Medical Policy

Policy Num:       05.001.015
Policy Name:    Advanced Therapies for Pharmacologic Treatment of Pulmonary Hypertension          
Policy ID:          [5.001.015]  [Ac / B / M+ / P+]  [5.01.09]

Last Review:      December 20, 2024
Next Review:      December 20, 2025
 

Related Policies: None

Advanced Therapies for Pharmacologic Treatment of Pulmonary Hypertension

summary

Description

Pulmonary hypertension (PH) is a chronic, progressive condition characterized by abnormally high pulmonary vascular pressure. Advanced therapies for PH are specialty medications intended to alter the natural history of the disease. These medications have been approved by the U.S. Food and Drug Administration (FDA) for 2 classes of PH: pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH). Pulmonary arterial hypertension is a rare and debilitating disease associated with abnormal proliferation of smooth muscle cells in the pulmonary arterial system, causing progressive right ventricular dilation and low cardiac output. Advanced therapy medications approved for PAH can be used as single agents or in combination. Chronic thromboembolic pulmonary hypertension is characterized by residual organized thrombi obstructing the pulmonary vasculature following acute or chronic pulmonary embolism. Currently, only 1 medication, the soluble guanylate cyclase stimulator riociguat, has been FDA approved for treatment of CTEPH.

Summary of Evidence

Pulmonary Arterial Hypertension

For individuals who have PAH who receive monotherapy using tyrosine kinase inhibitors or statins, the evidence includes no randomized controlled trials (RCTs) on tyrosine kinase inhibitors and 4 RCTs and a meta-analysis on statins. Relevant outcomes are overall survival, functional outcomes, hospitalizations, and treatment-related morbidity. A meta-analysis of RCTs evaluating statins for PAH did not find significantly better outcomes (ie, mortality, 6-minute walk distance) with study medication than with placebo. For imatinib (a tyrosine kinase inhibitor), there are no placebo-controlled studies evaluating efficacy. However, a 2016 safety study identified a high rate of adverse events in patients who took imatinib. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

For individuals who have PAH and inadequate response to monotherapy who receive add-on combination therapy using 2 drug classes FDA approved for treatment of PAH, the evidence includes RCTs and meta-analyses. Relevant outcomes are overall survival, functional outcomes, hospitalizations, and treatment-related morbidity. The most recent and comprehensive meta-analysis of RCTs was published in 2016. It included 17 RCTs comparing add-on combination therapy with monotherapy with at least 12 weeks of follow-up. The meta-analysis found significantly lower rates of clinical worsening and hospitalizations with add-on combination therapy, but mortality rates did not differ significantly between groups. In all RCTs selected for the 2016 meta-analysis, the combination therapy involved different drug combinations from different classes, although the specific combination of riociguat and phosphodiesterase type 5 inhibitors is contraindicated. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

For individuals who have PAH who receive initial combination therapy using 2 drug classes FDA approved for treatment of PAH, the evidence includes 2 RCTs and a retrospective study. Relevant outcomes are overall survival, functional outcomes, hospitalizations, and treatment-related morbidity. In the first study (AMBITION trial), among patients in the primary analysis set, there was a significantly lower rate of clinical failure at 6 months in the combination therapy group than in the monotherapy group. Clinical failure was defined as a complex composite endpoint that included death, hospitalizations, functional improvement, and other measures of disease progression. Study limitations include change in enrollment criteria during the trial and use of a complex composite outcome with multiple components. The other RCT did not find significant differences in outcomes between a group receiving initial combination therapy and the group receiving monotherapy at 16 weeks; this study had a small sample size and might have been underpowered to assess secondary outcomes. Multiple reviews of the AMBITION trial with an emphasis on functional improvement (6MWT) have led to guideline recommendations for making ambristentan plus tadalafil an appropriate initial treatment option. A retrospective study found similar 5- and 10-year overall survival for patients initiated on dual therapy or monotherapy. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

For individuals who have PAH who receive initial combination therapy using 3 drug classes FDA approved for treatment of PAH, the evidence includes a single RCT. Relevant outcomes are overall survival, functional outcomes, hospitalizations, and treatment-related morbidity. In the TRITON trial, initial triple therapy (n=123) with macitentan, tadalafil, and selexipag was compared to initial double therapy (n=124) with macitentan, tadalafil, and placebo in newly diagnosed, treatment-naïve patients with PAH. At week 26, the primary endpoint of change in pulmonary vascular resistance (PVR) was reduced by 54% and 52% with initial triple and dual therapy, respectively, but the between-group difference was not significant. Secondary endpoints were considered exploratory based on testing hierarchy, and potentially signaled a reduced risk for disease progression events with initial triple therapy. Overall, larger studies powered to find long-term benefits with triple therapy are needed to identify patients who may benefit from this treatment approach. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

Chronic Thromboembolic Pulmonary Hypertension

For individuals who have inoperable CTEPH or PH after surgery who receive a soluble guanylate cyclase stimulator (eg, riociguat), the evidence includes 2 RCTs. Relevant outcomes are overall survival, functional outcomes, hospitalizations, and treatment-related morbidity. The first double-blind, placebo-controlled RCT found that functional outcomes at 16 weeks improved significantly more in the group receiving riociguat than placebo. Both groups had a high proportion of adverse events, and 1 death was attributed to riociguat. In an extension study, the estimated 1-year survival rate was 97%. Thirteen deaths occurred, none of which were attributed to study medication. In the second RCT, the efficacy and safety of balloon pulmonary angioplasty (BPA) and riociguat were compared. At week 26, PVR reduction was more pronounced with BPA than with riociguat, but treatment-related serious adverse events were more common with BPA. A 52-week extension study found that add-on BPA or add-on riociguat had similar effects on PVR reduction. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

For individuals who have operable CTEPH who receive perioperative prostacyclin analogues, endothelin receptor antagonists, or riociguat, the evidence includes 1 small RCT on bosentan, retrospective noncomparative studies on epoprostenol and iloprost, and no trials on riociguat. Relevant outcomes are overall survival, functional outcomes, hospitalizations, and treatment-related morbidity. The few studies, with small numbers of patients and limited comparative data, do not provide sufficient evidence to determine whether mortality and PVR are reduced with any of these medications. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

Additional Information

This evidence review does not evaluate activin signaling inhibitors such as sotatercept-csrk (Winrevair).

OBJECTIVE

The objective of this evidence review is to determine whether advanced pharmacologic therapies, alone or in combination, improve the net health outcome in individuals who have pulmonary arterial hypertension or chronic thromboembolic pulmonary hypertension.

POLICY Statement

Pulmonary Arterial Hypertension (PAH)

Combination therapy for the treatment of PAH (World Health Organization [WHO] Group I) may be considered medically necessary when all of the following conditions are met (see Policy Guidelines section):

• Individuals have failed to demonstrate an adequate response to a single medication;

• Medications are from different therapeutic classes;

• Each medication is FDA-approved for treatment of pulmonary arterial hypertension WHO group 1.

Combination therapy with tadalafil and ambrisentan or tadalafil and macitentan as first-line treatment may be considered medically necessary in the treatment of treatment naïve individuals with PAH who have WHO Functional Class Groups II and III disease.

Combination therapy with macitentan, tadalafil, and selexipag as first-line treatment is considered investigational in the treatment of treatment naïve individuals with PAH.

Use of other advanced therapies for the pharmacologic treatment of PAH (WHO group 1) that are not approved by the U.S. Food and Drug Administration for this indication, including but not limited to imatinib, simvastatin, and atorvastatin, is considered investigational.

Pulmonary Hypertension

The use of epoprostenol, treprostinil, iloprost, bosentan, ambrisentan, macitentan, sildenafil, tadalafil, or vardenafil is considered investigational for the treatment of pulmonary hypertension (PH; WHO Groups 2-5), including but not limited to:

• PH associated with left heart diseases;

• PH associated with lung diseases and/or hypoxemia (including chronic obstructive pulmonary disease);

• PH due to chronic thrombotic and/or embolic disease;

• Miscellaneous group (ie, sarcoidosis, histiocytosis X, lymphangiomatosis).

Chronic Thromboembolic Pulmonary Hypertension

The use of riociguat (Adempas) for the treatment of chronic thromboembolic pulmonary hypertension (CTEPH; WHO group 4) may be considered medically necessary in the following conditions:

• Persistent PH after surgical thrombectomy, or

• Inoperable CTEPH.

The use of riociguat or medications specific to PAH to reduce pulmonary vascular resistance before surgery in individuals with CTEPH who are considered candidates for pulmonary endarterectomy is considered investigational.

The use of riociguat is considered investigational for the treatment of PH (WHO groups 2, 3, and 5), including but not limited to:

• PH associated with left heart diseases;

• PH associated with lung diseases and/or hypoxemia (including chronic obstructive pulmonary disease);

• Miscellaneous group (ie, sarcoidosis, histiocytosis X, lymphangiomatosis).

