Mortality in pulmonary arterial hypertension: prediction by the 2015 European pulmonary hypertension guidelines risk stratification model

Discussion

The main findings of the present study can be summarised as follows. 1) An abbreviated version of the risk stratification strategy proposed by the European PH guidelines using WHO FC, 6MWD, BNP or NT-proBNP, right atrial pressure, cardiac index and S_vO2 discriminated effectively between patients with a low, intermediate and high risk of death; 2) this risk stratification strategy was valid for baseline and follow-up assessments; 3) risk prediction proved accurate for subgroups of patients with I/D/H-PAH and CTD-PAH (except for the lack of a significant survival difference between low- and intermediate-risk CTD-PAH patients at baseline); and 4) the risk estimates proposed in the European PH guidelines with annual mortality risks of <5%, 5–10% and >10% in patients at low, intermediate or high risk, respectively, were confirmed in the present series, both at baseline as well as at follow-up.

In addition, among the patients who died, the likelihood of death attributed by the investigators to PAH increased from 38% in the low-risk group to 63% in the high-risk group. Although assigning causes of death is often associated with uncertainties, these findings suggest that a substantial proportion of patients, especially in the low-risk group, died from causes unrelated to PAH, which may be expected in a relatively old patient population.

Our data confirm and extend previous findings by Kylhammar et al. [6], who used basically the same subset of variables (plus right atrial area and the presence/absence of pericardial effusion). In that study, which included 530 Swedish patients with newly diagnosed PAH, the three risk groups had significantly different long-term survival rates, similar to our study. The present study was almost three times the size of the Swedish dataset. Together, these two studies comprise ∼2000 patients with PAH and provide independent validation of the ESC/ERS risk stratification strategy.

Some additional findings of the present study are worthy of discussion: in our series, 12% of the patients presented in the low-risk category at the time of diagnosis. This proportion increased to 24% at follow-up. In the Swedish PH registry, the proportion of low-risk patients was 23% at baseline and 29% at follow-up. The reasons for these differences are unclear and may partly reflect the slightly different variables used for risk assessment in the two studies. Of note, the proportion of patients with a low-risk profile was small in the two cohorts, both at baseline and at follow-up. According to the current PH guidelines, the main objective of PAH therapy is achieving and maintaining a low-risk profile [4, 5]. This treatment goal was not achieved in the majority of our patients. At the same time, our data indicate that combinations of PAH drugs were used in only 19% of all patients at baseline (i.e. within the first 3 months after diagnosis) and in 41% at follow-up. Even in the high-risk cohort, combination therapy was used in only 17% of the patients at baseline and in 36% at follow-up. Intravenous or subcutaneous prostacyclin analogues were virtually absent in this study (7% in high-risk patients at follow-up). Given that there is now ample evidence favouring the use of combination therapy in patients with PAH [10–13], and considering that the present ESC/ERS guidelines recommend initial combination therapy including intravenous prostacyclin for patients presenting at high risk [4, 5], it is surprising to see that monotherapy was still used in the majority of patients. One potential reason for this reluctance may be the fact that the patients in the present series were relatively old; it is possible that the presence of comorbidities may have led physicians to prefer monotherapies [7, 9]. In addition, the enrolment period for the present analysis started in 2009, when there was less evidence supporting the use of combination therapy in patients with PAH. It will be interesting to see whether the use of combination therapy increases in the future and whether this will be accompanied by better outcomes.

The 2015 ESC/ERS guidelines recommend a comprehensive risk assessment strategy based on 13 variables [4, 5]. Another widely used risk stratification tool is the REVEAL risk score, which consists of 19 variables, but has been shown to remain valid when fewer variables are used [14, 15]. The present study demonstrated that an abbreviated version of the ESC/ERS risk assessment strategy using only six or fewer selected variables provided accurate distinction between the risk groups. Variables closely linked to the mortality risk were 6MWD, WHO FC, BNP/NT-proBNP and S_vO2, whereas right atrial pressure and cardiac index performed less well. These findings are only partly in line with a previous study by Nickel et al. [16], which showed that among various variables used for risk stratification, only WHO FC, NT-proBNP, cardiac index and S_vO2 provided independent prognostic information. Hence, it seems possible to use a selected number of variables for accurate discrimination of risk groups. However, given the fact that several variables from echocardiography and cardiopulmonary exercise testing were not available for our present analysis, further studies are needed to determine the most reliable dataset.

Changes in the risk category, regardless of the direction, seem to be an accurate predictor of long-term survival and may therefore be considered end-points in future clinical trials. In the present series, 48% of the patients with newly diagnosed PAH had experienced a change in the risk category from baseline to follow-up, determined mainly by changes in functional class, 6MWD and BNP/NT-proBNP. Hence, a combination of simple and noninvasive tools provides important prognostic information. Previous long-term studies have focused on clinical worsening [10, 11, 17, 18], but our data suggest that statistical tools determining the net benefit, i.e. the ratio of patients who improve or worsen their risk category, could increase the power of clinical trials.

Our study had several strengths and limitations. Perhaps the greatest strength was the large number of prospectively documented, newly diagnosed patients with PAH. Hence, the sample size was large enough to provide sufficient patient numbers in all three risk strata and to allow subgroup analyses, at least for patients with I/D/H-PAH and for patients with CTD-PAH. However, further research is necessary to determine whether our risk calculation approach was appropriate or whether alternative models might provide even better prognostication. One of the most important limitations of our study was the fact that not all variables included in the risk stratification strategy proposed by the European PH guidelines were available. Information on disease progression, syncope, CPET and echocardiography were missing. In addition, and perhaps most importantly, follow-up haemodynamics were available only from 386 patients within 3 months and 2 years after inclusion, i.e. ∼35% of the patients who had follow-up data, which limits the ability of the present study to fully analyse the predictive value of invasive and noninvasive variables at follow-up. Further studies should determine whether a strategy based on a few selected parameters provides sufficient prognostic information and how much information follow-up haemodynamics add to noninvasive tools.

It may be seen as another limitation that patients enrolled in COMPERA tend to be relatively old, at least compared to other PAH registries. However, the data reflect the real-world scenario in the participating centres, particularly in Germany, and a PAH registry from Sweden has recently reported almost identical demographics [19].

In conclusion, our data show that an abbreviated version of the risk stratification strategy proposed by the current ESC/ERS PH guidelines provides an accurate prediction of mortality. The observed 1-year mortality rates are <5% in low-risk patients, between 5% and 10% in intermediate-risk patients and >10% in high-risk patients. Predictions were accurate for baseline as well as follow-up assessments. Further research is needed to determine which sets of variables have the best predictive performance and to assess the usefulness of risk categorisation strategies in clinical trials. In addition, our data show that a low-risk profile is achieved only in a minority of patients with PAH. Improving this figure should be a major objective of future research.