Pulmonary arterial hypertension-specific treatments

What follows is a brief overview: for more detailed information please refer to the “2022 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension” and to content published in this website by going to the Find knowledge section.

The treatment management for pulmonary arterial hypertension patients has evolved progressively in the past decades. It is characterised by a complex strategy that includes the initial evaluation of severity and the subsequent response to treatment. There are three well-known pathways that contribute to the pathogenesis of pulmonary arterial hypertension: the endothelin, Nitric Oxide (NO), and prostacyclin pathways. Treatments targeting these pathways are well established in clinical practice.

The current treatment strategy for pulmonary arterial hypertension patients can be divided into three main steps:

• The initial approach includes general measures (physical activity and supervised rehabilitation, pregnancy and birth control advice, post-menopausal hormonal therapy, elective surgery, infection prevention, psychosocial support, adherence to treatments, genetic counselling and travel), supportive therapy (oral anticoagulants, diuretics, O₂, digoxin), referral to expert centres and acute vasoreactivity testing for the indication of chronic calcium channel blocker (CCB) therapy.
• The second step includes initial therapy with high-dose CCBs in vasoreactive patients (also known as “responders”), or with drugs approved for pulmonary arterial hypertension in non-vasoreactive patients, according to the prognostic risk of the patient and the grade of recommendation and level of evidence for each individual compound or combination of compounds.
• The third part is related to the response to the initial treatment strategy; in the case of an inadequate response, the role of combinations of approved drugs (also know as combination therapy) and lung or heart-lung transplantation are proposed.

Calcium channel blockers (CCBs)

Calcium channel blockers are used as antihypertensive drugs, i.e., as medications to decrease blood pressure. Patients with pulmonary arterial hypertension who respond favourably to acute vaso-reactivity testing (see above) may respond favourably to treatment with calcium channel blockers.

• amlodipine (oral)
• diltiazem (oral)
• felodipine (oral)
• nifedipine (oral) 

Endothelin receptor antagonists (“ERAs”)

Activation of the endothelin system has been demonstrated in both plasma and lung tissue of pulmonary arterial hypertension patients. Although it is unclear if the increases in endothelin-1 plasma levels are a cause or a consequence of pulmonary hypertension, these data support a prominent role for the endothelin system in the pathogenesis of pulmonary arterial hypertension. Endothelin-1 exerts vasoconstrictor and mitogenic effects by binding to two distinct receptor isoforms in the pulmonary vascular smooth muscle cells, endothelin receptors type A and B.

• ambrisentan
• bosentan
• macitentan

Phosphodiesterase type 5 inhibitors (PDE-5 inhibtors) and guanylate cyclase stimulators

Inhibition of the cyclic guanosine monophosphate (cGMP) degrading enzyme phosphodiesterase type 5 results in vasodilation through the NO/cGMP pathway at sites expressing this enzyme.

• sildenafil (PDE-5 inhibitor, oral)
• tadalafil (PDE-5 inhibitor, oral)
• riociguat (guanylate cyclase stimulators, oral)

Prostacyclin analogues and prostacyclin receptor agonists

Prostacyclin is produced predominantly by endothelial cells and induces potent vasodilation of all vascular beds. This compound is the most potent endogenous inhibitor of platelet aggregation and also appears to have both cytoprotective and antiproliferative activities.

• beraprost (oral)
• selexipag (oral)
• iloprost (inhaled)
• treprostinil (subcutaneous or intravenous)
• epoprostenol (intravenous)

Combination therapy

Combination therapy—using two or more classes of drugs simultaneously—is also an attractive option for the management of pulmonary arterial hypertension, because three separate signalling pathways known to be involved in the disease can be addressed by specific drugs. Combination therapy may be applied sequentially or initially (upfront). Sequential combination therapy is the most widely utilised strategy both in RCTs and in clinical practice: from monotherapy there is an addition of a second and then a third drug in cases of inadequate clinical results or in cases of deterioration.

References

“2022 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension”, Marc Humbert, Gabor Kovacs, Marius M Hoeper, Roberto Badagliacca, Rolf M F Berger, Margarita Brida, Jørn Carlsen, Andrew J S Coats, Pilar Escribano-Subias, Pisana Ferrari, Diogenes S Ferreira, Hossein Ardeschir Ghofrani, George Giannakoulas, David G Kiely, Eckhard Mayer, Gergely Meszaros, Blin Nagavci, Karen M Olsson, Joanna Pepke-Zaba, Jennifer K Quint, Göran Rådegran, Gerald Simonneau, Olivier Sitbon, Thomy Tonia, Mark Toshner, Jean Luc Vachiery, Anton Vonk Noordegraaf, Marion Delcroix, Stephan Rosenkranz, European Heart Journal, January 26, 2022