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Impact of Pulmonary Capillary Wedge Pressure on Long-Term Mortality in Patients With Pulmonary Arterial Hypertension Treated With Parenteral Trepostinil
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Heart, Lung and Circulation (2017) xx, 1–7 1443-9506/04/$36.00 http://dx.doi.org/10.1016/j.hlc.2017.02.015
ORIGINAL ARTICLE
Impact of Pulmonary Capillary Wedge Pressure on Long-[47_TD$IF]term Mortality in Patients with Pulmonary Arterial Hypertension Treated with Parenteral Trepostinil Jignesh K. Patel, MD a*, Youlan Rao, PhD b, Paul Strachan, MD a a
Division of Pulmonary and Critical Care Medicine, Department of Medicine, State University of New York at Stony Brook, Stony Brook, NY, USA Biostatistics, United Therapeutics Corporation, Research Triangle Park, NC, USA
b
Received 5 May 2016; received in revised form 17 December 2016; accepted 12 February 2017; online published-ahead-of-print xxx
Background
The clinical impact of pulmonary capillary wedge pressure (PCWP) on long-term mortality among patients with pulmonary arterial hypertension (PAH) has been incompletely reported, particularly in relation to concomitant treprostinil administration. The goal of this study was to assess the impact of PCWP on longterm mortality in PAH patients treated with parenteral treprostinil.
Methods
We studied a cohort of 743 patients with PAH treated with parenteral treprostinil therapy. The long-term all-cause mortality was compared in patients with baseline mean PCWP 8 mmHg, 8 < PCWP 11 mmHg, and PCWP > 11 mmHg over four-year follow-up.
Results
Of the 743 patients studied, 280 patients (37.7%) had a baseline mean PCWP 8 mmHg, 233 patients (31.4%) had a mean PCWP of >8 mmHg and 11 mmHg, and 230 patients (31.0%) had a mean PCWP >11 mmHg. While patients with higher PCWP had higher mean right atrial and PA pressures, no difference was noted in cardiac output and pulmonary vascular resistance (PVR). All-cause mortality was similar between patients with PCWP 8 mmHg, 8 < PCWP 11 mmHg, and PCWP > 11 mmHg at one year (10.4% vs 9.9% vs 10.0%, p = 0.980) and four years (16.8% vs 21.9% vs 19.2%, p = 0.353) respectively. In multivariate analysis, PCWP was not independently predictive of four-year all-cause mortality [HR 1.00, 95%CI 0.95–1.05, p = 0.98 (per mmHg)]. Predictors of four-year mortality included older age [HR 1.02, 95%CI 1.00–1.03, p = 0.0091 (per year)], non[48_TD$IF]-Caucasian race, and higher PVR [HR 1.06, 95% CI 1.04–1.08, p < 0.0001 [49_TD$IF](per Woods Unit)].
Conclusions
In this study of patients with PAH receiving parenteral treprostinil, PCWP was not associated with longterm all-cause mortality. Further studies examining prognostic indicators in patients with PAH optimised on guideline-based therapies are warranted.
Keywords
Pulmonary capillary wedge pressure Pulmonary arterial hypertension Trepostinil
*Corresponding author at: Department of Medicine, Stony Brook University Medical Center, Health Science Center T17-040, USA. Tel.: +1 631 388 3878., Email: [email protected] © 2017 Australian and New Zealand Society of Cardiac and Thoracic Surgeons (ANZSCTS) and the Cardiac Society of Australia and New Zealand (CSANZ). Published by Elsevier B.V. All rights reserved.
Please cite this article in press as: Patel JK, et al. Impact of Pulmonary Capillary Wedge Pressure on Long-[47_TD$IF]term Mortality in Patients with Pulmonary Arterial Hypertension Treated with Parenteral Trepostinil. Heart, Lung and Circulation (2017), http://dx.doi.org/10.1016/j.hlc.2017.02.015
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Introduction
Methods
Pulmonary arterial hypertension (PAH) is a chronic, debilitating disease associated with significant morbidity and mortality [1,2]. It is defined by mean pulmonary artery pressure >25 mmHg, pulmonary vascular resistance >3 Woods units (WU), pulmonary capillary wedge pressure (PCWP) < 15 mmHg, and the absence of other causes of pulmonary hypertension [2]. The prevalence of PAH in the US is approximately 50,000 to 100,000 individuals [3]. Patient survival has dramatically improved as treatment options for PAH have become more advanced. While a PAH registry from the National Institute of Health from 1981 to 1985 had previously demonstrated a median survival of 2.8 years [4], more recent reports have demonstrated median survival times of more than 7 years given substantial therapeutic advances [5]. The predictors of mortality in PAH include male gender, age >65 years, PAH due to connective tissue disease, higher New York Heart Association (NYHA) functional class, lower 6-minute walk distance (6MWD), higher B-type natriuretic peptide (BNP), higher serum creatinine, pericardial effusion on echo, lower diffusion capacity (DLCO), higher right atrial (RA) pressure, lower cardiac output (CO), and higher pulmonary vascular resistance (PVR) [2,4]. While pulmonary capillary wedge pressure (PCWP) has been touted for its utility in management and prognosis of patients with left heart failure, the clinical impact of PCWP on long-term mortality among patients with PAH has been incompletely reported, particularly in relation to concomitant treprostinil administration. From the Registry to Evaluate Early and Long-Term PAH Disease Management (REVEAL registry), demographics and outcomes of patients diagnosed with PAH with PCWP 16 to 18[50_TD$IF]mmHg was compared to those with PCWP < 16 mmHg and no difference in mortality rates was noted [6]. The Flolan International Randomized Survival Trial (FIRST) in 1997 which involved epoprosenol infusion in patients with NYHA Class II heart failure and elevated PCWP demonstrated improved cardiac output, decreased PCWP and decreased PVR in patients treated with epoprostenol compared to standard of care [7]. However, no difference in 6MWD or quality of life was noted between the both arms and the trial was terminated early due to a strong trend toward all-cause mortality in the epoprostenol arm. Pulmonary arterial hypertenstion patients with PCWP in the higher range of ‘‘normal” may not be true ‘‘PAH” but rather early heart failure with preserved ejection fraction (HFpEF). These patients may have a suboptimal long-term response to pulmonary vasodilator therapy, especially prostacyclin therapy. Accordingly, we postulated that in patients with PAH treated with parenteral treprostinil, the long-term mortality of patients with higher PCWP would be worse compared to their counterparts with lower PCWP.
