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Department of Medicine, University of Calgary, Calgary, Alberta, CanadaDepartment of Medicine, Division of Respirology, University of Toronto, Toronto, Ontario, Canada
Department of Medicine, Division of Respirology, University of Calgary, Calgary, Alberta, CanadaDepartment of Medicine, Division of Pulmonary Medicine, University of Alberta, Edmonton, Alberta, Canada
Department of Medicine, Division of Respirology, University of Calgary, Calgary, Alberta, CanadaDepartment of Medicine, Division of Pulmonary Medicine, University of Alberta, Edmonton, Alberta, Canada
Risk stratification is fundamental in the management of pulmonary arterial hypertension (PAH). Pulmonary artery pulsatility index (PAPi), defined as pulmonary arterial pulse pressure divided by right atrial pressure (RAP), is a hemodynamic index shown to predict acute right ventricular (RV) dysfunction in several settings. Our objective was to test the prognostic utility of PAPi in a diverse multicentre cohort of patients with PAH.
Methods
A multi-centre retrospective cohort study of consecutive adult patients with a new diagnosis of pulmonary arterial hypertension (PAH) on right heart catheterization (RHC) between January 2016 and December 2020 was undertaken across four major centres in Canada. Hemodynamic data, clinical data, and outcomes were collected. The association between PAPi and other hemodynamic variables and mortality was assessed by receiver-operating characteristic (ROC) curves and Cox proportional hazards modeling.
Results
We identified 590 patients with a mean age 61.4±15.5 years with 66.3% being female. A low PAPi (defined as < 5.3) was associated with higher mortality at 1 year 10.2% vs. 5.2% (P=0.02). In a multivariable model including age, sex, body mass index and functional class, a low PAPi was associated with mortality at 1 year (AUC of 0.64, 95% CI 0.55-0.74). However, high RAP (> 8 mmHg) was similarly predictive of mortality with an AUC of 0.65.
Conclusion
PAPi was associated with mortality in a large incident PAH cohort. However, it’s discriminative value was not higher than RAP alone.
Introduction
Pulmonary arterial hypertension (PAH) is a progressive chronic disease characterized by pulmonary vascular remodeling, eventually culminating in right ventricular (RV) failure and death if untreated(
). The most recent guidelines for the diagnosis and treatment of PAH propose a risk stratification tool based on multiple variables, including hemodynamic parameters such as mean right atrial pressure (mRAP), cardiac index (CI), and mixed venous oxygen saturation (SvO2)(
2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension: The Joint Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS): Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC), International Society for Heart and Lung Transplantation (ISHLT).
). A comprehensive assessment is recommended as no single variable provides sufficient diagnostic and prognostic information. Additional markers may be beneficial for further refining assessment of prognosis, which is fundamental as it guides therapeutic decisions, including listing for transplantation.
RV function and RV-pulmonary arterial (PA) coupling are strongly associated with prognosis in PAH(6). RV-PA coupling, defined by a ratio of end-systolic to arterial elastances, has been shown to detect developing RV failure(
). Additionally, this parameter has been shown to be an independent predictor of survival in patients with PAH(8). The pulmonary artery pulsatility index (PAPi), defined as the ratio of the PA pulse pressure to the mRAP, has been proposed as an easily derivable marker of RV-PA coupling. Since its initial description in patients with acute inferior wall myocardial infarction, it has not yet received widespread evaluation in a large multicentre study of patients with PAH(9). The objectives of this study were to investigate the association between PAPi and mortality in patients with PAH, and to determine whether it provides superior prognostic value compared to other hemodynamic variables from right heart catheterization (RHC).
Methods
Study design and population
This was a retrospective, multi-center cohort study across four pulmonary hypertension expert referral centres participating in the Canadian Pulmonary Hypertension Registry (CPHR) in Canada (Vancouver, Calgary, Ottawa, Hamilton). The study was coordinated through the University of British Columbia (H21-03574) and institutional ethics board approval was obtained at each participating center. Eligible patients were identified through a structured chart review by study authors (NB, AA, JS, JW, NH, LM). All incident patients with a clinical diagnosis of PAH confirmed on RHC between January 1, 2016 to Dec 31, 2020 were included. In this study, the hemodynamic criteria for PAH proposed by the 6th World Symposium on PH were used (pulmonary arterial pressure (mPAP) > 20 mmHg, a pulmonary arterial wedge pressure ≤ 15 mmHg and a pulmonary vascular resistance > 3 WU). Other causes of PH, including patients with group 2 (PH due to left heart disease), group 3 (PH due to lung disease and/or hypoxia), group 4 (PH due to pulmonary artery obstructions), and group 5 (PH with unclear and/or multifactorial mechanisms) were excluded. Patients with missing hemodynamic data were excluded from the analysis. Patient demographics including age, sex, body mass index (BMI), and etiology of PH as determined by the treating specialist were obtained from electronic medical records or clinical files. Hemodynamic variables were extracted from baseline RHCs. The primary outcome was all-cause mortality at 1 year following the index RHC, as determined from clinic records. We chose to analyze survival at 1 year as longer-term survival was expected to be more strongly influenced by response to PAH therapy as opposed to baseline hemodynamic parameters.