POLICY GUIDELINES

Treatment with epoprostenol requires 3 steps: initial dose-ranging, catheter insertion and portable pump attachment, and catheter and pump maintenance.

• An initial dose-ranging study is typically performed as an inpatient. The pulmonary capillary wedge pressure is monitored, and the drug infusion rate is increased until a dose-limiting pharmacologic effect such as nausea, vomiting, or headache is elicited. Some practitioners may consider the initial dose-ranging study optional.

• Insertion of central venous catheter and attachment to portable infusion pump. Because rebound pulmonary hypertension may recur if the drug is abruptly withdrawn, the drug labeling advises that all individuals have access to a backup infusion pump and intravenous infusion set.

• For ongoing maintenance of the portable infusion pump and treatment of complications related to the pump, complications include catheter thrombosis, sepsis, and pump malfunction. In clinical trials, a cold pouch and frozen gel packs were used to facilitate extended use at ambient temperatures.

Treatment with iloprost requires the use of a specialized dispensing device.

Oral treprostinil should only be prescribed by a physician with expertise in treating pulmonary arterial hypertension, including administration of infused prostanoids.

For combination treatment, riociguat should not be combined with a phosphodiesterase type 5 inhibitor (sildenafil, tadalafil, vardenafil).

This evidence review does not evaluate activin signaling inhibitors such as sotatercept-csrk (Winrevair).

Coding

See the Codes table for details.

BENEFIT APPLICATION

BlueCard/National Account Issues

State or federal mandates (eg, Federal Employee Program) may dictate that certain U.S. Food and Drug Administration‒approved devices, drugs, or biologics may not be considered investigational, and thus these devices may be assessed only by their medical necessity.

Benefits are determined by the group contract, member benefit booklet, and/or individual subscriber certificate in effect at the time services were rendered.  Benefit products or negotiated coverages may have all or some of the services discussed in this medical policy excluded from their coverage.

bACKGROUND

Pharmacologic Therapies for Pulmonary Hypertension

This evidence review addresses advanced pharmacologic therapies for pulmonary hypertension (PH). Advanced pharmacologic therapies are newer specialty pharmacy drugs specifically intended to impact the natural history of PH, rather than supportive medications that treat disease manifestations. These newer specialty pharmacy drugs have been approved by the U.S. Food and Drug Administration (FDA) only for a subset of classes of PH (World Health Organization [WHO] groups 1 and 4, discussed below); as a result, BCBSA only addresses classes of PH for which advanced pharmacologic therapies are approved.

Pulmonary Hypertension

Classification

The 2019 WHO classification of PH, which is based on the consensus of an international group of experts at the Sixth World Symposium on Pulmonary Hypertension, is the most widely used system in clinical care and research.^1, There are 5 WHO categories of PH based on the etiology of the pulmonary hypertension:

Group 1: Pulmonary arterial hypertension (PAH)

Group 2: PH due to left heart disease

Group 3: PH due to chronic lung disease and/or hypoxemia

Group 4: PH due to chronic thromboembolic disease (chronic thromboembolic pulmonary hypertension [CTEPH])

Group 5: PH due to mixed or uncertain causes.

For each category, there are numerous subcategories indicating more specific disease etiologies. For example, in WHO group 1, the most common subcategory is idiopathic PAH, which is a disorder of unknown etiology categorized by abnormal proliferation of blood vessels in the pulmonary arterial system. Other classification systems, such as those developed by the American College of Cardiology Foundation and American Heart Association, are very similar but have differences in the subcategories of group 1.

Disease Description

Pulmonary hypertension is defined as increased arterial pressure in the lung vasculature.^2, Increased pulmonary pressure can be caused by primary abnormalities in the pulmonary vascular system; it can also be caused by other abnormalities in the cardiac or pulmonary organs, which may lead to secondary elevations in pulmonary arterial pressure. A definitive diagnosis of PH is usually made following measurement of pulmonary arterial pressure by right heart catheterization. A pulmonary arterial pressure of at least 20 mmHg confirms the diagnosis.^1,3,

Clinical symptoms of PH are related to right-sided heart failure and impaired oxygen delivery by the lungs. Warning signs are nonspecific but often present as a constellation of symptoms including dyspnea on exertion, fatigue, weakness, and syncope.^4, High pulmonary pressures lead to increased work of the right ventricle. This chronic hemodynamic overload leads to low cardiac output and progressive right ventricular dilatation. In advanced disease, signs of right-sided heart failure occur (eg, abdominal distension, hepatic congestion, pedal edema). Without treatment, the disease is progressive and eventually fatal; however, the natural history and rapidity of progression is variable. Premature death most commonly results from complications of right heart failure.

There are also differences in the pathophysiology, clinical manifestations, and natural history of each PH category. Only categories relevant to this evidence review (WHO groups 1 [PAH] and 4 [CTEPH]) are discussed herein.

The WHO further classifies patients with pulmonary hypertension based on functional ability:

Class I: No limitations with ordinary physical activity

Class II: Ordinary physical activity results in symptoms. Comfortable at rest.

Class III: Less than ordinary physical activity results in symptoms. Comfortable at rest.

Class IV: Inability to perform any physical activity without symptoms. Symptoms present at rest.

While PH can be diagnosed at any age, including children, the incidence of disease increases with age.^5, Generally, PH is more common in people 75 years of age or older, as well as in women and non-Hispanic Black people. According to a 2017 statement from the American Thoracic Society (ATS), the impact of health disparities on the diagnosis, treatment, and clinical outcome of patients with PAH has not been systematically investigated.^6,However, lower socioeconomic status, particularly lower income, has been associated with worse functional class and more advanced PAH at presentation.

Treatment

Conventional therapies considered in all patients with PH regardless of etiology include medications to treat heart failure (diuretics, angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, digoxin), oxygen therapy, and exercise. Lung transplantation and combined heart-lung transplantation have been performed in patients with PH that is refractory to medical management. There are also specific therapies for each WHO group. For example, anticoagulation is a treatment option in WHO group 1 and lifelong anticoagulation and consideration of surgical thrombectomy are treatment options for appropriate patients in group 4.^3,

Advanced Pharmacologic Therapies

Advanced pharmacologic therapies for PH are defined as newer specialty pharmacy drugs specifically intended to impact the natural history of PH, rather than treat disease manifestations (see Table 1 for specific agents). These specialty drugs can be administered as single agents or in various combinations. Advanced pharmacologic therapies are FDA approved for treatment of PH groups 1 and 4; therefore, these classes are discussed further.

World Health Organization Group 1 (pulmonary arterial hypertension )

Table 1 lists the classes of medications with FDA approvals for treatment of PAH.

Table 1. Approved Medication Classes for Treating Pulmonary Arterial Hypertension

  IP: prostacyclin receptor, also known as the prostaglandin I2 receptor or IP; PDE: phosphodiesterase.

World Health Organization Group 4 (chronic thromboembolic pulmonary hypertension)

The single medication currently FDA approved for treatment of CTEPH is riociguat. Riociguat stimulates soluble guanylate cyclase, both directly and indirectly, by increasing sensitivity of the enzyme to nitric oxide. Thus, riociguat may be effective for conditions in which endogenous nitric oxide (a vasodilator) is depleted.^7,

Regulatory Status

Table 2 summarizes advanced therapies for treatment of PAH (WHO group 1) and CTEPH (WHO group 4) and their current regulatory status (see Appendix Tables 1 and 2 for functional classes).

Table 2. Regulatory Status of Advanced Treatments of Pulmonary Arterial Hypertension and Chronic Thromboembolic Pulmonary Hypertension

  CTD: connective tissue disease; CTEPH: chronic thromboembolic pulmonary hypertension; DPI: dry powder inhaler; FDA: U.S. Food and Drug Administration; IV: intravenous; PAH: pulmonary arterial hypertension; PH: pulmonary hypertension; NYHA: New York Heart Association; SC: subcutaneous; WHO: World Health Organization. a Mean dose in a controlled clinical trial at 12 wk was 3.4 mg twice daily. Maximum doses studied were 12 mg twice daily in a 12-wk blinded study and 21 mg twice daily in an open-label long-term study.

RATIONALE

This evidence review was created in January 1998 and has been updated regularly with searches of the PubMed database. The most recent literature update was performed through October 2, 2024.

Evidence reviews assess the clinical evidence to determine whether the use of a technology improves the net health outcome. Broadly defined, health outcomes are length of life, quality of life, and ability to function, including benefits and harms. Every clinical condition has specific outcomes that are important to patients and to managing the course of that condition. Validated outcome measures are necessary to ascertain whether a condition improves or worsens; and whether the magnitude of that change is clinically significant. The net health outcome is a balance of benefits and harms.

