Background
Pulmonary arterial hypertension is a pathophysiological disorder complicating both of cardiovascular and respiratory diseases. It is defined by a mPAP ≥ 25 mmHg, a pulmonary artery wedge pressure (PAWP) ≤ 15 mmHg and a pulmonary vascular resistance(PVR) > 3 Wood units (WU) without other causes of pre-capillary PH [
1,
2].
The 2015 ESC/ERS(European Society of Cardiology/European Respiratory Society) PH guidelines strongly recommend a comprehensive regular assessment of patients with PAH since there is no single variable that provides sufficient diagnostic and prognostic information instead of a multidimensional approach [
1,
3]. Based on the evaluation of multiple variables, PAH patients can be categorized as low, intermediate or high risk with estimated one-year mortality of < 5%, 5–10% and > 10%, respectively [
3]. The basic program should include the functional class(FC) and at least one measurement of exercise capacity. It is also recommended to obtain some information on right ventricular (RV) function [
1].
However, an individual patient is unlikely to have all variables indicative of merely one strata, thus the physician’s decision on the overall risk is subjective and the assessment could vary between different physicians [
3]. One approach which can distinctly classify the risk strata of PAH is the French registry risk equation, which unfortunately concerns sex, 6MWD and cardiac output merely [
3,
4]. Another one is the risk assessment score of Registry to Evaluate Early and Long-Term Pulmonary Arterial Hypertension Disease Management (REVEAL) which is a simplified risk score based on the prognostic equation, and is designed to be simple and easy enough to be adopted in everyday clinical practice, compared with the relatively complex REVEAL risk equation [
5]. However, RHC is not readily available or accessible or suitable or acceptable for every patient anytime. Besides, regardless of the right atrial pressure(RAP), cardiac index (CI) and mixed venous oxygen saturation (SvO2) assessed by right heart catheterization (RHC) being the most robust indicators of RV function and prognosis, and providing important prognostic information both at the time of diagnosis and during follow-up, whereas mPAP in RHC provides little prognostic information [
6‐
10]. In addition, some of the variables in the REVEAL risk score, such as age and PAH etiology, are not modifiable offsetting the change of modifiable variables, and potentially leading to an inaccurate evaluation of the patient’s prognosis [
3]. The last but not least, the variable of vital signs such as resting systolic BP and heart rate in the REVEAL risk score is inconsistent and unreliable. Consequently, we postulated whether a modified risk assessment score could be the better approach for the prognostic assessment of PAH.
Discussion
Clinical daily assessment is a critical method to evaluate patients with PH, for determining disease severity and prognosis as well as disease management, and should be performed regularly with a combination of variables [
1,
3]. Although the existing risk assessment approaches have been validated to be valid in predicting survival rates in multiple cohorts [
4,
5,
11], there are still some defectives which reserved potential rooms for improvement. In consequence, this study was aimed at developing a modified risk assessment score of PAH. For the model establishment of this modified risk assessment score of PAH, we deliberated our desirable determinants on the principle of validity, accuracy, simplicity and convenience. The incentives that we applied those four determinants to be the variables of our modified risk assessment score was not only that they were the basic program most frequently used in PH centers [
1], but also they were qualified to be mostly correlated with mortality in a multivariate analysis. Also the score provided quantitative assessments rather than qualitative ones, since the latter might vary dramatically between physicians [
12].
WHO FC is one of the most valid predictors of survival, for both diagnosis and follow-up notwithstanding its variability [
6,
7,
13,
14]. A deteriorating FC is one of the most serious sign of disease progression [
7,
8]. 6MWD is the result of 6-min walking test (6MWT) which is a sub-maximal exercise test. It is the most inexpensive and familiar exercise test frequently used in PH centers. The overall treatment goal for patients with PAH is to achieve a low-risk status which usually means being in WHO-FC II, mostly together with a normal or near normal 6MWD [
1,
15‐
20]. BNP/NT-proBNP levels represent myocardial dysfunction and provide prognostic information at the time of diagnosis or during follow-up [
21]. NT-proBNP is regarded as a stronger predictor of prognosis compared with BNP [
22]. Echocardiography is an important follow-up approach due to RV function is a crucial determinant of outcome in PH [
1]. On the contrary, clinical signs of right heart failure, progression of symptoms, syncope and pericardial effusion of echocardiography in which all the severity are difficult to stratify were excluded from the mRASP in order to improve accuracy. Since life expectancy has been improved for patients with PAH warranting noninvasive approaches for prognostic assessment, and there has been no evidence that receiving regular RHC is associated with better outcomes than a non-invasive follow-up strategy [
1], HC was not included in the mRASP. The reason we did not use the serial risk score assessments was that it involved the variables of two different time points resulting in the poor feasibility of the assessment of newly diagnosed patients or patients whose last assessment scores are not available [
23].
