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Most Patients Are At Intermediate Risk At Diagnosis1
Setting time-bound clinical goals is critical to ensure patients achieve low-risk status and to optimize long-term outcomes.2
Intermediate risk carries a poor prognosis, and according to a recent retrospective analysis, 70% of patients with PAH fall within the intermediate-risk category at diagnosis—and the majority are still there at first follow-up.1,2
Guideline recommendations for achieving low-risk status in these patients include2,3:
Multiparameter risk assessment
Initial therapy based on risk
Reassessment of risk within 3-6 months of starting therapy
Study Data Indicate 2 Intermediate-Risk Groups4
Standard assessments use a 3-strata model to define a patient’s risk status (low, intermediate, and high risk). However, the vast population of intermediate-risk patients may lead to their individual treatment needs being overlooked. Upon closer look at this population, recent study data indicate 2 distinct intermediate-risk groups.4
Clinical Parameters in 4-Strata Model4
| 2 Distinct Intermediate-Risk Groups | ||||
|---|---|---|---|---|
| LOW RISK | Intermediate-Low | Intermediate-HIGH | HIGH RISK | |
| FC | I or II | – | III | IV |
| 6MWD | >440 m | 440-320 m | 319-165 m | <165 m |
| BNP or NT-proBNP | <50 ng/L | 50-199 ng/L | 200-800 ng/L | >800 ng/L |
| <300 ng/L | 300-649 ng/L | 650-1100 ng/L | >1100 ng/L | |
| LOW RISK | |
|---|---|
| FC | I or II |
| 6MWD | >440 m |
| BNP or NT-proBNP | <50 ng/L |
| <300 ng/L |
| 2 Distinct Intermediate-Risk Groups | |
|---|---|
| Intermediate-Low | |
| FC | – |
| 6MWD | 440-320 m |
| BNP or NT-proBNP | 50-199 ng/L |
| 300-649 ng/L | |
| Intermediate-High | |
|---|---|
| FC | III |
| 6MWD | 319-165 m |
| BNP or NT-proBNP | 200-800 ng/L |
| 650-1100 ng/L |
| HIGH RISK | |
|---|---|
| FC | IV |
| 6MWD | <165 m |
| BNP or NT-proBNP | >800 ng/L |
| >1100 ng/L |
Patients who had the following data available were included in this analysis4:
- Treatment-naïve adults (≥18 years) newly diagnosed with any form of PAH between 2009 and 2020
- At least 1 follow-up available
- Baseline hemodynamics showing mPAP ≥25 mm Hg, PAWP ≤15 mm Hg, and PVR >3 WU
- All 3 variables of interest (FC, 6MWD, and BNP or NT-proBNP) available at baseline
The analysis took data from COMPERA and calculated risk at diagnosis and first follow-up between 3 and 12 months after treatment initiation based on refined cutoff values for FC, 6MWD, and BNP or NT-proBNP. Since very few patients were classified as FC I, and FC II has been shown to be associated with good long-term survival, both went into the low-risk group. The refined cutoff values for 6MWD and BNP were adopted from REVEAL. No NT-proBNP cutoff value was available to distinguish intermediate-low and intermediate-high risk, so the optimal cutoff was determined using the highest predictive value.4
Take a closer look at how the 4-strata assessment model was created and utilized.
Outcomes Differ Between Intermediate-Risk Groups4
In many cases, the 3-strata model might not be nuanced enough to show prognostically relevant changes within the intermediate-risk group at follow-up. The 4-strata model, however, does show a statistically significant impact between intermediate-low and intermediate-high risk patients regarding long-term outcomes. Thus, the distinction between these 2 groups can support clinical decision-making to help intermediate-risk patients reach low-risk status.4
See additional data from the French PH Registry validating the 4-strata assessment approach.†
*Article may be restricted by a paywall for nonsubscribers.
