Although significant advances have been achieved in the understanding, treatment, and outcomes of pulmonary arterial hypertension (PAH) in recent decades, long-term survival rates remain low.1 Results from REVEAL (ClinicalTrials.gov Identifier: NCT00370214) demonstrated a median survival of 7 years in this patient population, which faces the challenges of disease progression and increased frequency of hospitalizations.1-3
As reported in a new review published in the American Journal of Respiratory and Critical Care Medicine, the results of several studies indicate that a “low-risk” patient profile is a feasible treatment goal and that this outcome is linked with improved survival.4 The authors advocated for the use of a risk calculator aimed at achieving a low-risk profile in PAH trials.
“Thus, along with improving PAH treatment options, developing appropriate and accurate risk prediction is essential to make rational and individualized treatment decisions and, as such, improve outcomes in PAH,” according to a related editorial.5 The authors emphasized the shortcomings of clinical gestalt in assessing risk, noting that most clinicians overestimate the accuracy of their judgment. It has been reported that the least-skilled diagnosticians have the highest levels of overconfidence and the greatest likelihood of making an error.6 Such observations further underscore the need for accurate scoring systems.
The review examined several relevant studies that have explored the PAH risk tools most commonly used in clinical practice: the US Registry to Evaluate Early and Long-term PAH Disease Management (REVEAL) risk calculator and the European Society of Cardiology/European Respiratory Society (ESC/ERS) guidelines.
In 3 studies of the ESC/ERS guidelines, a low-risk profile was achieved by 30%, 24%, and 41.5% of patients by follow-up.7-9 In a study investigating the use of REVEAL, 51% of patients were found to be at low risk 12 months after enrollment.10 It is possible that the number of patients achieving low-risk status would be even greater with the increased use of dual- or triple-combination therapy, which only 15% to 50% of patients received in these 4 studies.
While the findings demonstrated an inverse correlation between better outcomes and lower-risk criteria, these criteria were achieved by a minority of participants. In addition, each study utilized different end points with different parameters, making these calculators not easily interchangeable or applicable to every patient.
Both the ESC/ERS risk tool and the REVEAL risk score have limitations that would need to be overcome before they could be utilized in trials that include low-risk profile as an outcome. In the ESC/ERS studies, for example, the registries were prospective while the analyses were retrospective. Additionally, there was substantial loss to follow-up and the approach does not weigh criteria based on relative importance, nor has it been prospectively validated.
Like the ESC/ERS tool, prospective validation is lacking for the REVEAL score, and some of the variables included in REVEAL are not commonly observed – such as pulmonary vascular resistance >32 Wood units – or are subjective. The review authors noted that a recently proposed updated version of the REVEAL score may resolve some of its current limitations.11 “Another limitation of both approaches is the lack of data demonstrating the ability to discriminate risk at the bedside for an individual patient in terms of positive and negative predictive values” they stated.
The Cardiology Advisor discussed the remaining needs that could facilitate the development of accurate risk assessment tools for PAH with Harrison W. Farber, MD, professor of medicine at Boston University School of Medicine and director of the Pulmonary Hypertension Center at Boston Medical Center, who is an author of the editorial.
The Cardiology Advisor: Why is there a need for more accurate risk assessment tools for PAH, and how might these shift the current approach to treatment?
Dr Farber: Currently, the risk assessment tools are not complete; some only cover incident patients, some do not cover all subgroups of PAH patients, some do not predict clinical worsening or hospitalization, some do not use weighted variables, and none have been validated prospectively. Also, although as clinicians we think we can judge risk adequately, that has been proven false numerous times. So, until we can judge risk accurately – and have the tools to do this – we will not be treating patients in the best way possible.
Cardiology Advisor: What are some of the remaining needs for developing such a tool?
Dr Farber: The 3 major needs that still remain are: to find tools that are applicable to both incident and prevalent patients; to develop tools that have been validated in prospective clinical trials – parameters that have been studied and are not just expert opinion – such as the 6-minute walk test and level of brain natriuretic peptide; and to develop a tool that is easy to use, reproducible, and can be used at all clinic visits. In sum, we still have a lot of work to do to develop proven parameters.
Cardiology Advisor: What are the main takeaways for pulmonologists, and how can they support this goal?
Dr Farber: We need to get everyone in the field to agree that we need accurate risk tools for this disease. We can work together to find the best parameters and tools, and we can then test the tools to prove their accuracy and use them to the benefit of patients with PAH.
- Benza RL, Miller DP, Barst RJ, Badesch DB, Frost AE, McGoon MD. An evaluation of longterm survival from time of diagnosis in pulmonary arterial hypertension from the REVEAL Registry. Chest. 2012;142(2):448-456.
- Frantz RP, Schilz RJ, Chakinala MM, et al. Hospitalization and survival in patients using epoprostenol for injection in the PROSPECT observational study. Chest. 2015;147(2):484-494.
- Frost AE, Badesch DB, Miller DP, Benza RL, Meltzer LA, McGoon MD. Evaluation of the predictive value of a clinical worsening definition using 2-year outcomes in patients with pulmonary arterial hypertension: a REVEAL Registry analysis. Chest. 2013;144(5):1521-1529.
- Weatherald, J, Boucly A, Sahay S, Humbert M, Sitbon O. The low-risk profile in pulmonary arterial hypertension: time for a paradigm shift to goal-oriented clinical trial endpoints? Am J Respir Crit Care Med. 2018;197(7):860-868.
- Farber HW, Benza RL. Risk assessment tools in pulmonary arterial hypertension. Prognosis for prospective trials? Am J Respir Crit Care Med. 2018;197(7):843-845.
- Berner ES, Graber ML. Overconfidence as a cause of diagnostic error in medicine. Am J Med. 2008;121(5 Suppl):S2-S23.
- Kylhammar D, Kjellström B, Hjalmarsson C, et al; on behalf of SveFPH and SPAHR. A comprehensive risk stratiﬁcation at early follow-up determines prognosis in pulmonary arterial hypertension [published online June 1, 2017]. Eur Heart J. doi:10.1093/eurheartj/ehx257
- Boucly A, Weatherald J, Savale L, et al. Risk assessment, prognosis and guideline implementation in pulmonary arterial hypertension. Eur Respir J. 2017;50(2):1700889.
- Hoeper MM, Kramer T, Pan Z, et al. Mortality in pulmonary arterial hypertension: prediction by the 2015 European pulmonary hypertension guidelines risk stratiﬁcation model. Eur Respir J. 2017;50(2):1700740.
- Benza RL, Miller DP, Foreman AJ, et al. Prognostic implications of serial risk score assessments in patients with pulmonary arterial hypertension: a Registry to Evaluate Early and Long-Term Pulmonary Arterial Hypertension Disease Management (REVEAL) analysis. J Heart Lung Transplant. 2015;34(3):356-361.
- Benza RL, Elliott CG, Farber HW, et al. Updated risk score calculator for pulmonary arterial hypertension patients. J Heart Lung Transplant. 2017;36(4):S19.