To assess whether the evidence is sufficient to draw conclusions about the net health outcome of a technology, 2 domains are examined: the relevance and the quality and credibility. To be relevant, studies must represent 1 or more intended clinical use of the technology in the intended population and compare an effective and appropriate alternative at a comparable intensity. For some conditions, the alternative will be supportive care or surveillance. The quality and credibility of the evidence depend on study design and conduct, minimizing bias and confounding that can generate incorrect findings. The randomized controlled trial (RCT) is preferred to assess efficacy; however, in some circumstances, nonrandomized studies may be adequate. Randomized controlled trials are rarely large enough or long enough to capture less common adverse events and long-term effects. Other types of studies can be used for these purposes and to assess generalizability to broader clinical populations and settings of clinical practice.

Promotion of greater diversity and inclusion in clinical research of historically marginalized groups (e.g., People of Color [African-American, Asian, Black, Latino and Native American]; LGBTQIA (Lesbian, Gay, Bisexual, Transgender, Queer, Intersex, Asexual); Women; and People with Disabilities [Physical and Invisible]) allows policy populations to be more reflective of and findings more applicable to our diverse members. While we also strive to use inclusive language related to these groups in our policies, use of gender-specific nouns (e.g., women, men, sisters, etc.) will continue when reflective of language used in publications describing study populations.

Population Reference No. 1 

Pulmonary Arterial Hypertension Monotherapy Using Tyrosine Kinase Inhibitors or Statins

Clinical Context and Therapy Purpose

The purpose of monotherapy using tyrosine kinase inhibitors (TKIs) or statins is to provide a treatment option that is an alternative to or an improvement on existing therapies in patients with pulmonary arterial hypertension (PAH).

The following PICO was used to select literature to inform this review.

Populations

The relevant population of interest is individuals with PAH. Pulmonary arterial hypertension is characterized pathophysiologically by abnormal proliferation of pulmonary artery smooth muscle cells in the arteries.^2, This causes a decrease in the size of the pulmonary artery lumen, decreased reactivity of the vascular bed, increased pulmonary vascular resistance (PVR), and elevated pressure in the pulmonary circulation. Idiopathic PAH is the most common type of PAH and is more prevalent in women than in men. It often affects women in the third or fourth decade, resulting in a very high burden of illness for young, otherwise healthy patients. Median 1-year survival has been estimated to be 85%, and median 5-year survival has been estimated to be 57%.^8,

Interventions

The therapy being considered is monotherapy using TKIs or statins.

Tyrosine kinase inhibitors and statins were not developed as PAH-specific therapy and are not approved by the FDA for treatment of PAH.

Comparators

The following therapies are currently being used to treat PAH: conventional therapy and different PAH-specific drugs.

Outcomes

The general outcomes of interest are overall survival, functional outcomes (such as 6-minute walking distance [6MWD]), hospitalizations, and treatment-related morbidity. Follow-up ranges from months to years to monitor outcomes.

Study Selection Criteria

Methodologically credible studies were selected using the following principles:

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;

• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.

• To assess longer term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.

• Studies with duplicative or overlapping populations were excluded.

Review of Evidence

Tyrosine Kinase Inhibitors

No RCTs were identified that evaluated imatinib as monotherapy for patients with PAH. The safety of imatinib in patients with PAH was assessed by Frost et al (2015) in a long-term extension of an RCT of imatinib as add-on third-line therapy.^9, A total of 144 patients entered the extension study (66 patients had been on imatinib for 24 weeks, 78 patients were switching to imatinib from placebo). One hundred thirty-five (94%) of 144 patients discontinued the extension study, and about one-third of the patients discontinued because of adverse events. When the study was terminated (due to a high dropout rate), the mean exposure to imatinib was 931 days in the group who took imatinib in the original RCT, and 590 days in the ex-placebo group. Seventeen (12%) of the 144 patients died during the study or within 30 days of leaving it. Serious adverse events (other than death) occurred in 40 (60.6%) patients in the group originally taking imatinib, and 53 (67.9%) in the ex-placebo group. The trialists concluded that imatinib should not be used off-label for treatment of PAH.

Statins

Anand et al (2016) published a systematic review of placebo-controlled RCTs evaluating statins for treating PAH.^10, Reviewers identified 4 RCTs, of which 2 evaluated simvastatin, 1 assessed atorvastatin, and 1 evaluated rosuvastatin. The total sample size was 387; 1 study had 220 patients, and the others had fewer than 100 patients each. The primary outcomes of the review were mortality and change in 6MWD from baseline to follow-up. A pooled analysis of data from 3 trials did not find a significant benefit of statins on mortality (odds ratio [OR], 0.75; 95% confidence interval [CI], 0.32 to 1.74; I²=0%). Similarly, a pooled analysis of 3 trials did not find a significant benefit of statins on the 6MWD (weighted mean difference [WMD], -9.27 meters; 95% CI, -27.7 to 9.2 meters; I²=1.7%).

The largest trial assessed in the Anand systematic review was published by Zeng et al (2012).^11, This was a 6-month, double-blind, placebo-controlled randomized trial of 220 Chinese patients with PAH (83%) or chronic thromboembolic pulmonary hypertension (CTEPH; 6%) in World Health Organization (WHO) functional class II or III. Patients received atorvastatin 10 mg orally daily or matching placebo in addition to supportive care (diuretics, digoxin, warfarin). After 6 months, the mean difference in 6MWD (atorvastatin - placebo) was 2.5 meters (95% CI, -33 to 38 meters). There was no statistically significant difference between treatment groups in the proportion of patients who improved or deteriorated in WHO functional class or in hemodynamic parameters (right atrial pressure, pulmonary artery pressure, cardiac index, PVR, or mixed venous oxygen saturation). There were 9 (8%) deaths in the atorvastatin group and 11 (10%) deaths in the placebo group (p=.31). The trialists concluded: “Atorvastatin 10 mg daily has no beneficial effect on the natural history of PAH or CTEPH over 6 months.”

Section Summary: Pulmonary Arterial Hypertension Monotherapy Using Tyrosine Kinase Inhibitors or Statins

There are no RCTs evaluating the efficacy of TKIs for PAH and 4 RCTs on statins for PAH. A meta-analysis of RCTs evaluating statins for PAH did not report significantly better outcomes (ie, mortality, 6MWD) with the study medication than with placebo. For imatinib, a TKI, there are no placebo-controlled studies evaluating efficacy. However, a 2016 safety study identified a high rate of adverse effects in patients who took imatinib.

Summary of Evidence

For individuals who have PAH who receive monotherapy using TKIs or statins, the evidence includes no RCTs on TKIs and 4 RCTs and a meta-analysis on statins. Relevant outcomes are overall survival, functional outcomes, hospitalizations, and treatment-related morbidity. A meta-analysis of RCTs evaluating statins for PAH did not find significantly better outcomes (ie, mortality, 6MWD) with study medication than with placebo. For imatinib (a TKI), there are no placebo-controlled studies evaluating efficacy. However, a 2016 safety study identified a high rate of adverse events in patients who took imatinib. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

Population Reference No. 2

Pulmonary Arterial Hypertension Therapy Treated with Add-On Combination Therapies

Clinical Context and Therapy Purpose

The purpose of add-on combination therapy using 2 drug classes FDA approved for treatment of PAH is to provide a treatment option that is an alternative to or an improvement on existing therapies in patients with PAH and inadequate response to monotherapy.

The following PICO was used to select literature to inform this review.

Populations

The relevant population of interest is individuals with PAH and inadequate response to monotherapy.

Interventions

The therapy being considered is add-on combination therapy using 2 drug classes FDA approved for treatment of PAH.

Comparators

The following therapies are currently being used to treat PAH: different PAH-specific drugs or drug combinations.

Outcomes

The general outcomes of interest are overall survival, functional outcomes, hospitalizations, and treatment-related morbidity. Follow-up of months to years is of interest to monitor outcomes.

Study Selection Criteria

Methodologically credible studies were selected using the following principles:

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;

• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.

• To assess longer term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.

• Studies with duplicative or overlapping populations were excluded.

Review of Evidence

Systematic Reviews

Meta-analyses have considered various combinations of medications; all of the individual trials included in the meta-analyses used medications from different classes. In addition, all trials used combination therapy as add-on treatment for patients with an inadequate response to a single medication. (Several trials in the Lajoie et al [2016]^12, meta-analysis included a combination of patients on baseline therapy and treatment-naïve patients.) Key recent meta-analyses are described in Table 3.

Table 3. Key Meta-Analyses of RCTs Assessing Add-On Combination Therapy versus Monotherapy

   6MWD: 6-minute walk distance; AHRQ: Agency for Healthcare Research and Quality; CI: confidence interval; MD: mean difference; OR: odds ratio; PAH: pulmonary arterial hypertension; RCT: randomized controlled trial; RR: relative risk. a Clinical worsening: Composite outcome defined differently across studies but generally included death, admission to hospital due to worsening PAH, lung transplantation, symptom progression, and treatment escalation.