†This was a retrospective analysis of prospectively collected data in the French PH Registry. The inclusion criteria and the cutoff values for WHO FC, 6MWD, and NT-proBNP/BNP were the same as those derived and used in the COMPERA 2.0 analysis. Long-term outcomes were assessed according to the 4-strata score at baseline and at the time of first follow-up within 3-24 months after diagnosis (N=2082).5
Although Improvement to intermediate-low risk is associated with improved clinical outcomes, low-risk status remains the goal.4
6MWD=6-minute walk distance; BNP=B-type natriuretic peptide; FC=functional class; mPAP=mean pulmonary arterial pressure; NT-proBNP=N-terminal pro–B-type natriuretic peptide; PAH=pulmonary arterial hypertension; PAWP=pulmonary artery wedge pressure; PH=pulmonary hypertension; PVR=pulmonary vascular resistance; REVEAL=Registry to Evaluate Early and Long-Term Pulmonary Arterial Hypertension Disease Management; WHO=World Health Organization; WU=Wood units.
Important Safety Information
Warnings and Precautions
- Chronic intravenous (IV) infusions of Remodulin delivered using an external infusion pump with an indwelling central venous catheter are associated with the risk of blood stream infections (BSIs) and sepsis, which may be fatal. Therefore, continuous subcutaneous (SC) infusion is the preferred mode of administration.
- Avoid abrupt withdrawal or sudden large reductions in dosage of Remodulin, which may result in worsening of PAH symptoms.
- Titrate slowly in patients with hepatic or renal insufficiency, because such patients will likely be exposed to greater systemic concentrations relative to patients with normal hepatic or renal function.
- Remodulin is a pulmonary and systemic vasodilator. In patients with low systemic arterial pressure, treatment with Remodulin may produce symptomatic hypotension.
- Remodulin inhibits platelet aggregation and increases the risk of bleeding.
Adverse Reactions
- In clinical studies of SC Remodulin infusion, the most common adverse events reported were infusion site pain and infusion site reaction (redness, swelling, and rash). These symptoms were sometimes severe and sometimes required treatment with narcotics or discontinuation of Remodulin. The IV infusion of Remodulin with an external infusion pump has been associated with a risk of blood stream infections, arm swelling, paresthesias, hematoma, and pain. Other common adverse events (≥3% more than placebo) seen with either SC or IV Remodulin were headache (27% vs. 23%), diarrhea (25% vs. 16%), nausea (22% vs. 18%), rash (14% vs. 11%), jaw pain (13% vs. 5%), vasodilatation (11% vs. 5%), edema (9% vs. 3%), and hypotension (4% vs. 2%).
Drug Interactions
- Remodulin dosage adjustment may be necessary if inhibitors or inducers of CYP2C8 are added or withdrawn.
Specific Populations
- In patients with mild or moderate hepatic insufficiency, decrease the initial dose of Remodulin to 0.625 ng/kg/min of ideal body weight, and monitor closely. Remodulin has not been studied in patients with severe hepatic insufficiency.
- Safety and effectiveness of Remodulin in pediatric patients have not been established.
- It is unknown if geriatric patients respond differently than younger patients. Caution should be used when selecting a dose for geriatric patients.
- There are no adequate and well-controlled studies with Remodulin in pregnant women. It is not known whether treprostinil is excreted in human milk or if it affects the breastfed infant or milk production.
Indication
Remodulin is a prostacyclin vasodilator indicated for the treatment of pulmonary arterial hypertension (PAH; WHO Group 1) to diminish symptoms associated with exercise. Studies establishing effectiveness included patients with NYHA Functional Class II-IV symptoms and etiologies of idiopathic or heritable PAH (58%), PAH associated with congenital systemic-to-pulmonary shunts (23%), or PAH associated with connective tissue diseases (19%).
In patients with PAH requiring transition from epoprostenol, Remodulin is indicated to diminish the rate of clinical deterioration. Consider the risks and benefits of each drug prior to transition.
REMISIhcpMAY2021
Please see accompanying Full Prescribing Information for Remodulin.
For additional information, visit www.RemodulinPro.com or call Customer Service at 1-877-UNITHER (1-877-864-8437).
Important Safety Information
Warnings and Precautions
- Chronic intravenous (IV) infusions of Remodulin delivered using an external infusion pump with an indwelling central venous catheter are associated with the risk of blood stream infections (BSIs) and sepsis, which may be fatal. Therefore, continuous subcutaneous (SC) infusion is the preferred mode of administration.