Hemodynamic variables
RHC were performed by experienced operators according to routine clinical care. During RHC, the zero line was set at the mid-thoracic height. Measurements were obtained from hemodynamic tracing according to current guidelines. Variables measured during the RHC included, but were not limited to, the mRAP; systolic (sPAP), diastolic (dPAP), and mean pulmonary artery pressures (mPAP); pulmonary arterial wedge pressure (PAWP); and SvO2. Cardiac output and index were determined by either thermodilution or Fick method, at the discretion of the operator. However, the thermodilution method was preferred in the absence of shunting. PAPi was calculated as pulmonary artery pulse pressure (sPAP – dPAP) divided by mRAP. PAPi was compared to other parameters shown to have prognostic importance in PAH, including the RV stroke work index (RVSWi), effective PA elastance (PAE), and PA capacitance (PAC).
PAPi was analyzed as a continuous variable, and also by dichotomizing it into a binary variable. We used our data to find the cutoff value associated with the optimal c-statistic, and also investigated the use of cutoff values published in previous literature(
). As mRAP and CI already have well known reference ranges, we dichotomized these values accordingly. A high mRAP was defined as greater than 8 mmHg and a low CI was defined as less than or equal to 2.4 L/min/m2(
Categorical variables were summarized as numbers and percentages, whereas continuous variables were summarized as mean values ± standard deviations. Comparisons between groups were done using the chi-square test or the Kruskal-Wallis test, as appropriate.
To assess the association between each hemodynamic parameter and 1-year mortality, we constructed a multivariate logistic regression model and its corresponding AUC curve; each model was adjusted for age, BMI, sex and advanced functional class.
For each hemodynamic parameter, we also produced a Cox proportional hazards model adjusted for the same covariates as above to also assess the association between the hemodynamic parameter and 1-year mortality via hazards ratios. These last regressions were performed as a sensitivity analysis to confirm the findings from our logistic regressions despite Cox models being a time to event analysis.
Statistical significance was determined as a P-value < 0.01.
Results
We identified 590 incident patients with PAH from the participating centres. Table 1 demonstrates the baseline characteristics for the total cohort, and for patients who had survived at one year vs. those who did not. The mean age was 61.4±15.5 years, and 66.3% were female. The majority had idiopathic PAH (51.5%). Only 2 patients underwent a lung transplant over the time course of the study. Table 2 shows all hemodynamic variables tested, analyzed as continuous variables. Neither PAPi nor any other of the variables tested were significantly different for survivors vs. non-survivors (P > 0.01 for each).
Table 1Baseline characteristics of total cohort, and based on survival status at 1 year
1-year Mortality
0 (N=547)
1 (N=43)
Total (N=590)
P-value
Age
61.2 (15.44)
64.4 (16.19)
61.4 (15.51)
0.15481
Female, n (%)
365 (66.7%)
26 (60.5%)
391 (66.3%)
0.40302
PAH subtype, n (%)
1)iPAH
274 (51.3%)
23 (53.5%)
297 (51.5%)
2)Heritable
3 (0.6%)
0 (0.0%)
3 (0.5%)
3)Drug and toxins
20 (3.7%)
0 (0.0%)
20 (3.5%)
4)CTD
187 (35.0%)
8 (18.6%)
195 (33.8%)
5)CHD
30 (5.6%)
3 (7.0%)
33 (5.7%)
6)Portal hypertension
11 (2.1%)
8 (18.6%)
19 (3.3%)
7)HIV
4 (0.7%)
0 (0.0%)
4 (0.7%)
Low Risk, functional class ( WHO FC 1,2) n (%)
169 (30.9%)
11 (25.6%)
180 (30.5%)
0.46622
Height, Mean (SD)
164.8 (9.81)
165.0 (11.48)
164.8 (9.92)
0.94521
Weight, Mean (SD)
79.2 (22.33)
75.8 (20.53)
79.0 (22.20)
0.30441
Body mass index, Mean (SD)
29.1 (7.73)
27.8 (6.70)
29.0 (7.66)
0.36461
Lung transplant, n (%)
2 (0.4%)
0 (0.0%)
2 (0.3%)
0.69122
PAPi= Pulmonary artery pulsatility index, IPAH =idiopathic pulmonary arterial hypertension, CTD=connective tissue disease, CHD=congenital heart disease, HIV=human immunodeficiency virus, BMI = body mass index, WHO FC= world health organization functional class, SD=standard deviation
As the purpose of this work was to evaluate PAPi specifically, we evaluated whether dichotomizing PAPI into low PAPi vs. high PAPi gave a stronger association with mortality. We investigated the ideal value of PAPi that would perform best in a multivariate model. The ideal cutoff value for our data was 5.1, giving an area under the curve of 0.66. However, as this value was very close to the cuttoff value of 5.3 used in previous work(
), we decided to use that same cutoff to maintain consistency in the literature.