Study Population The present study included three previously published treatment trials for PAH involving parenteral trepostinil conducted by United Therapeutics. Two trials (TRUST, SC-TRE) were multicentre, randomised, doubleblind, placebo-controlled treatment trials [8,9] and one was an open-label extension study of the SC-TRE trial which followed patients being treated with subcutaneous treprostinil for four additional years [10]. For our analyses, data from the SC-TRE (both randomised and open-label studies) and TRUST trials were combined to create one large cohort. Inclusion and exclusion criteria for each trial have been published previously [8,9]. Patients from all trials were included regardless of the treatment allocation. The study population included 978 patients with PAH treated with parenteral treprostinil therapy. Of these, 235 patients were excluded due to absence of data regarding baseline PCWP. Of the remaining 743 patients, long-term all-cause mortality was compared in patients with baseline mean PCWP 8 mmHg (lowest tertile), 8 < PCWP 11 mmHg (intermediate tertile), and PCWP >11 mmHg (highest tertile) over four-year follow-up. Demographic data and clinical history were recorded in these patients. The demographic and baseline medical history data extracted included age, gender, race, height, weight, aetiology of PAH, baseline 6MWD, baseline BORG dyspnoea score, and NYHA functional class. Baseline haemodynamic data recorded included cardiac output (litres/minute) (obtained via thermodilution or Fick), pulmonary vascular resistance [Woods units (WU)], mean right atrial (RA) pressure (mmHg), mean PA pressure (mmHg), and mean PCWP (mmHg). Outcomes of interest were all-cause mortality at one year, two years, three years, and four years.
Statistical Analysis The present study was confined to 743 patients with PAH treated with parenteral trepostinil for whom right heart catheterisation was performed at baseline. The results of baseline mean PCWP were categorised into PCWP 8 mmHg (lowest tertile), 8 < PCWP 11 mmHg (intermediate tertile), and PCWP > 11 mmHg (highest tertile). Categorical variables are presented as percentages and compared with the chi-squared test or Fisher’s exact test, if applicable. Continuous variables are presented as means standard deviation and compared using one-way ANOVA. Multivariable logistic regression was utilised to determine the independent predictors of all-cause mortality for each consecutive year up to and including four years. Predictors for the logistic regression were selected based on statistical significance in the univariate analysis (p < 0.05) and included age, race, PVR, and PCWP. Kaplan-Meier survival curve was constructed to compare mortality over four years between patients with PCWP 8 mmHg, 8 < PCWP 11 mmHg, and PCWP > 11 mmHg. SPSS version
Please cite this article in press as: Patel JK, et al. Impact of Pulmonary Capillary Wedge Pressure on Long-[47_TD$IF]term Mortality in Patients with Pulmonary Arterial Hypertension Treated with Parenteral Trepostinil. Heart, Lung and Circulation (2017), http://dx.doi.org/10.1016/j.hlc.2017.02.015
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PCWP and Survival in Trepostinil-treated PAH
23.0 (SPSS, Inc. Chicago, IL) was used for data analysis and a two-tailed p-value of 0.05 was regarded as statistically significant.
Results Of the 743 patients studied, 280 patients (37.7%) had a baseline mean PCWP 8 mmHg, 233 patients (31.4%) had a mean PCWP of >8 mmHg and 11mmHg, and 230 patients (31.0%) had a mean PCWP > 11 mmHg. Age and gender were similar between all groups (Table 1). Patients with higher PCWP had higher weights. Aetiology of PAH was similar between all groups, with idiopathic PAH and congenital systemic-to-pulmonic shunts serving as the predominant aetiologies. No difference in baseline 6MWD, BORG dyspnoea score, or NYHA functional class was noted between the groups (Table 2). While patients with higher PCWP had higher mean right atrial and PA pressures, no difference was noted in cardiac output and pulmonary vascular resistance (PVR). All-cause mortality was similar between the three groups during each consecutive year from one to four years (Table 3, Figure 1). Kaplan-Meier curve demonstrates no difference in survival up to four years between patients with PCWP of
>8 mmHg and 11 mmHg, and 230 patients (31.0%) had a mean PCWP > 11 mmHg (Figure 2). In multivariate analysis, PCWP was not independently predictive of four-year allcause mortality (Tables 4 and 5). Predictors of mortality at four years included older age [Hazard Ratio (HR) 1.02, 95% Confidence Interval (CI) 1.00–1.03], non[48_TD$IF]-Caucasian race, and higher PVR (HR 1.06, 95% CI 1.04–1.08).
Discussion The principal findings of this analysis of a contemporary cohort of patients with PAH receiving parenteral trepostinil are the following: (1) all-cause mortality rates are 10.1% and 19.2% at one and four years respectively; (2) PCWP is not associated with rates of intermediate- or long-term mortality; and (3) independent predictors of long-term mortality in this population include older age, non[48_TD$IF]-Caucasian race, and higher PVR. There is a paucity of data regarding the prognostic role of PCWP in PAH and few studies to date have examined the association between PCWP and clinical outcomes in PAH patients, particularly in relation to concomitant parenteral trepostinil administration. In the [51_TD$IF]Registry to Evaluate Early And Long-term PAH Disease Management (REVEAL) registry, over 1,800 patients with PAH and PCWP 18 mmHg,
Table 1 Demographics and Medical History. Overall (n = 743)
PCWP 8 mmHg (n = 280)
8 < PCWP 11 mmHg (n = 233)
PCWP > 11 mmHg
Age (years)
45 15
45 15
44 15
45 16
0.963
Male gender Race
164 (22.1%)
49 (17.5%)
56 (24.0%)
59 (25.7%)
0.060 0.3831
Caucasian
577 (77.7%)
217 (77.5%)
180 (77.3%)
180 (78.3%)
African American
41 (5.5%)
18 (6.4%)
16 (6.9%)
7 (3.0%)
Asian
61 (8.2%)
19 (6.8%)
17 (7.3%)
25 (10.9%)
Hispanic
51 (6.9%)
23 (8.2%)
16 (6.9%)
12 (5.2%)
Native American
4 (0.5%)
1 (0.4%)
1 (0.4%)
2 (0.9%)
Other
9 (1.2%)
2 (0.7%)
3 (1.3%)
4 (1.7%)
Weight (kg) Height (cm)
71 20 163 10
68 18 162 9
71 19 163 11
74 22 163 9
0.006 0.742
Body mass index (kg/m2)
27 7
26 7
27 6
28 8
0.005 0.8451
Aetiology of PAH
1
[3_TD$IF]p Value
(n = 230)
PPH/Idiopathic
410 (55.3%)
145 (52.0%)
129 (55.6%)
136 (59.1%)
Systemic sclerosis
51 (6.9%)
20 (7.2%)
18 (7.8%)
13 (5.7%)
Limited [35_TD$IF]scleroderma
26 (3.5%)
9 (3.2%)
11 (4.7%)
6 (2.6%)
Mixed [36_TD$IF]connective tissue disease Systemic Lupus Erythematosus
25 (3.4%) 33 (4.5%)
10 (3.6%) 14 (5.0%)
7 (3.0%) 12 (5.2%)
8 (3.5%) 7 (3.0%)
Overlap [37_TD$IF]syndrome
4 (0.5%)
1 (0.4%)
3 (1.3%)
0 (0.0%)
Congenital [38_TD$IF]syst-to-pulm shunts
130 (17.5%)
55 (19.7%)
36 (15.5%)
39 (17.0%)
Porto pulmonary [39_TD$IF]hypertension
25 (3.4%)
11 (3.9%)
6 (2.6%)
8 (3.5%)
Thromboembolic [40_TD$IF]disease
35 (4.7%)
13 (4.7%)
9 (3.9%)
13 (5.7%)
Collagen [41_TD$IF]vascular disease
2 (0.3%)
1 (0.4%)
1 (0.4%)
0 (0.0%)
Monte Carlo estimation is used to approximate the P value of exact test.
