Medical Management of Chronic Thromboembolic Pulmonary Hypertension

Duration and Choice of Anticoagulation

Even though a known thrombophilia is identified in a minority of CTEPH patients (32% in the international CTEPH registry¹), this population is considered a high risk for recurrent venous thromboembolic events and thus, lifelong anticoagulation is recommended. Traditionally, vitamin K antagonists (VKAs) have been used.² With the increasing use of direct-acting oral anticoagulants (DOACs) as safe and effective treatments for acute venous thromboembolism (VTE), more patients have been using this class of medications for long-term anticoagulation in the setting of CTEPH. There are no direct head-to-head trials comparing these 2 anticoagulation strategies; only observational registry data are available.

VKAs have been used most frequently, given a longer period of bioavailability, and are generally reported to be safe and efficacious at preventing recurrent VTE in CTEPH patients. Jujo-Sanada et al³ observed major bleeding in 8.1%/person-year and recurrent VTE in 1.2%/person-year in their retrospective cohort of CTEPH patients on VKAs, while Henkens et al⁴ reported major bleeding events at 2.4%/person-year in CTEPH patients.

As DOAC therapy has gained traction for treatment of acute VTE with several studies demonstrating similar efficacy for prevention of recurrent VTE and fewer bleeding events,⁵ more patients with CTEPH have remained on DOAC therapy as their anticoagulant of choice. Registry data have provided some perspective on using DOAC therapy in the CTEPH patient population, although several controversies regarding safety and efficacy of this class of drugs remain.⁶

Bunclark et al⁷ published a large retrospective analysis specifically dedicated to evaluating VKA compared with DOAC therapy. In this cohort, 794 patients on VKAs and 204 patients on DOAC therapy had PTE surgery at the United Kingdom national PTE center from 2007 to 2018. Both groups of patients had similar hemodynamic and functional status improvement after PTE and major bleeding events were equivalent (0.67%/person-year versus 0.68%/person-year). Patients on DOAC therapy had higher rates of recurrent VTE after stabilization on oral anticoagulation therapy (4.62%/person-year) compared with those on VKAs (0.76%/person-year), although survival was similar between the 2 groups.⁷ A retrospective analysis of surgical specimens presented solely in abstract form suggested a higher rate of acute or subacute thrombi in the CTEPH tissue in patients on DOAC therapy (13.3%) compared to those on VKAs (6.7%).⁸ Finally, a recent study using the EXPERT registry (an international, multicenter prospective registry of 841 patients treated with riociguat for pulmonary arterial hypertension or CTEPH) collected data regarding hemorrhagic events and recurrent thromboembolic events in patients with CTEPH on VKA and DOAC therapy. The authors reported no difference in absolute rates of hemorrhagic events or any difference in rates of exposure-adjusted hemorrhagic events between VKA and DOAC therapy (9.5% and 12.1% respectively). However, while recurrent thromboembolic events had low absolute numbers overall, the exposure-adjusted event rate was lower in patients treated with VKAs compared those treated with DOACs (1.7% and 4.6% respectively). While data are limited and these are retrospective studies, it does call into question the efficacy of DOACs for anticoagulation in CTEPH.⁹

Conversely, Sena et al¹⁰ examined rates of bleeding events, death, and recurrent VTE in 501 patients with CTEPH-412 patients on VKAs and 134 on DOACs. There was no difference in survival or recurrent VTE, but in patients treated with VKAs there were higher rates of major bleeding events (odds ratio: 1.94; 95% confidence interval: 1.05–3.62).¹⁰ Overall, more studies need to be done to help settle the question of efficacy of DOAC therapy in CTEPH patient populations.

Anticoagulation in Special Patient Populations

VKAs are the preferred method of anticoagulation in patients with anti-phospholipid antibody syndrome (APS), particularly high-risk triple-positive APS. This recommendation comes from several observational cohort studies as well as a randomized open-label non-inferiority study in which patients with triple-positive APS had higher rates of recurrent thromboembolic events and shorter event-free survival on DOAC therapy compared to VKA.^11,12

Another special situation is bariatric surgery. Absorption of any DOAC could be potentially reduced by Roux-en-Y gastric bypass, because all the drugs in this class require some degree of absorption in the proximal small bowel.¹³ Regarding gastric banding or sleeve gastrectomy, given that the surface area of the stomach is dramatically reduced, medications that primarily rely on the stomach for absorption can be impacted (dabigatran, edoxaban, and rivaroxaban).¹³ Low-molecular-weight heparin or VKA may be more appropriate in this patient population.

