Recent advances in the management of pulmonary arterial hypertension: lessons from the upfront combination of ambrisentan and tadalafil

ABSTRACT

Introduction

The sixth World Symposium of Pulmonary Hypertension (sixth WSPH) brought to the forefront for the first time the value of earlier, aggressive management with an upfront oral combination in patients with pulmonary arterial hypertension (PAH) of low or intermediate risk. This was prompted by results from the AMBITION study (ambrisentan + tadalafil). A literature search was conducted to collect all evidence provided by upfront treatment with this combination, as well as other combinations under investigation at the time the manuscript was prepared.

Areas covered

The value of an upfront oral combination with ambrisentan and tadalafil is reviewed on the basis of topics discussed at the sixth WSPH, such as evidence in different PAH etiologies, according to risk stratification and in so-called ‘atypical’ patients where monotherapy is still recommended. Evidence in clinical practice is also reviewed. New evidence about the value of the upfront oral combination is also commented. Finally, tendencies in primary endpoints to assess the effect of PAH-targeted therapies (time to clinical worsening and hemodynamics) and their value are also reviewed.

Expert opinion

All above-mentioned aspects are put into perspective with regard to the impact of new advances on improving PAH management in clinical practice.

KEYWORDS:

• Pulmonary arterial hypertension
• ambrisentan
• tadalafil
• risk assessment
• right ventricle
• pulmonary vascular resistance
• hemodynamics
• treatment

Article highlights

• The 6^th World Symposium on Pulmonary Hypertension (sixth WSPH) underpinned the value of an upfront combination to treat patients with pulmonary arterial hypertension (PAH), independently of their risk (except specific subsets where evidence is lacking).

• Evidence for this approach in patients at low or intermediate risk was provided for the first time by the AMBITION study (ambrisentan + tadalafil), both in idiopathic and connective tissue-associated PAH, independently of risk status. Real-world evidence is further supporting the value of the upfront combination with ambrisentan and tadalafil in clinical practice.

• A sub-study of the ‘atypical’ population (i.e. elderly patients or patients with relevant cardiopulmonary comorbidities) excluded from the primary analysis of the AMBITION study showed potential benefit for the upfront combination in this population, albeit lower than in ‘classic’ PAH patients. These results should be interpreted with caution, however, given the possibility of misdiagnosis.

• Event-driven studies (time to clinical worsening) provide a realistic view of the long-term effect of PAH-targeted treatment on disease course. Other variables provide more a rapid means of measuring the effectiveness of treatments in order to guide treatment decisions.

• Reducing the hemodynamic burden of the right ventricle is emerging as a new treatment target, given its association with the clinical status and prognosis of patients.

Acknowledgments

The authors are grateful to Beatriz Viejo, PhD for her exceptional medical writing assistance. The authors also acknowledge the support of Content Ed Net (Madrid, Spain), for editorial assistance of the manuscript.

Declaration of interest

L Gómez Climent declares employment and stock ownership of GSK. JI Diago Cabezudo has declared being an employee of GSK and declares stock ownership. MF Perelló has declared being an employee of GSK. P Escribano-Subias reports personal fees from Janssen, personal fees from MSD, personal fees from GlaxoSmithKline for Advisory Board, Consulting and Speaker, and grants from Janssen through Institution, outside the submitted work. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was funded by GSK.