Please cite this article in press as: Patel JK, et al. Impact of Pulmonary Capillary Wedge Pressure on Long-[47_TD$IF]term Mortality in Patients with Pulmonary Arterial Hypertension Treated with Parenteral Trepostinil. Heart, Lung and Circulation (2017), http://dx.doi.org/10.1016/j.hlc.2017.02.015
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Table 2 Baseline Functional Status and Haemodynamic Data. Overall
PCWP 8 mmHg
8 < PCWP 11 mmHg
PCWP > 11 mmHg
(n = 743)
(n = 280)
(n = 233)
(n = 230)
Baseline 6MWD (metres)
323 88
323 91
325 89
319 84
0.639
Baseline BORG [42_TD$IF]dyspnoea score
4.3 2.4
4.3 2.4
4.2 2.3
4.4 2.5
0.738 0.1441[34_TD$IF]
NYHA [43_TD$IF]functional class Class II
103 (13.9%)
39 (13.9%)
38 (16.3%)
26 (11.3%)
Class III
581 (78.2%)
224 (80.0%)
170 (73.0%)
187 (81.3%)
Class IV
59 (7.9%)
17 (6.1%)
25 (10.7%)
17 (7.4%)
4.0 1.5
3.9 1.2
4.2 1.6
4.1 1.7
0.178
Pulmonary vascular resistance (WU)
14.1 7.2
14.5 6.4
13.7 7.3
14.0 8.0
0.067
Right atrial pressure, mean (mmHg)
10.4 6.0
8.5 5.4
10.3 5.9
12.7 6.0
<0.001
59 16
57 16
59 15
62 15
<0.001
10 4
62
10 1
14 2
<0.001
Cardiac output (litre/minute)
PA pressure, mean (mmHg) Baseline PCWP, mean (mmHg) 1
[3_TD$IF]p Value
Monte Carlo estimation is used to approximate the P value of exact test.
Table 3 All-Cause Mortality. Overall (n = 741)
PCWP 8 mmHg (n = 280)
8 < PCWP 11 mmHg (n = 233)
PCWP > 11 mmHg (n = 230)
[3_TD$IF]p Value
1-year mortality
75 (10.1%)
29 (10.4%)
23 (9.9%)
23 (10.0%)
0.980
2-year mortality
115 (15.5%)
40 (14.3%)
39 (16.7%)
36 (15.7%)
0.753
3-year mortality
136 (18.4%)
45 (16.1%)
47 (20.2%)
44 (19.2%)
0.461
4-year mortality
142 (19.2%)
47 (16.8%)
51 (21.9%)
44 (19.2%)
0.353
were categorised into those with PCWP 12 mmHg, 13 mmHg < PCWP 15 mmHg, and those with PCWP 16– 18 mmHg [11]. Patients with a PCWP of 16–18 mmHg were older, more obese, had a lower 6MWD, and had a higher incidence of systemic hypertension, diabetes mellitus, sleep apnoea, renal insufficiency, cardiomyopathy, and atrial fibrillation than patients with lower PCWP. Five-year survival rates were similarly low in all PCWP subgroups – 58%, 55%, and 49% for PCWP 12 mmHg,
13 mmHg < PCWP 15 mmHg, and PCWP 16–18 mmHg respectively [6]. Our study demonstrated lower overall mortality rates than prior literature. The REVEAL registry noted a 15% and 43% mortality rate at one and five years respectively in over 2,600 PAH patients [5]. Studies involving PAH patients receiving trepostinil have documented one- and four-year all-cause mortality at 12% and 30% respectively [12]. Our findings are consistent with previous studies identifying age, race, and PVR as
Figure 1 All-Cause Mortality Rates at Years 1–4 in Patients with (1) PCWP 8 mmHg, (2) PCWP 9–11 mmHg, and (3) PCWP >11 mmHg. Please cite this article in press as: Patel JK, et al. Impact of Pulmonary Capillary Wedge Pressure on Long-[47_TD$IF]term Mortality in Patients with Pulmonary Arterial Hypertension Treated with Parenteral Trepostinil. Heart, Lung and Circulation (2017), http://dx.doi.org/10.1016/j.hlc.2017.02.015
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PCWP and Survival in Trepostinil-treated PAH
Figure 2 Kaplan-Meier Curve Demonstrating Survival up to 4 years in Patients [Group 0 (PCWP 8 mmHg), Group 1 (PCWP 9–11 mmHg), and Group 2 (PCWP > 11 mmHg).
Table 4 Multivariate Analysis of Predictors of All-Cause Mortality. Hazard Ratio
95% Confidence Interval
[4_TD$IF]p Value
1-Year Mortality PCWP 8 mmg (vs 8 < PCWP 11 mmHg)
1.14
0.65–1.99
PCWP > 11 mmHg (vs 8 < PCWP 11 mmHg)
1.08
0.60–1.96
0.8025
Pulmonary Vascular Resistance (per WU)
1.06
1.04–1.09
<0.0001
PCWP 8 mmg (vs 8 < PCWP 11 mmHg)
0.91
0.58–1.42
0.6824
PCWP > 11 mmHg (vs 8 < PCWP 11 mmHg)
0.98
0.62–1.56
0.9370
[45_TD$IF]Caucasian versus Non-Caucasian
0.62
0.39–0.97
0.0368
Pulmonary Vascular Resistance (per WU)
1.06
1.04–1.08
<0.0001
0.85 0.99
0.56–1.29 0.65–1.51
0.4473 0.9520
0.6436
2-Year Mortality
3-Year Mortality PCWP 8 mmg (vs 8 < PCWP 11 mmHg) PCWP > 11 mmHg (vs 8 < PCWP 11 mmHg) Age (per year)
1.02
1.00–1.03
0.0181
[45_TD$IF]Caucasian versus Non-Caucasian
0.63
0.41–0.97
0.0356
Pulmonary Vascular Resistance (per WU)
1.06
1.04–1.08
<0.0001
PCWP 8 mmg (vs 8 < PCWP 11 mmHg)
0.79
0.53–1.18
0.2480
PCWP > 11 mmHg (vs 8 < PCWP 11 mmHg) Age (per year)
0.90 1.02
0.60–1.37 1.00–1.03
0.6345 0.0089
[45_TD$IF]Caucasian versus Non-Caucasian
0.64
0.42–0.99
0.0448
Pulmonary [46_TD$IF]vascular resistance (per WU)
1.06
1.04–1.08
<0.0001
4-Year Mortality
Variables included in the model: PCWP group, age, race, and pulmonary vascular resistance.
