Intravenous Prostanoids in Systemic Sclerosis-Associated Pulmonary Arterial Hypertension

A Single-Centre Experience

Maria Vlachou; Hossam Fayed; Adele Dawson; Sally Reddecliffe; Alexander Stevenson; Ross J Thomson; Benjamin Emmanuel Schreiber; J. Gerry Coghlan

Disclosures

Rheumatology. 2022;61(3):1106-1114.

Abstract and Introduction

Abstract

Objectives: The current study evaluates survival rates among SSc-associated pulmonary arterial hypertension (SSc-PAH) patients on i.v. prostanoids, and short-term impact of i.v. prostanoids on clinical and haemodynamic parameters.

Methods: Baseline demographics, invasive and non-invasive data, European Society of Cardiology (ESC) score and REVEAL score of 81 SSc-PAH patients (median age 61 years, interquartile range 54–67 years, 84% females) were prospectively recorded, from November 2006 till November 2020, before initiation of i.v. prostanoids, and at first formal reassessment. Survival data were retrieved from National Health Service Spine and hospital databases.

Results: Significant improvements in clinical and haemodynamic parameters in response to i.v. prostanoid therapy were documented. Functional class (FC) (16.6% improved by 1FC, P =0.041), mean pulmonary arterial pressure (−6.5 mmHg, P =0.036), pulmonary vascular resistance (−2.6 WU, P =0.012), cardiac index (Q/m²) (+0.7 l/min/m², P =0.003) and mixed venous oxygen saturation (SvO₂) (+3%, P =0.036) improved. Estimated survival for CTD-PAH patients on i.v. prostanoids was 64%, 31% and 18%, at 1 year, 3 years and 5 years, respectively. Independent baseline predictors of mortality were older age (HR: 1.043, 95% CI: 1.011–1.075, P =0.007), higher N-terminal pro-brain natriuretic peptide levels (HR: 2.191, 95% CI: 1.131–4.243, P =0.020), and lower SvO₂ levels (HR: 0.962, 95% CI: 0.926–0.998, P =0.039). High ESC risk or high and very high REVEAL score was associated with significantly worse survival compared with patients with lower risk scores, both at baseline and when reassessed after a median of 6.5 months.

Conclusions: Survival among SSc-PAH patients on i.v. prostanoids remains poor, risk scoring at baseline and after 6.5 months of therapy improves prognostication.

Introduction

Pulmonary arterial hypertension (PAH) is a disorder of the pulmonary vasculature associated with progressive narrowing of the distal pulmonary arteries, leading to an inexorable rise in vascular resistance, increased right ventricular workload and ultimately to right heart failure and death.^[1–3] The cause of this disorder remains unknown in most cases (idiopathic PAH, IPAH), where the driver is known congenital heart disease-associated PAH and CTD-associated PAH (CTD-PAH), while an increasing proportion is being identified as associated with genetic mutations (heritable PAH).^[1,2]

Advances in orally administered treatments have been dramatic over the past 20 years, with substantial prognostic and clinical benefits being clearly demonstrated in IPAH and more recently in CTD-PAH, including systemic sclerosis-associated PAH (SSc-PAH), the dominant subgroup.^[4,5]

Chronically administered i.v. epoprostenol was the first treatment shown to improve outcomes in PAH and remains the most effective treatment available.^[1,6,7] While clinical benefit was demonstrated in patients with SSc-PAH, unlike IPAH, mortality benefit has not been demonstrated.^[1,6–9]

Patients with SSc-PAH are generally much older than those with IPAH, have multisystem disease with lung and cardiac involvement, dexterity issues, and are more prone to pulmonary veno-occlusive disease (PVOD) – which may lead to pulmonary oedema when treated with prostanoids.^[9–11] The decision to initiate i.v. prostanoid therapy in patients with CTD-PAH is necessarily more nuanced, and the limited published data on efficacy and tolerability may contribute to delayed escalation in treatment or non-compliance with guidelines.

The limited published data in the CTD-PAH population has not addressed the haemodynamic or serological response, nor the value of risk profiling in predicting outcome.^[9,11–13] Further limited detail has been provided on the tolerability of treatment or the impact of PVOD, known to be prevalent in this population.^[11,12]

We have evaluated the impact of i.v. prostanoid therapy in a contemporary cohort of SSc-PAH patients treated at the Royal Free Hospital to determine whether survival has indeed improved, whether risk scores at initiation of i.v. therapy and at first formal re-evaluation add value and we describe the tolerability of such treatment.

