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MP 5.01.09 Advanced Therapies for Pharmocological Treatment of Pulmonary Hypertension

Medical Policy    

Section
Prescription Drug

Original Policy Date
01/1998

Last Review Status/Date
Reviewed with literature search/3:2014

Issue
3:2014
  Return to Medical Policy Index

Disclaimer

Our medical policies are designed for informational purposes only and are not an authorization, or an explanation of benefits, or a contract.  Receipt of benefits is subject to satisfaction of all terms and conditions of the coverage.  Medical technology is constantly changing, and we reserve the right to review and update our policies periodically.


Description

Pulmonary hypertension (PH) refers to the presence of abnormally high pulmonary vascular pressure.

  • A subset of patients is considered to have pulmonary arterial hypertension (PAH), a rare and debilitating disease associated with progressive right ventricular dilation and low cardiac output. Several advanced therapies, including prostacyclin analogs, endothelin receptor antagonists, phosphodiesterase type 5 (PDE5) inhibitors, and a soluble guanylate cyclase stimulator are available to treat PAH. Combination advanced therapy also has been proposed.
  • Another subset of patients is considered to have chronic thromboembolic pulmonary hypertension (CTEPH), characterized by residual organized thrombi obstructing the pulmonary vasculature. Most patients have a history of acute pulmonary embolism. Standard treatment for CTEPH is pulmonary endarterectomy. The soluble guanylate cyclase stimulator, riociguat, is the only medication currently U.S. Food and Drug Administration (FDA)-approved to treat CTEPH.

Background

PH refers to the presence of abnormally high pulmonary vascular pressure. The World Health Organization (WHO) classifies patients with PH into 5 groups based on the etiology of the condition. These groups differ in their clinical presentation, diagnostic findings, and response to treatment.

Pulmonary Arterial Hypertension

Classification

Group 1, pulmonary arterial hypertension (PAH), includes disorders in which pulmonary hypertension is associated with abnormalities of the pulmonary arterial system. The classification of pulmonary arterial hypertension (group 1) devised in 2003 following the 3rd World Symposium on Pulmonary Arterial Hypertension, is as follows(1):

  1. Pulmonary arterial hypertension (PAH)
    1. Idiopathic (IPAH)
    2. Familial (FPAH)
    3. Associated with (APAH):
      1. Collagen vascular disease
      2. Congenital systemic-to-pulmonary shunts
      3. Portal hypertension
      4. HIV infection
      5. Drugs and toxins
      6. Other (thyroid disorders, glycogen storage disease, Gaucher’s disease, hereditary hemorrhagic telangiectasia, hemoglobinopathies, myeloproliferative disorders, splenectomy)
    4. Associated with significant venous or capillary involvement:
      1. Pulmonary veno-occlusive disease (PVOD)
      2. Pulmonary capillary hemangiomatosis (PCH)
    5. Persistent pulmonary hypertension of the newborn

In 2013, based on the consensus of an international group of experts at the 5th World Symposium on Pulmonary Hypertension, modifications to the classification of PAH were proposed.(2) A key difference from the earlier classification, which is still used by the American College of Cardiology Foundation/American Heart Association (ACCF/AHA), is the category of “Group 1 prime,” defined as pulmonary veno-occlusive disease (PVOD) and/or pulmonary capillary hemangiomatosis (PCH), and “Group 1 prime,” defined as persistent pulmonary hypertension of the newborn (PPHN). The ACCF/AHA nomenclature lists these conditions as subcategories of Group 1. Further, the 2013 World Symposium classification moved PH associated with chronic hemolytic anemia to Group 5, Pulmonary hypertension with unclear multifactorial mechanisms. The updated classification of Group 1 PAH, with key changes in bold, is as follows(2):

  1. Pulmonary arterial hypertension (PAH)
    1. Idiopathic (IPAH)
    2. Heritable
      1. BMPR2
      2. ALK1, ENG, SMAD9, CAV1, KCNK3
      3. Unknown
    3. Drug and toxin-induced
    4. Associated with:
      1. Connective tissue disorder
      2. HIV infection
      3. Portal hypertension
      4. Congenital heart diseases
      5. Schistosomiasis

1'. Pulmonary veno-occlusive disease (PVOD) and/or pulmonary capillary hemangiomatosis (PCH)

1". Persistent pulmonary hypertension of the newborn (PPHN)

Disease Description

PAH is a rare and debilitating disease characterized by abnormal proliferation and contraction of pulmonary artery smooth muscle cells. This condition 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 (initially with normal left-sided pressures) and leads to overload-induced progressive right ventricular dilation and low cardiac output. Premature death commonly results from right heart failure.