Please cite this article in press as: Patel JK, et al. Impact of Pulmonary Capillary Wedge Pressure on Long-[47_TD$IF]term Mortality in Patients with Pulmonary Arterial Hypertension Treated with Parenteral Trepostinil. Heart, Lung and Circulation (2017), http://dx.doi.org/10.1016/j.hlc.2017.02.015
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Table 5 Multivariate Analysis of Predictors of All-Cause Mortality. [4_TD$IF]p Value
Hazard Ratio
95% Confidence Interval
1-Year Mortality PCWP (per mmHg)
0.97
0.91–1.04
Age (per year)
1.00
0.99–1.02
0.6693
[45_TD$IF]Caucasian versus Non-Caucasian
0.71
0.41–1.24
0.2284
Pulmonary Vascular Resistance (per WU)
1.06
1.04–1.09
<0.0001
PCWP (per mmHg)
0.99
0.94–1.05
0.7320
Age (per year) [45_TD$IF]Caucasian versus Non-Caucasian
1.01 0.62
1.00–1.02 0.39–0.97
0.1257 0.0369
Pulmonary Vascular Resistance (per WU)
1.06
1.04–1.09
<0.0001
PCWP (per mmHg)
1.00
0.95–1.05
0.9406
Age (per year)
1.02
1.00–1.03
0.0168
[45_TD$IF]Caucasian versus Non-Caucasian
0.62
0.40–0.97
0.0341
Pulmonary Vascular Resistance (per WU)
1.06
1.04–1.08
<0.0001
PCWP (per mmHg)
1.00
0.95–1.05
0.9754
Age (per year)
1.02
1.00–1.03
0.0091
[45_TD$IF]Caucasian versus Non-Caucasian
0.64
0.41–0.98
0.0405
Pulmonary Vascular Resistance (per WU)
1.06
1.04–1.08
<0.0001
0.4390
2-Year Mortality
3-Year Mortality
4-Year Mortality
poor prognostic indicators in PAH. Higher functional class and/or no or worse change in functional class has also been documented as an independent predictor of mortality [13–15]. A sub-analysis of the REVEAL registry demonstrated that in PAH patients with NYHA Class III, improvement from NYHA Class III to I/II was associated with better survival versus patients who remained in NYHA Class III regardless of PAH aetiology [13]. Other prognosticators have included connective tissue disease-related PAH (versus idiopathic PAH), lower mixed venous oxygen saturation, elevated RA pressure, and more recently, the ratio of RA pressure to PCWP [14,16].
Study Limitations Several limitations to this study exist. As all studies of retrospective data, there is potential error in data entry and by omission. Information regarding other prognostic confounders, including presence of other medical comorbidities (e.g. diabetes mellitus, hypertension, etc.) [17,18], echocardiographic variables (e.g. right-sided chamber size, function, and pressures, severity of tricuspid regurgitation, presence of pericardial effusion, etc.) [19], diffusion capacity [20], laboratory values (i.e. haemoglobin and BNP) [21,22], medication profile, and smoking status, was not collected. Data regarding adherence to guideline-recommended therapies in PAH patients was also not collected. Despite these limitations, we have assessed long-term outcomes in patients with PAH receiving parenteral trepostinil and identified important prognostic variables in this population.
Conclusions In conclusion, in this study of patients with PAH receiving concomitant parenteral treprostinil, PCWP was not associated with long-term all-cause mortality. Further studies examining prognostic indicators in patients with PAH optimised on guideline-based therapies are warranted.
Author Contributions Conception or design of the work: JKP, PS; Statistical analysis: YR; Data interpretation: JKP, PS; Drafting the work or revising it critically for important intellectual content: JKP, PS; Final approval of the version to be published: JKP, YR, PS; Agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved: JKP, YR, PS.
Disclosures Jignesh Patel MD: The author has no significant conflicts of interest with any companies or organisation whose products or services may be discussed in this article. Youlan Rao PhD: The author is an employee of United Therapeutics, the company which conducted and analysed these clinical trials.
Please cite this article in press as: Patel JK, et al. Impact of Pulmonary Capillary Wedge Pressure on Long-[47_TD$IF]term Mortality in Patients with Pulmonary Arterial Hypertension Treated with Parenteral Trepostinil. Heart, Lung and Circulation (2017), http://dx.doi.org/10.1016/j.hlc.2017.02.015
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Paul Strachan MD: The author has received research support from: Actelion, Bayer, Genentech/Intermune, Sanofi and United Therapeutics. The author is on the speaker’s bureau for Boehringer Ingelheim, Genentech/Intermune, Gilead and United Therapeutics. The author has received consulting fees from Genentech/Intermune.
[10]
[11]
[12]
Acknowledgements
[13]
We sincerely appreciate the statistical support provided by United Therapeutics. [14]
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randomized, placebo-controlled trial. Am J Respir Crit Care Med 2002;165(6):800–4 (SC-TRE). Barst RJ, Galie N, Naeije R, Simonneau G, Jeffs R, Arneson C, et al. Longterm outcome in pulmonary arterial hypertension patients treated with subcutaneous treprostinil. Eur Respir J 2006;28(6):1195–203. Badesch DB, Raskob GE, Elliott CG, Krichman AM, Farber HW, Frost AE, et al. Pulmonary arterial hypertension: baseline characteristics from the REVEAL Registry. Chest 2010;137:376–87. Barst RJ, Galie N, Naeije R, Simonneau G, Jeffs R, Arneson C, et al. Longterm outcome in pulmonary arterial hypertension patients treated with subcutaneous treprostinil. The European Respiratory Journal 2006;28:1195–203. Barst RJ, Chung L, Zamanian RT, Turner M, McGoon MD. Functional class improvement and 3-year survival outcomes in patients with pulmonary arterial hypertension in the REVEAL Registry. Chest 2013;144:160–8. Benza RL, Gomberg-Maitland M, Naeije R, Arneson CP, Lang IM. Prognostic factors associated with increased survival in patients with pulmonary arterial hypertension treated with subcutaneous treprostinil in randomized, placebo-controlled trials. The Journal of Heart and Lung Transplantation: the official publication of the International Society for Heart Transplantation 2011;30:982–9. Bajwa AA, Qureshi T, Shujaat A, Seeram V, Jones LM, Al-Saffar F, et al. Predicting the Need for Upfront Combination Therapy in Pulmonary Arterial Hypertension. Journal of Cardiovascular Pharmacology and Therapeutics 2015;20:395–400. Fares WH, Bellumkonda L, Tonelli AR, Carson SS, Hassoun PM, Trow TK, et al. Right atrial pressure/pulmonary artery wedge pressure ratio: A more specific predictor of survival in pulmonary arterial hypertension. J Heart Lung Transplant 2016;35(June (6)):760–7. Benson L, Brittain EL, Pugh ME, Austin ED, Fox K, Wheeler L, et al. Impact of diabetes on survival and right ventricular compensation in pulmonary arterial hypertension. Pulmonary Circulation 2014;4:311–8. Poms AD, Turner M, Farber HW, Meltzer LA, McGoon MD. Comorbid conditions and outcomes in patients with pulmonary arterial hypertension: a REVEAL registry analysis. Chest 2013;144(1):169–76. Austin C, Alassas K, Burger C, Safford R, Pagan R, Duello K, et al. Echocardiographic assessment of estimated right atrial pressure and size predicts mortality in pulmonary arterial hypertension. Chest 2015;147:198–208. Chung L, Domsic RT, Lingala B, Alkassab F, Bolster M, Csuk ME, et al. Survival and predictors of mortality in systemic sclerosis-associated pulmonary arterial hypertension: outcomes from the pulmonary hypertension assessment and recognition of outcomes in scleroderma registry. Arthritis Care Res (Hoboken) 2014;66(3):489–95. Brittain EL, Janz DR, Austin ED, Bastarache JA, Wheeler LA, Ware LB, et al. Elevation of plasma cell-free hemoglobin in pulmonary arterial hypertension. Chest 2014;146(6):1478–85. Fritz JS, Blair C, Oudiz RJ, Dufton C, Olschewski H, Despain D, et al. Baseline and follow-up 6-min walk distance and brain natriuretic peptide predict 2-year mortality in pulmonary arterial hypertension. Chest 2013;143(2):315–23.