Inoperable Disease

For patients who are not able to be offered PTE surgery, because their vascular occlusions are inaccessible or because their degree of PH is elevated out of proportion to thrombotic burden or they have prohibitive medical comorbidities, vasodilator therapy can be considered. In the small number of clinical trials that have been conducted in this patient population, the hemodynamic thresholds at which to consider vasodilator therapy were variable—typically patients were included with a mean pulmonary artery pressure (mPAP) ≥ 25 mm Hg and a pulmonary arterial wedge pressure (PAWP) ≤ 15 mm Hg—the hemodynamic definition of CTEPH provided in the 2015 European Respiratory Society (ERS) guidelines.¹⁶ However, pulmonary vascular resistance (PVR) thresholds varied from trial to trial. In practice, vasodilatory therapy is typically considered with mPAP ≥ 25 mm Hg, pulmonary arterial wedge pressure ≤ 15 mm Hg and PVR ≥ 240 dynes/s/cm⁵ (PVR of 3 Wood units [WU]). In 2019 the 6th World Symposium on PH proposed a new hemodynamic definition, lowering the threshold from mPAP ≥ 25 mm Hg to an mPAP of > 20 mm Hg.¹⁷ It is not yet clear if this new definition is applicable to patients with CTEPH. The ongoing MACiTEPH trial (NCT04271475; macitentan 75 mg daily versus placebo) is the first RCT to enroll CTEPH patients with this new hemodynamic definition of PH.¹⁸

Vasodilators Prior to PTE

There are not robust data from RCTs to currently suggest that there is a benefit from using pulmonary vasodilators prior to PTE surgery in operable patients. In spite of this, registry data reveal that a substantial proportion of operable patients are on vasodilators prior to surgery.¹ Although preoperative treatment has been reported to improve preoperative hemodynamics, it has no effects on post-PTE outcomes and may induce unnecessary delay to a potentially curative surgical intervention.¹⁹ Data from the international CTEPH registry showed that preoperative bridging therapy was not only associated with no improvement in PTE outcomes, but also with worsened long-term survival, although in this case patients who were bridged with medical therapy to PTE likely represented a population with more severe baseline disease.²⁰ A prospective clinical trial was being conducted studying the safety and efficacy of riociguat as a bridging therapy to PTE surgery (NCT03273257), but unfortunately it was stopped due to slower than expected recruitment brought on by the COVID-19 pandemic.²¹ At this time, it is not recommended to routinely provide bridging therapy with vasodilators if a patient is a PTE candidate, as operability assessment is a crucial early step after diagnosis that should not be delayed.

Residual PH after PTE

The exact hemodynamic definition of residual PH after PTE is not established, nor is a standard time for measurement in the postoperative course. The 2015 ERS guidelines recommend performing a right heart catheterization 3 to 6 months after PTE. In the immediate postoperative period residual PH has been associated with increased operative (30-day) mortality. A PVR > 500 dynes/s/cm⁵ (PVR of 6.25 WU) was associated with higher mortality (10.3% versus 0.9% respectively) in a cohort of 1500 patients who received PTE at the University of San Diego between 1999 and 2010.²²

Regarding outcomes in patients who survive the immediate postoperative period, clinically meaningful definitions of residual PH have varied. In a retrospective national cohort study in the United Kingdom, which defined residual PH as mPAP ≥ 25 mm Hg and PVR > 240 dynes/s/cm⁵ (PVR of 3 WU), 162 patients had hemodynamic assessment 3 months after PTE surgery. The authors reported no difference in 1- and 3-year survival when comparing those with residual PH to those without.²³ Until 2019, mPAP ≥ 25 mm Hg and PVR > 240 dynes/s/cm⁵ (PVR of 3 WU) was the hemodynamic definition of CTEPH at the time of diagnosis, as well as the hemodynamic definition of precapillary PH.¹⁶ It is interesting to note that these thresholds may be too sensitive to differentiate poor outcomes in postoperative patients with residual PH.

