Background

Venous thromboembolism, clinically presenting as deep vein thrombosis or pulmonary embolism (PE), is globally the third most frequent acute cardiovascular syndrome behind myocardial infarction and stroke. Annual incidence for acute PE ranges from 39 to 115 per 100,000. Abnormal persistence thrombi as fibrous residua combined with a variable microscopic pulmonary vasculopathy may lead to chronic thromboembolic pulmonary hypertension (CTEPH) in few cases with inflammatory risk factors. CTEPH causes exercise limitation, right heart failure, and premature death in more than 50% of untreated patients within 5 years of diagnosis.¹ Besides lifelong anticoagulation, surgical endarterectomy is the treatment of choice in patients with CTEPH affecting proximal major pulmonary arteries. However, more than half of CTEPH patients are not operated on because of distal lesions that are inaccessible to surgery or because of comorbidities. The new hope for not-operated CTEPH is balloon pulmonary angioplasty. This interventional procedure was initiated in Europe, and over the years Japanese interventionists have improved and refined the procedure to make it effective and safe.² The principle of balloon pulmonary angioplasty is breaking and dislodging intravascular fibrotic obstructions with traditional percutaneous equipment, restoring flow while the obstructive material is pushed sideways. This interventional procedure is currently being adapted and established in expert European and US pulmonary hypertension centers, with great success addressing a large unmet need.

Recent Achievements With Medical Treatments

Remodeling of small pulmonary vessels with a diameter >500 mcm has been described in patients with CTEPH.³ These lesions are similar to those observed in pulmonary arterial hypertension (PAH).⁴ Endothelial cell dysfunction has been demonstrated in small pulmonary arteries from PAH patients, involving pharmacologically accessible pathways such as endothelin-1, nitric oxide (NO), and prostacyclin.⁵ These findings have provided a strong rationale leading to the development of initial oral combination therapy targeting the endothelin-1 and NO pathways in patients with PAH, which is now standard of care for PAH where combination treatment has been demonstrated to be more efficacious than monotherapy.⁶ The French Pulmonary Hypertension Reference Centre has proposed that initial upfront combination of riociguat and endothelin receptor antagonists be used in CTEPH,⁷ similar to PAH, to achieve a more pronounced hemodynamic improvement.

Currently, only a single drug targeting the NO pathway, riociguat, is approved for CTEPH. A second drug targeting the endothelin-1 pathway, macitentan, has been submitted to health authorities for market authorization in the United States and in Europe, all based on the concept that distal vasculopathy serves as an additional treatment target outside of the classical mechanical treatment by surgery or balloon pulmonary angioplasty.

CHEST-1 (A Study to Evaluate Efficacy and Safety of Oral BAY63-2521 in Patients With CTEPH) was a 16-week, randomized, double-blinded phase III trial investigating the efficacy and safety of riociguat in patients with non-operable and persistent/recurrent CTEPH. Riociguat has a dual mode of action, sensitizing sGC to endogenous NO by stabilizing NO-sGC binding and directly stimulating sGC via a different binding site, independent of NO. This restores the NO-sGC-cyclic guanosine monophosphate (cGMP) pathway and increases generation of cGMP.⁸ The improvement of clinical endpoints in the CHEST-1 trial and sustained improvement in CHEST-2 (BAY63-2521 - Long-term Extension Study in Patients With Chronic Thromboembolic Pulmonary Hypertension), the open-label extension trial, substantiated the approval of riociguat for the treatment of non-operable and persistent/recurrent CTEPH.⁹

Recently, MERIT-1 (Clinical Study to Assess the Efficacy, Safety and Tolerability of Macitentan in Subjects With Inoperable Chronic Thromboembolic Pulmonary Hypertension), a 16-week phase II trial with macitentan, a dual-endothelin receptor antagonist, reported statistically significant improvement of pulmonary vascular resistance.⁹ This study included only patients diagnosed as non-operable, and the use of background PAH therapy was permitted. Approximately 2/3 of patients were on phosphodiesterase-5 inhibitors or oral/inhaled prostacyclin.

Ambrisentan was tested in CTEPH, but the study was stopped prematurely after 30 of the 160 planned patients had been enrolled.

The majority of patients enrolled in all these trials was classified in World Health Organization Functional Class II/III, and randomized long-term data investigating PAH-targeted treatments in patients with severe non-operable CTEPH were lacking. This gap of evidence was closed with CTREPH (Efficacy and Tolerability of Subcutaneously Administered Treprostinil Sodium in Patients With Severe (Non-operable) Chronic Thromboembolic Pulmonary Hypertension), a double-blind, phase III, randomized, controlled trial.¹⁰ CTREPH is the first trial of subcutaneous treprostinil over a treatment period of 24 weeks investigating the effects and safety of this drug in patients with severe non-operable and persistent/recurrent CTEPH. The biggest challenge in this trial was the set of inevitable side effects caused by subcutaneous administration of treprostinil. We used a low-dose comparator with about 5 ng/kg/min, and the high-dose treatment group reached 30 ng/kg/min. Thus, potential unblinding in the active treatment arm was avoided. Approximately 30% of patients were on riociguat, endothelin receptor antagonists, and phosphodiesterase-5 inhibitors, alone or in combination. Despite a severely diseased study population (N-terminal pro–B-type natriuretic peptide above 2000 pg/mL), despite the well-known side-effect profile of subcutaneous treprostinil, and despite the low-dose comparator, significant changes in 6-minute walk distance, hemodynamics, and World Health Organization Functional Class were observed. At 24 weeks, 6-minute walk distance had improved by 45·4m in the high-dose intention-to-treat population, and by 60·3m in the high-dose per-protocol population. Thus, this drug serves patients with severe CTEPH who do not tolerate riociguat or need combination therapy. In retrospect, doses should have been much higher in the high-dose group. Meanwhile, a vast majority of patients originally randomized in the CTREPH trial have been subjected to balloon pulmonary angioplasty, and mean pulmonary artery pressures have been significantly lowered by roughly 20% as in the Japanese registry¹¹ (compared with 7% in the 30 ng/kg/min arm of CTREPH).

