Chronic thromboembolic pulmonary hypertension: Pulmonary hypertension-specific therapy

INTRODUCTION — In patients with chronic thromboembolic pulmonary hypertension (CTEPH), pulmonary thromboendarterectomy (PTE) is the only potentially curative therapy. However, some patients are not suitable candidates for PTE, have persistent pulmonary hypertension (PH) after PTE, or need a bridge to PTE. In such patients, PH-specific therapy is often administered.

PH-specific therapy refers to the use of medications that target the PH itself (ie, pulmonary vasodilators and remodeling agents). These agents lower the pulmonary vascular resistance (PVR) and pulmonary artery pressure with the goal of improving exercise capacity and oxygenation. Importantly, PH-specific therapy is not curative and its effects are relatively modest [1-4].

Selecting suitable patients and choosing a PH-specific therapy are reviewed here. The diagnosis of CTEPH and the general approach to assessing patients for PTE are described separately. (See "Epidemiology, pathogenesis, clinical manifestations and diagnosis of chronic thromboembolic pulmonary hypertension" and "Chronic thromboembolic pulmonary hypertension: Initial management and evaluation for pulmonary artery thromboendarterectomy" and "Chronic thromboembolic pulmonary hypertension: Pulmonary thromboendarterectomy".)

The approach outlined in this topic is, for the most part, consistent with guidelines set out by several international societies [3,5-7].

PATIENT SELECTION — In patients with chronic thromboembolic pulmonary hypertension (CTEPH), the two most common indications for pulmonary hypertension (PH)-specific therapy are patients with inoperable CTEPH and patients with persistent CTEPH following pulmonary thromboendarterectomy (PTE) or, rarely, following balloon pulmonary angioplasty.

The use of PH-specific therapy as a bridge to PTE is an uncommon indication.

PH-specific therapy is not administered routinely preoperatively, since it is not of proven benefit and may delay time to referral for surgery [8].

Inoperable CTEPH — Patients may not be operative candidates due to a personal choice, the anatomic distribution of their disease, the extent of their disease, or their comorbidities. The decision that a patient's disease is inoperable should only be made after a comprehensive evaluation at a center with experience in the management of CTEPH (algorithm 1). Further details on the evaluation of patients for PTE are provided separately. (See "Chronic thromboembolic pulmonary hypertension: Initial management and evaluation for pulmonary artery thromboendarterectomy", section on 'Evaluation for pulmonary thromboendarterectomy'.)

Data to support this indication are derived from small randomized trials and several observational studies, the details of which are discussed below. (See 'Medication selection' below.)

Persistent CTEPH — A small proportion of patients have a suboptimal hemodynamic and functional outcome following PTE (15 to 51 percent; on average 30 percent). Many patients in this population are treated with PH-specific therapy. A management strategy for patients with residual PH after PTE that allocates therapy based upon functional status is discussed separately. (See "Chronic thromboembolic pulmonary hypertension: Pulmonary thromboendarterectomy", section on 'Residual pulmonary hypertension'.)

Data that support the use of PH-specific therapies in this population are derived from subgroup analyses in randomized trials and observational studies that included patients with both inoperable and persistent CTEPH [9-11]. In these studies, approximately one-third of the study population had persistent CTEPH following thromboendarterectomy. These data are discussed below. (See 'Medication selection' below.)

Variable definitions of persistent PH following PTE have been used with no consensus among experts. While we and others define it as pulmonary vascular resistance (PVR) ≥300 dynes-sec/cm^-5 (≥3.75 Wood units), others use a mean pulmonary artery pressure ≥30 mmHg [12,13].

Bridge to surgery — Although controversial, we use PH-specific therapy in patients with severe life-threatening CTEPH as a therapeutic bridge to definitive PTE; examples include patients with hemodynamic indices of severe PH and evidence of severe right heart failure [8,14]. In this setting, PH-specific therapy is used as a lifesaving strategy to help patients survive to definitive surgical intervention. There is no single agent that is superior in this setting, although riociguat is commonly used. (See "Chronic thromboembolic pulmonary hypertension: Initial management and evaluation for pulmonary artery thromboendarterectomy", section on 'Medical therapy as a bridge to surgery (not routine)' and 'WHO functional class IV (severe symptoms)' below.)