The results of the present study demonstrated that the one-year survival rates predicted by the mRASP matched the actually observed ones. This validated the validity of mRASP which was derived from the establishment cohort for assessing one-year survival rates in the validation cohort. In our opinion, a valid risk assessment score of PAH should have excellent applicability, generalizability and adaptability for PAH cohorts with various characteristics, and outstanding discriminatory power to distinguish the potential survival from mortality. We noticed that patients in the validation cohort appeared to be more severe than those in the establishment cohort in regard to WHO FC, and believed that it was due to the validation cohort had more newly diagnosed patients who had never received any PAH-specific therapy than the establishment cohort. Nevertheless, from another perspective, it reveals the excellent applicability, generalizability and adaptability of the mRASP in different cohorts with different severity. It is worth noting that otherwise than the study of Benza et al. [
5] there is a plunge of survival rate between the intermediate-risk stratum and the high-risk stratum in the validation cohort similar to what happened in the establishment cohort. Between score of 5 points and 6 points, the survival rate descends from more than 90% to almost its half, meanwhile, the mortality rate ascends approximately 6 folds. It may suggest that a score of 6 points could potentially be a cutoff value which implies the prognosis may deteriorate dramatically if patients’ risk scores exceed it, distinctly differentiating the potential survival from mortality.
The next comparison showed that the predictive efficacy for one-year survival rate by the mRASP score was similar to that by the REVEAL score. In the study of Benza et al. in 2012 [
5], the REVEAL simplified risk score calculator were demonstrated to have good discriminatory power in patients with PAH. Afterwards, this risk assessment tool has been validated to be effective in the prediction of survival in several cohorts, demonstrating its prognostic generalizability in different PAH populations [
4,
11]. It is the mostly recognized risk assessment score for PAH to date. Nevertheless, due to some problematic issues we encountered in the application of REVEAL score such as the poor accessibility of RHC, instability of vital signs, non-modifiable determinants, inspiring us to search for some solution through this study. The conception of the mRASP was an overlapping of determinants in the TABLE 13 of 2015 ESC/ERS PH guidelines and the score calculator of the REVEAL score. The original purpose of designing was aimed to inherit their pros and discard their cons to generate a simplified standardized algorithm which could be highly applicable and valid under most circumstances by means of validating the generalizability of those cut-off values in parameters from expert opinion or consensus which might be highly representative. Also the four selected variables was validated to be mostly correlated with mortality in a multivariate analysis. Since finally the two risk assessment tools did not display much distinction on validity from each other, the mRASP could be regarded as a risk assessment model with noninvasiveness, accuracy, simplicity, and convenience comparable with the REVEAL score.
Regardless of the advantages that the mRASP has, several issues must be addressed for its clinical application. It is noteworthy that since RHC is absent in the mRASP, clinicians should apply it with discretion whilst therapeutic decisions can be generated from the results [
1]. It also should be noted that even though the mRASP may provide prognostic information to guide therapeutic decisions, the individual application must be performed carefully in light of that it is too population-based to precisely predict individual patient, being similar to the REVEAL score or French risk equation. In other words, when it comes to an individual patient, all risk assessments should be applied under the circumstances of considering the patient’s history and the corresponding PAH-specific therapy. Another important issue is that patients should not calculate their risk themselves for avoiding the misinterpretation. It is the responsibility of medical professionals to discuss the results of risk assessment and to consider the next steps [
3]. Another issue that cannot be overlooked is that even though we endeavored to optimize the designing of mRASP as much as possible, it is potentially possible that other designs can achieve the same or even better assessment effect. For example, recently Boucly et al. built a risk assessment model composed of the following determinants: WHO FC I or II, 6MWD > 440 m, RAP < 8 mmHg and CI ≥ 2.5 L·min
− 1·m
− 2, which could accurately predict the prognosis of incident PAH in a retrospective study [
24]. However, as said in the article, it remained unknown whether the addition of echocardiography or cardiopulmonary exercise testing to their criteria could further improve the prognostic power [
24]. In another study, Hoeper et al. validated the validity of risk assessment strategy in 2015 European PH guidelines with a model composed of WHO FC, 6MWD, BNP or NT-pro BNP, right atrial pressure, cardiac index and mixed venous oxygen saturation [
25]. However, this model is still invasive not being suitable for daily clinical practice. In any case, novel assessment models invariably require prospective validation. As our recognition and management of PAH advances, predictive tools will need updating to reflect current practice [
4].
The strength of this study is that we prospectively validated the validity of the newly designed risk score, by contrast with the REVEAL score. Nevertheless, limitations also exist in this study. First of all, the sample volume is not very large. The validation of the mRASP in another large cohort is warranted in the future. Secondly, in the development of mRASP score by retrospectively reviewing the establishment cohort, the risk score-related assessments were not performed at mandatory visits undermining the quality of the study more or less. Thirdly, since this study did not involve the predictive efficacy of the mRASP for the survival rate beyond 1 year or for the survival rate in other groups of PH, we have no comments to make on it. The study regarding the long-term risk assessment of PAH or of other groups of PH with the mRASP is warranted in the future.The last but not least, since all patients assessed in our cohorts were all of Chinese population, this risk assessment score may not be applicable for other races.
Acknowledgements
We sincerely thank Dr. Lan Wang, Dr. Jian Guo, Dr. Sugang Gong, Dr. Jing He, Dr. Qinhua Zhao, Dr. Rong Jiang, Dr. Cijun Luo, Dr. Hongling Qiu, Dr. Wenhui Wu, Dr. Minqi Liu, Dr. Tianxiang Chen, Dr. Xingxing Sun, and Dr. Chuanyu Wang of Department of Cardiopulmonary Circulation, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China, for their assistance in this study.