These meta-analyses of add-on combination therapy had mixed findings but generally found improvements in some outcomes compared with a single medication. The most recent and comprehensive meta-analysis found significantly lower rates of hospitalizations and less clinical worsening with the addition of a second class of medications compared with a single medication. Several meta-analyses found significantly greater exercise capacity, as measured by 6MWD, with add-on combination therapy; however, the additional distance walked may not be clinically significant. The 2013 Agency for Healthcare Research and Quality comparative effectiveness review by McCrory et al (2013) indicated that 33 meters is generally considered the minimally important difference in distance walked in 6MWD.^13, None of the meta-analyses found significantly less all-cause mortality with add-on combination therapy.

Randomized Controlled Trials

Randomized controlled trials have evaluated various medication combinations for treating PAH. These combinations include, but are not limited to, prostacyclin analogues and endothelin receptor antagonists,^15,16,17, phosphodiesterase (PDE) inhibitors and endothelin receptor antagonists,^18,19, and prostacyclin analogues and PDE inhibitors.^15,20, A RCT evaluating riociguat plus sildenafil (PDE type 5 [PDE5] inhibitors) concluded that this combination is contraindicated.^21, These RCTs are included in the meta-analyses described above and will not be comprehensively summarized herein. Below is a summary of subsequently published RCTs with notable characteristics.

In the FREEDOM-EV trial, 690 patients with Group I PAH were randomized to oral treprostinil or placebo add-on therapy 30 days or longer after beginning treatment with sildenafil, tadalafil, bosentan, ambrisentan, macitentan, or riociguat. The primary outcome was time to clinical worsening (death; hospitalization due to worsening PAH; initiation of inhaled or parenteral prostacyclin therapy; disease progression; or unsatisfactory long-term clinical response).^22, At follow-up of 24 weeks, clinical worsening occurred in 26% of the oral treprostinil group compared with 36% of placebo participants (hazard ratio, 0.74; 95% CI, 0.56 to 0.97; p=.028). Discontinuation due to adverse events was more common in the treprostinil–assigned participants (18.8%) than in placebo participants (4.1%). This trial was the basis for an expanded FDA indication for treprostinil to include delaying disease progression in patients with PAH.

Section Summary: Therapy Using Add-On Combination Therapies

Numerous RCTs of different combinations of medication and meta-analyses of RCTs have been conducted. In all RCTs included in the 2016 meta-analysis, combination therapy involved drugs from different classes, although the specific combination of riociguat and PDE5 inhibitors is contraindicated. The 2016 meta-analysis is the most recent and comprehensive. It included 17 RCTs of add-on combination therapy versus monotherapy, with at least 12 weeks of follow-up; while mortality rates did not differ significantly between the 2 groups, the meta-analysis reported significantly lower rates of clinical worsening and hospitalizations for the group receiving combination therapy.

Summary of Evidence

For individuals who have PAH and inadequate response to monotherapy who receive add-on combination therapy using 2 drug classes FDA approved for treatment of PAH, the evidence includes RCTs and meta-analyses. Relevant outcomes are overall survival, functional outcomes, hospitalizations, and treatment-related morbidity. The most recent and comprehensive meta-analysis of RCTs was published in 2016. It included 17 RCTs comparing add-on combination therapy with monotherapy with at least 12 weeks of follow-up. The meta-analysis found significantly lower rates of clinical worsening and hospitalizations with add-on combination therapy, but mortality rates did not differ significantly between groups. In all RCTs selected for the 2016 meta-analysis, the combination therapy involved different drug combinations from different classes, although the specific combination of riociguat and PDE type 5 inhibitors is contraindicated. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

Population Reference No. 3 

Pulmonary Arterial Hypertension Therapy Using Initial Combination Therapies

Initial Dual Therapy

Clinical Context and Therapy Purpose

The purpose of initial combination therapy using 2 drug classes FDA approved for treatment of PAH is to provide a treatment option that is an alternative to or an improvement on existing therapies in patients with PAH.

The following PICO was used to select literature to inform this review.

Populations

The relevant population of interest is individuals with PAH.

Interventions

The therapy being considered is initial combination therapy using 2 drug classes FDA approved for treatment of PAH.

Comparators

The following therapeutic strategy is currently being used to treat PAH: initial monotherapy, followed by combination therapy if monotherapy fails.

Outcomes

The general outcomes of interest are overall survival, functional outcomes hospitalizations, and treatment-related morbidity. Follow-up from months to years is of interest to monitor outcomes.

Study Selection Criteria

Methodologically credible studies were selected using the following principles:

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;

• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.

• To assess longer term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.

• Studies with duplicative or overlapping populations were excluded.

Review of Evidence

Randomized Controlled Trials

Two RCTs specifically evaluating initial combination therapy in patients with PAH were identified.

The Ambrisentan and Tadalafil in Patients with Pulmonary Arterial Hypertension (AMBITION) trial, reported by Galie et al (2015) randomized patients to initial treatment with ambrisentan (an endothelin receptor antagonist), tadalafil (a PDE inhibitor), or a combination of these 2 medications.^23, A total of 610 adults aged 18 to 75 years with WHO functional class II or III symptoms of WHO group 1 PAH underwent randomization, but the entry criteria changed during the trial. The primary endpoint was the first event of clinical failure in a time-to-event analysis. Clinical failure was a composite endpoint including death, hospitalization for worsening PAH, disease progression, and unsatisfactory long-term clinical response. Mean duration of trial participation in the 500 patients included in the primary analysis set was 609 days. In these patients, the primary endpoint of clinical failure occurred in 46 (18%) of 253 patients in the combination therapy group, in 43 (34%) of 126 in the ambrisentan group, and in 34 (28%) of 121 in the tadalafil group. The clinical failure rate was significantly lower in the combined treatment group than in the ambrisentan group (p<.001) or the tadalafil group (p=.005). Serious adverse events among patients in the primary analysis set occurred in 92 (36%) patients in the combined treatment group, 45 (36%) patients in the ambrisentan group, and 50 (41%) patients in the tadalafil group (no significant difference among groups).

The Bosentan Randomized trial of Endothelin Antagonist Therapy for PAH (BREATHE-2) trial, reported by Humbert et al (2004) compared epoprostenol alone with the combination of epoprostenol plus bosentan.^24, The trial was multicenter, double-blind, and placebo-controlled. It included 33 patients with PAH who were scheduled to begin treatment with epoprostenol. After 2 days of epoprostenol therapy, patients were randomized to add bosentan (n=22) or placebo (n=11). The double-blind treatment duration was 16 weeks, and the primary efficacy outcome was change in total pulmonary resistance. Five (15%) of 33 patients did not complete the trial. At 16 weeks, mean change in total pulmonary resistance did not differ significantly between groups (-36.3 dyns^-1cm⁵ ± 4.3% in the combination treatment group vs. -22.6 dyns^-1cm⁵ ± 4.3% in the epoprostenol plus placebo group, p=.08). Secondary outcomes also did not differ significantly between groups. For example, the median 6MWD increased 68 meters in the combination treatment group and 74 meters in the epoprostenol plus placebo group. Moreover, the modified New York Heart Association functional class improved for 59% (13 of 22) of patients in the combination treatment group and 45% (5 of 11) of patients in the epoprostenol plus placebo group, a difference that was not statistically significant.

Tables 4 and 5 summarize the characteristics and results of the AMBITION and BREATHE-2 trials.

Table 4. Key Characteristics of the AMBITION and BREATHE-2 Trials

   FC: functional class; NR: not reported; NYHA: New York Heart Association; PAH: pulmonary arterial hypertension; RCT: randomized controlled trial; WHO: World Health Organization; y: year(s). a Modified intention-to-treat population.

Table 5. Key Results of the AMBITION and BREATHE-2 Trials

   6MWD: 6-minute walk distance; CI: confidence interval; Combo: combination; FC: functional class; HR: hazard ratio; IQR: interquartile range; Mono: monotherapy; NC: no change; SEM: standard error of the mean; TPR: total pulmonary resistance. a Classes in the 2 systems have similar characteristics.  b Defined as death, hospitalization or worsening pulmonary arterial hypertension, disease progression, or unsatisfactory long-term clinical response.

Tables 6 and 7 summarize the important study relevance, design, and conduct limitations of the RCTs discussed above.

Table 6. Study Relevance Limitations of the AMBITION and BREATHE-2 Trials

   The study limitations stated in this table are those notable in the current review; this is not a comprehensive gaps assessment.  a Population key: 1. Intended use population unclear; 2. Clinical context is unclear; 3. Study population is unclear; 4. Study population not representative of intended use. b Intervention key: 1. Not clearly defined; 2. Version used unclear; 3. Delivery not similar intensity as comparator; 4. Not the intervention of interest. c Comparator key: 1. Not clearly defined; 2. Not standard or optimal; 3. Delivery not similar intensity as intervention; 4. Not delivered effectively. d Outcomes key: 1. Key health outcomes not addressed; 2. Physiologic measures, not validated surrogates; 3. No CONSORT reporting of harms; 4. Not establish and validated measurements; 5. Clinical significant difference not prespecified; 6. Clinical significant difference not supported. e Follow-Up key: 1. Not sufficient duration for benefit; 2. Not sufficient duration for harms.