Raising the hemodynamic threshold for defining residual PH after PTE may better differentiate patients who can benefit from vasodilator therapy. A retrospective study from the United Kingdom national CTEPH registry of 881 patients who underwent PTE surgery demonstrated that an mPAP ≥ 38 mm Hg and PVR > 425 dynes/s/cm⁵ (PVR of 5.3 WU) measured 3 to 6 months after surgery was associated with worse long-term survival. In this cohort, mPAP ≥ 30 mm Hg and PVR ≥ 318 dynes/s/cm⁵ (PVR of 3.9 WU) was associated with initiation of vasodilator therapy.²⁴ An observational cohort study of 441 patients who underwent PTE in Sweden and Denmark between 1994 and 2020 demonstrated that using a threshold of mPAP ≥ 30 mm Hg measured 48 hours after PTE was associated with worse long-term survival, and this relationship strengthened after excluding patients who experienced operative mortality.²⁵

Further studies will hopefully inform exact definitions of clinically meaningful residual PH after PTE and assist in standardization of the timing of initiation of vasodilator therapy or referral for post-PTE balloon angioplasty.

Nitric Oxide Pathway

Riociguat, a soluble guanylate cyclase stimulator, is currently the only US Food and Drug Administration (FDA)-approved pulmonary vasodilator for treatment of inoperable or residual CTEPH. In CHEST-1, a RCT comprised of 261 patients with inoperable CTEPH or residual PH after PTE, riociguat significantly increased exercise capacity and reduced PVR after 16 weeks compared to placebo.²⁶ There was also an improvement in biomarkers of right ventricular function (N-terminal pro-brain natriuretic peptide [NT-proBNP]) as well as World Health Organization functional class and there was no significant difference in serious safety events. Importantly, in this study, operability was determined by a central adjudication committee of international CTEPH experts.

Sildenafil, a phosphodiesterase type 5 inhibitor (PDE5i) was studied in a very small population of patients with inoperable CTEPH and demonstrated an improvement in PVR compared with placebo, without an improvement in 6-minute walk distance at 12 weeks.²⁷

Endothelin Receptor Antagonists

Two endothelin receptor antagonists have been studied in CTEPH: bosentan and macitentan. In the BENEFiT RCT comparing bosentan to placebo in 157 patients with inoperable CTEPH or residual PH after PTE, bosentan did not impact 6-minute walk distance, which was the primary endpoint; however, a significant reduction in PVR was seen.²⁸ Because the trial did not meet its primary endpoint for improvement in exercise capacity, bosentan did not gain regulatory approval.

The safety and efficacy of macitentan was studied in the MERIT-1 study, a phase 2 placebo-controlled RCT. Eighty patients with inoperable CTEPH were randomized to macitentan or placebo and the study found an improvement in PVR, exercise capacity, and NT-proBNP.²⁹ Patients were permitted to be on background PDE5i or oral prostacylins and there was still a treatment effect, suggesting some benefit from combination therapy in CTEPH. The FDA requested further study after an initial request for approval for macitentan for CTEPH, and there is a clinical trial currently enrolling to further define efficacy and safety of macitentan for inoperable CTEPH as well as residual PH after PTE (NCT04271475).¹⁸

Prostacylins

A single RCT examined long-term use of subcutaneous treprostinil (a prostacyclin analogue) in 105 patients with inoperable CTEPH.³⁰ High-dose (~30 ng/kg/min) subcutaneous treprostinil compared to low-dose (~3 ng/kg/min) resulted in improvement in PVR, exercise capacity, functional class, and NT-proBNP; approximately one third of these patients were on background vasodilator therapies.³⁰ Although not FDA approved, it is used off label in clinical practice for severe disease, and has been approved in Europe.

The oral prostacyclin agonist selexipag is approved in Japan based on an RCT that showed improvements in PVR at 20 weeks, but no effect on 6-minute walk distance.³¹ An international multicenter RCT of selexipag (a prostacyclin receptor agonist) for CTEPH was recently stopped due to futility (NCT03689244)³²; more detailed results of this study are currently awaited.