Table 3 shows the characteristics for low PAPi and high PAPi, respectively. At one year, 43 (7%) of the patients had died. Table 4 shows the number of deaths for low and high PAPi, CI and mRAP. In the univariate analysis, a PAPi of <5.3 was seen in 58% of patients that died at 1 year compared to 40% of surviving patients (P=0.02). Similarly, a mRAP > 8 mmHg was seen in 65% of patients who died and 47% of patients who survived (P=0.03). Neither baseline functional class nor cardiac index > 2.4 L/min/m2 were associated with mortality at 1 year, nor was age as a continuous variable.
Table 3Characteristics of patients with high vs. low PAPI
Low PAPi (N=246)
High PAPi (N=345)
P-value
Age, Mean (SD)
60.8 (16.34)
61.9 (14.87)
0.6326
Female, n (%)
161 (65.4%)
231 (67.0%)
0.7019
Etiology of PAH, n (%)
0.8547
1)iPAH
129 (52.4%)
168 (48.7%)
2)Heritable
1 (0.4%)
2 (0.6%)
3)Drugs and toxins
11 (4.5%)
9 (2.6%)
4)CTD
78 (31.7%)
118 (34.2%)
5)CHD
12 (4.9%)
21 (6.1%)
6)Portal hypertension
7 (2.8%)
12 (3.5%)
7)HIV
1 (0.4%)
3 (0.9%)
Low risk functional class (1,2) n (%)
67 (27.2%)
114 (33.0%)
0.1311
Height, Mean (SD)
164.7 (9.95)
164.8 (9.91)
0.8999
Weight, Mean (SD)
83.9 (25.19)
75.5 (19.10)
0.0003
BMI, Mean (SD)
30.9 (8.89)
27.7 (6.37)
<.0001
Lung transplant, n (%)
2 (0.8%)
0 (0.0%)
0.0934
PAPi= Pulmonary artery pulsatility index, IPAH =idiopathic pulmonary arterial hypertension, CTD=connective tissue disease, CHD=congenital heart disease, HIV=human immunodeficiency virus, BMI = body mass index
We constructed receiver operator curves to investigate the ability of PAPi and other parameters to discriminate 1-year mortality. In a multivariate model including age, sex, BMI and functional class, PAPi was associated with 1-year mortality with an AUC of 0.64, 95% CI 0.55-0.73. (Table 5, Figure 1). Similarly, mRAP > 8 mmHg was also able to predict mortality with a similar AUC of 0.65, 95% CI 0.56-0.74. A cardiac index of < 2.4 was not predictive of mortality. Kaplan-Meier curves were created for high vs low PAPi and mRAP (Figure 2). As shown, survival curves for PAPi < 5.3 and mRAP > 8 up to 1 year post catheterization were similar. Table 3 shows the adjusted estimates for the logistic regression and Cox Proportional Hazards Models for each of the three hemodynamic variables evaluated.
Table 5Logistic and Cox proportional hazards model adjusted estimates for haemodynamic parameters
Logistic Regression
Cox PH
Haemodynamic
Adjusted estimates
Adjusted estimates
Parameter:
OR (95% CI)
P-value
AUC (95% CI)
HR (95% CI)
P-value
PAPi<5.3
2.4 (1.2 ,4.6)
0.009
0.64 (0.55, 0.73)
2.5 (1.3 ,4.6)
0.006
mRAP>=8
2.5 (1.3 ,4.8)
0.009
0.65 (0.56 ,0.74)
2.56 (1.32 ,4.98)
0.006
Cardiac index>=2.4
1.1 (0.6 ,2.2)
0.793
0.59 (0.51 ,0.68)
0.99 (0.51 ,1.92)
0.971
PAPi = Pulmonary artery pulsatility index, mRAP=mean right atrial pressure, AUC = area under curve, Cox PH = Cox proportional hazards
We performed a subgroup analysis, stratifying for sex. The results for PAPi are shown in Table 6. Given the low number of events seen for both females and males, the confidence intervals are wide, and P was > 0.01 for both. The model appeared to perform better for males compared to females, with a higher AUC (0.73 vs.0.66). However, this difference was not related to PAPi, but the other parameters in the model.