Importantly, PH-specific therapy should not be routinely used as a preoperative therapy and, in particular, should not delay appropriate referral for PTE.

There are limited data that support this indication, which are discussed in the sections below. (See 'WHO functional class IV (severe symptoms)' below.)

MEDICATION SELECTION — Pulmonary hypertension (PH)-specific therapy should only be administered at specialized PH centers. The principles of medication selection, administration, and follow-up of patients with chronic thromboembolic pulmonary hypertension (CTEPH; group 4 PH) who receive PH-specific therapy are generally similar to that of patients with group 1 pulmonary arterial hypertension (PAH) (table 1 and table 2); the exceptions are that vasoreactivity testing is not performed, since patients are rarely vasoreactive, and, for those in whom oral therapy is chosen, the drug of choice is riociguat. (See "Treatment of pulmonary arterial hypertension (group 1) in adults: Pulmonary hypertension-specific therapy", section on 'Pretreatment evaluation'.)

Small randomized trials and observational studies suggest that PH-specific therapy for patients with inoperable or persistent CTEPH has hemodynamic and symptomatic benefits. However, these benefits are modest compared with those that can be achieved with pulmonary thromboendarterectomy (PTE) [1].

Few studies of individual agents have shown improved survival, although one retrospective review of patients with CTEPH reported a similar one- and three-year survival among patients who were medically treated for inoperable CTEPH compared with patients who were surgically treated (82 versus 88 percent; 70 versus 76 percent) [15]. However, these data are fundamentally flawed. Rigorous studies are required before firm conclusions can be made regarding a survival benefit from PH-specific therapy compared with surgical therapy. (See "Chronic thromboembolic pulmonary hypertension: Pulmonary thromboendarterectomy", section on 'Long term outcomes'.)

Pre-treatment evaluation

Pulmonary artery catheterization without vasoreactivity testing — Similar to patients with group 1 PAH, we ensure that patients with CTEPH who are selected for PH-specific therapy have had a recent pulmonary artery catheterization study prior to the initiation of therapy (eg, within a few weeks). Pulmonary artery catheterization has usually been done as part of the initial diagnostic investigation for CTEPH but may need to be repeated if symptoms have progressed since the original diagnosis. (See "Epidemiology, pathogenesis, clinical manifestations and diagnosis of chronic thromboembolic pulmonary hypertension", section on 'Diagnostic evaluation'.)

Unlike patients with group 1 PAH, vasoreactivity testing prior to the initiation of therapy is not necessary in patients with CTEPH, because they are rarely vasoreactive [16]. (See "Treatment of pulmonary arterial hypertension (group 1) in adults: Pulmonary hypertension-specific therapy", section on 'Vasoreactivity testing (select patients)'.)

Assess factors that influence agent selection — Similar to group 1 PAH, many factors affect agent selection in this population including patient preference, cost, availability, safety, route of administration, and functional class World Health Organization (WHO) (table 3 and table 4 and table 5), the details of which are provided separately. (See "Treatment of pulmonary arterial hypertension (group 1) in adults: Pulmonary hypertension-specific therapy", section on 'Pretreatment evaluation'.)

Medication options — PH-specific medications used to treat CTEPH were developed to treat patients with group 1 PAH (table 2). They include parenteral prostanoids (epoprostenol, treprostinil, iloprost), soluble guanylate cyclase stimulants (riociguat), endothelin receptor antagonists (ERAs; bosentan, ambrisentan, macitentan), phosphodiesterase-5 inhibitors (sildenafil, tadalafil), and oral prostanoid agonists (selexipag) (table 1).

