The Disease

Chronic thromboembolic pulmonary hypertension (CTEPH) is caused by an obstruction of the pulmonary arteries due to non-resolving pulmonary emboli. Despite effective anticoagulation therapy of at least 3 months, perfusion defects persist and lead to pulmonary hypertension, which is defined as mean pulmonary arterial pressure of at least 25 mmHg and a pulmonary arterial wedge pressure ≤15 mmHg.¹

State-of-the-Art Treatments

Pulmonary endarterectomy remains the preferred treatment of CTEPH because the procedure is potentially curative. Nevertheless, many patients are not eligible for pulmonary endarterectomy due to inaccessible thromboembolic lesions or substantial comorbidities that exclude them from surgical consideration; patients may also choose not to have the procedure.² Balloon pulmonary angioplasty (BPA) is being assessed as an emerging therapeutic option for the treatment of CTEPH, and it addresses changes in medium- to small-sized pulmonary arteries.³

The similarities in microvascular changes in pulmonary arterial hypertension (PAH) and CTEPH provide the basis for targeting the microvascular component of CTEPH with PAH-specific medical therapies.⁴ Riociguat, a stimulator of soluble guanylate cyclase, is the first drug that has been approved for patients with inoperable CTEPH. In the pivotal CHEST-1 (Chronic Thromboembolic Pulmonary Hypertension Soluble Guanylate Cyclase–Stimulator Trial 1) study, improvements in pulmonary hemodynamics and physical capacity were shown.⁵

The MERIT-1 Study

Macitentan, a dual endothelin-receptor antagonist, has been shown to delay disease progression in patients with PAH.⁶

To assess the efficacy, safety, and tolerability of 10 mg macitentan in patients with inoperable CTEPH, a prospective, randomized, placebo-controlled, double-blind, multicentre, parallel-group Phase-II-study (MERIT-1 [Clinical Study to Assess the Efficacy, Safety and Tolerability of Macitentan in Subjects With Inoperable Chronic Thromboembolic Pulmonary Hypertension]) was performed.⁷ A total of 80 inoperable patients with symptomatic pulmonary hypertension in World Health Organization Functional Classes II-IV, a pulmonary vascular resistance (PVR) of at least 400 dyn·s/cm5, and a 6-minute-walk distance of 150-450 m was randomized in a 1:1 ratio into 2 treatment groups to receive either oral macitentan 10 mg or placebo over a treatment period of 24 weeks. Patients with more advanced disease in World Health Organization Functional Class III or IV at baseline were allowed to receive pulmonary hypertension background therapy, including phosphodiesterase type 5 inhibitors or oral/inhaled prostanoids. There was a significant (16%) reduction in PVR with macitentan compared with placebo (95% confidence level: -30%, -1%; p = 0.04 intention to treat). This was consistent across all subgroups, including the patients receiving background pulmonary-hypertension-specific therapy at baseline. The exercise capacity significantly improved after 24 weeks of treatment, with a 35-meter improvement in the 6-minute-walk distance of patients receiving macitentan, compared with 1-meter improvement in the placebo group. Macitentan was well-tolerated in this patient population. The most common adverse event in the macitentan group was peripheral oedema (9 out of 40 patients; 23%) and decreased haemoglobin (6 out of 40 patients; 15%). Thus, safety was comparable with the known safety profile for macitentan from previous clinical studies.

Results in the Context of Established and Emerging Therapies

The results of the MERIT-1 study emphasize the aspect of vascular remodelling and the microvascular component characterizing CTEPH as a progressive vasculopathy of distal pulmonary arteries and arterioles. CTEPH starts with complete and/or partial occlusion of a variable number of pulmonary arterial branches. These fixed lesions are unlikely to be the target of drug therapy. On the other hand, redirection of blood flow into non-occluded vessels results in higher pressures and flow-induced shear stress, promoting microvascular constriction and remodelling. This microvascular part of the disease resembles many features of PAH, which may explain comparable responsiveness to some drugs that also showed efficacy in PAH.^5,8,9

In contrast to the earlier CHEST-1 study with riociguat, patients on background therapy with other PAH medications were allowed to be included in the MERIT-1 trial. In the field of PAH, combination therapy has become the mainstay of medical treatment. This leads to the conclusion that combination therapy might also play a role in patients with inoperable CTEPH. Future studies should be performed that include patients with riociguat as a combination therapy because it is the only drug approved in inoperable CTEPH so far.