Table 6Logistic and Cox proportional hazards model adjusted estimates for PAPi, stratified by sex
As shown in Table 7, we did notice an association between BMI and both mRAP and PAPi. As BMI increased, we saw strong association with increasing mRAP, and a decrease in the median PAPi. The association between BMI appeared stronger with mRAP compared to PAPi. However, the mean PAPi still remained in the low risk range for the highest BMI category.
2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension: The Joint Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS): Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC), International Society for Heart and Lung Transplantation (ISHLT).
In this large, multicenter Canadian study of 590 patients with incident PAH, we found that PAPi was not associated with survival when analyzed as a continuous variable. However, when analyzed as low vs. high PAPi with a cutoff of 5.3, low PAPi was associated with a higher 1-year mortality. The ability of PAPi to discriminate 1-year mortality was no different than that of RAP alone.
This is the largest study to evaluate the clinical significance and prognostic utility of PAPi in a PAH population. The PAPi is a novel hemodynamic parameter of RV-PA coupling that has recently been found to be useful in predicting outcomes in a variety of states influenced by RV function. It predicts right ventricular (RV) dysfunction in patients with acute inferior wall myocardial infarction or after left ventricular assist device implantation(
). Additionally, a lower PAPi was associated with decreased left ventricular ejection fraction, more severe tricuspid regurgitation, inferior vena cava dilatation, and lower cardiac index. In PAH, the literature on PAPi is limited to small and predominantly single center studies. Lim et al investigated the association between PAPi and survival in a population of 102 patients with PAH from Singapore(
). These patients were recruited over a large time range from 2003 to 2016, during which therapeutic options and use combination therapy changed significantly. Another study by Mazimba and colleagues evaluated the association between PAPi and survival in the historical National Institutes of Health (NIH) primary PH database in which baseline PAPi was predictive of survival(
). However, it should be noted that the NIH study cohort predates the development of modern PAH therapy and is therefore of limited relevance in the modern care of PAH. We limited our population to the modern era of combination therapy use (after the publication of the AMBITION trial and the 2015 European Society of Cardiology/European Respiratory Society Guidelines(
2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension: The Joint Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS): Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC), International Society for Heart and Lung Transplantation (ISHLT).
)), making these results more applicable to modern practice.
In our study, PAPi was associated with 1-year mortality only when dichotomized. Moreover, many other prognostic parameters were not associated with morality at 1 year. The primary reason for this discrepancy is likely low statistical power, as only 7% mortality was noted in 1 year. When PAPi was dichotomized, it was associated with mortality, but the association was not stronger than mPAP alone. Similar findings were seen in the Lim et al. study. We chose a shorter term follow up of 1 year in our study, understanding that response to PAH therapy would likely be a greater predictor of survival over the long term compared to baseline hemodynamic data. Our analysis adjusted for age, sex, BMI and functional class at baseline, and found a similar AUC for PAPi as seen by Lim and colleagues. Interestingly, neither our study nor the Lim et al. study showed an association between baseline cardiac index and mortality despite the fact it is an established prognostic variable from older studies(
). Data from the French PAH registry in the modern era also found that baseline hemodynamic variables were not associated with long-term survival whereas follow-up hemodynamic variables were(
). Together, these data support the concept that prognosis is not so much governed by baseline hemodynamics as it is response to therapy. We strongly suspect that differential changes in hemodynamics with initiation of PAH therapy also explains the limited prognostic utility of baseline PAPi and the other hemodynamic parameters tested. However, once decompensation and right sided heart failure with elevated RA pressures has developed, there may a signal of worse survival that persists despite initiation of therapy.
This study has some limitations to acknowledge. The design was retrospective and observational based on registry data, which has inherent limitations and bias. Additionally, lack of follow up RHC is a limitation as it was not routinely done in each centre, making it impossible to evaluate associations between survival and follow up PAPi or change in PAPi after initial therapy. We were not powered to investigate other outcomes of interest, such as lung transplantation or hospital admission for PAH. We did not employ a competing risks model for lung transplantation and mortality, however the number of patients transplanted within 1 year was so low that omitting this is justifiable. The major strength of our study is the large multicenter nature, with well phenotyped patients who were diagnosed and treated in PAH expert centres. An additional strength is the limitation of inclusion to patients diagnosed in the modern era of initial combination therapy.
Conclusions
As in other studies, we found the association between PAPi and survival was modest, and not superior to RA pressure alone. Our findings cast further doubt as to whether PAPi is a useful measure in PAH, and on the long-term prognostic utility of baseline hemodynamic measures in the era of effective early combination therapy.
2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension: The Joint Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS): Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC), International Society for Heart and Lung Transplantation (ISHLT).
None of the authors have relevant relationships to declare pertaining to this work.
Submission declaration:
This work is original. It has not been published elsewhere and is not under consideration with any other journal. The work was approved by all authors.
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