WHO class I (asymptomatic or minimally symptomatic) — Patients with CTEPH rarely present with WHO functional class I symptoms (table 3) since patients in this class are typically asymptomatic. However, in theory, not every patient in this category may need or want therapy. Thus, the decision to initiate PAH-specific therapy should be based on objective hemodynamic parameters to avoid ongoing progression of PH and personal preference. For those who do not receive or decline therapy, we closely observe clinically for PH progression.

WHO class II or III (mild to moderate symptoms) — In most CTEPH patients with WHO functional class II to III symptoms (table 3), we initiate monotherapy with an oral agent, typically riociguat. This approach is based upon small randomized trials and observational studies that have demonstrated improved exercise capacity, functional class, and pulmonary hemodynamics in patients with CTEPH, among which riociguat has the strongest evidence in favor of a benefit. No robust evidence has suggested a survival benefit. (See 'Choosing an oral agent' below.)

Occasionally, in patients with severe class III symptoms or class III symptoms that are rapidly progressive, we administer a parenteral prostanoid, the details of which are discussed below. (See 'Parenteral prostanoid' below.)

Choosing an oral agent — In patients with CTEPH who have WHO functional class II to III (table 3), we typically administer oral riociguat (table 1), provided that there are no contraindications. Our preference for riociguat is based upon demonstrated efficacy in randomized trials in patients with inoperable CTEPH or persistent CTEPH following surgery as well as a favorable safety profile and our clinical experience with this agent. These data are discussed below. (See 'Riociguat' below.)

As alternatives, bosentan (ERA) or sildenafil (phosphodiesterase inhibitor) are appropriate as oral agents with favorable hemodynamic and safety profiles in patients with CTEPH. If bosentan or sildenafil are not tolerated, macitentan and ambrisentan (ie, oral ERAs) are additional alternatives [17,18]. These data are discussed below. (See 'Riociguat' below and 'Other oral options' below.)

Oral therapy is rarely administered as a bridge to surgery since most patients with this indication are severely ill. (See 'WHO functional class IV (severe symptoms)' below.)

Riociguat — Studies of riociguat in patients with inoperable CTEPH and WHO functional class II to III (table 3) have reported improved exercise capacity and pulmonary hemodynamics [10,11,19-22].

Best illustrating this is a multicenter, randomized, placebo-controlled trial (CHEST-1) that studied 261 patients with inoperable CTEPH (189 patients) or persistent PH following PTE (72 patients) [10]. At 16 weeks, compared with placebo, patients on riociguat (0.5 to 2.5 mg three times daily) had an improved six-minute walking distance (6MWD; increased by 39 m versus decreased by 6 m), and pulmonary vascular resistance (PVR; decreased by 226 dynes-sec/cm^-5 [2.8 Wood units] versus increased by 23 dynes-sec/cm^-5 [0.28 Wood units]). Outcomes were similar when a prespecified analysis was performed in the subgroup of patients with persistent CTEPH. Riociguat had a favorable safety profile with no reported difference between the two most common adverse events, which were right ventricular failure (3 percent) and syncope (2 to 3 percent).

A follow-up long-term extension study (CHEST-2) reported that prolonged therapy for up to two years with riociguat resulted in a similar efficacy and safety profile [11,22].

Other oral options — Small, randomized trials and observational data support improved exercise capacity and pulmonary hemodynamics in patients with CTEPH receiving ERAs and phosphodiesterase-5 inhibitors:

●ERAs – Several small studies in patients with CTEPH have shown that the ERAs, particularly oral bosentan, improve physiologic parameters, symptoms and/or exercise capacity [9,17,23-25].

•Bosentan – A systematic review of 10 observational studies and 1 randomized trial (BENEFiT) reported that bosentan resulted in a baseline increase in exercise capacity as measured by 6MWD (weighted mean difference [WMD] 35.9 meters, 95% CI 33.6-38.2 meters), a decrease in pulmonary artery pressure (WMD 2.62 mmHg, 95% CI 2.44-2.8), and an increase in cardiac index (WMD 0.23 L/min/m², 95% CI 0.22-0.25 L/min/m²) [24].

