Despite therapeutic advancements made over the last few years, pulmonary arterial hypertension (PAH) remains a severe clinical condition. However, one new aspect of PAH care strategy that has led to improved clinical outcomes is the use of risk stratification models to decide on the most appropriate treatment plan for individual patients with this condition. 

“The current treatment strategy is based on the severity of the newly diagnosed PAH patient as assessed by a multiparametric risk stratification approach,” Galiè and colleagues write in the European Respiratory Journal. “The current treatment algorithm provides the most appropriate initial strategy, including monotherapy, or double or triple combination therapy.” 

Four factors form the backbone of risk stratification strategy in PAH: (1) World Health Organization functional class (WHO FC), (2) 6-minute walk distance (6MWD) greater than 440 m, (3) right atrial pressure less than 8 mmHg, and (4) cardiac index greater than or equal to 2.5 L min−1 m−2. N-terminal pro-brain natriuretic peptide (NT-proBNP) less than300 ng L−1 plasma levels or mixed venous oxygen saturation (SvO2) less than 65% as low-risk criteria was assessed where this data were available.


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The most common approach is to stratify patients into 3 risk categories: low, intermediate, and high. However, some scientists are of the opinion that these 3 categories are too broad and that it would make better sense to subdivide the “intermediate” category into “intermediate-low” and “intermediate-high.” 

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In the European Respiratory Journal, Hoeper and colleagues investigated the merits of a 4-category risk stratification model and whether it led to improved clinical outcomes. 

Four Risk Strata 

“We hypothesized that a subdivision into four risk strata (low, intermediate-low, intermediate-high, and high) . . . might improve risk stratification,” Hoeper and coauthors write. 

They used the COMPERA database to investigate the merits of a refined risk stratification model that included new cut-off levels. COMPERA is an ongoing registry for PAH launched in 2007. It collects data on any patient who receives targeted therapies for PAH. Approximately 80% of the data come from Germany, while the rest come from 12 other European countries. 

The inclusion criteria were treatment-naïve patients with newly diagnosed PAH with at least one follow-up data point available. In addition, three variables of interest—WHO FC, 6MWD, NT-proBNP—must be available at baseline. A total of 1655 patients were included in the final analysis. 

Hoeper and colleagues devised a new 4-stratum model for PAH risk stratification: 

Points assigned234
WHO FCI or IIIIIIV
6MWD>400440-320319-165<165
BNP, ng.L-1<5050-199200-800>800
NT-proBNP, ng L-1<300300-649650-1100>1100

According to this 4-stratum model, 5.6% of patients were classified as low risk, 24.2% as intermediate-low risk, 55% as intermediate-high risk, and 16.2% as high risk.

So how does this 4-stratum model compare with the older 3-stratum model in which patients were classified between 3 categories (low, intermediate, and high risk)? Researchers discovered that a very low percentage of patients were classified as “low risk” upon diagnosis. In addition, they reported that changes between intermediate-low and intermediate-high risk categories from the 3- to the 4-stratum model were associated with changes in long-term mortality risk. 

In addition, Hoeper and colleagues report that patients who were classified as being in the high or intermediate-high risk category had a strong likelihood of reaching intermediate-low risk profile but a very poor likelihood of reaching a low risk profile. 

Commenting on the merits of the 4-stratum model, Hoeper et al write, “An intermediate-high risk status at baseline may prompt physicians to initiate a more aggressive therapeutic approach, especially when keeping in mind a recent publication from France on the effects of initial treatment strategies on long-term survival.” 

The Value of Sensitive Risk Stratification 

The point of the whole exercise by Hoeper and colleagues was to investigate whether a more detailed risk stratification strategy can yield further benefits in helping physicians devise appropriate treatment strategies to improve patient outcomes. 

“An intermediate-high risk category at follow-up was associated with a high mortality risk and should trigger treatment escalation whenever reasonably possible,” they write. “Hence, the distinction between intermediate-low and intermediate-high risk can support clinical decision-making.” 

Risk stratification models in PAH translate to a type of algorithm that can simplify clinical decision making. Similar models already exist for other conditions, such as gastroesophageal reflux and hypertension. Clinical algorithms help take the guesswork out of the equation and streamline decision making because they are made based on objective measures instead of subjective reports.

Read more about PAH treatment

This is what the 4-stratum model hopes to achieve: giving physicians a framework by which they can decide the best treatment strategies, based on an individual patient’s risk category. 

Nevertheless, the 4-stratum model has its limitations. For example, the registry that it is based on lacks standardized visit schedules and may have missing values. In addition, some patients might have been lost to follow-up. Also, the 4-stratum model is based on 4 variables; future risk stratification models might choose to include more to increase their sensitivity.

It is vital that any proposed risk stratification models are associated with specific treatments and treatment-related outcomes. As research into PAH therapeutics continues, medical researchers might choose to revisit existing risk stratification models. The more sensitive the risk stratification model and the more accurate the algorithms that flow from it, the greater the likelihood of securing better clinical outcomes for patients with PAH. 

References

Hoeper MM, Pausch C, Olsson KM, et al. COMPERA 2.0: a refined four-stratum risk assessment model for pulmonary arterial hypertensionEur Respir J. 2022;60(1):2102311. doi:10.1183/13993003.02311-2021

Galiè N, Channick RN, Frantz RP, et al. Risk stratification and medical therapy of pulmonary arterial hypertensionEur Respir J. 2019;53(1):1801889. doi:10.1183/13993003.01889-2018