Table 7. Study Design and Conduct Limitations of the AMBITION and BREATHE-2 Trials

   The study limitations stated in this table are those notable in the current review; this is not a comprehensive gaps assessment. a Allocation key: 1. Participants not randomly allocated; 2. Allocation not concealed; 3. Allocation concealment unclear; 4. Inadequate control for selection bias. b Blinding key: 1. Not blinded to treatment assignment; 2. Not blinded outcome assessment; 3. Outcome assessed by treating physician. c Selective Reporting key: 1. Not registered; 2. Evidence of selective reporting; 3. Evidence of selective publication. d Data Completeness key: 1. High loss to follow-up or missing data; 2. Inadequate handling of missing data; 3. High number of crossovers; 4. Inadequate handling of crossovers; 5. Inappropriate exclusions; 6. Not intent to treat analysis (per protocol for noninferiority trials). e Power key: 1. Power calculations not reported; 2. Power not calculated for primary outcome; 3. Power not based on clinically important difference. f Statistical key: 1. Intervention is not appropriate for outcome type: (a) continuous; (b) binary; (c) time to event; 2. Intervention is not appropriate for multiple observations per patient; 3. Confidence intervals and/or p values not reported; 4.Comparative treatment effects not calculated.

Observational Studies

A retrospective study evaluated the long-term survival of patients with idiopathic, heritable, or anorexigen-induced PAH categorized according to the initial treatment strategy (monotherapy, dual therapy, or triple-combination therapy).^25, Data were abstracted from the French Pulmonary Hypertension Registry (January 2006 to December 2018) and included 984 patients initiated on monotherapy, 551 initiated on dual therapy, and 76 initiated on triple therapy. The 5-year survival rate for patients who were initiated on dual therapy or monotherapy was 61% for both groups; similarly, the 10-year survival rate for patients initiated on dual therapy or monotherapy was 43% for both groups.

Section Summary: Pulmonary Arterial Hypertension Therapy Using Initial Dual Combination Therapies

Two RCTs have compared 6 months of initial combination therapy versus monotherapy for PAH. A long-term retrospective study comparing overall survival between treatments was also published. In the AMBITION trial, among patients in the primary analysis set, there was a significantly lower rate of clinical failure at 6 months in the group receiving both ambrisentan plus tadalafil than in the monotherapy groups. Rates of adverse events were similar across groups. Data interpretation of this study is difficult because the trialists changed enrollment criteria during the trial and used a complex composite outcome with multiple components. The other RCT did not find significant differences in outcomes between a group receiving initial combined therapy with bosentan and epoprostenol and a group receiving monotherapy at 16 weeks; this study had a small sample size and might have been underpowered for secondary outcomes. Both trials lacked a clinically relevant comparison between initial combination therapy and initial monotherapy followed by combination therapy for patients with an inadequate response. A retrospective study found similar 5- and 10-year overall survival for patients initiated on dual therapy or monotherapy.

Summary of Evidence

For individuals who have PAH who receive initial combination therapy using 2 drug classes FDA approved for treatment of PAH, the evidence includes 2 RCTs and a retrospective study. Relevant outcomes are overall survival, functional outcomes, hospitalizations, and treatment-related morbidity. In the first study (AMBITION trial), among patients in the primary analysis set, there was a significantly lower rate of clinical failure at 6 months in the combination therapy group than in the monotherapy group. Clinical failure was defined as a complex composite endpoint that included death, hospitalizations, functional improvement, and other measures of disease progression. Study limitations include change in enrollment criteria during the trial and use of a complex composite outcome with multiple components. The other RCT did not find significant differences in outcomes between a group receiving initial combination therapy and the group receiving monotherapy at 16 weeks; this study had a small sample size and might have been underpowered to assess secondary outcomes. Multiple reviews of the AMBITION trial with an emphasis on functional improvement (6MWT) have led to guideline recommendations for making ambristentan plus tadalafil and appropriate initial treatment option. A retrospective study found similar 5- and 10-year overall survival for patients initiated on dual therapy or monotherapy. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

Population Reference No. 4 

Initial Triple Therapy

Clinical Context and Therapy Purpose

The purpose of initial combination therapy using 3 drug classes FDA approved for treatment of PAH is to provide a treatment option that is an alternative to or an improvement on existing therapies in patients with PAH.

The following PICO was used to select literature to inform this review.

Populations

The relevant population of interest is individuals with PAH.

Interventions

The therapy being considered is initial combination therapy using 3 drug classes FDA approved for treatment of PAH.

Comparators

The following therapeutic strategy is currently being used to treat PAH: initial dual therapy.

Outcomes

The general outcomes of interest are overall survival, functional outcomes, hospitalizations, and treatment-related morbidity. Follow-up from months to years is of interest to monitor outcomes.

Study Selection Criteria

Methodologically credible studies were selected using the following principles:

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;

• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.

• To assess longer term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.

• Studies with duplicative or overlapping populations were excluded.

Review of Evidence

Randomized Controlled Trials

One RCT specifically evaluating initial triple combination therapy in patients with PAH was identified.

The Efficacy and Safety of Initial Triple Versus Initial Dual Oral Combination Therapy in Patients With Newly Diagnosed Pulmonary Arterial Hypertension (TRITON) was a multicenter, double-blind, RCT comparing initial triple therapy (n=123) with macitentan, tadalafil, and selexipag to initial double therapy (n=124) with macitentan, tadalafil, and placebo in newly diagnosed, treatment-naive patients with PAH (Table 8).^26, At baseline, approximately 80% of patients had WHO functional class II or III symptoms. At week 26, the primary endpoint of change in PVR was reduced by 54% and 52% with initial triple and dual therapy, respectively, but the between-group difference was not significant. Secondary endpoints were considered exploratory based on testing hierarchy, and potentially signaled a reduced risk for disease progression events with initial triple therapy (rate ratio, 0.39; 95% CI, 0.15 to 1.00). Overall, larger studies powered to find long-term benefits with triple therapy are needed to identify patients who may benefit from this treatment approach.

Table 8. Summary of Key RCT Characteristics

   RCT: randomized controlled trial; WHO: World Health Organization. 

Table 9. Summary of Key RCT Results

   6MWD: 6-minute walk distance; AE: adverse event; CI: confidence interval; NR: not reported; NT-proBNP, N-terminal pro–brain natriuretic peptide; PVR: pulmonary vascular resistance; RCT: randomized controlled trial.

The purpose of the study limitations tables (see Tables 10 and 11) is to display notable limitations identified in the RCT. This information is synthesized as a summary of the body of evidence following each table and provides the conclusions on the sufficiency of evidence supporting the position statement.

Table 10. Study Relevance Limitations

   The study limitations stated in this table are those notable in the current review; this is not a comprehensive gaps assessment.  a Population key: 1. Intended use population unclear; 2. Study population is unclear; 3. Study population not representative of intended use; 4, Enrolled populations do not reflect relevant diversity; 5. Other. b Intervention key: 1. Not clearly defined; 2. Version used unclear; 3. Delivery not similar intensity as comparator; 4. Not the intervention of interest (e.g., proposed as an adjunct but not tested as such); 5: Other. c Comparator key: 1. Not clearly defined; 2. Not standard or optimal; 3. Delivery not similar intensity as intervention; 4. Not delivered effectively; 5. Other. d Outcomes key: 1. Key health outcomes not addressed; 2. Physiologic measures, not validated surrogates; 3. Incomplete reporting of harms; 4. Not establish and validated measurements; 5. Clinically significant difference not prespecified; 6. Clinically significant difference not supported; 7. Other. e Follow-Up key: 1. Not sufficient duration for benefit; 2. Not sufficient duration for harms; 3. Other.

Table 11. Study Design and Conduct Limitations

   The study limitations stated in this table are those notable in the current review; this is not a comprehensive gaps assessment. a Allocation key: 1. Participants not randomly allocated; 2. Allocation not concealed; 3. Allocation concealment unclear; 4. Inadequate control for selection bias; 5. Other. b Blinding key: 1. Participants or study staff not blinded; 2. Outcome assessors not blinded; 3. Outcome assessed by treating physician; 4. Other. c Selective Reporting key: 1. Not registered; 2. Evidence of selective reporting; 3. Evidence of selective publication; 4. Other. d Data Completeness key: 1. High loss to follow-up or missing data; 2. Inadequate handling of missing data; 3. High number of crossovers; 4. Inadequate handling of crossovers; 5. Inappropriate exclusions; 6. Not intent to treat analysis (per protocol for noninferiority trials); 7. Other. e Power key: 1. Power calculations not reported; 2. Power not calculated for primary outcome; 3. Power not based on clinically important difference; 4. Other. f Statistical key: 1. Analysis is not appropriate for outcome type: (a) continuous; (b) binary; (c) time to event; 2. Analysis is not appropriate for multiple observations per patient; 3. Confidence intervals and/or p values not reported; 4. Comparative treatment effects not calculated; 5. Other.  

