What is the recommended approach for risk stratification in a patient with connective tissue disease-associated pulmonary arterial hypertension (CTD-PAH) being treated with Selexipag (selective IP receptor agonist)?

Risk Stratification in CTD-PAH Patients on Selexipag

Patients with connective tissue disease-associated pulmonary arterial hypertension (CTD-PAH) being treated with selexipag should be risk-stratified using the ESC/ERS 4-strata risk assessment method every 3-6 months, with the treatment goal being achievement and maintenance of low-risk status. 1

Risk Stratification Framework

The ESC/ERS 4-Strata Risk Model

The current standard uses a comprehensive multi-parameter assessment that classifies patients into four risk categories based on estimated 1-year mortality 1:

• Low risk: <5% estimated 1-year mortality
• Intermediate-low risk: 5-10% estimated 1-year mortality
• Intermediate-high risk: 5-10% estimated 1-year mortality
• High risk: >10% estimated 1-year mortality

Key Parameters for Risk Assessment

Clinical and functional measures 1:

• WHO Functional Class: Target FC I-II (low risk); FC III indicates intermediate risk; FC IV indicates high risk
• 6-Minute Walk Distance (6MWD): Target >440 meters (low risk); 165-440m (intermediate risk); <165m (high risk)
• Syncope: Absence indicates low risk; occasional syncope with exertion indicates intermediate risk; repeated syncope indicates high risk

Biomarkers and hemodynamics 1:

• BNP/NT-proBNP levels: Normal or near-normal indicates low risk; moderately elevated indicates intermediate risk; markedly elevated indicates high risk
• Right atrial pressure: <8 mmHg (low risk); 8-14 mmHg (intermediate risk); >14 mmHg (high risk)
• Cardiac index: >2.5 L/min/m² (low risk); 2.0-2.4 L/min/m² (intermediate risk); <2.0 L/min/m² (high risk)

Imaging findings 1:

• Right atrial area on echo: <18 cm² (low risk); 18-26 cm² (intermediate risk); >26 cm² (high risk)
• Pericardial effusion: Absence indicates low risk; presence indicates intermediate-high or high risk

Assessment Timing and Follow-Up

Regular monitoring schedule 1:

• Perform comprehensive risk assessment every 3-6 months in stable patients
• Reassess 3-6 months after any treatment changes, including selexipag initiation or dose escalation
• Conduct immediate reassessment with any clinical worsening

Required assessments at each visit 1:

• Medical assessment and WHO functional class determination
• ECG
• 6-minute walk test with Borg dyspnea score
• Basic laboratory work: blood count, BNP/NT-proBNP, creatinine, sodium, potassium, liver enzymes, bilirubin
• Echocardiography every 6-12 months or with clinical changes

Extended assessments 1:

• Right heart catheterization should be considered every 6-12 months or after treatment changes to objectively assess hemodynamic response
• Cardiopulmonary exercise testing provides additional prognostic information, particularly in younger patients where 6MWD targets may be insufficient

Treatment Goals and Response Criteria

Primary treatment goal 1:

• Achievement and maintenance of low-risk status is the recommended treatment target
• This translates to WHO FC I-II, 6MWD >440m, normal or near-normal BNP, and preserved right ventricular function

Inadequate response definition 1:

• Intermediate-risk status should be considered inadequate for most PAH patients and warrants treatment escalation
• High-risk status mandates immediate treatment intensification

CTD-PAH Specific Considerations

Higher baseline risk profile 1, 2:

• CTD-PAH patients, particularly those with systemic sclerosis, represent a higher-risk subgroup compared to idiopathic PAH
• In real-world selexipag studies, 67-70% of CTD-PAH patients were at intermediate or high risk at treatment initiation despite background therapy 2, 3
• CTD-PAH patients are typically older (median age 60-68 years) with more cardiovascular comorbidities 4, 2

Prognostic implications 1, 4, 2:

• The 4-strata risk assessment remains prognostic in CTD-PAH patients treated with selexipag
• One-year survival estimates range from 98% (low risk) to 80% (high risk), with 2-year survival dropping to 67% in high-risk patients 4
• CTD-PAH patients show 85% 1-year and 71% 2-year survival in real-world selexipag cohorts 2

Treatment Escalation Based on Risk Status

For patients remaining at intermediate or high risk 1, 5:

• Consider adding intravenous prostacyclin analogues (epoprostenol) for WHO FC III/IV or high-risk patients
• Evaluate for riociguat as alternative or additional therapy
• Reassess at 3-6 months after escalation

Common pitfall to avoid 4, 2:

• Real-world data shows only 45% of patients achieve low/intermediate-low risk at selexipag initiation, suggesting delayed treatment escalation
• This represents a missed opportunity—earlier and more frequent risk assessment with proactive treatment escalation before clinical deterioration occurs is critical

Practical Implementation Algorithm

1. At selexipag initiation: Perform complete baseline risk assessment using all available parameters 1

2. At 3-6 months post-initiation: Repeat full assessment to determine treatment response 1

3. Classify overall risk: When parameters fall into different risk categories, use clinical judgment weighing the overall pattern, with particular attention to WHO FC, 6MWD, and BNP 1

4. Define treatment response 1:

   • Adequate: Achievement/maintenance of low-risk profile
   • Inadequate: Persistence at intermediate or high risk—escalate therapy

5. Continue monitoring: Every 3-6 months indefinitely in stable patients 1