- Avoid abrupt withdrawal or sudden large reductions in dosage of Remodulin, which may result in worsening of PAH symptoms.
- Titrate slowly in patients with hepatic or renal insufficiency, because such patients will likely be exposed to greater systemic concentrations relative to patients with normal hepatic or renal function.
- Remodulin is a pulmonary and systemic vasodilator. In patients with low systemic arterial pressure, treatment with Remodulin may produce symptomatic hypotension.
- Remodulin inhibits platelet aggregation and increases the risk of bleeding.
Adverse Reactions
- In clinical studies of SC Remodulin infusion, the most common adverse events reported were infusion site pain and infusion site reaction (redness, swelling, and rash). These symptoms were sometimes severe and sometimes required treatment with narcotics or discontinuation of Remodulin. The IV infusion of Remodulin with an external infusion pump has been associated with a risk of blood stream infections, arm swelling, paresthesias, hematoma, and pain. Other common adverse events (≥3% more than placebo) seen with either SC or IV Remodulin were headache (27% vs. 23%), diarrhea (25% vs. 16%), nausea (22% vs. 18%), rash (14% vs. 11%), jaw pain (13% vs. 5%), vasodilatation (11% vs. 5%), edema (9% vs. 3%), and hypotension (4% vs. 2%).
Drug Interactions
- Remodulin dosage adjustment may be necessary if inhibitors or inducers of CYP2C8 are added or withdrawn.
Specific Populations
- In patients with mild or moderate hepatic insufficiency, decrease the initial dose of Remodulin to 0.625 ng/kg/min of ideal body weight, and monitor closely. Remodulin has not been studied in patients with severe hepatic insufficiency.
- Safety and effectiveness of Remodulin in pediatric patients have not been established.
- It is unknown if geriatric patients respond differently than younger patients. Caution should be used when selecting a dose for geriatric patients.
- There are no adequate and well-controlled studies with Remodulin in pregnant women. It is not known whether treprostinil is excreted in human milk or if it affects the breastfed infant or milk production.
Indication
Remodulin is a prostacyclin vasodilator indicated for the treatment of pulmonary arterial hypertension (PAH; WHO Group 1) to diminish symptoms associated with exercise. Studies establishing effectiveness included patients with NYHA Functional Class II-IV symptoms and etiologies of idiopathic or heritable PAH (58%), PAH associated with congenital systemic-to-pulmonary shunts (23%), or PAH associated with connective tissue diseases (19%).
In patients with PAH requiring transition from epoprostenol, Remodulin is indicated to diminish the rate of clinical deterioration. Consider the risks and benefits of each drug prior to transition.
REMISIhcpMAY2021
Please see accompanying Full Prescribing Information for Remodulin.
For additional information, visit www.RemodulinPro.com or call Customer Service at 1-877-UNITHER (1-877-864-8437).
References: 1. Boucly A, Savale L, Jais X, et al. Association between initial treatment strategy and long-term survival in pulmonary arterial hypertension. Am J Respir Crit Care Med. 2021;204(7):842-854. 2. Cascino TM, McLaughlin VV. Upfront combination therapy for pulmonary arterial hypertension: time to be more ambitious than AMBITION. Am J Respir Crit Care Med. 2021;204(7):756-759. 3. Galiè N, Channick RN, Frantz RP, et al. Risk stratification and medical therapy of pulmonary arterial hypertension. Eur Respir J. 2019;53(1):1801889. doi:10.1183/13993003.01889-2018. 4. Hoeper MM, Pausch C, Olsson KM, et al. COMPERA 2.0: a refined 4-strata risk assessment model for pulmonary arterial hypertension. Eur Respir J. 2021;2102311. doi:10.1183/13993003.02311-2021. 5. Boucly A, Weatherald J, Savale L, et al. External validation of a refined 4-strata risk assessment score from the French pulmonary hypertension Registry. Eur Respir J. 2021;2102419. doi:10.1183/13993003.02419-2021.