Section Summary: Pulmonary Arterial Hypertension Therapy Using Initial Triple Combination Therapies

For individuals who have PAH who receive initial combination therapy using 3 drug classes FDA approved for treatment of PAH, the evidence includes 1 RCT. In the TRITON trial, initial triple therapy (n=123) with macitentan, tadalafil, and selexipag was compared to initial double therapy (n=124) with macitentan, tadalafil, and placebo in newly diagnosed, treatment-naive patients with PAH, most of whom had WHO functional class II or III symptoms. At week 26, the primary endpoint of change in PVR was reduced by 54% and 52% with initial triple and dual therapy, respectively, but the between-group difference was not significant. Secondary endpoints were considered exploratory based on testing hierarchy, and potentially signaled a reduced risk for disease progression events with initial triple therapy. The frequency of serious adverse events was similar in both groups. Overall, larger studies powered to find long-term benefits with triple therapy are needed to identify patients who may benefit from this treatment approach.

Summary of Evidence

For individuals who have PAH who receive initial combination therapy using 3 drug classes FDA approved for treatment of PAH, the evidence includes a single RCT. Relevant outcomes are overall survival, functional outcomes, hospitalizations, and treatment-related morbidity. In the TRITON trial, initial triple therapy (n=123) with macitentan, tadalafil, and selexipag was compared to initial double therapy (n=124) with macitentan, tadalafil, and placebo in newly diagnosed, treatment-naive patients with PAH. At week 26, the primary endpoint of change in PVR was reduced by 54% and 52% with initial triple and dual therapy, respectively, but the between-group difference was not significant. Secondary endpoints were considered exploratory based on testing hierarchy, and potentially signaled a reduced risk for disease progression events with initial triple therapy. Overall, larger studies powered to find long-term benefits with triple therapy are needed to identify patients who may benefit from this treatment approach. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

Population Reference No. 5 

Inoperable Chronic Thromboembolic Pulmonary Hypertension Monotherapy

Clinical Context and Therapy Purpose

The purpose of soluble guanylate cyclase stimulator (eg, riociguat) is to provide a treatment option that is an alternative to or an improvement on existing therapies in patients with inoperable CTEPH or pulmonary hypertension (PH) after surgery.

The following PICO was used to select literature to inform this review.

Populations

The relevant populations of interest are individuals with inoperable CTEPH or PH after surgery. Chronic thromboembolic pulmonary hypertension primarily occurs after acute or chronic pulmonary embolism. Progressive pulmonary vascular remodeling (thrombi organization, fibrous stenosis, microvascular changes) obstructs pulmonary arteries, leading to PH and right heart failure.^2,27, Estimated CTEPH incidence among patients who survive an acute pulmonary embolism ranges from 0.6% to 3.8%.^2,28, However, many patients have no clinical history of pulmonary embolism, and CTEPH is likely underdiagnosed. The severity and prognosis are variable, depending on the extent of lung damage caused by prior thromboembolism and the degree to which future episodes can be prevented.

Interventions

The therapy being considered is a soluble guanylate cyclase stimulator (eg, riociguat).

Comparators

The following therapy is currently being used to treat inoperable CTEPH or PH after surgery: standard of care.

Outcomes

The general outcomes of interest are overall survival, functional outcomes, hospitalizations, and treatment-related morbidity. Follow-up over years is of interest to monitor outcomes.

Study Selection Criteria

Methodologically credible studies were selected using the following principles:

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;

• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.

• To assess longer term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.

• Studies with duplicative or overlapping populations were excluded.

Review of Evidence

Randomized Controlled Trials

Riociguat

The pivotal Chronic Thromboembolic Pulmonary Hypertension Soluble Guanylate Cyclase–Stimulator Trial 1 (CHEST-1) trial, published by Ghofrani et al (2013), assessed the efficacy and safety of riociguat to treat CTEPH.^29, CHEST-1 was a double-blind RCT in 261 adults who had inoperable CTEPH (n=188 [72%]) or persistent PH after pulmonary endarterectomy (n=73 [28%]). Patients receiving PAH medications were excluded. Patients were randomized to receive placebo or riociguat 3 times daily, and doses were titrated to 0.5 to 2.5 mg. Doses were optimized during the first 8 weeks, and the optimized dose was continued for 8 additional weeks. The primary efficacy outcome was change in 6MWD at 16 weeks.

Two hundred forty-two (93%) patients from both groups completed the trial; 77% of completers in the riociguat group continued at the maximum dose to week 16. Mean change in 6MWD, the primary efficacy outcome, was +39 meters in the riociguat group and -6 meters in the placebo group (least-squares mean difference, 46 meters; 95% CI, 25 to 67 meters; p<.001). Results were consistent across multiple sensitivity analyses and predefined subgroups (eg, baseline WHO functional class). Adverse events that occurred more commonly in the riociguat group (vs. placebo) included headache (25% vs. 14%), dizziness (23% vs. 12%), stomach upset (18% vs. 8%), vomiting (10% vs. 3%), diarrhea (10% vs. 5%), and hypotension (9% vs. 3%), respectively. The most common serious adverse events were right ventricular failure (3% in each group), syncope (2% riociguat vs. 3% placebo), and hemoptysis (2% riociguat). One patient died due to acute renal failure attributed to riociguat.

Additional data on secondary outcomes from CHEST-1 were published by Kim et al (2017).^30, Study findings generally favored the riociguat group. At week 16, compared with baseline, PVR significantly decreased in the riociguat group (-29%) compared with the placebo group (+3%). There were also significantly improved outcomes in the riociguat group versus placebo for other hemodynamic outcomes (eg, systemic vascular resistance, mean pulmonary arterial pressure, diastolic pulmonary artery pressure, cardiac output, mixed venous oxygen saturation, mean arterial pressure, diastolic pressure gradient; p<.001 for each).

CHEST-2 (2015) was an extension study that included patients in CHEST-1 who did not withdraw due to clinical worsening. All patients in CHEST-2 received open-label riociguat. Simonneau et al (2015) published results of an interim analysis in which most patients had received 1 or more years of treatment.^31, A total of 243 patients entered CHEST-2, and at the data cutoff for the analysis, 179 (76%) had received more than 1 year of treatment. The estimated overall survival rate at 1 year was 97% (95% CI, 93% to 98%). In an analysis assuming that all patients who dropped out of the study had died, the estimated 1-year survival rate was 93% (95% CI, 88% to 96%). The rate of clinical worsening-free survival at 1 year was 88% (95% CI, 83% to 92%). Adverse events occurred in 228 (96%) patients, most commonly nasopharyngitis (23%), dizziness (19%), and peripheral edema (18%). Serious adverse events occurred in 100 (42%) patients. Thirteen patient deaths occurred during CHEST-2, none of which was considered drug-related by the investigators.

An RCT by Jais et al (2022), Riociguat Versus Balloon Pulmonary Angioplasty in Non-operable Chronic thromboEmbolic Pulmonary Hypertension (RACE), compared the efficacy and safety of balloon pulmonary angioplasty (BPA) versus riociguat in patients with inoperable CTEPH.^32, In this open-label trial done in 23 French PAH centers, treatment-naïve adults with newly diagnosed, inoperable CTEPH and PVR of more than 320 dyns^-1cm⁵ were randomized to receive riociguat 1 to 2.5 mg 3 times daily (n=53) or BPA (n=52). At week 26, the geometric mean PVR decreased to 39.9% (95% CI, 36.2 to 44) of baseline PVR in the BPA group and 66.7% (60.5 to 73.5) of baseline PVR in the riociguat group (ratio of geometric means, 0.60; 95% CI, 0.52 to 0.69; p<.0001). The change in 6MWD was not significantly different between the BPA (50.3 m) and riociguat (44.1 m) group (treatment effect, 6.14 m; 95% CI, -18.12 to 30.4 m; p=.62). Treatment-related serious adverse events were more frequently observed in patients in the BPA (42%) versus the riociguat (9%) group. Patients who completed the RACE trial continued into an ancillary 26-week follow-up during which symptomatic patients with PVR of more than 320 dyns^-1cm⁵ benefited from add-on riociguat after BPA or add-on BPA after riociguat. Amongst patients who completed the initial 26-week trial, criteria for add-on riociguat was met by 18 of 51 patients in the BPA group, and criteria for add-on BPA was met by 36 of 48 patients in the riociguat group. At week 52, the exploratory analysis showed that the geometric mean of PVR decreased to 35% (95% CI, 31.7 to 38.7) of the baseline value in the group who received add-on riociguat, and decreased to 38.6% (95% CI, 35 to 42.6) in the group who received add-on BPA (ratio of geometric means, 0.91; 95% CI, 0.79 to 1.04; p=.18).

