Prognosis and response to first-line single and combination therapy in pulmonary arterial hypertension

Figures & data

Figure 1. Selection of patients for the treatment response analysis. PAH, pulmonary arterial hypertension; IPAH, idiopathic pulmonary arterial hypertension; HPAH, hereditary pulmonary arterial hypertension; CTD-PAH, connective tissue disease-associated pulmonary arterial hypertension; RHC, right heart catheterization.

Table I. Characteristics at first right-heart catheterization for the entire study population.

	All patients	IPAH/HPAH	CTD-PAH
Gender
Male	24 (31.2%)	16 (41%)	8 (21.1%)
Female	53 (68.8%)	23 (59%)	30 (78.9%)
Age (years)	58.0 ± 16.7 (n = 77)	54.7 ± 19.0 (n = 39)	61.5 ± 13.4 (n = 38)
WHO-FC
I	0 (0%)	0 (0%)	0 (0%)
II	10 (13.2%)	5 (13.2%)	5 (13.2%)
III	47 (61.8%)	27 (71%)	20 (52.6%)
IV	19 (25%)	6 (15.8%)	13 (34.2%)
Treatment regimens
ERA	45 (58.4%)	19 (48.7%)	26 (68.4%)
PDE5i	8 (10.4%)	5 (12.8%)	3 (7.9%)
PC inhalation	3 (3.9%)	3 (7.7%)	0 (0%)
PC intravenous	1 (1.3%)	0 (0%)	1 (2.6%)
CCB	2 (2.6%)	2 (5.1%)	0 (0%)
Two drugs	16 (20.8%)	8 (20.5%)	8 (21.1%)
Three drugs	2 (2.6%)	2 (5.1%)	0 (0%)
MPAP (mmHg)	46.9 ± 12.9 (n = 76)	51.2 ± 14.2 (n = 38)	42.6 ± 9.9 (n = 38)
MRAP (mmHg)	6.1 ± 5.7 (n = 75)	5.7 ± 5.0 (n = 37)	6.5 ± 6.3 (n = 38)
CI (l·min^− 1·m^− 2)	2.4 ± 0.7 (n = 76)	2.2 ± 0.5 (n = 38)	2.6 ± 0.8 (n = 38)
PVRI (WU·m^− 2)	18.9 ± 9.1 (n = 76)	21.9 ± 9.5 (n = 38)	15.8 ± 7.7 (n = 38)
PCWP (mmHg)	7.0 ± 4.4 (n = 76)	7.2 ± 3.7 (n = 38)	6.7 ± 5.0 (n = 38)
TPG (mmHg)	39.9 ± 12.2 (n = 76)	44.0 ± 13.3 (n = 38)	35.8 ± 9.6 (n = 38)
DPG (mmHg)	19.5 ± 10.4 (n = 76)	23.6 ± 9.9 (n = 38)	15.5 ± 9.3 (n = 38)
RVSWI (g·m^− 2·beat^− 1)	15.7 ± 5.5 (n = 74)	16.5 ± 6.1 (n = 36)	14.9 ± 4.8 (n = 38)
MRAP/CI (mmHg/(l·min^− 1·m^− 1))	3.7 ± 3.3 (n = 64)	3.2 ± 2.5 (n = 33)	4.1 ± 3.9 (n = 31)

IPAH, idiopathic pulmonary arterial hypertension; HPAH, hereditary pulmonary arterial hypertension; CTD-PAH, connective tissue disease-associated pulmonary arterial hypertension; WHO-FC, World Health Organization functional class; ERA, endothelin receptor antagonist; PDE5i, phosphodiesterase-5 inhibitor; PC, prostacyclin; CCB, calcium channel blocker; MPAP, mean pulmonary arterial pressure; MRAP, mean right atrial pressure; CI, cardiac index; PVRI, pulmonary vascular resistance index; PCWP, pulmonary capillary wedge pressure; TPG, transpulmonary gradient; DPG, diastolic pulmonary vascular pressure gradient; RVSWI, right ventricular stroke work index

Figure 2. 1-, 2- and 3-year survival rates, respectively, for (A) the entire study population, (B) IPAH/HPAH- and CTD-PAH patients, respectively, and the proportion of patients that started first-line single therapy and who were still alive on single therapy at 1-, 2- and 3-years, respectively, from treatment start for (C) the entire study population and (D) IPAH/HPAH- and CTD-PAH patients, respectively. IPAH, idiopathic pulmonary arterial hypertension; HPAH, hereditary pulmonary arterial hypertension; CTD-PAH, connective tissue disease-associated pulmonary arterial hypertension. Our findings support that survival has improved, as compared with untreated patients in the 1991 NIH registry study, which reported a median survival of 2.8 years for patients with primary pulmonary hypertension, and only approximately one year for patients with associated Raynaud phenomenon (A, B). Our data also show that a large proportion of patients who started on first-line single therapy required early treatment escalation (C, D).

Table II. Baseline characteristics and haemodynamic response to first-line single- and combination therapy, respectively, in IPAH/HPAH and CTD-PAH.

