Assessment of Risk of Disease Progression in Pulmonary Arterial Hypertension: Insights from an International Survey of Clinical Practice

Pulmonary arterial hypertension (PAH) is a progressive, severely debilitating and incurable disease characterised by increased pulmonary vascular resistance and pulmonary arterial pressure, which ultimately leads to right heart failure and death. Although survival has improved in the modern management era [1‐3] compared with historical data [4], the prognosis remains poor [5]. Therefore, assessment of a patient’s risk of disease progression and mortality has become an essential part of PAH management and is now centred around risk-based treatment algorithms [6‐9].

Based on a growing body of evidence, the current guidance [8, 9] from leading experts recommends regular multi-parametric risk assessment whereby patients are classified as being at low (< 5%), intermediate (5–10%) or high (> 10%) risk of 1-year mortality [6‐9]. It is recommended that a comprehensive assessment should be conducted at baseline (i.e. diagnosis/treatment initiation); in the event of clinical worsening, at least every 6–12 months routinely; and 3–6 months after a change in therapy [7‐9]. To aid risk classification, the 2015 European Society of Cardiology (ESC)/European Respiratory Society (ERS) pulmonary hypertension (PH) guidelines outline 9 determinants of prognosis, comprising 13 variables and their corresponding low-, intermediate- and high-risk thresholds. These variables include clinical and functional assessments, biochemical markers, and imaging and haemodynamic parameters [9]. The patient’s overall risk at a given timepoint is a composite measure of the individual variables, which may not all fall into the same risk category. It is the patients’ overall risk that is to be used to drive decisions on whether and how to escalate treatment, with the goal of achieving/maintaining a low-risk status [6‐9].

Translating all available measures and indicators of patient risk into a single risk category can pose a significant challenge for the treating physician and, as a result, research has focused on development of standardised tools and protocols for risk stratification. Several groups have retrospectively analysed data from prospective PAH registries to develop scoring systems that can aid risk assessment in clinical practice. For example, the Registry to Evaluate Early and Long-Term PAH Disease management (REVEAL) has been used to develop a calculator in which measurements for 12–14 variables are entered and their prognostic values weighted in order to derive a final risk score [10, 11]. Other studies have also taken a systematic approach to accurately predict risk of mortality, with the aim of developing a tool/scoring system that could be easily implemented in clinical practice without placing too much burden on the patient. These include analyses performed using data from the Swedish PAH Registry [12] and the Comparative, Prospective Registry of Newly Initiated Therapies for Pulmonary Hypertension (COMPERA) study [13], which assigned risk to patients newly diagnosed with PAH using a scoring system whereby an overall risk score was obtained by averaging scores based on at least two measurements across 6–8 of the 13 variables outlined in the ESC/ERS guidelines. Each of these risk assessment strategies were able to accurately stratify patients according to their 1-year mortality estimates [10‐13]. In another study, data from the French PH Registry were used to calculate patients’ risk according to the number of low-risk criteria present from a total of 3, 4 or 5 variables, and found that a greater number of low-risk criteria was indicative of better survival [14]. While the approaches taken in each of the studies described above differed, all point to the same conclusions: that regular risk assessment can and should be performed.

While there is now a clear mandate for risk assessment in the management of PAH, how this is implemented in clinical practice remains unclear. To the best of our knowledge, this is the first international study conducted to investigate how physicians currently assess risk of clinical worsening or death in patients with PAH, and how closely they adhere to the recommendations on risk assessment in the 2015 ESC/ERS guidelines. The aim of this study was to investigate how physicians assess PAH patient risk in clinical practice and to explore differences and similarities between the risk category assigned to patients by the treating physician (gestalt judgement of risk) and the risk category calculated using a published algorithm for risk assessment (calculated risk) [13].

In recent years, the assessment of clinical worsening or death in patients with PAH has become increasingly important for informing treatment decisions, with experts now recommending physicians perform multi-parametric risk assessment regularly at routine appointments [6‐9]. To our knowledge, this is the first international survey of physicians to investigate how risk assessment is currently being implemented in clinical practice and the results show that there are differences between physicians’ gestalt judgement of patient risk and patient risk as calculated using an objective algorithm. It is important to note that 41% of the patients were excluded from the risk calculation analysis due to insufficient measurements, indicating that risk assessment as recommend in the ESC/ERS guidelines may often not be performed.