Please cite this article in press as: Patel JK, et al. Impact of Pulmonary Capillary Wedge Pressure on Long-[47_TD$IF]term Mortality in Patients with Pulmonary Arterial Hypertension Treated with Parenteral Trepostinil. Heart, Lung and Circulation (2017), http://dx.doi.org/10.1016/j.hlc.2017.02.015
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ORIGINAL ARTICLE
Impact of Pulmonary Capillary Wedge Pressure on Long-[47_TD$IF]term Mortality in Patients with Pulmonary Arterial Hypertension Treated with Parenteral Trepostinil Jignesh K. Patel, MD a*, Youlan Rao, PhD b, Paul Strachan, MD a a
Division of Pulmonary and Critical Care Medicine, Department of Medicine, State University of New York at Stony Brook, Stony Brook, NY, USA Biostatistics, United Therapeutics Corporation, Research Triangle Park, NC, USA
b
Received 5 May 2016; received in revised form 17 December 2016; accepted 12 February 2017; online published-ahead-of-print xxx
Background
The clinical impact of pulmonary capillary wedge pressure (PCWP) on long-term mortality among patients with pulmonary arterial hypertension (PAH) has been incompletely reported, particularly in relation to concomitant treprostinil administration. The goal of this study was to assess the impact of PCWP on longterm mortality in PAH patients treated with parenteral treprostinil.
Methods
We studied a cohort of 743 patients with PAH treated with parenteral treprostinil therapy. The long-term all-cause mortality was compared in patients with baseline mean PCWP 8 mmHg, 8 < PCWP 11 mmHg, and PCWP > 11 mmHg over four-year follow-up.
Results
Of the 743 patients studied, 280 patients (37.7%) had a baseline mean PCWP 8 mmHg, 233 patients (31.4%) had a mean PCWP of >8 mmHg and 11 mmHg, and 230 patients (31.0%) had a mean PCWP >11 mmHg. While patients with higher PCWP had higher mean right atrial and PA pressures, no difference was noted in cardiac output and pulmonary vascular resistance (PVR). All-cause mortality was similar between patients with PCWP 8 mmHg, 8 < PCWP 11 mmHg, and PCWP > 11 mmHg at one year (10.4% vs 9.9% vs 10.0%, p = 0.980) and four years (16.8% vs 21.9% vs 19.2%, p = 0.353) respectively. In multivariate analysis, PCWP was not independently predictive of four-year all-cause mortality [HR 1.00, 95%CI 0.95–1.05, p = 0.98 (per mmHg)]. Predictors of four-year mortality included older age [HR 1.02, 95%CI 1.00–1.03, p = 0.0091 (per year)], non[48_TD$IF]-Caucasian race, and higher PVR [HR 1.06, 95% CI 1.04–1.08, p < 0.0001 [49_TD$IF](per Woods Unit)].
Conclusions
In this study of patients with PAH receiving parenteral treprostinil, PCWP was not associated with longterm all-cause mortality. Further studies examining prognostic indicators in patients with PAH optimised on guideline-based therapies are warranted.
Keywords
Pulmonary capillary wedge pressure Pulmonary arterial hypertension Trepostinil
*Corresponding author at: Department of Medicine, Stony Brook University Medical Center, Health Science Center T17-040, USA. Tel.: +1 631 388 3878., Email: [email protected] © 2017 Australian and New Zealand Society of Cardiac and Thoracic Surgeons (ANZSCTS) and the Cardiac Society of Australia and New Zealand (CSANZ). Published by Elsevier B.V. All rights reserved.
Please cite this article in press as: Patel JK, et al. Impact of Pulmonary Capillary Wedge Pressure on Long-[47_TD$IF]term Mortality in Patients with Pulmonary Arterial Hypertension Treated with Parenteral Trepostinil. Heart, Lung and Circulation (2017), http://dx.doi.org/10.1016/j.hlc.2017.02.015
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Introduction
Methods
Pulmonary arterial hypertension (PAH) is a chronic, debilitating disease associated with significant morbidity and mortality [1,2]. It is defined by mean pulmonary artery pressure >25 mmHg, pulmonary vascular resistance >3 Woods units (WU), pulmonary capillary wedge pressure (PCWP) < 15 mmHg, and the absence of other causes of pulmonary hypertension [2]. The prevalence of PAH in the US is approximately 50,000 to 100,000 individuals [3]. Patient survival has dramatically improved as treatment options for PAH have become more advanced. While a PAH registry from the National Institute of Health from 1981 to 1985 had previously demonstrated a median survival of 2.8 years [4], more recent reports have demonstrated median survival times of more than 7 years given substantial therapeutic advances [5]. The predictors of mortality in PAH include male gender, age >65 years, PAH due to connective tissue disease, higher New York Heart Association (NYHA) functional class, lower 6-minute walk distance (6MWD), higher B-type natriuretic peptide (BNP), higher serum creatinine, pericardial effusion on echo, lower diffusion capacity (DLCO), higher right atrial (RA) pressure, lower cardiac output (CO), and higher pulmonary vascular resistance (PVR) [2,4]. While pulmonary capillary wedge pressure (PCWP) has been touted for its utility in management and prognosis of patients with left heart failure, the clinical impact of PCWP on long-term mortality among patients with PAH has been incompletely reported, particularly in relation to concomitant treprostinil administration. From the Registry to Evaluate Early and Long-Term PAH Disease Management (REVEAL registry), demographics and outcomes of patients diagnosed with PAH with PCWP 16 to 18[50_TD$IF]mmHg was compared to those with PCWP < 16 mmHg and no difference in mortality rates was noted [6]. The Flolan International Randomized Survival Trial (FIRST) in 1997 which involved epoprosenol infusion in patients with NYHA Class II heart failure and elevated PCWP demonstrated improved cardiac output, decreased PCWP and decreased PVR in patients treated with epoprostenol compared to standard of care [7]. However, no difference in 6MWD or quality of life was noted between the both arms and the trial was terminated early due to a strong trend toward all-cause mortality in the epoprostenol arm. Pulmonary arterial hypertenstion patients with PCWP in the higher range of ‘‘normal” may not be true ‘‘PAH” but rather early heart failure with preserved ejection fraction (HFpEF). These patients may have a suboptimal long-term response to pulmonary vasodilator therapy, especially prostacyclin therapy. Accordingly, we postulated that in patients with PAH treated with parenteral treprostinil, the long-term mortality of patients with higher PCWP would be worse compared to their counterparts with lower PCWP.