In the only randomized placebo-controlled trial (BENEFiT) of 157 patients with inoperable CTEPH or persistent CTEPH after thromboendarterectomy who had WHO functional class II to IV, 16 weeks of bosentan improved PVR and cardiac index compared with placebo [9]. The same benefit was seen in the subgroup of patients with persistent CTEPH. However, there was no improvement in exercise capacity with bosentan.

•Macitentan – The safety and feasibility of macitentan in improving the PVR and 6MWD in patients with inoperable CTEPH has also been reported [17,25].

•Ambrisentan – The Amber 1 trial compared ambrisentan with placebo in 33 patients with inoperable CTEPH. Although the study was terminated early due to futility of enrollment, positive trends in 6MWD, PVR, and N-terminal pro-B-type natriuretic peptide (NT-proBNP) were noted [18].

●Phosphodiesterase-5 inhibitors (sildenafil, tadalafil) – In a randomized trial of 19 patients with inoperable CTEPH, 12 weeks of sildenafil improved WHO functional class and PVR, but there was no difference in exercise capacity, compared with placebo [26]. The control patients were then provided open-label sildenafil. At 12 months, all patients had improved exercise capacity, symptom score, and PVR compared with baseline. Other nonrandomized trials support these results [26-29]. (See "Treatment of pulmonary arterial hypertension (group 1) in adults: Pulmonary hypertension-specific therapy".)

Preliminary data have suggested that selexipag is well tolerated and improves PVR in patients with inoperable or persistent CTEPH [30]. Further data are needed before it can be used routinely.

Dual versus monotherapy — We typically start with monotherapy (most often riociguat) and escalate to combination therapy (dual or triple therapy), if there is limited or no response to a single agent.

Unlike patients in group 1 PAH (table 2) in whom benefit has been shown for initiating dual therapy, it is unknown if a similar approach benefits patients with CTEPH (group 4 PH). In one study, survival for up to five years in patients treated with combination therapy was similar to patients treated with monotherapy [31].

When combination therapy is administered, we ensure that agents of the same class are not coadministered and that riociguat is not coadministered with a phosphodiesterase inhibitor (eg, sildenafil, tadalafil), in order to avoid severe hypotension. (See "Treatment of pulmonary arterial hypertension (group 1) in adults: Pulmonary hypertension-specific therapy", section on 'Combination oral therapy'.)

WHO functional class IV (severe symptoms) — For patients who have WHO functional class IV and sometimes patients with severe functional class III (table 3), we typically use a parenteral prostanoid (eg, intravenous epoprostenol and intravenous or subcutaneous treprostinil) (table 1). This preference is based upon the proven efficacy and extensive clinical experience with these agents in patients with group 1 PAH and limited observational data in the CTEPH population (table 2). If response to monotherapy is suboptimal, we use a parenteral prostanoid-containing combination regimen (two or three drugs from a different class). On rare occasions for patients with a dramatic response to combination therapy, we attempt to wean the parenteral agent. (See "Treatment of pulmonary arterial hypertension (group 1) in adults: Pulmonary hypertension-specific therapy".)

Parenteral prostanoid — A small number of studies report benefit from prostanoids for patients with inoperable CTEPH [27,32-38]:

●Intravenous epoprostenol – A retrospective cohort study evaluated the effects of epoprostenol in 27 patients with inoperable CTEPH and WHO functional class III to IV (table 3) [34]. Three months of therapy with epoprostenol improved the PVR, pulmonary artery pressure, and exercise capacity. (See "Treatment of pulmonary arterial hypertension (group 1) in adults: Pulmonary hypertension-specific therapy".)

