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negative feedback loop through degradation of cGMP via different phosphodiesterases, among which subtype 5 (PDE5) is abundantly expressed in the pulmonary vasculature.388 Phosphodiesterase 5 inhibitors and sGC stimulators must not be combined with each other and with nitrates, as this can result in systemic hypotension.389

6.3.3.3.1 Sildenafil. Sildenafil is an orally active, potent, and select-

ive inhibitor of PDE5. Several RCTs of patients with PAH treated with sildenafil (with or without background therapy) have confirmed favourable results on exercise capacity, symptoms, and/or haemodynamics.390–392 The approved dose of sildenafil is 20 mg t.i.d. Most side effects of sildenafil are mild to moderate and mainly related to vasodilation (headache, flushing, and epistaxis).

6.3.3.3.2 Tadalafil. Tadalafil is a once-daily administered PDE5i. An

RCT of 406 patients with PAH (53% on background bosentan therapy) treated with tadalafil at doses up to 40 mg o.d. showed favourable results on exercise capacity, symptoms, haemodynamics, and time to clinical worsening.393 The side effect profile was similar to that of sildenafil.

6.3.3.3.3 Riociguat. While PDE5is augment the nitric oxide–cGMP

pathway by slowing cGMP degradation, sGC stimulators enhance cGMP production by directly stimulating the enzyme, both in the presence and absence of endogenous nitric oxide.394 An RCT of 443 patients with PAH (44% and 6% on background therapy with ERAs or prostacyclin analogues, respectively) treated with riociguat up to 2.5 mg t.i.d. showed favourable results on exercise capacity, haemodynamics, WHO-FC, and time to clinical worsening.395 The side effect profile was similar to that of PDE5is.

6.3.3.4 Prostacyclin analogues and prostacyclin receptor agonists

The prostacyclin metabolic pathway (Figure 7) is dysregulated in patients with PAH, with less prostacyclin synthase expressed in PAs and reduced prostacyclin urinary metabolites.396 Prostacyclin analogues and prostacyclin receptor agonists induce potent vasodilation, inhibit platelet aggregation, and also have both cytoprotective and anti-proliferative activities.397 The most common adverse events observed with these compounds are related to systemic vasodilation and include headache, flushing, jaw pain, and diarrhoea.

6.3.3.4.1 Epoprostenol. Epoprostenol has a short half-life (3–

5 min) and needs continuous i.v. administration via an infusion pump and a permanent tunnelled catheter. A thermo-stable formulation is available to maintain stability up to 48 h.398 Its efficacy has been demonstrated in three unblinded RCTs in patients with IPAH (WHO-FC III and IV)399,400 and SSc-associated PAH.401 Epoprostenol improved symptoms, exercise capacity, haemodynamics, and mortality.399 Long-term, persistent efficacy has also been shown in IPAH,212,245 as well as in other associated PAH conditions.402–404 Serious adverse events related to the delivery system include pump malfunction, local site infection, catheter obstruction, and sepsis. Recommendations for preventing central venous catheter bloodstream infections have been proposed.405,406

6.3.3.4.2 Iloprost. Iloprost is a prostacyclin analogue approved for

inhaled administration. Inhaled iloprost has been evaluated in one RCT, in which six to nine repetitive iloprost inhalations were compared with placebo in treatment-naïve patients with PAH or CTEPH.407 The study showed an increase in exercise capacity and improvement in symptoms, PVR, and clinical events in the iloprost group compared with the placebo group.

6.3.3.4.3. Treprostinil. Treprostinil is available for s.c., i.v., inhaled, and oral administration. Treprostinil s.c. improved exercise capacity, haemodynamics, and symptoms in PAH.408 Infusion-site pain was the most common adverse effect, which led to treatment discontinuation in 8% of cases.408 Based on its chemical stability, i.v. treprostinil may also be administered via implantable pumps, improving convenience and likely decreasing the occurrence of line infections.409,410 Inhaled treprostinil improved the 6MWD, NT-proBNP, and quality of life measures in patients with PAH on background therapy with either bosentan or sildenafil.411 Inhaled treprostinil is not approved in Europe. Oral treprostinil has been evaluated in two RCTs of patients with PAH on background therapy with bosentan and/or sildenafil. In both trials, the primary endpoint—6MWD—did not reach statistical significance.412,413 An additional RCT in treatment-naïve patients with PAH showed improved 6MWD.414 An event-driven RCT that enrolled 690 patients with PAH demonstrated that oral treprostinil reduced the risk of clinical worsening events in patients who were receiving oral monotherapy with ERAs or PDE5is.415 Oral treprostinil is not approved in Europe.

6.3.3.4.4 Beraprost. Beraprost is a chemically stable and orally ac-

tive prostacyclin analogue. Two RCTs have shown a modest, shortterm improvement in exercise capacity in patients with PAH;416,417 however, there were no haemodynamic improvements or long-term outcome benefits. Beraprost is not approved in Europe.

6.3.3.4.5 Selexipag. Selexipag is an orally available, selective, pros-

tacyclin receptor agonist that is chemically distinct from prostacyclin, with different pharmacology. In a pilot RCT in patients with PAH (receiving stable ERA and/or PDE5i therapy), selexipag reduced PVR after 17 weeks.418 An event-driven, phase 3 RCT that enrolled 1156 patients419 showed that selexipag alone or on top of mono or double therapy with an ERA and/or a PDE5i reduced the relative risk of composite morbidity/mortality events by 40%. The most common side effects were headache, diarrhoea, nausea, and jaw pain.

6.3.4 Treatment strategies for patients with

idiopathic, heritable, drug-associated, or connective tissue disease-associated pulmonary arterial hypertension Pulmonary arterial hypertension is a rare and life-threatening disease and should be managed, where possible, at PH centres in close collaboration with the patient’s local physicians. This section describes drug treatment and is focused on nonvasoreactive patients with IPAH/HPAH/DPAH and on patients with PAH associated with connective tissue disease (PAH-CTD). Information on the dosing of PAH medication is summarized in Table 19. For other forms of PAH, treatment strategies have to be modified (see Section 7). The approach to vasoreactive patients with IPAH/HPAH/DPAH is described in Section 6.3.3.1. Downloaded from academic.oup.com/eurheartj/article/43/38/3618/6673929 by guest on 07 October 2026