Study Population The present study included three previously published treatment trials for PAH involving parenteral trepostinil conducted by United Therapeutics. Two trials (TRUST, SC-TRE) were multicentre, randomised, doubleblind, placebo-controlled treatment trials [8,9] and one was an open-label extension study of the SC-TRE trial which followed patients being treated with subcutaneous treprostinil for four additional years [10]. For our analyses, data from the SC-TRE (both randomised and open-label studies) and TRUST trials were combined to create one large cohort. Inclusion and exclusion criteria for each trial have been published previously [8,9]. Patients from all trials were included regardless of the treatment allocation. The study population included 978 patients with PAH treated with parenteral treprostinil therapy. Of these, 235 patients were excluded due to absence of data regarding baseline PCWP. Of the remaining 743 patients, long-term all-cause mortality was compared in patients with baseline mean PCWP 8 mmHg (lowest tertile), 8 < PCWP 11 mmHg (intermediate tertile), and PCWP >11 mmHg (highest tertile) over four-year follow-up. Demographic data and clinical history were recorded in these patients. The demographic and baseline medical history data extracted included age, gender, race, height, weight, aetiology of PAH, baseline 6MWD, baseline BORG dyspnoea score, and NYHA functional class. Baseline haemodynamic data recorded included cardiac output (litres/minute) (obtained via thermodilution or Fick), pulmonary vascular resistance [Woods units (WU)], mean right atrial (RA) pressure (mmHg), mean PA pressure (mmHg), and mean PCWP (mmHg). Outcomes of interest were all-cause mortality at one year, two years, three years, and four years.
Statistical Analysis The present study was confined to 743 patients with PAH treated with parenteral trepostinil for whom right heart catheterisation was performed at baseline. The results of baseline mean PCWP were categorised into PCWP 8 mmHg (lowest tertile), 8 < PCWP 11 mmHg (intermediate tertile), and PCWP > 11 mmHg (highest tertile). Categorical variables are presented as percentages and compared with the chi-squared test or Fisher’s exact test, if applicable. Continuous variables are presented as means standard deviation and compared using one-way ANOVA. Multivariable logistic regression was utilised to determine the independent predictors of all-cause mortality for each consecutive year up to and including four years. Predictors for the logistic regression were selected based on statistical significance in the univariate analysis (p < 0.05) and included age, race, PVR, and PCWP. Kaplan-Meier survival curve was constructed to compare mortality over four years between patients with PCWP 8 mmHg, 8 < PCWP 11 mmHg, and PCWP > 11 mmHg. SPSS version
Please cite this article in press as: Patel JK, et al. Impact of Pulmonary Capillary Wedge Pressure on Long-[47_TD$IF]term Mortality in Patients with Pulmonary Arterial Hypertension Treated with Parenteral Trepostinil. Heart, Lung and Circulation (2017), http://dx.doi.org/10.1016/j.hlc.2017.02.015
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PCWP and Survival in Trepostinil-treated PAH
23.0 (SPSS, Inc. Chicago, IL) was used for data analysis and a two-tailed p-value of 0.05 was regarded as statistically significant.
Results Of the 743 patients studied, 280 patients (37.7%) had a baseline mean PCWP 8 mmHg, 233 patients (31.4%) had a mean PCWP of >8 mmHg and 11mmHg, and 230 patients (31.0%) had a mean PCWP > 11 mmHg. Age and gender were similar between all groups (Table 1). Patients with higher PCWP had higher weights. Aetiology of PAH was similar between all groups, with idiopathic PAH and congenital systemic-to-pulmonic shunts serving as the predominant aetiologies. No difference in baseline 6MWD, BORG dyspnoea score, or NYHA functional class was noted between the groups (Table 2). While patients with higher PCWP had higher mean right atrial and PA pressures, no difference was noted in cardiac output and pulmonary vascular resistance (PVR). All-cause mortality was similar between the three groups during each consecutive year from one to four years (Table 3, Figure 1). Kaplan-Meier curve demonstrates no difference in survival up to four years between patients with PCWP of
>8 mmHg and 11 mmHg, and 230 patients (31.0%) had a mean PCWP > 11 mmHg (Figure 2). In multivariate analysis, PCWP was not independently predictive of four-year allcause mortality (Tables 4 and 5). Predictors of mortality at four years included older age [Hazard Ratio (HR) 1.02, 95% Confidence Interval (CI) 1.00–1.03], non[48_TD$IF]-Caucasian race, and higher PVR (HR 1.06, 95% CI 1.04–1.08).