This study captured which parameters physicians measure and how often they do so, based on both physicians’ recollection of their usual practice and on which measurements were present in the PRFs. These 2 sets of information were broadly aligned and demonstrate that most physicians evaluate progression of symptoms, clinical signs of right heart failure and WHO FC, with NT-proBNP levels, CPET and haemodynamics being less frequently assessed. Overall, haemodynamics and CPET were the parameters least likely to be measured at follow-up, which is not in contravention of the guidelines, as they suggest assessment of these every 6–12 months [8, 9], nor is it unexpected, given that many centres do not have access to CPET and many do not perform right heart catheterisation routinely to avoid potentially unnecessary invasive procedures [15]. However, it does seem to disagree with the results from the maximum-difference scaling survey, which demonstrated that physicians consider haemodynamics as the second-most important parameter for assessing prognosis. This apparent misalignment may be partly explained by the finding that physicians stated that they measure these 2 parameters more often at baseline than at follow-up visits. Given the inclusion criterion that patients must currently be receiving an endothelin receptor antagonist and that, for all patients with a value reported, the time from diagnosis was at least 13 months, the most recent clinic visit for these patients was likely to have been a follow-up visit. In addition, the exact timing of the last visit was not captured in this survey, so another possible reason for misalignment may be that it did not fall within the timeframe suggested for these assessments.

Our study demonstrates a discordance between physicians’ gestalt judgement of risk and calculated risk. For example, of the patients judged to be at low risk (n = 118), 80% were calculated to be at higher risk and of the patients judged to be at high risk (n = 81), 69% were calculated to be at lower risk. The reasons for this lack of agreement are not clear, but could be due to several factors. First, physicians may not be measuring enough parameters to produce an accurate algorithm-based estimate of risk. In the Hoeper analysis, 95.3% of patients had at least 4 variables measured and 55.4% had all 6 [13], compared with 12.2% and 6.3% in this study, respectively. In addition, it is possible that physicians may not agree with, or strictly apply, the parameter thresholds given in the guidelines. Finally, a physician’s clinical gestalt is based on more than just the assessments used in the algorithm to calculate risk, such as the patient’s disease aetiology, age, gender and comorbidities, as well as the physicians’ overall feeling of how the patient is doing as compared to previous consultations. Importantly, as this study did not capture outcome data, we do not know how well the physicians’ gestalt judgement of risk would stratify patients according to their 1-year risk of mortality and how that compares to the methods implemented by Hoeper et al. [13]. The potential for under- and over-estimation of risk should be further explored, as this can have profound detrimental impacts on patients’ lives, such as increasing the likelihood of clinical worsening and death in patients at intermediate or high risk, and potentially subjecting low-risk patients to unnecessary treatments and/or assessments, further impacting their quality of life.

Limitations of this study include selection bias and recall bias, which are inherent to all surveys, and that the results may be different from those that would be obtained in countries not studied. The main limitation of this study is the lack of clinical outcome data, which prevents evaluation of the effectiveness of gestalt judgement in stratifying patients according to their 1-year risk of mortality. Furthermore, more qualitative data would be required to better understand why physicians choose to assess certain variables and not others, and what potential barriers they face, in order to reconcile the observed differences between perceived and calculated risk. Finally, it would be interesting to compare how physicians’ gestalt compares to risk scores derived using other methods, such as the approach published by Boucly et al. [14]. However, the French approach stratifies patients according to the number of variables defined as low risk in the ESC/ERS guidelines and does not directly categorize patients as ‘low’, ‘medium’ or ‘high’ risk. Given this, a comparison could not be performed here.

Overall, the results of this survey demonstrate that multi-parametric risk assessment is being performed in clinical practice, but not always to the extent recommended in the 2015 ESC/ERS guidelines [8, 9]. Further study would be required to establish how well physicians’ gestalt estimates a patient’s risk of disease progression and to determine whether more regular assessment of objective measures could improve the accuracy of patient risk stratification.