IPAH is the most common type of PAH and is more prevalent in women than in men. Familial PAH often results from a mutation in bone morphogenetic protein receptor-2 (BMPR2) and is inherited as an autosomal dominant disease. PAH is also associated with congenital heart disease, connective tissue diseases, drugs and toxins, HIV, portal hypertension, hemoglobinopathies, and myeloproliferative disorders. The diagnosis of PAH requires confirmation with a complete right heart catheterization. The current hemodynamic definition of PAH is a mean pulmonary artery pressure greater than 25 mm Hg; a pulmonary capillary wedge pressure, or left ventricular end-diastolic pressure less than or equal to 15 mm Hg; and a PVR greater than 3 Wood units.

Baseline Assessment of PAH

A baseline assessment to determine PAH severity is often performed before initiating therapy. This assessment includes the following key measures:

Functional impairment: The functional significance of PAH is determined by measuring exercising capacity and determining New York Heart Association (NYHA) or WHO functional class. The WHO functional classification recognizes the importance of near syncope and syncope. Syncope is thought to worsen the prognosis in patients with PAH. Although not explicitly stated, PAH patients who have experienced a syncopal episode are generally assigned to WHO functional class IV.

The New York Heart Association (NYHA) Classification- functional classification

Class I patients with no limitation of activities; they suffer no symptoms from ordinary activities.

Class II patients with slight, mild limitation of activity; they are comfortable with rest or mild exertion.

Class III patients with marked limitation of activity; they are comfortable only at rest

Class IV patients who should be at complete rest, confined to bed or chair; any physical activity brings on discomfort and symptoms occur at rest

World Health Organization (WHO)- functional classification for pulmonary arterial hypertension

Class I no limitation of clinical activity; ordinary physical activity does not cause dyspnea or fatigue

Class II slight limitation in physical activity; ordinary physical activity produces dyspnea, fatigue, chest pain, or near-syncope; no symptoms at rest

Class III marked limitation of physical activity; less than ordinary physical activity produces dyspnea, fatigue, chest pain, or near-syncope; no symptoms at rest

Class IV unable to perform any physical activity without symptoms; dyspnea and/or fatigue present at rest; discomfort increased by any physical activity

Hemodynamic derangement: Pulmonary artery systolic pressure and right ventricular function can be estimated by echocardiography. Right heart catheterization is performed to accurately measure the hemodynamic parameters and confirm PAH. Right heart catheterization is often deferred until advanced therapy is indicated because it is an invasive procedure. Patients with PAH typically undergo an invasive hemodynamic assessment and an acute vasoreactivity test before the initiation of advanced therapy. The acute vasoreactivity test involves administration of a short-acting vasodilator, then measuring hemodynamic response with a right heart catheter. Agents commonly used include epoprostenol, adenosine, and inhaled nitric oxide. An acute vasoreactivity test is considered positive if mean pulmonary artery pressure decreases by at least 10 mm Hg and to a value less than 40 mm Hg, with an increased or unchanged cardiac output and a minimally reduced or unchanged systemic blood pressure. Patients with a positive vasoreactivity test are candidates for a trial of calcium channel blocker (CCB) therapy. In contrast, patients with a negative vasoreactivity test should be treated with alternative agents; CCBs have not been shown to be beneficial in these patients and may be harmful.

