Non-Vasoreactive PAH: What to Do When ERA + PDE5i Dual Therapy Fails to Achieve Low-Risk Profile

Clinical Scenario

This protocol addresses adults with non-vasoreactive idiopathic, heritable, or drug-associated PAH — or PAH associated with connective tissue disease — who have a negative acute pulmonary vasoreactivity test, no cardiopulmonary comorbidities, and who are currently at low or intermediate risk of death.

Previous Treatment: Goal Not Reached

First-line oral combination therapy with an endothelin receptor antagonist (ERA) plus a phosphodiesterase 5 inhibitor (PDE5i) — the recommended initial dual approach in this population — did not result in achieving or maintaining a low-risk profile. Risk stratification is based on WHO functional class (WHO-FC), six-minute walk distance (6MWD), and BNP/NT-proBNP. Failure to reach or sustain that low-risk threshold on optimised dual therapy is the trigger for escalation to this protocol.

Next-Step Approach (Partial Overview)

Escalation centres on modifying the existing ERA/PDE5i regimen — either by adding a third agent from a distinct mechanistic pathway, or by substituting one component of the dual therapy with an agent acting through an alternative route. The complete escalation algorithm, specific agents, and sequencing are available in the full structured protocol.

Instant Access to Structured Evidence-Based Regimens

References

DOI: 10.1093/eurheartj/ehac237

This section describes drug treatment and is focused on non-vasoreactive patients with IPAH/HPAH/DPAH and on patients with PAH associated with connective tissue disease (PAH-CTD).

For patients presenting at low or intermediate risk, initial combination therapy with an ERA and a PDE5i is recommended.

Cardiopulmonary comorbidities are conditions associated with an increased risk of left ventricular diastolic dysfunction, and include obesity, hypertension, diabetes mellitus, and coronary heart disease; pulmonary comorbidities may include signs of mild parenchymal lung disease and are often associated with a low DLCO (<45% of the predicted value).

In patients with IPAH/HPAH/DPAH who present at intermediate–low risk of death while receiving ERA/PDE5i therapy, the addition of selexipag should be considered

In patients with IPAH/HPAH/DPAH who present at intermediate–low risk of death while receiving ERA/PDE5i therapy, switching from PDE5i to riociguat may be considered

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