Balloon Pulmonary Angioplasty and Medical Treatment May Be Complementary

Balloon pulmonary angioplasty is targeting vascular obstruction of any severity in vessels with a diameter >500 mcm. Medical treatment addresses a different part of the pulmonary vascular bed, namely mechanically inaccessible precapillary arterioles and post-capillary venules (presumably also bronchial arteries). Therefore, and based on unpublished observations, there is an additive effect of balloon pulmonary angioplasty and medical therapies. We have recently observed that improvement in pulmonary vascular resistance and cardiac output enhanced by the addition of subcutaneous treprostinil in patients with CTEPH who are undergoing balloon pulmonary angioplasty. Although treprostinil, riociguat, and macitentan predominantly increase cardiac output, a robust change in mean pulmonary arterial pressure appears to be achievable exclusively by balloon pulmonary angioplasty.

Key Points

• CTEPH is a pulmonary vascular disease condition that relies on precise imaging of pulmonary arterial segmentation, identification of typical CTEPH lesions, and functional characterization of dependent vascular beds.
• First-line treatment is pulmonary endarterectomy in expert centers, with CTEPH teams deciding.
• Patients with non-operable CTEPH should undergo evaluation for balloon pulmonary angioplasty, with and without medical treatment.
• Medical treatments mainly increase cardiac output, and balloon pulmonary angioplasty predominantly decreases mean pulmonary arterial pressure.
• Randomized data are lacking on combination of medical therapies with balloon pulmonary angioplasty.
• Preliminary data suggest that upfront combination treatments are most effective.
• Preliminary data suggest that addition of subcutaneous treprostinil in patients with CTEPH who are undergoing balloon pulmonary angioplasty improves hemodynamics.

References

1. Lang IM, Madani M. Update on chronic thromboembolic pulmonary hypertension. Circulation 2014;130:508-18.
2. Mizoguchi H, Ogawa A, Munemasa M, Mikouchi H, Ito H, Matsubara H. Refined balloon pulmonary angioplasty for inoperable patients with chronic thromboembolic pulmonary hypertension. Circ Cardiovasc Interv 2012;5:748-55.
3. Dorfmüller P, Günther S, Ghigna MR, et al. Microvascular disease in chronic thromboembolic pulmonary hypertension: a role for pulmonary veins and systemic vasculature. Eur Respir J 2014;44:1275-88.
4. Moser KM, Bloor CM. Pulmonary vascular lesions occurring in patients with chronic major vessel thromboembolic pulmonary hypertension. Chest 1993;103:685-92.
5. Humbert M, Lau EM, Montani D, Jaïs X, Sitbon O, Simonneau G. Advances in therapeutic interventions for patients with pulmonary arterial hypertension. Circulation 2014;130:2189-208.
6. Galiè N, Humbert M, Vachiery JL, et al. 2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension: The Joint Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS): Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC), International Society for Heart and Lung Transplantation (ISHLT). Eur Heart J 2016;37:67-119.
7. Kim NH, Delcroix M, Jais X, et al. Chronic thromboembolic pulmonary hypertension. Eur Respir J 2019;53:1801915.
8. Sandner P, Becker-Pelster EM, Stasch JP. Discovery and development of sGC stimulators for the treatment of pulmonary hypertension and rare diseases. Nitric Oxide 2018;77:88-95.
9. 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.
10. Sadushi-Kolici R, Jansa P, Kopec G, et al. Subcutaneous treprostinil for the treatment of severe non-operable chronic thromboembolic pulmonary hypertension (CTREPH): a double-blind, phase 3, randomised controlled trial. Lancet Respir Med 2019;7:239-48.
11. 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.

Keywords: Hypertension, Pulmonary, Pulmonary Artery, Phosphodiesterase 5 Inhibitors, Nitric Oxide, Endothelin Receptor Antagonists, Guanosine Monophosphate, Venous Thromboembolism, Arterioles, Venules, Risk Factors, Bronchial Arteries, Mortality, Premature, Natriuretic Peptide, Brain, Arterial Pressure, Pyrimidines, Epoprostenol, Pyrazoles, Sulfonamides, Phenylpropionates, Pyridazines, Peptide Fragments, Pulmonary Embolism, Endarterectomy, Vascular Resistance, Venous Thrombosis, Cardiac Output, Myocardial Infarction, Stroke, Heart Failure, Comorbidity, Endothelial Cells, Angioplasty, Receptors, Endothelin, Drug Delivery Systems, Longitudinal Studies

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