Medical Management of PAH

Conventional therapies considered in all patients with PAH regardless of etiology include diuretics, oxygen therapy, anticoagulants, digoxin, and exercise. Digoxin has been shown to have beneficial effects when used with caution (ie, patients may be at higher risk for digitalis toxicity and require close monitoring). Patients with a positive vasoreactivity test can undergo a trial of CCBs. Patients with a negative vasoreactivity test require advanced therapy with prostacyclin analogs, endothelin receptor antagonists, PDE5 inhibitors, or a soluble guanylate cyclase stimulator. Various combinations of treatments have also been suggested. Lung transplantation and combined heart-lung transplantation have been performed in patients who are refractory to medical management. Objective assessments to measure treatment response include improvement in exercise capacity (6-minute walk test [6MWT], cardiopulmonary exercise test, treadmill test), hemodynamics, and survival.

Table 1 summarizes advanced therapies for treatment of PAH (WHO Group 1) and their current regulatory status:

Table 1: Advanced Treatments of PAH and Their Regulatory Status

Drug (Brand Name) Manufacturer FDA Approval Date

Route(s) of Administration Dose Range

FDA-Approved Indications

Prostacyclin analogues

Epoprostenol sodium (FLOLAN®) GlaxoSmithKline FDA approved 1995

  • Continuous intravenous
  • (IV) infusion via central venous catheter using an ambulatory infusion pump
  • 1-20 ng/kg/min
  • Treatment of pulmonary arterial hypertension (PAH) (WHO Group I) to improve exercise capacity. Studies establishing effectiveness included predominantly patients with NYHA Functional Class III-IV symptoms and etiologies of idiopathic or heritable PAH or
  • PAH associated with connective tissue diseases.
 

Treprostinil sodium (REMODULIN®) United Therapeutics Corp. FDA approved 2002

  • Continuous subcutaneous (SC) infusion
  • IV infusion (if SC infusion not tolerated)
  • 0.625-1.25 ng/kg/min
  • Treatment of PAH (WHO Group 1) to diminish symptoms associated with exercise. Studies establishing effectiveness included patients with NYHA Functional Class II-IV symptoms.
  • Patients who require transition from Flolan, to reduce the rate of clinical deterioration
 

(TYVASO®) United Therapeutics Corp. FDA approved 2009

  • Inhalation via nebulizer; specific to 1 pulmonary drug delivery system
  • 18-54 µg, 4 times/day
  • Treatment of PAH (WHO Group 1) to improve exercise ability. Studies establishing effectiveness included predominately patients with NYHA Functional Class III symptoms
 

Iloprost (VENTAVIS®) Actelion Pharmaceuticals FDA approved 2004

  • Inhalation via nebulizer using a specific pulmonary drug delivery system
  • 2.5-5 µg, 6-9 times/day
  • Treatment of PAH (WHO Group 1) to improve a composite end point consisting of exercise tolerance, symptoms (NYHA Class), and lack of deterioration. Studies establishing effectiveness predominately included patients with NYHA Functional Class III-IV symptoms
 

Beraprost NOT APPROVED IN U.S. & E.U. Failed reviews Approved in Japan for treatment of PAH

  • Oral
  • No FDA-approved indications for PAH
 

Endothelin receptor antagonists

   

Bosentan (TRACLEER®) Actelion Pharmaceuticals FDA approved 2001; patent protection expires 2015

  • Oral
  • 62.5-125 mg 2 times/day
  • Treatment of PAH (WHO Group 1) to improve exercise ability and to decrease clinical worsening. Studies establishing effectiveness predominantly included patients with NYHA Functional Class II-IV symptoms.
 

Ambrisentan (LETAIRIS®) Gilead Sciences, Inc. FDA approved 2007

  • Oral
  • 5-10 mg/day
  • Treatment of PAH (WHO Group 1) to improve exercise ability and delay clinical worsening. Studies establishing effectiveness predominantly included patients with NYHA Functional Class II-III symptoms.
 

Macitentan (OPSUMIT®) Actelion Pharmaceuticals FDA approved 2013

  • Oral
  • 10 mg daily
  • Treatment of PAH (WHO Group 1) to delay disease progression (defined as death, initiation of intravenous or subcutaneous prostanoids, or clinical worsening of PAH [decreased 6-minute walk distance, worsened PAH symptoms, and need for additional PAH treatment]). Macitentan also reduced hospitalization for PAH.
 