Treprostinil

Sadushi-Kolici et al (2019) conducted a 24-week, double-blind RCT assessing the efficacy and safety of treprostinil, a prostacyclin analogue, for the treatment of inoperable CTEPH.^33, One hundred five patients were enrolled in the study, 53 randomly assigned to receive high-dose subcutaneous treprostinil (target dose approximately 30 ng/kg/min at week 12) and 52 assigned to receive a low dose (target dose approximately 3 ng/kg/min at week 12). The primary endpoint was 6MWD at week 24. At week 24, the marginal mean 6MWD in the high-dose group improved by 44.98 m (95% CI, 27.52 to 62.45 m), and the low-dose group improved by 4.29 m (95% CI, -13.34 to 21.92 m); treatment effect was 40.69 m (95% CI, 15.86 to 65.53 m; p=.0016). Patients in both groups (high-dose group n=9 [17%]; low-dose group n=10 [19%]) experienced serious adverse events, but the most common adverse events reported were infusion site pain and other infusion site reactions.

Section Summary: Inoperable Chronic Thromboembolic Pulmonary Hypertension Monotherapy

There is only 1 FDA-approved medication for this indication: riociguat. TwoRCTs and their extension studies have been published. One double-blind, placebo-controlled RCT found that functional outcomes at 16 weeks improved significantly more in the group receiving riociguat. Both groups had a high proportion of adverse events, and 1 death was attributed to riociguat. In the extension study, the estimated 1-year survival rate was 97%. Thirteen deaths occurred, none of which was attributed to study medication. In the second RCT, the efficacy and safety of BPA and riociguat were compared. At week 26, PVR reduction was more pronounced with BPA than with riociguat, but treatment-related serious adverse events were more common with BPA. A 52-week extension study found that add-on BPA or add-on riociguat had similar effects on PVR reduction.

Summary of Evidence

Summary of Evidence

For individuals who have inoperable CTEPH or PH after surgery who receive a soluble guanylate cyclase stimulator (eg, riociguat), the evidence includes 2 RCTs. Relevant outcomes are overall survival, functional outcomes, hospitalizations, and treatment-related morbidity. The first double-blind, placebo-controlled RCT found that functional outcomes at 16 weeks improved significantly more in the group receiving riociguat than placebo. Both groups had a high proportion of adverse events, and 1 death was attributed to riociguat. In an extension study, the estimated 1-year survival rate was 97%. Thirteen deaths occurred, none of which were attributed to study medication. In the second RCT, the efficacy and safety of BPA and riociguat were compared. At week 26, PVR reduction was more pronounced with BPA than with riociguat, but treatment-related serious adverse events were more common with BPA. A 52-week extension study found that add-on BPA or add-on riociguat had similar effects on PVR reduction. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome. .

Population Reference No. 6

Perioperative Chronic Thromboembolic Pulmonary Hypertension Therapy

Clinical Context and Therapy Purpose

The purpose of perioperative prostacyclin analogues, endothelin receptor antagonists, and riociguat is to provide a treatment option that is an alternative to or an improvement on existing therapies in patients with operable CTEPH.

For patients with CTEPH who are eligible for pulmonary endarterectomy, preoperative elevation of PVR (>1100 Wood units) can increase operative mortality rates to 6% to 10%.^34,

The following PICO was used to select literature to inform this review.

Populations

The relevant population of interest is individuals with operable CTEPH.

Interventions

The therapies being considered are perioperative prostacyclin analogues, endothelin receptor antagonists, and riociguat.

Comparators

The following therapy is currently being used to treat operable CTEPH: pulmonary endarterectomy alone.

Outcomes

The general outcomes of interest are overall survival, functional outcomes, hospitalizations, and treatment-related morbidity. Follow-up of weeks to months is of interest to monitor outcomes.

Study Selection Criteria

Methodologically credible studies were selected using the following principles:

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;

• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.

• To assess longer term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.

• Studies with duplicative or overlapping populations were excluded.

Review of Evidence

Prostacyclin Analogues (Prostanoids)

Epoprostenol

One nonrandomized comparative study was identified. Nagaya et al (2003) reported retrospectively on 33 patients with CTEPH who underwent pulmonary endarterectomy.^34, Twelve patients with preoperative PVR greater than 1200 Wood units received preoperative epoprostenol for a mean of 6 weeks. There were statistically significant reductions in PVR before and after surgery in both groups and no statistically significant difference in PVR between groups at 1 month after surgery (mean PVR, >300 Wood units in both groups). The only patient who died within 30 days postsurgery was in the epoprostenol group (overall mortality rate, 3.0%; 8.3% in the epoprostenol group vs. 0% in the comparator group).

Iloprost

Kramm et al (2003) reported on the effect of inhaled iloprost in the perioperative period.^35, Ten patients with a mean PVR of 972 Woods units received inhaled iloprost at 3 time points: immediately before surgery, on admission to the intensive care unit after surgery, and at 12 or more hours postsurgery. Preoperative inhalation did not affect PVR. After surgery, PVR decreased 10% and 22% after each postoperative dose compared with placebo (saline) inhalation at the same time points; however, all postoperative measurements (pre- and posttreatment) were less than 360 Wood units. One patient died 17 days after surgery due to persistent PH (10% mortality rate).

Endothelin Receptor Antagonists

Bosentan

Reesink et al (2010) reported on the results from a single-blind RCT of 26 patients with CTEPH who were eligible for pulmonary endarterectomy.^36, Mean baseline total pulmonary resistance was approximately 1000 Wood units. Fourteen patients received bosentan for 16 weeks before surgery; 1 patient developed liver enzyme elevations 6 times the upper limit of normal and was excluded from efficacy analyses. Eleven patients in the bosentan group and 10 patients in the non-bosentan group underwent pulmonary endarterectomy. Mortality rates within 30 days of surgery were 9% and 30%, respectively.

Soluble Guanylate Cyclase Stimulators

Riociguat

No trials evaluating riociguat for peri operative therapy were identified.

Section Summary: Perioperative Chronic Thromboembolic Pulmonary Hypertension Treatment

The few studies identified, all with small numbers of patients and limited comparative data, do not provide sufficient evidence to determine whether mortality and PVR are improved with any of these medications. High-quality RCTs are needed to determine whether perioperative treatment with advanced medications improves outcomes for this population.

Summary of Evidence

For individuals who have operable CTEPH who receive perioperative prostacyclin analogues, endothelin receptor antagonists, or riociguat, the evidence includes 1 small RCT on bosentan, retrospective noncomparative studies on epoprostenol and iloprost, and no trials on riociguat. Relevant outcomes are overall survival, functional outcomes, hospitalizations, and treatment-related morbidity. The few studies, with small numbers of patients and limited comparative data, do not provide sufficient evidence to determine whether mortality and PVR are reduced with any of these medications. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

Supplemental Information

The purpose of the following information is to provide reference material. Inclusion does not imply endorsement or alignment with the evidence review conclusions.

Clinical Input From Physician Specialty Societies and Academic Medical Centers

While the various physician specialty societies and academic medical centers may collaborate with and make recommendations during this process, through the provision of appropriate reviewers, input received does not represent an endorsement or position statement by the physician specialty societies or academic medical centers, unless otherwise noted.

2014 Input

In response to requests, input was received from 4 academic medical centers (5 reviewers) and 1 professional pharmacy society while this policy was under review in 2014. Input focused on:

• The use of riociguat and pulmonary arterial hypertension-specific medications to reduce pulmonary vascular resistance preoperatively in patients with chronic thromboembolic pulmonary hypertension who are candidates for pulmonary endarterectomy. There was consensus among reviewers that riociguat is investigational in this setting and that pulmonary arterial hypertension-specific medications are investigational in this setting.

• The use of riociguat in patients with chronic thromboembolic pulmonary hypertension who are candidates for pulmonary endarterectomy but prefer medical treatment. Results were mixed on this question.

2011 Input

In response to requests, input was received from 4 academic medical centers while this policy was under review in 2011. Input focused on combination therapy. Two academic medical centers disagreed with the 2010 policy statement that combination therapy is considered investigational (other than when changing from 1 medication to another). The other 2 centers had mixed input; both thought there were situations when combination therapy is medically necessary.

Practice Guidelines and Position Statements

Guidelines or position statements will be considered for inclusion in ‘Supplemental Information' if they were issued by, or jointly by, a US professional society, an international society with US representation, or National Institute for Health and Care Excellence (NICE). Priority will be given to guidelines that are informed by a systematic review, include strength of evidence ratings, and include a description of management of conflict of interest.

