addition evaluated bias-resistant and adjudication agnostic respiratory averaged pressures which were all internally consistent demonstrating internal validity.

Conclusion

Inhaled treprostinil in ILD-PH improves exercise CO reserve at the cost of modest worsening of physiological shunting, pulmonary venous hypertension, and arterial hypoxemia. These data provide new insights into the mechanisms underlying clinical effects of treprostinil on exercise intolerance in ILD-PH.