	First-line single therapy			First-line combination therapy			Single- vs. combination therapy p-value
	Before treatment	Follow-up	p-value	Before treatment	Follow- up	p-value
Gender
Male	11 (27.5%)	N/A	N/A	4 (30.8%)	N/A	N/A	N/A
Female	29 (72.5%)	N/A	N/A	9 (69.2%)	N/A	N/A	N/A
Age (years)	59.4 ± 15.6 (n = 40)	N/A	N/A	48.1 ± 19.1 (n = 13)	N/A	N/A	N/A
WHO-FC
I	0 (0%)	N/A	N/A	0 (0%)	N/A	N/A	N/A
II	8 (20%)	N/A	N/A	0 (0%)	N/A	N/A	N/A
III	23 (57.5%)	N/A	N/A	11 (84.6%)	N/A	N/A	N/A
IV	9 (22.5%)	N/A	N/A	2 (15.4%)	N/A	N/A	N/A
MPAP (mmHg)	46.6 ± 12.7 (n = 40)	44.3 ± 14.1 (n = 40)	0.048*	53.6 ± 14.2 (n = 13)	49.3 ± 14.4 (n = 13)	0.037*	0.354
MRAP (mmHg)	4.5 ± 4.8 (n = 39)	5.0 ± 4.3 (n = 40)	0.154	6.2 ± 3.9 (n = 13)	6.2 ± 3.4 (n = 13)	0.949	0.545
CI (l·min.^1·m^− 2)	2.4 ± 0.6 (n = 40)	2.5 ± 0.8 (n = 40)	0.071	2.1 ± 0.6 (n = 13)	2.4 ± 0.5 (n = 13)	0.042*	0.325
PVRI (WU·m^− 2)	18.3 ± 8.8 (n = 40)	16.4 ± 9.2 (n = 40)	0.040*	24.4 ± 8.9 (n = 13)	18.2 ± 8.9 (n = 13)	0.001*	0.017*
PCWP (mmHg)	7.2 ± 5.1 (n = 40)	7.8 ± 4.8 (n = 40)	0.177	5.4 ± 3.1 (n = 13)	7.2 ± 3.4 (n = 13)	0.100	0.454
TPG (mmHg)	39.4 ± 11.4 (n = 40)	36.6 ± 12.6 (n = 40)	0.011*	48.2 ± 13.1 (n = 13)	42.1 ± 15.2 (n = 13)	0.002*	0.116
DPG (mmHg)	18.5 ± 10.0 (n = 40)	15.1 ± 10.6 (n = 40)	0.004*	27.2 ± 10.5 (n = 13)	21.9 ± 9.9 (n = 13)	0.004*	0.351
RVSWI (g·m^− 2·beat^− 1)	16.5 ± 4.4 (n = 39)	16.6 ± 4.4 (n = 39)	0.951	16.4 ± 7.5 (n = 12)	18.7 ± 7.2 (n = 13)	0.076	0.106
MRAP/CI (mmHg/(l·min^− 1·m^− 1))	3.0 ± 2.8 (n = 30)	2.7 ± 2.0 (n = 35)	0.811	3.4 ± 2.4 (n = 13)	3.0 ± 1.5 (n = 12)	0.353	0.490

A * indicates statistical significance (p < 0.05).

IPAH, idiopathic pulmonary arterial hypertension; HPAH, hereditary pulmonary arterial hypertension; CTD-PAH, connective tissue disease-associated pulmonary arterial hypertension; N/A, not applicable; WHO-FC, World Health Organization functional class; MPAP, mean pulmonary arterial pressure; MRAP, mean right atrial pressure; CI, cardiac index; PVRI, pulmonary vascular resistance index; PCWP, pulmonary capillary wedge pressure; TPG, transpulmonary gradient; DPG, diastolic pulmonary vascular pressure gradient; RVSWI, right ventricular stroke work index

Table III. Age-adjusted HR/SD for death or transplantation for variables at baseline and first RHC follow-up as well as of changes in variables from baseline to follow-up.

Parameter	Baseline			First RHC follow-up			Change from baseline to follow-up
	n	HR/SD	95% CI	n	HR/SD	95% CI	n	HR/SD	95% CI
MPAP	71	1.2	0.9–1.6	53	1.4	0.9–2.2	53	1.1	0.7–1.6
MRAP	70	1.5	1.1–2.0*	53	1.3	0.9–1.8	52	1.0	0.7–1.5
CI	71	0.9	0.6–1.2	53	0.6	0.4–1.1	53	0.8	0.5–1.2
PVRI	71	1.4	1.0–2.0	53	1.6	1.1–2.4*	53	1.4	0.9–2.1
DPG	71	1.2	0.9–1.7	52	1.5	0.9–2.3	52	1.1	0.8–1.5
TPG	71	1.2	0.9–1.7	53	1.5	0.9–2.3	53	1.1	0.7–1.6
RVSWI	69	0.8	0.6–1.1	52	0.6	0.4–1.0	53	0.8	0.5–1.2
MRAP/CI	59	1.5	1.1–2.1*	47	1.4	1.0–2.1	40	1.1	0.7–1.8
WHO-FC	71	1.8	1.3–2.5*	31	1.6	0.9–3.0	31	0.7	0.4–1.1
6MWD	47	0.4	0.2–0.7*	38	0.4	0.2–0.7*	29	1.2	0.7–2.0

A * indicates statistical significance (p < 0.05).

HR, hazard ratio; 95% CI, 95% confidence interval; MPAP, mean pulmonary arterial pressure; MRAP, mean right atrial pressure; CI, cardiac index; PVRI, pulmonary vascular resistance index; DPG, diastolic pulmonary vascular pressure gradient; TPG, transpulmonary gradient; RVSWI, right ventricular stroke work index; WHO-FC, World Health Organization functional class; 6MWD, 6 min walking distance.