Macitentan (Mac) Treats Pulmonary Hypertension, It Does Not Cause It
Macitentan (Mac) is an endothelin receptor antagonist that is used to treat pulmonary hypertension, not cause it. In fact, it significantly reduces morbidity and mortality in patients with pulmonary arterial hypertension by improving pulmonary vascular resistance and delaying disease progression 1.
Mechanism of Action and Therapeutic Use
Macitentan works by:
- Blocking both endothelin A (ETA) and endothelin B (ETB) receptors 2
- Preventing the binding of endothelin-1 (ET-1), which plays a critical role in the pathophysiology of pulmonary arterial hypertension 2
- Causing vasodilation through inhibition of the endothelin pathway, which reduces pulmonary vascular resistance
Evidence Supporting Therapeutic Benefit
The SERAPHIN trial, a landmark study, demonstrated that macitentan:
- Reduced the risk of first PAH-related event or all-cause death by 45% compared to placebo 1
- Decreased the risk of all-cause hospitalization and PAH-related hospitalization 3
- Improved outcomes regardless of whether patients were receiving other PAH therapies at baseline 1
A recent 2024 study showed that a fixed-dose combination of macitentan and tadalafil significantly improved pulmonary vascular resistance compared to either medication as monotherapy 4.
Clinical Guidelines Support
Multiple clinical guidelines support the use of endothelin receptor antagonists like macitentan for pulmonary hypertension:
The American Heart Association/American College of Cardiology guidelines specifically recommend:
- "Chronic pulmonary vascular targeted therapy (ie, phosphodiesterase type 5 inhibitors, soluble guanylate cyclase stimulators, endothelin receptor antagonists, and prostanoids) should be continued unless contraindicated or not tolerated in patients with pulmonary hypertension who are undergoing noncardiac surgery" 5
Guidelines also suggest that patients with pulmonary hypertension should be evaluated by specialists, particularly those with:
- Group 1 pulmonary hypertension (pulmonary arterial hypertension)
- High pulmonary pressures (>70 mm Hg)
- Moderate or greater right ventricular dilation/dysfunction
- Pulmonary vascular resistance >3 Wood units 5
Beyond PAH: Additional Benefits
Research suggests macitentan may have additional benefits:
- A 2018 study showed that macitentan reduced progression of TGF-β1-induced pulmonary fibrosis and associated pulmonary hypertension in an animal model 6
- It protected endothelial cells from myofibroblast differentiation and apoptosis, demonstrating potential benefits beyond pure vasodilation 6
Safety Profile
Common side effects of macitentan include:
- Headache
- Nasopharyngitis
- Anemia 1
Clinical Implications
For clinicians managing patients with pulmonary hypertension:
- Macitentan is an important treatment option for PAH, not a causative agent
- It should be continued perioperatively in patients undergoing non-cardiac surgery unless specifically contraindicated
- Patients with PAH should ideally be evaluated by pulmonary hypertension specialists before major procedures
In summary, macitentan is a therapeutic agent that improves outcomes in pulmonary arterial hypertension and does not cause the condition. Its dual endothelin receptor antagonism provides significant clinical benefits in reducing morbidity and mortality in this challenging disease.