What is the role of Tadalafil (tadalafil) in the treatment of Pulmonary Hypertension (PH)?

Role of Tadalafil in Pulmonary Hypertension

Tadalafil 40 mg once daily is an effective first-line oral therapy for treatment-naive patients with WHO functional class II-III pulmonary arterial hypertension (PAH), improving exercise capacity, delaying clinical worsening, and enhancing quality of life, though initial combination therapy with ambrisentan plus tadalafil is now preferred over monotherapy for most patients. 1

Mechanism and Pharmacology

Tadalafil is a phosphodiesterase-5 (PDE-5) inhibitor with 10,000-fold greater affinity for PDE-5 compared to other PDE inhibitors, causing nitric oxide-mediated vasodilation in the pulmonary vasculature with a half-life of 17.5 hours allowing once-daily dosing. 2

Evidence for Monotherapy

Treatment-Naive Patients with WHO FC II-III

• Tadalafil 40 mg once daily significantly improves 6-minute walk distance (6MWD) by 33 meters compared to placebo (the primary endpoint in the pivotal PHIRST trial). 1, 3
• In treatment-naive patients specifically, tadalafil 40 mg increased 6MWD by 44 meters at 16 weeks. 3
• Tadalafil delays time to clinical worsening with a 68% relative risk reduction compared to placebo. 1, 2
• Improvements in WHO functional class occur, though less consistently than with 6MWD. 1
• Cardiopulmonary hemodynamics improve significantly. 1
• Health-related quality of life improves across six of eight SF-36 domains and EQ-5D index scores. 4, 5

Dosing Considerations

• The recommended and FDA-approved dose is 40 mg once daily. 1
• Treatment with more than 40 mg once daily has not been studied and is not recommended. 1
• Lower doses (2.5,10,20 mg) showed less consistent benefit, with only the 40 mg dose meeting the primary endpoint threshold. 1

Combination Therapy: The Preferred Approach

Initial Combination Therapy (Treatment-Naive Patients)

For treatment-naive PAH patients with WHO FC II-III, initial combination therapy with ambrisentan 10 mg plus tadalafil 40 mg daily is now recommended over monotherapy. 1, 6

• The AMBITION trial demonstrated that initial combination therapy improved time to clinical failure compared to either monotherapy alone. 1
• Median change in 6MWD was 49 meters with combination therapy versus 24 meters with pooled monotherapy (p<0.001). 1
• This represents a weak recommendation with moderate quality evidence due to only one supporting trial, but the clinical benefit is clear. 1

Sequential Combination Therapy (Add-On to Existing Treatment)

For patients already on ambrisentan who remain symptomatic, adding tadalafil 40 mg daily improves 6MWD by 54.4 meters. 1

• This improvement was statistically significant (p=0.042) compared to placebo (18.3 meters). 1
• This is a weak recommendation with low quality evidence based on a single study. 1

Background Therapy Considerations

• In patients already receiving bosentan as background therapy, tadalafil 40 mg increased 6MWD by 23 meters (not statistically significant). 3
• Approximately half of patients in the PHIRST trial were on background endothelin receptor antagonist therapy. 1

Clinical Application Algorithm

For Treatment-Naive PAH Patients:

WHO FC II-III:

1. First choice: Initiate ambrisentan 10 mg + tadalafil 40 mg daily as initial combination therapy. 1, 6
2. Alternative (if combination not feasible): Tadalafil 40 mg once daily as monotherapy. 1

WHO FC IV or rapidly progressing disease:

• Do not use tadalafil as initial therapy; initiate continuous IV epoprostenol instead, as it is the only treatment proven to reduce mortality in high-risk patients. 1, 6

For Patients Already on Monotherapy:

On ambrisentan alone with inadequate response:

• Add tadalafil 40 mg daily. 1

On tadalafil alone with inadequate response:

• Add ambrisentan 10 mg daily or consider adding an inhaled prostanoid. 1

On bosentan or other ERA:

• Tadalafil 40 mg can be added, though benefit may be more modest. 1, 3

Safety and Tolerability

• Tadalafil is generally well tolerated with adverse events that are mild to moderate in intensity. 3, 5
• The most common adverse event is headache (42% of patients). 2
• Discontinuation rates are typically low. 5
• Adverse event profile is similar to placebo in controlled trials. 2

Critical Contraindications and Warnings

Tadalafil must not be combined with riociguat (a soluble guanylate cyclase stimulator) due to risk of systemic hypotension. 1

• Male patients on riociguat should be cautioned not to use PDE-5 inhibitors for erectile dysfunction. 1
• This contraindication applies to all PDE-5 inhibitors, not just tadalafil. 6

Comparison to Sildenafil

• Both tadalafil and sildenafil are PDE-5 inhibitors with similar efficacy profiles. 1
• Tadalafil offers once-daily dosing (40 mg) versus sildenafil's three-times-daily dosing (20 mg TID, up to 80 mg TID). 1
• The choice between them often depends on patient preference for dosing frequency and individual tolerability. 5
• There is limited head-to-head comparative data, and neither can be definitively recommended preferentially. 1

Long-Term Efficacy

• Preliminary extension data from the PHIRST trial suggest improvements in 6MWD are maintained for up to 1 year with tadalafil 40 mg once daily. 3
• Tadalafil appears effective in maintaining clinical stability and reducing disease progression over extended periods. 7

Special Populations

PAH Associated with Connective Tissue Disease

• Response to tadalafil (and other PAH therapies) is generally less impressive in systemic sclerosis-associated PAH compared to idiopathic PAH. 1
• Extrapolation of efficacy from IPAH trials may be problematic in other PAH subgroups. 1

Pediatric Patients

• Tadalafil received FDA approval in 2009 for adults with PAH. 2
• Limited data exist for pediatric use, though some open-label studies suggest potential benefit. 1

Common Pitfalls to Avoid

1. Do not use tadalafil doses other than 40 mg once daily – lower doses showed inconsistent benefit and higher doses are unstudied. 1

2. Do not use tadalafil as monotherapy in WHO FC IV patients – these high-risk patients require IV epoprostenol as initial therapy. 1, 6

3. Do not combine tadalafil with riociguat – this combination causes dangerous hypotension. 1, 6

4. Do not delay adding therapy if monotherapy fails – patients who remain symptomatic on adequate doses of single agents should have therapy escalated promptly. 1

5. Do not use tadalafil empirically without confirming PAH diagnosis – right heart catheterization is mandatory before initiating PAH-specific therapy, as treatment differs fundamentally by PH classification. 8

Monitoring and Treatment Goals

• Reassess patients every 3-6 months with functional class assessment, 6MWD testing, and echocardiography. 6
• Treatment goals include achieving WHO FC I-II and 6MWD >440 meters. 6
• If goals are not met on tadalafil monotherapy, escalate to combination therapy rather than increasing tadalafil dose beyond 40 mg. 1