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Most Patients Are At Intermediate Risk At Diagnosis1

Intermediate risk, or moderate PAH, carries a poor prognosis, and according to a prospective analysis of the COMPERA registry, 70% of patients with PAH fell within the intermediate-risk category at diagnosis.1

Risk Status at Diagnosis (N=1588)1*

Moderate PAH risk status at diagnosis

Patients were selected from the COMPERA database according to these criteria1:

Treatment-naïve patients newly diagnosed with PAH between 2009 and 2016

At least 1 follow-up available

Baseline hemodynamics showing mPAP ≥25 mm Hg, PAWP ≤15 mm Hg, and PVR >240 dynes•sec•cm-5

At least 2 of the 6 listed variables available at baseline (WHO FC, 6MWD, BNP or NT-proBNP, RAP, CI, and SvO2)

*Numbers do not add up to 100% due to rounding.

The intermediate-risk group of PAH can be tricky because many of our intermediate-risk patients will, on the surface, look relatively stable.

—A PAH Expert

TIMELY FOLLOW-UPS ARE IMPORTANT

Refined cutoff levels for 3- to 6-month follow-up assessment2

There are a significant number of patients at intermediate risk at baseline. Following up with the 4-strata model helps facilitate more granular decision-making and better define the needs of these patients.2

Clinical parameters in 4-strata model2,3

2 Distinct Intermediate-Risk Groups
LOW RISK Intermediate-Low Intermediate-HIGH HIGH RISK
FC I or II III IV
6MWD >440 m 320-440 m 165-319 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 320-440 m
BNP
or
NT-proBNP
50-199 ng/L
300-649 ng/L
Intermediate-High
FC III
6MWD 165-319 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 analysis3:

  • 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.3

Patients may be at higher risk than they appear3,4

Risk Status at First Follow-up (N=1414)3

Intermediate PAH patient risk status at first follow-up

TO HELP PATIENTS ACHIEVE LOW-RISK STATUS IN A TIMELY MANNER, PRIORITIZE 3- TO 6-MONTH MILESTONES FOR ASSESSMENT AND RESPONSE.2

6MWD=6-minute walk distance; BNP=B-type natriuretic peptide; CI=cardiac index; FC=functional class; mPAP=mean pulmonary arterial pressure; NT-proBNP=N-terminal pro–B-type natriuretic peptide; PAH=pulmonary arterial hypertension; PAWP=pulmonary arterial wedge pressure; PVR=pulmonary vascular resistance; RAP=right atrial pressure; REVEAL=Registry to Evaluate Early and Long-Term Pulmonary Arterial Hypertension Disease Management; SvO2=mixed venous oxygen saturation; 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. 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. doi:10.1183/13993003.00740-2017. 2. Humbert M, Kovacs G, Hoeper MM, et al; ESC/ERS Scientific Document Group. 2022 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension. Eur Heart J. 2022;43(38):3618-3731. 3. Hoeper MM, Pausch C, Olsson KM, et al. COMPERA 2.0: a refined four-stratum risk assessment model for pulmonary arterial hypertension. Eur Respir J. 2022;60(1):2102311. doi:10.1183/13993003.02311-2021. 4. Sahay S, Tonelli AR, Selej M, et al. Risk assessment in patients with functional class II pulmonary arterial hypertension: comparison of physician gestalt with ESC/ERS and the REVEAL 2.0 risk score. PLoS One. 2020;15(11):e0241504. doi:10.1371/journal.pone.0241504.