Pulmonary arterial hypertension: assessing risk to improve prognosis

KEYWORDS:

• Pulmonary hypertension
• risk assessment
• treatment
• risk stratification
• improvement

Risk stratification to predict early mortality among patients with pulmonary arterial hypertension (PAH) was introduced in the 2015 ESC/ERS guidelines [1]. It is a comprehensive assessment based on clinical measurements and data collected from patients with PAH at time of diagnosis and during follow-up. Multiple parameters are recommended as no single parameter itself provides sufficient prognostic information [1,2]. The aim is to carefully assess disease severity and treatment response in order to identify patients who might benefit from intensified PAH-targeted therapy early in the course of the disease. The purpose is to achieve a low-risk profile, as early as possible after diagnosis, and to maintain the low-risk profile over time. Such a strategy for risk assessment was recently evaluated in three large registry PAH-populations, the Swedish PAH registry SPAHR [3], the French PH registry [4], and the multi-national European PH registry COMPERA [5]. The results from these studies were strikingly similar and showed that patients exhibiting a low-risk profile at time of diagnosis had a clearly better survival rate, as compared to those with intermediate or high-risk profiles, up to 5 years from diagnosis. Of further importance, regardless of risk profile at time of diagnosis, patients that improved to low-risk profile at early follow-up had a similar 5-year survival to those with a low-risk status at diagnosis and to those who remained at low risk at follow-up. The risk stratification tool [1,3] has subsequently been used in the SPAHR population by Hjalmarsson et al. to evaluate the effect of age and comorbidity on outcome [6]. Younger patients more often reached the goal of a low-risk profile than elderly patients, potentially due to different PAH-phenotypes, differences in treatment response or treatment allocation, or possibly reflecting the effect of an increased comorbidity burden with older age. Still, in all age groups, a low-risk profile was related to a markedly better 5-year survival than intermediate or high-risk profiles. The REVEAL risk score, developed almost a decade ago, identified predictors of survival in the American REVEAL registry PAH population [7]. It was subsequently, in a prospective design, validated in patients with newly diagnosed PAH [8], resulting in a risk score including 12 variables. The main difference from the ESC/ERS risk assessment is that the REVEAL risk score uses weighted parameters and includes non-modifiable variables such as underlying cause of PAH, age, and gender [7–9].

The ESC/ERS risk stratification tool provides a new, simple strategy assessing risk in relation to the response to individualized PAH therapy. However, evaluation of the risk stratification tool has been crude and no systematic comparisons of the specific clinical and hemodynamic measures included in the algorithm has been performed. With the REVEAL risk score in mind, it would be interesting to investigate the need of weighing the ESC/ERS risk assessment parameters versus each other, in order to further refine the tool.

To a large extent, the variables and cut-off values suggested in the ESC/ERS risk stratification [1] was based on expert opinion. It is reasonable to assume that with technical advancements and improved understanding of the disease, adjustments of parameters and limits may be suggested to further improve the method. For example, the use of a predicted 6-minute walked distance (6MWD), adjusted for age and sex [10], instead of the actual walked distance, may give a more accurate estimate of exercise capacity when cardiopulmonary exercise test is not performed. Also, the need for adding specific parameters, such as sex, age, underlying clinical condition, and specific comorbidities to the risk assessment tool at baseline may be evaluated in the future. Though non-modifiable and not possible to affect by PAH treatment, these variables all have an impact on mortality [1,6,11] and thus will affect prognosis and survival and might add to the discriminative, predictive value of the risk assessment tools.

In the ESC/ERS guidelines [1], it is stated that a comprehensive risk stratification should include at least functional class (FC), one measurement of exercise capacity, e.g., 6MWD or results from the cardiopulmonary exercise test, and one measure on right ventricle function, e.g., BNP/NT-proBNP or echocardiography, to safely assess the risk. The three published evaluations of the ESC/ERS risk assessment tool followed this approach. All included measurements of WHO or NYHA FC, 6MWD, right atrial pressure, and cardiac index. Thus, as all three studies [3–5] showed that low-risk profile was associated with a better survival, one might conclude that only these four parameters, common between the three analyses, were needed to assess risk. However, only Boucly et al. [4] selected patients with all four measurements available, whereas Kylhammar et al. [3] and Hoeper et al. [5] did not have this restriction for inclusion in their analyses. Instead, Kylhammar et al. and Hoeper et al. allowed for additional variables, such as BNP/NT-proBNP and mixed venous oxygen saturation (SvO2). Kylhammar et al. also included right atrial area and the presence of pericardial effusion as well. But, neither Kylhammar et al. nor Hoeper et al. reported any restrictions as of a minimum of variables available for inclusion in the analyses. This implies that further studies are needed in order to determine which variables are most predictive of outcome, or if variables are interchangeable. Nevertheless, using a simplified model, as suggested in the sub-study by Boucly et al. [4], may have its advantages, as this might facilitate the use of risk assessment by all sites that treat and evaluate PAH patients. A retrospective analysis [12] that applied the REVEAL risk score [8] to a French registry cohort and a previously developed French registry risk equation [13] to the American REVEAL registry cohort adds to this discussion. The French registry risk equation included only three variables; sex, 6MWD, and cardiac output. The authors concluded that both these risk assessment tools proved to be effective in accurately predicting survival, thus indicating their prognostic generalizability in different PAH populations [12].

The aging PAH population adds complexity to the risk assessment [14]. With age follows an increased comorbidity burden and frailty, which might hamper the treatment of these patients and the probability to achieve a low or at least lower, risk profile. Hjalmarsson et al. showed that age, presence of ischemic heart disease, and kidney dysfunction independently predicted a worse survival [6]. These non-modifiable factors are important determinants of outcome, and they certainly add to the prognostic power of the risk assessment tool at the time of diagnosis, while their use at subsequent evaluations is probably of more limited value. Nevertheless, it is important to keep in mind that older patients have a distinct clinical profile and, conceivably, a different response to intervention.

To be useful in daily practice, the risk stratification tool should be simple enough and in-line with current follow-up strategies and the patient population of today. Adding sex-adjusted variables and taking comorbidity into account may, nevertheless, improve the risk assessment tool for future patients. In a next step and in line with the increased survival, the utility of risk assessment during the course of the disease should be validated as well as its validity in the different PAH subgroups. However, based on research results published during the last years in this area, our opinion is that using any of the available risk assessment models [3–5,7,8,15] is better than using none.

To conclude, studies published to date, independent of risk assessment tool, all support systematic assessment of risk at time of diagnosis and at early follow-up. This might provide an opportunity to adjust treatment on an individual level, with the aim of improving survival of patients with PAH.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.