An important alternative to drug therapy in inoperable CTEPH is BPA¹⁰ when (partial) distal occlusions are present. Currently, due to the absence of comparative studies, the decision between drug therapy and BPA is demanding, however, recent guidelines recommend to pre-treat inoperable patients with riociguat, before considering BPA.¹ Two studies in France and Japan (The RACE trial [Riociguat Versus Balloon Pulmonary Angioplasty in Non-operable Chronic Thromboembolic Pulmonary Hypertension] and the Multicenter Randomized controlled trial based on Balloon Pulmonary Angioplasty for chronic thromboembolic pulmonary hypertension) may increase our knowledge in this regard. Patients in the French study with inoperable CTEPH are being randomised to BPA or medical therapy with riociguat and subsequently undergo a crossover. The primary endpoint is change in PVR at week 26.

The combination of targeted medical and interventional treatment showed additive effects on physical capacity and pulmonary hemodynamics in patients with inoperable CTEPH.¹¹ Most experts in the field consider a multimodal approach, including sequential or combined application of two or more available treatment options, as the recommended therapy for patients with CTEPH.¹

In conclusion, the MERIT-1-study emphasizes the role of vascular remodelling in CTEPH and the amenability to drug therapy and furthermore paves the way for future studies focusing on combination therapy in CTEPH.

References

1. Kim NH, Delcroix M, Jais X, et al. Chronic thromboembolic pulmonary hypertension. Eur Respir J 2019;53:1801915.
2. Delcroix M, Lang I, Pepke-Zaba J, et al. Long-Term Outcome of Patients With Chronic Thromboembolic Pulmonary Hypertension: Results From an International Prospective Registry. Circulation 2016;133:859-71.
3. Lang I, Meyer BC, Ogo T, et al. Balloon pulmonary angioplasty in chronic thromboembolic pulmonary hypertension. Eur Respir Rev 2017;26:160119.
4. Lang IM, Dorfmüller P, Vonk Noordegraaf A. The Pathobiology of Chronic Thromboembolic Pulmonary Hypertension. Ann Am Thorac Soc 2016;13:S215-21.
5. Ghofrani HA, D'Armini AM, Grimminger F, et al. Riociguat for the treatment of chronic thromboembolic pulmonary hypertension. N Engl J Med 2013;369:319-29.
6. Pulido T, Adzerikho I, Channick RN, et al. Macitentan and morbidity and mortality in pulmonary arterial hypertension. N Engl J Med 2013;369:809-18.
7. Ghofrani HA, Simonneau G, D'Armini AM, et al. Macitentan for the treatment of inoperable chronic thromboembolic pulmonary hypertension (MERIT-1): results from the multicentre, phase 2, randomised, double-blind, placebo-controlled study. Lancet Respir Med 2017;5:785-794.
8. Jaïs X, D'Armini AM, Jansa P, et al. Bosentan for treatment of inoperable chronic thromboembolic pulmonary hypertension: BENEFiT (Bosentan Effects in iNopErable Forms of chronIc Thromboembolic pulmonary hypertension), a randomized, placebo-controlled trial. J Am Coll Cardiol 2008;52:2127-34.
9. Suntharalingam J, Treacy CM, Doughty NJ, et al. Long-term use of sildenafil in inoperable chronic thromboembolic pulmonary hypertension. Chest 2008;134:229-236.
10. Ogawa A, Satoh T, Fukuda T, et al. Balloon Pulmonary Angioplasty for Chronic Thromboembolic Pulmonary Hypertension: Results of a Multicenter Registry. Circ Cardiovasc Qual Outcomes 2017;10:e004029.
11. Wiedenroth CB, Ghofrani HA, Adameit MSD, et al. Sequential treatment with riociguat and balloon pulmonary angioplasty for patients with inoperable chronic thromboembolic pulmonary hypertension. Pulm Circ 2018;8:2045894018783996.

Keywords: Hypertension, Pulmonary, Pulmonary Artery, Phosphodiesterase 5 Inhibitors, Double-Blind Method, Prostaglandins, Arterioles, Constriction, Arterial Pressure, Intention to Treat Analysis, Prospective Studies, Pulmonary Wedge Pressure, Pyrimidines, Sulfonamides, Pyrazoles, Endarterectomy, Endothelin Receptor Antagonists, Hypertension, Pulmonary, Vascular Resistance, Comorbidity, Disease Progression, Edema, Hemoglobins, Angioplasty

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