Data in patients with CTEPH who received epoprostenol as a bridge to PTE are limited. In one retrospective case series, 12 patients with severe CTEPH (defined as a PVR >1200 dynes-sec/cm⁵) who were treated with epoprostenol for a mean of 46 days prior to PTE had a 28 percent decrease in PVR preoperatively compared with baseline [14]. Patients who received preoperative epoprostenol had a higher postoperative mortality compared with a group of patients who did not receive medical therapy preoperatively. The latter may be explained by the fact that untreated patients had milder disease. Nonetheless, these results also suggest that PH-specific therapy is not indicated for routine pre-operative care. Further trials in this population are pending.

●Subcutaneous treprostinil – In a randomized trial of patients with inoperable, persistent, or recurrent CTEPH, and who had class III or IV symptoms, high-dose subcutaneous treprostinil (target dose 30 ng/kg/minute) resulted in improved 6MWD compared with a low-dose strategy (target dose 3 ng/kg/minute; increased by 45 meters versus 4.3 meters) [39]. The adverse effects were similar in both groups and were mostly site-related reactions (eg, pain, redness, swelling). (See "Treatment of pulmonary arterial hypertension (group 1) in adults: Pulmonary hypertension-specific therapy".)

In an uncontrolled trial of 28 patients with severe inoperable CTEPH, subcutaneous treprostinil improved the PVR and was associated with five-year survival rate of 53 percent compared with 16 percent among historical controls [35].

●Inhaled iloprost – One trial randomly assigned 203 patients with WHO class II to IV PH, 57 of whom had inoperable CTEPH, to receive inhaled iloprost or placebo for 12 weeks [36]. Inhaled iloprost improved exercise capacity, functional class, pulmonary hemodynamics, symptoms, and quality of life. While the beneficial effect of inhaled iloprost in CTEPH is supported by additional studies, the high frequency of its administration (six to nine times per day) often discourages its use [27,37,38]. (See "Treatment of pulmonary arterial hypertension (group 1) in adults: Pulmonary hypertension-specific therapy".)

●Inhaled treprostinil – One study reported that the effect of inhaled treprostinil in combination with sildenafil in patients with CTEPH was similar to that in patients with PAH [40].

Combination dual or triple therapy — For patients who are refractory to or progress rapidly on monotherapy, we add a second or a third agent from a different class to a parenteral prostanoid. Phosphodiesterase inhibitors and guanylate cyclase stimulants should not be coadministered, due to harm from hypotension.

ADMINISTRATION — Pulmonary hypertension (PH)-specific therapy should only be administered by a PH specialist. Initiation and escalation of therapy are similar to that in patients with group 1 pulmonary arterial hypertension (PAH) (table 2). (See "Treatment of pulmonary arterial hypertension (group 1) in adults: Pulmonary hypertension-specific therapy", section on 'Nonvasoreactive patients'.)

FOLLOW UP — For patients with chronic thromboembolic pulmonary hypertension (CTEPH) who are not responsive to, do not tolerate, or decline pulmonary hypertension (PH)-specific therapy, the selection of alternative or additional agents and treatment of refractory patients are similar to that of patients with group 1 pulmonary arterial hypertension (PAH). In addition, some patients may be candidates for balloon pulmonary angioplasty. These details are provided separately. (See "Treatment of pulmonary arterial hypertension (group 1) in adults: Pulmonary hypertension-specific therapy", section on 'Follow-up' and "Treatment of pulmonary arterial hypertension (group 1) in adults: Pulmonary hypertension-specific therapy", section on 'Refractory patients' and "Chronic thromboembolic pulmonary hypertension: Initial management and evaluation for pulmonary artery thromboendarterectomy", section on 'Percutaneous balloon pulmonary angioplasty'.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Pulmonary hypertension in adults".)

