What is the treatment protocol for pulmonary hypertension using Adempas (Ríociguat)?

Riociguat (Adempas) Treatment Protocol for Pulmonary Hypertension

Riociguat is strongly recommended as first-line therapy for patients with inoperable chronic thromboembolic pulmonary hypertension (CTEPH) or persistent/recurrent CTEPH after pulmonary endarterectomy (PEA), with a Class I, Level B recommendation based on clinical evidence. 1

Indications for Riociguat

Riociguat (Adempas) is approved for two specific types of pulmonary hypertension:

1. Chronic Thromboembolic Pulmonary Hypertension (CTEPH)

   • For inoperable CTEPH
   • For persistent/recurrent CTEPH after surgical treatment 1

2. Pulmonary Arterial Hypertension (PAH)

   • To improve exercise capacity
   • To improve WHO functional class 1

Dosing Protocol

Initial Dosing and Titration

1. Starting dose: 1 mg three times daily
2. Titration schedule:
   • Increase by 0.5 mg three times daily every 2 weeks
   • If systolic blood pressure remains >95 mmHg and patient shows no signs of hypotension
   • Maximum dose: 2.5 mg three times daily 1

Dose Adjustments for Special Populations

• Hepatic impairment: Titrate with caution
• Renal impairment: Titrate with caution
• Elderly patients: Titrate with caution
• Smokers: May require higher doses (smoking reduces riociguat plasma levels) 2

Monitoring Requirements

Before Initiation

1. Complete pulmonary hypertension workup including:
   • Right heart catheterization
   • Pulmonary vascular resistance measurement
   • WHO functional class assessment
   • 6-minute walk distance test (6MWD)
   • N-terminal pro-BNP levels 1

During Treatment

1. Blood pressure monitoring: At each dose increase and regularly during treatment
2. Clinical assessment: Every 3-6 months including:
   • WHO functional class
   • 6-minute walk distance
   • N-terminal pro-BNP levels
   • Signs of clinical worsening 1

Contraindications and Precautions

Absolute Contraindications

1. Concomitant use with PDE-5 inhibitors (sildenafil, tadalafil) - severe hypotension risk
2. Pregnancy - riociguat is contraindicated in pregnancy
3. Pulmonary veno-occlusive disease 1

Precautions

1. Hypotension risk: Monitor blood pressure regularly
2. Bleeding risk: Increased risk, particularly in patients on anticoagulants
3. Smoking: Reduces plasma levels by 50-60% 2

Management of Side Effects

Common Side Effects

1. Hypotension (14%): Dose reduction may be necessary
2. Headache (13%): Usually transient, can be managed with analgesics
3. Dyspepsia (9%): Consider proton pump inhibitors if persistent
4. Dizziness: Caution patients about operating machinery 3

Treatment Algorithm for CTEPH

1. Diagnosis of CTEPH confirmed
2. Assessment of operability by multidisciplinary team
3. If operable: Pulmonary endarterectomy (PEA)
4. If inoperable OR persistent/recurrent PH after PEA:
   • Start riociguat therapy with dose titration as described above
   • Lifelong anticoagulation is also recommended for all CTEPH patients 1

Treatment Algorithm for PAH

1. Treatment-naïve PAH patients:

   • Assess risk status (low, intermediate, high)
   • For low/intermediate risk: Consider riociguat monotherapy or initial combination therapy
   • For high risk: Consider combination therapy including IV prostacyclin analogue 1

2. PAH patients already on PDE-5 inhibitors with inadequate response:

   • Consider switching to riociguat (requires washout period)
   • Recent evidence shows improved outcomes when switching from PDE-5i to riociguat in patients with inadequate response 3

Clinical Efficacy Outcomes

Riociguat has demonstrated significant improvements in:

• 6-minute walk distance (mean increase of 30m compared to placebo)
• Pulmonary vascular resistance (decrease of 223 dyn/s/cm^5)
• WHO functional class
• Time to clinical worsening 1

Long-term data shows sustained benefits in exercise and functional capacity for up to 1 year 4.

Important Considerations

• Treatment should be initiated and monitored at specialized pulmonary hypertension centers by physicians experienced in treating PAH/CTEPH 1
• The combination of riociguat and PDE-5 inhibitors is strictly contraindicated due to risk of severe hypotension 1
• Riociguat has shown superior efficacy to inhaled nitric oxide in improving pulmonary hemodynamics 5

By following this protocol, clinicians can optimize the use of riociguat for appropriate patients with pulmonary hypertension, potentially improving outcomes including exercise capacity, functional status, and delaying clinical worsening.