Discussion The principal findings of this analysis of a contemporary cohort of patients with PAH receiving parenteral trepostinil are the following: (1) all-cause mortality rates are 10.1% and 19.2% at one and four years respectively; (2) PCWP is not associated with rates of intermediate- or long-term mortality; and (3) independent predictors of long-term mortality in this population include older age, non[48_TD$IF]-Caucasian race, and higher PVR. There is a paucity of data regarding the prognostic role of PCWP in PAH and few studies to date have examined the association between PCWP and clinical outcomes in PAH patients, particularly in relation to concomitant parenteral trepostinil administration. In the [51_TD$IF]Registry to Evaluate Early And Long-term PAH Disease Management (REVEAL) registry, over 1,800 patients with PAH and PCWP 18 mmHg,
Table 1 Demographics and Medical History. Overall (n = 743)
PCWP 8 mmHg (n = 280)
8 < PCWP 11 mmHg (n = 233)
PCWP > 11 mmHg
Age (years)
45 15
45 15
44 15
45 16
0.963
Male gender Race
164 (22.1%)
49 (17.5%)
56 (24.0%)
59 (25.7%)
0.060 0.3831
Caucasian
577 (77.7%)
217 (77.5%)
180 (77.3%)
180 (78.3%)
African American
41 (5.5%)
18 (6.4%)
16 (6.9%)
7 (3.0%)
Asian
61 (8.2%)
19 (6.8%)
17 (7.3%)
25 (10.9%)
Hispanic
51 (6.9%)
23 (8.2%)
16 (6.9%)
12 (5.2%)
Native American
4 (0.5%)
1 (0.4%)
1 (0.4%)
2 (0.9%)
Other
9 (1.2%)
2 (0.7%)
3 (1.3%)
4 (1.7%)
Weight (kg) Height (cm)
71 20 163 10
68 18 162 9
71 19 163 11
74 22 163 9
0.006 0.742
Body mass index (kg/m2)
27 7
26 7
27 6
28 8
0.005 0.8451
Aetiology of PAH
1
[3_TD$IF]p Value
(n = 230)
PPH/Idiopathic
410 (55.3%)
145 (52.0%)
129 (55.6%)
136 (59.1%)
Systemic sclerosis
51 (6.9%)
20 (7.2%)
18 (7.8%)
13 (5.7%)
Limited [35_TD$IF]scleroderma
26 (3.5%)
9 (3.2%)
11 (4.7%)
6 (2.6%)
Mixed [36_TD$IF]connective tissue disease Systemic Lupus Erythematosus
25 (3.4%) 33 (4.5%)
10 (3.6%) 14 (5.0%)
7 (3.0%) 12 (5.2%)
8 (3.5%) 7 (3.0%)
Overlap [37_TD$IF]syndrome
4 (0.5%)
1 (0.4%)
3 (1.3%)
0 (0.0%)
Congenital [38_TD$IF]syst-to-pulm shunts
130 (17.5%)
55 (19.7%)
36 (15.5%)
39 (17.0%)
Porto pulmonary [39_TD$IF]hypertension
25 (3.4%)
11 (3.9%)
6 (2.6%)
8 (3.5%)
Thromboembolic [40_TD$IF]disease
35 (4.7%)
13 (4.7%)
9 (3.9%)
13 (5.7%)
Collagen [41_TD$IF]vascular disease
2 (0.3%)
1 (0.4%)
1 (0.4%)
0 (0.0%)
Monte Carlo estimation is used to approximate the P value of exact test.
Please cite this article in press as: Patel JK, et al. Impact of Pulmonary Capillary Wedge Pressure on Long-[47_TD$IF]term Mortality in Patients with Pulmonary Arterial Hypertension Treated with Parenteral Trepostinil. Heart, Lung and Circulation (2017), http://dx.doi.org/10.1016/j.hlc.2017.02.015
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Table 2 Baseline Functional Status and Haemodynamic Data. Overall
PCWP 8 mmHg
8 < PCWP 11 mmHg
PCWP > 11 mmHg
(n = 743)
(n = 280)
(n = 233)
(n = 230)
Baseline 6MWD (metres)
323 88
323 91
325 89
319 84
0.639
Baseline BORG [42_TD$IF]dyspnoea score
4.3 2.4
4.3 2.4
4.2 2.3
4.4 2.5
0.738 0.1441[34_TD$IF]
NYHA [43_TD$IF]functional class Class II
103 (13.9%)
39 (13.9%)
38 (16.3%)
26 (11.3%)
Class III
581 (78.2%)
224 (80.0%)
170 (73.0%)
187 (81.3%)
Class IV
59 (7.9%)
17 (6.1%)
25 (10.7%)
17 (7.4%)
4.0 1.5
3.9 1.2
4.2 1.6
4.1 1.7
0.178
Pulmonary vascular resistance (WU)
14.1 7.2
14.5 6.4
13.7 7.3
14.0 8.0
0.067
Right atrial pressure, mean (mmHg)
10.4 6.0
8.5 5.4
10.3 5.9
12.7 6.0
<0.001
59 16
57 16
59 15
62 15
<0.001
10 4
62
10 1
14 2
<0.001
Cardiac output (litre/minute)
PA pressure, mean (mmHg) Baseline PCWP, mean (mmHg) 1
[3_TD$IF]p Value
Monte Carlo estimation is used to approximate the P value of exact test.
Table 3 All-Cause Mortality. Overall (n = 741)
PCWP 8 mmHg (n = 280)
8 < PCWP 11 mmHg (n = 233)
PCWP > 11 mmHg (n = 230)
[3_TD$IF]p Value
1-year mortality
75 (10.1%)
29 (10.4%)
23 (9.9%)
23 (10.0%)
0.980
2-year mortality
115 (15.5%)
40 (14.3%)
39 (16.7%)
36 (15.7%)
0.753
3-year mortality
136 (18.4%)
45 (16.1%)
47 (20.2%)
44 (19.2%)
0.461
4-year mortality
142 (19.2%)
47 (16.8%)
51 (21.9%)
44 (19.2%)
0.353
were categorised into those with PCWP 12 mmHg, 13 mmHg < PCWP 15 mmHg, and those with PCWP 16– 18 mmHg [11]. Patients with a PCWP of 16–18 mmHg were older, more obese, had a lower 6MWD, and had a higher incidence of systemic hypertension, diabetes mellitus, sleep apnoea, renal insufficiency, cardiomyopathy, and atrial fibrillation than patients with lower PCWP. Five-year survival rates were similarly low in all PCWP subgroups – 58%, 55%, and 49% for PCWP 12 mmHg,
13 mmHg < PCWP 15 mmHg, and PCWP 16–18 mmHg respectively [6]. Our study demonstrated lower overall mortality rates than prior literature. The REVEAL registry noted a 15% and 43% mortality rate at one and five years respectively in over 2,600 PAH patients [5]. Studies involving PAH patients receiving trepostinil have documented one- and four-year all-cause mortality at 12% and 30% respectively [12]. Our findings are consistent with previous studies identifying age, race, and PVR as
Figure 1 All-Cause Mortality Rates at Years 1–4 in Patients with (1) PCWP 8 mmHg, (2) PCWP 9–11 mmHg, and (3) PCWP >11 mmHg. Please cite this article in press as: Patel JK, et al. Impact of Pulmonary Capillary Wedge Pressure on Long-[47_TD$IF]term Mortality in Patients with Pulmonary Arterial Hypertension Treated with Parenteral Trepostinil. Heart, Lung and Circulation (2017), http://dx.doi.org/10.1016/j.hlc.2017.02.015
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PCWP and Survival in Trepostinil-treated PAH
Figure 2 Kaplan-Meier Curve Demonstrating Survival up to 4 years in Patients [Group 0 (PCWP 8 mmHg), Group 1 (PCWP 9–11 mmHg), and Group 2 (PCWP > 11 mmHg).
