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.
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.
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.
This evidence review does not evaluate activin signaling inhibitors such as sotatercept-csrk (Winrevair).
This policy is designed to address medical guidelines that are appropriate for the majority of individuals with a particular disease, illness, or condition. Each person's unique clinical circumstances may warrant individual consideration, based on review of applicable medical records.
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.
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).
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).
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CPT |
93503 |
Insertion and placement of flow-directed catheter (eg, Swan-Ganz) for monitoring purposes (ie, as part of dose- ranging study) |
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ICD-10-PCS |
ICD-10-PCS codes are only used for inpatient services. There is no specific ICD-10-PCS code for the initiation of this therapy. |
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3E013GC, 3E033GC |
Administration, physiological systems and anatomical regions, introduction, percutaneous, other therapeutic substance, code by body part (subcutaneous tissue or peripheral vein) |
| HCPCS | J1325 | Injection, epoprostenol, 0.5 mg |
| J3285 | Injection, treprostinil, 1 mg | |
| K0455 | Infusion pump used for uninterrupted parenteral administration of medication (eg, epoprostenol or treprostinil) | |
| K0730 | Controlled dose inhalation drug delivery system | |
| Q4074 | Iloprost, inhalation solution, FDA-approved final product, noncompounded, administered through DME, up to 20 mcg | |
| S0088 | Imatinib, 100 mg | |
| S0090 | Sildenafil citrate, 25 mg | |
| S0155 | Sterile dilutant for epoprostenol, 50 ml | |
| S9347 | Home infusion therapy, uninterrupted, long-term, controlled rate intravenous or subcutaneous infusion therapy (eg, epoprostenol); administrative services, professional pharmacy services, care coordination, all necessary supplies and equipment (drugs and nursing visits coded separately), per diem |
| ICD-10-CM | I27.0 | Primary pulmonary hypertension |
| I27.20 -I27.29 | Other secondary pulmonary hypertension code range | |
| I27.89 | Other specified pulmonary heart diseases | |
| I27.9 | Pulmonary heart disease, unspecified |
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).
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.
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.
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.
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 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.
Table 1 lists the classes of medications with FDA approvals for treatment of PAH.
| Class | Definition |
| Prostacyclin analogues | Prostacyclin is an endogenously produced vasodilator. Analogues of prostacyclin mimic the vasodilatory action of endogenous prostacyclin. |
| Prostacyclin receptor agonists | The approved drug in this class, selexipag, and its active metabolite are selective for the IP receptor and thus differ from other prostanoid receptors. |
| Endothelin receptor antagonists | Endothelin 1 is a potent vasoconstrictor and is found in increased concentrations in the lungs of patients with familial hypercholesterolemia. Endothelin receptor antagonists block the action of endothelin, thus resulting in vasoconstriction. |
| PDE inhibitors | PDE inhibitors are cyclic guanosine monophosphate inhibitors. Cyclic guanosine monophosphate inhibition results in reduced breakdown and longer duration of nitric oxide, which is a potent vasodilator. |
| Soluble guanylate cyclase stimulator | Riociguat is a first-in-class oral soluble guanylate cyclase stimulator |
IP: prostacyclin receptor, also known as the prostaglandin I2 receptor or IP; PDE: phosphodiesterase.
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,
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).
| Drug (Brand) Name Manufacturer FDA Approval Date |
Routes of Administration Dose Range | FDA Approved Indications |
| Prostacyclin analogue (ie, prostanoids) | ||
| Epoprostenol sodium (Flolan®) GlaxoSmithKline 1995 |
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| Epoprostenol sodium (Veletri®) Actelion Pharmaceuticals 1995 |
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| Treprostinil sodium (Remodulin®) United Therapeutics 2002 |
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| Treprostinil (Tyvaso®, Tyvaso® DPI) United Therapeutics 2009 |
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| Treprostinil (Orenitram®) United Therapeutics 2013 |
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| Iloprost (Ventavis®) Actelion Pharmaceuticals 2004 |
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| Beraprost NOT APPROVED IN U.S. AND E.U. Failed reviews Approved in Japan for PAH |
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| Prostacyclin receptor agonists | ||
| Selexipag (Uptravi®) Actelion Pharmaceuticals 2015 |
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| Endothelin receptor antagonists | ||
| Bosentan (Tracleer®) Actelion Pharmaceuticals 2001 |
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| Ambrisentan (Letairis®) Gilead Sciences 2007 |
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| Macitentan (Opsumit®) Actelion Pharmaceuticals 2013 |
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| Phosphodiesterase inhibitors | ||
| Sildenafil citrate (Revatio®) Pfizer Labs 2005 |
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| Tadalafil (Adcirca®) Eli Lilly 2009 |
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| Vardenafil (Levitra®) 2003 |
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| Soluble guanylate cyclase stimulator | ||
| Riociguat (Adempas®) Bayer HealthCare 2013 |
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| Tyrosine kinase inhibitors | ||
| Imatinib (Gleevec®) 2001 |
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| Statins | ||
| Simvastatin 1991 |
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| Atorvastatin 1999 |
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| Combination Therapies | ||
Macitentan/tadalafil (Opsynvi®) Actelion Pharmaceuticals 2024 |
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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.