Pulmonary Arterial Hypertension

American College of Cardiology Foundation et al

In 2009, the American College of Cardiology Foundation and American Heart Association released an expert consensus document on pulmonary hypertension (PH) developed with 3 other medical associations.^2, This evidenced-based treatment algorithm stated that “in general, patients with poor prognostic indexes should be initiated on parenteral therapy, while patients with class II or early II symptoms commonly commence therapy with either endothelin receptor antagonists or PDE5 [phosphodiesterase type 5] inhibitors.” The consensus report also cautioned “against widespread treatment of non-PAH [pulmonary arterial hypertension] PH” until patient benefit has been proven in clinical trials. On the topic of combination therapy, the authors encouraged enrollment into randomized controlled trials evaluating combination therapy.

American College of Chest Physicians

In 2019, the American College of Chest Physicians (ACCP) updated their guidelines on pharmacologic therapy for PAH in adults.^38, Relevant new recommendations include:

• For patients with PAH who are treatment naive with World Health Organization (WHO) functional class (FC) II or class III symptoms, “an initial combination therapy with ambrisentan and tadalafil to improve 6MWD [6-minute walk distance]” is suggested (a weak recommendation with moderate quality evidence).

• “For stable or symptomatic PAH patients on background therapy with ambrisentan,” a weak recommendation with low-quality evidence is made for the addition of tadalafil to improve 6MWD.

• To delay time to clinical worsening in treatment naive PAH patients with WHO FC II symptoms, the guidelines recommend bosentan, macitentan, or riociguat (all ungraded consensus-based statements).

• To improve 6MWD for treatment-naive patients with WHO FC III symptoms, the guidelines recommend bosentan (strong recommendation, moderate quality evidence), ambrisentan (strong recommendation, low quality evidence), sildenafil (strong recommendation, low-quality evidence), tadalafil (ungraded consensus-based statement), or riociguat (ungraded consensus-based statement).

• To delay time to clinical worsening in PAH patients who are treatment naive with WHO FC III symptoms, the guidelines recommend macitentan, tadalafil, or riociguat (all ungraded consensus-based statements).

• For patients with PAH who are treatment-naive, have WHO functional class II or class III symptoms, and “who are not candidates for, or who have failed, CCB [calcium channel blocker] therapy, ” monotherapy with an “approved endothelin receptor antagonist (E RA), phosphodiesterase-5 (PDE-5) inhibitor (PDE5I), or … riociguat" is advised for patients who are "unwilling or unable to tolerate combination therapy" with ambrisentan and tadalafil.

• For patients with PAH in WHO functional class III “who have evidence of rapid progression of their disease...“initial treatment with a parenteral prostanoid” should be considered". , For patients with a "poor clinical prognosis despite treatment with one or two classes of oral agents,” consideration of the “addition of a parenteral or inhaled prostanoid” is recommended.

• For patients with PAH who are treatment-naive and have WHO functional class IV symptoms, initial therapy with a parenteral prostanoid agent” is recommended. If patients “are unable or do not desire to manage parenteral prostanoid therapy,” combination treatment with “an inhaled prostanoid” and “an oral PDE5I and an ERA” is recommended.

In 2013, the ACCP and American Heart Association released a joint policy statement, The Choosing Wisely Top Five List in Adult Pulmonary Medicine.^39, The list includes a recommendation to not routinely offer advanced vasoactive agents approved only for the management of PAH to patients with disease resulting from left heart disease or hypoxemic lung disease (group II or III PH).

American Thoracic Society

The American Thoracic Society (ATC), in their 2013 practice guideline on diagnosis, risk stratification, and management of PAH of sickle cell disease (SCD), strongly recommends against PAH-specific therapy “[f]or all patients with SCD with elevated TRV [tricuspid regurgitant velocity] alone or elevated NT-pro-BNP [N-terminal pro-brain natriuretic peptide] alone, and for patients with SCD with RHC [right heart catheterization]-confirmed PH with elevated pulmonary artery wedge pressure and low pulmonary vascular resistance.^40,

“However, for select patients with SCD with RHC-confirmed PH who have elevated pulmonary vascular resistance and normal pulmonary capillary wedge pressure, [the guidelines] make a weak recommendation for either prostacyclin agonist or endothelin receptor antagonist therapy and a strong recommendation against phosphodiesterase-5 inhibitor therapy.”

In an official statement on pulmonary hypertension phenotypes, the ATC (2014) asserts that “[r]apid advances in mechanistic understanding of PH, improved imaging methods and new modalities, and the emergence of innovative biomarkers…offer an opportunity to define PH phenotypes more precisely on the basis of pathobiology, which is crucial in such a heterogenous syndrome...Accurate phenotyping of PH can be used in research studies to increase homogeneity of study cohorts."^41,

“In addition, once the ability of the phenotypes to predict outcomes has been validated, phenotyping may also be useful for determining prognosis and guiding treatment.” Defining phenotypes will enable testing “whether selective targeting of care” will afford the opportunity to use “the wide array of medications so that patients can live longer and more satisfying lives.”^41,

European Society of Cardiology

The 2022 European Society of Cardiology (ESC)/ European Respiratory Society (ERS) guidelines on the diagnosis and treatment of PH was endorsed by the International Society for Heart and Lung Transplantation (ISHLT). ^3, Relevant guideline recommendations are as follows:

• "For treatment of non-vasoreactive patients with idiopathic, heritable, or drug-associated pulmonary arterial hypertension who present without cardiopulmonary comorbidities, and present at high risk of death, initial combination therapy with a PDE5i, an ERA, and i.v./s.c. prostacyclin analogues should be considered
• For patients with idiopathic, heritable, or drug-associated PAH without cardiopulmonary comorbidities, initial combination therapy with ambrisentan and tadalafil is recommended. Initial combination therapy with macitentan and tadalafil is [also] recommended. Initial combination therapy with other ERAs and PDE5is should be considered. Initial combination therapy with macitentan, tadalafil, and selexipag is not recommended.
• For sequential drug combination therapy for patients with idiopathic, heritable, or drug-associated PAH, the addition of macitentan to PDE5is or oral/inhaled prostacyclin analogues is recommended to reduce the risk of morbidity/mortality events. The addition of oral treprostinil to ERA or PDE5i/ riociguat monotherapy is [also] recommended to reduce the risk of morbidity/mortality events. The addition of bosentan to sildenafil is not recommended to reduce the risk of morbidity/mortality events. The addition of riociguat to bosentan should be considered to improve exercise capacity"

Chronic Thromboembolic Pulmonary Hypertension

American College of Cardiology Foundation and American Heart Association

The 2009 American College of Cardiology Foundation and American Heart Association expert consensus document on PH, recommended pulmonary endarterectomy for eligible patients with chronic thromboembolic pulmonary hypertension (CTEPH).^2,

The panel noted that pharmacotherapy with PAH-specific medications may benefit CTEPH patients who are ineligible for pulmonary endarterectomy due to significant distal disease or comorbidity; patients who have persistent PH due to residual distal disease after pulmonary endarterectomy; and patients eligible for pulmonary endarterectomy who are considered high risk due to poor functional status or hemodynamics and may benefit from presurgical treatment with intravenous epoprostenol.

The panel recommended that PAH-specific medications be used for CTEPH patients only when “appropriate secondary preventive measures, including anticoagulation, have been instituted” and “the patient’s symptoms suggest that PAH-specific therapy may yield clinical benefit.”

American Heart Association

An American Heart Association (AHA) scientific statement (2011) makes the following recommendations for medical therapy and pulmonary endarterectomy in patients with CTEPH:^42,

1. Patients with CTEPH should be promptly evaluated for pulmonary endarterectomy, even with mild symptoms.

2. Patients with CTEPH “should receive indefinite therapeutic anticoagulation in the absence of contraindications.”

3. “PAH (WHO Group I)-specific medical therapy may be considered for patients with CTEPH who are not surgical candidates…or who have residual pulmonary hypertension after operation not amenable to repeat pulmonary endarterectomy…."

4. “PAH (WHO Group I)-specific medical therapy should not be used in lieu of pulmonary endarterectomy or delay evaluation for pulmonary endarterectomy for patients with…CTEPH who are or may be surgical candidates.”

U.S. Preventive Services Task Force Recommendations

Not applicable.

Medicare National Coverage

There is no national coverage determination. In the absence of a national coverage determination, coverage decisions are left to the discretion of local Medicare carriers.

Ongoing and Unpublished Clinical Trials

Some currently ongoing and unpublished trials that might influence this review are listed in Table 12.

Table 12. Summary of Key Trials

  NCT: national clinical trial. a Denotes industry-sponsored or cosponsored trial.

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Codes

Policy History

Appendix

Appendix Table 1. New York Heart Association Functional Classification

Appendix Table 2. WHO Functional Classification for Pulmonary Arterial Hypertension

  WHO: World Health Organization