Table 4 Multivariate Analysis of Predictors of All-Cause Mortality. Hazard Ratio
95% Confidence Interval
[4_TD$IF]p Value
1-Year Mortality PCWP 8 mmg (vs 8 < PCWP 11 mmHg)
1.14
0.65–1.99
PCWP > 11 mmHg (vs 8 < PCWP 11 mmHg)
1.08
0.60–1.96
0.8025
Pulmonary Vascular Resistance (per WU)
1.06
1.04–1.09
<0.0001
PCWP 8 mmg (vs 8 < PCWP 11 mmHg)
0.91
0.58–1.42
0.6824
PCWP > 11 mmHg (vs 8 < PCWP 11 mmHg)
0.98
0.62–1.56
0.9370
[45_TD$IF]Caucasian versus Non-Caucasian
0.62
0.39–0.97
0.0368
Pulmonary Vascular Resistance (per WU)
1.06
1.04–1.08
<0.0001
0.85 0.99
0.56–1.29 0.65–1.51
0.4473 0.9520
0.6436
2-Year Mortality
3-Year Mortality PCWP 8 mmg (vs 8 < PCWP 11 mmHg) PCWP > 11 mmHg (vs 8 < PCWP 11 mmHg) Age (per year)
1.02
1.00–1.03
0.0181
[45_TD$IF]Caucasian versus Non-Caucasian
0.63
0.41–0.97
0.0356
Pulmonary Vascular Resistance (per WU)
1.06
1.04–1.08
<0.0001
PCWP 8 mmg (vs 8 < PCWP 11 mmHg)
0.79
0.53–1.18
0.2480
PCWP > 11 mmHg (vs 8 < PCWP 11 mmHg) Age (per year)
0.90 1.02
0.60–1.37 1.00–1.03
0.6345 0.0089
[45_TD$IF]Caucasian versus Non-Caucasian
0.64
0.42–0.99
0.0448
Pulmonary [46_TD$IF]vascular resistance (per WU)
1.06
1.04–1.08
<0.0001
4-Year Mortality
Variables included in the model: PCWP group, age, race, and pulmonary vascular resistance.
Please cite this article in press as: Patel JK, et al. Impact of Pulmonary Capillary Wedge Pressure on Long-[47_TD$IF]term Mortality in Patients with Pulmonary Arterial Hypertension Treated with Parenteral Trepostinil. Heart, Lung and Circulation (2017), http://dx.doi.org/10.1016/j.hlc.2017.02.015
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Table 5 Multivariate Analysis of Predictors of All-Cause Mortality. [4_TD$IF]p Value
Hazard Ratio
95% Confidence Interval
1-Year Mortality PCWP (per mmHg)
0.97
0.91–1.04
Age (per year)
1.00
0.99–1.02
0.6693
[45_TD$IF]Caucasian versus Non-Caucasian
0.71
0.41–1.24
0.2284
Pulmonary Vascular Resistance (per WU)
1.06
1.04–1.09
<0.0001
PCWP (per mmHg)
0.99
0.94–1.05
0.7320
Age (per year) [45_TD$IF]Caucasian versus Non-Caucasian
1.01 0.62
1.00–1.02 0.39–0.97
0.1257 0.0369
Pulmonary Vascular Resistance (per WU)
1.06
1.04–1.09
<0.0001
PCWP (per mmHg)
1.00
0.95–1.05
0.9406
Age (per year)
1.02
1.00–1.03
0.0168
[45_TD$IF]Caucasian versus Non-Caucasian
0.62
0.40–0.97
0.0341
Pulmonary Vascular Resistance (per WU)
1.06
1.04–1.08
<0.0001
PCWP (per mmHg)
1.00
0.95–1.05
0.9754
Age (per year)
1.02
1.00–1.03
0.0091
[45_TD$IF]Caucasian versus Non-Caucasian
0.64
0.41–0.98
0.0405
Pulmonary Vascular Resistance (per WU)
1.06
1.04–1.08
<0.0001
0.4390
2-Year Mortality
3-Year Mortality
4-Year Mortality
poor prognostic indicators in PAH. Higher functional class and/or no or worse change in functional class has also been documented as an independent predictor of mortality [13–15]. A sub-analysis of the REVEAL registry demonstrated that in PAH patients with NYHA Class III, improvement from NYHA Class III to I/II was associated with better survival versus patients who remained in NYHA Class III regardless of PAH aetiology [13]. Other prognosticators have included connective tissue disease-related PAH (versus idiopathic PAH), lower mixed venous oxygen saturation, elevated RA pressure, and more recently, the ratio of RA pressure to PCWP [14,16].
Study Limitations Several limitations to this study exist. As all studies of retrospective data, there is potential error in data entry and by omission. Information regarding other prognostic confounders, including presence of other medical comorbidities (e.g. diabetes mellitus, hypertension, etc.) [17,18], echocardiographic variables (e.g. right-sided chamber size, function, and pressures, severity of tricuspid regurgitation, presence of pericardial effusion, etc.) [19], diffusion capacity [20], laboratory values (i.e. haemoglobin and BNP) [21,22], medication profile, and smoking status, was not collected. Data regarding adherence to guideline-recommended therapies in PAH patients was also not collected. Despite these limitations, we have assessed long-term outcomes in patients with PAH receiving parenteral trepostinil and identified important prognostic variables in this population.
Conclusions In conclusion, in this study of patients with PAH receiving concomitant parenteral treprostinil, PCWP was not associated with long-term all-cause mortality. Further studies examining prognostic indicators in patients with PAH optimised on guideline-based therapies are warranted.
Author Contributions Conception or design of the work: JKP, PS; Statistical analysis: YR; Data interpretation: JKP, PS; Drafting the work or revising it critically for important intellectual content: JKP, PS; Final approval of the version to be published: JKP, YR, PS; Agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved: JKP, YR, PS.
Disclosures Jignesh Patel MD: The author has no significant conflicts of interest with any companies or organisation whose products or services may be discussed in this article. Youlan Rao PhD: The author is an employee of United Therapeutics, the company which conducted and analysed these clinical trials.
Please cite this article in press as: Patel JK, et al. Impact of Pulmonary Capillary Wedge Pressure on Long-[47_TD$IF]term Mortality in Patients with Pulmonary Arterial Hypertension Treated with Parenteral Trepostinil. Heart, Lung and Circulation (2017), http://dx.doi.org/10.1016/j.hlc.2017.02.015
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Paul Strachan MD: The author has received research support from: Actelion, Bayer, Genentech/Intermune, Sanofi and United Therapeutics. The author is on the speaker’s bureau for Boehringer Ingelheim, Genentech/Intermune, Gilead and United Therapeutics. The author has received consulting fees from Genentech/Intermune.
[10]
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Acknowledgements
[13]
We sincerely appreciate the statistical support provided by United Therapeutics. [14]
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Please cite this article in press as: Patel JK, et al. Impact of Pulmonary Capillary Wedge Pressure on Long-[47_TD$IF]term Mortality in Patients with Pulmonary Arterial Hypertension Treated with Parenteral Trepostinil. Heart, Lung and Circulation (2017), http://dx.doi.org/10.1016/j.hlc.2017.02.015