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Table 1. Baseline characteristics of the SSc-PAH patients prior to commencement of intravenous prostanoids
	SSc-PAH (n = 81)
Age at pre-prostanoids (years)	61 (54–67)
Female gender, n (%)	68 (84%)
Time from PAH diagnosis to initiation of intravenous treatment (months)	24.1 (5.5–50.4)
Lung disease	21 (25.9%)
Oral treatment before intravenous treatment
None
Monotherapy	3 (3.7%)
Dual combination	15 (18.5%)
	63 (77.8%)
WHO FC
III, n (%)	61 (75.3%)
i.v., n (%)	20 (24.7%)
6-min walking distance (metres)	175 (123–268)
NT-proBNP (ng/l)	2157 (1164.8–4403.5)
Right atrial pressure (mmHg)	10 (7–14)
Mean pulmonary arterial pressure (mmHg)	51.2 ± 8.5
Pulmonary vascular resistance (Wood units)	10 (7.2–12.6)
Pulmonary capillary wedge pressure (mm)	10.3 ± 3.2
Cardiac index (L/min/m2)	2.3 (2–3)
SvO₂ (%)	60.2 ± 8.4
Treprostinil, n (%)	27 (32.3%)
Epoprostenol, n (%)	54 (66.7%)
ESC risk assessment
Low	1 (1.2%)
Intermediate	47 (58%)
High	33 (40.7%)
REVEAL score
Low	3 (3.7%)
Average	10 (12.3%)
Moderate	26 (32.1%)
High	35 (43.2%)
Very high	7 (8.6%)

ESC: European Society of Cardiology; NT-proBNP: N-terminal pro-brain natriuretic peptide; SSc-PAH: systemic sclerosis-associated pulmonary arterial hypertension; SvO₂: mixed venous oxygen saturation; WHO FC: World Health Organization Functional Class. Continuous variables are presented as mean ± standard deviation or median (interquartile range, IQR).

Table 2. Differences in baseline and follow-up characteristics in SSc-PAH patients before and after initiation of intravenous prostanoids
	Baseline (n = 60)	Follow-up (n = 60)	P-value
WHO FC n (%)
I	0 (0 %)	0 (0%)
II	0 (0 %)	8 (13.3%)	0.041
III	48 (80 %)	42 (70%)
i.v.	12 (20 %)	10 (16.7%)
6-min walking distance (metres)	180 (132–325)	237 (132–338)	0.070
NT-proBNP (ng/l)	1970 (1024–3879)	1398.5 (560–4416)	0.622
Right atrial pressure (mmHg)	10 (7.3–12.8)	9(6.3–12)	0.528
Mean pulmonary arterial pressure (mmHg)	52.5 (43.3–56.8)	46 (40–54)	0.036
Pulmonary vascular resistance (Wood units)	9.9 (7.7–12.3)	7.3 (5.2–10.9)	0.012
Pulmonary capillary wedge pressure (mmHg)	10 (8–13)	10 (9–11)	0.655
Cardiac index (L/min/m2)	2.3 (2–3)	3(2–3.5)	0.003
SVO₂ (%)	62 (56–67)	65 (58–71)	0.036
ESC score
Low	1 (1.7%)	8 (13.3%)	0.048
Intermediate	39 (65%)	36 (60 %)
High	20 (33.3%)	16 (26.7%)
REVEAL score
Low	2 (3.3%)	8 (13.3%)
Average	9 (15%)	8 (13.3%)	0.028
Moderate	21 (35%)	23(38.3%)
High	24 (40%)	18 (30 %)
Very high	4 (6.7%)	3 (5%)

ESC: European Society of Cardiology; NT-proBNP: N-terminal pro-brain natriuretic peptide; PAH: pulmonary arterial hypertension; SSc-PAH: SSc-associated pulmonary arterial hypertension; SvO₂: mixed venous oxygen saturation; WHO FC: World Health Organization Functional Class. Continuous variables are presented as mean ± standard deviation or median (interquartile range, IQR).
Bold values represent statistically significant results (P <0.05).

Table 3. Univariable and multivariables associates of baseline determinants of mortality in SSc-PAH patients, before commencement of intravenous prostanoids
Clinical variables	Univariable analysis		Multivariable analysis
Clinical variables	HR (95% CI)	P-value	HR (95% CI)	P-value
Time of initiation of intravenous prostanoids after diagnosis	1.000 (0.992, 1.008)	0.969
Lung disease	1.263 (0.715, 2.229)	0.421
Oral treatment before intravenous treatment
None vs monotherapy	2.067 (0.461, 9.273)	0.343
None vs combination therapy	1.772 (0.429, 7.325)	0.430
Age, years	1.036 (1.008, 1.064)	0.011	1.043(1.011, 1.075)	0.007
Gender	1.234(0.586, 2.600)	0.580
WHO FC	1.495 (0.842, 2.654)	0.170
Log NT pro-BNP (ng/l)	2.597 (1.419, 4.756)	0.002	2.191(1.131, 4.243)	0.020
6-min walking distance (metres)	0.999 (0.997, 1.001)	0.369
Right atrial pressure (mmHg)	1.032 (0.985, 1.081)	0.191
Mean pulmonary arterial pressure (mmHg)	1.026 (0.991, 1.063)	0.143
Pulmonary vascular resistance (Wood units)	1.043 (0.983, 1.107)	0.159
Pulmonary capillary wedge pressure (mmHg)	0.984(0.906, 1.068)	0.695
Cardiac index (L/min/m2)	1.033 (0.712, 1.500)	0.862
SvO₂ (%)	0.953 (0.923, 0.985)	0.005	0.962(0.926, 0.998)	0.039

HR: hazard ratio; NT-proBNP: N-terminal pro-brain natriuretic peptide; SSc-PAH: SSc-associated pulmonary arterial hypertension; SvO₂: mixed venous oxygen saturation; WHO FC: World Health Organization Functional Class.
Bold values represent statistically significant results (P <0.05).