SUMMARY AND RECOMMENDATIONS

●Definition and context - Surgical pulmonary thromboendarterectomy (PTE) is the only potentially curative therapy for patients with chronic thromboembolic pulmonary hypertension (CTEPH). However, a limited number of patients with CTEPH are treated with pulmonary hypertension (PH)-specific therapy. PH-specific therapy refers to the use of pulmonary vasodilators and remodeling agents to lower the pulmonary vascular resistance (PVR) and pulmonary artery pressure, thereby improving symptoms and signs such as exercise capacity and oxygenation. The benefits of PH-specific therapy are modest compared with those that can be achieved with surgery. Indications and recommendations for PTE are provided separately. (See 'Introduction' above and "Chronic thromboembolic pulmonary hypertension: Pulmonary thromboendarterectomy".)

●Patient selection - In patients with CTEPH, the two most common indications for PH-specific therapy are patients with inoperable CTEPH and patients with a suboptimal hemodynamic and functional outcome following PTE (or balloon angioplasty). The use of PH-specific therapy as a bridge to PTE is an uncommon indication that is reserved for patients with severe or immediately life-threatening PH and right heart failure. (See 'Patient selection' above.)

●Medication selection - PH-specific therapy should only be administered at specialized PH centers. The principles of agent selection, administration, and follow-up of patients with CTEPH (group 4 PH) who receive PH-specific therapy are similar to that of patients with group 1 pulmonary arterial hypertension (PAH) (table 2 and table 1 and table 5 and table 4). However, patients with CTEPH do not need vasoreactivity testing and, for those in whom oral medications are indicated, riociguat is the drug of choice. (See 'Medication selection' above and 'Pre-treatment evaluation' above and "Treatment of pulmonary arterial hypertension (group 1) in adults: Pulmonary hypertension-specific therapy", section on 'Pretreatment evaluation'.)

•Patients with CTEPH rarely present with World Health Organization (WHO) functional class I (table 3) since patients in this class are typically asymptomatic or minimally symptomatic. Not everyone in this category may need therapy. The decision to initiate PAH-specific therapy in this population should be based on objective hemodynamic parameters to avoid ongoing progression of PH and personal preference. For those who do not receive or decline therapy, we closely observe for PH progression. (See 'WHO class I (asymptomatic or minimally symptomatic)' above.)

•For most patients who are not severely ill (ie, WHO functional class II or III), we suggest initiating oral riociguat rather than other agents (Grade 2C). This approach is based upon one randomized trial and several observational studies that report improved exercise capacity and pulmonary hemodynamics in patients with inoperable or persistent CTEPH who receive riociguat. Reasonable alternatives for oral therapy include bosentan or sildenafil based upon their favorable hemodynamic and safety profiles in patients with CTEPH. In most patients we initiate monotherapy and add in a second or third agent if symptoms progress. (See 'WHO class II or III (mild to moderate symptoms)' above.)

•For patients who are severely ill (ie, WHO functional class IV and, occasionally patients with severe class III symptoms or rapidly progressive disease), we suggest initiating a parenteral prostanoid (intravenous epoprostenol or treprostinil) rather than an alternative agent (Grade 2C). This preference is based upon the proven efficacy and extensive clinical experience with these agents in patients with group 1 PAH and limited data in CTEPH patients. (See 'WHO functional class IV (severe symptoms)' above.)

•For patients who are refractory to monotherapy or progress rapidly despite therapy, we add a second or a third agent in a different class. Phosphodiesterase inhibitors and guanylate cyclase stimulants should not be coadministered, due to harm from hypotension. (See 'Dual versus monotherapy' above and 'Combination dual or triple therapy' above.)

●Follow-up - Initiation, follow-up, and escalation of PH-specific therapy and treatment of refractory patients with CTEPH are similar to that in patients with group 1 PAH (table 2). (See "Treatment of pulmonary arterial hypertension (group 1) in adults: Pulmonary hypertension-specific therapy", section on 'Nonvasoreactive patients' and "Treatment of pulmonary arterial hypertension (group 1) in adults: Pulmonary hypertension-specific therapy", section on 'Follow-up' and "Treatment of pulmonary arterial hypertension (group 1) in adults: Pulmonary hypertension-specific therapy", section on 'Refractory patients'.)