Phosphodiesterase (PDE5) inhibitors

Sildenafil citrate (REVATIO®) Pfizer Labs FDA approved 2005

  • Oral
  • 20 mg 3 times/day
  • Treatment of PAH to improve exercise ability
  • August 2012: FDA recommended that Revatio not be prescribed to children (ages 1-17) for PAH. (Product has not been approved for the treatment of PAH in children.)
 

Tadalafil (ADCIRCA®) Eli Lilly FDA approved 2009

  • Oral
  • 40 mg once/day
  • Treatment of PAH (WHO Group 1) to improve exercise ability and delay clinical worsening. Studies establishing effectiveness predominately included patients with NYHA Functional Class II-III symptoms.
 

Vardenafil (LEVITRA®) FDA approved (but not for PAH)

  • Oral
  • No FDA-approved indications for PAH. One randomized trial outside of U.S.
 

Soluble guanylate cyclase stimulator

Riociguat (ADEMPAS®) Bayer HealthCare FDA approved 2013

  • Oral
  • 0.5-2.5 mg 3 times/day
  • Treatment of PAH (WHO Group 1) to improve exercise capacity, improve WHO functional class and to delay clinical worsening
  • Treatment of persistent or recurrent chronic thromboembolic pulmonary hypertension (CTEPH) (WHO Group 4) after surgical treatment or inoperable CTEPH to improve exercise capacity and WHO functional class
 

Tyrosine kinase inhibitors

   

Imatinib (GLEEVEC®)FDA approved (but not for PAH)

  • Oral
  • No FDA-approved indications for PAH. One pilot randomized trial as add-on medication.
 

Statins

Simvastatin FDA approved (but not for PAH)

  • Oral
  • No FDA-approved indications for PAH. One randomized trial with and without aspirin showed no effect on exercise ability.
 

Atorvastatin FDA approved (but not for PAH)

  • Oral
  • No FDA-approved indications for PAH. One randomized trial showed no clinical benefit compared with placebo.
 

It is important to emphasize that the approved treatments for PAH (WHO Group 1) have serious side effects. With the exception of riociguat, which is also FDA-approved to treat chronic thromboembolic PH (WHO Group 4), none have been shown to be effective in patients with other forms of PH.

Chronic Thromboembolic Pulmonary Hypertension

Classification

In the WHO classification, CTEPH comprises Group 4. The 2003 WHO and current ACCF/AHA classification divide CTEP into 3 groups: proximal, distal, and nonthrombotic, eg, caused by tumor, parasites, or foreign material.(1) The first 2 groups distinguish proximal CTEPH, which may be treated with pulmonary thromboendarterectomy, from distal CTEPH, which is inaccessible to surgery; however, this distinction can be difficult to make in clinical practice. Additionally, clinical presentation, radiologic findings, and management of CTEPH vary across etiology.(2) For these reasons, the updated 2009 WHO classification includes only a single CTEPH category with no subcategories.

Disease Description

CTEPH primarily occurs after acute or chronic pulmonary embolism. Progressive pulmonary vascular remodeling (thrombi organization, fibrous stenosis, and microvascular changes) obstructs pulmonary arteries, leading to PH and right heart failure.(3,4) Estimated CTEPH incidence among patients who survive an acute pulmonary embolism ranges from 0.6% to 3.8%.(4,5) However, many patients have no clinical history of pulmonary embolism, and CTEPH is likely underdiagnosed. Additional risk factors include splenectomy, chronic inflammatory states, and hypercoagulability due to the presence of anticardiolipin antibody or elevated factor VIII levels. Diagnosis is made by ventilation-perfusion scan showing large areas of mismatch (segmental or larger). Pulmonary angiography confirms the diagnosis and indicates operability (ie, the extent of proximal and distal disease).(4)

Baseline Assessment of CTEPH

Functional impairment: Functional classification is determined using both NYHA and WHO scales previously described. Patients who are ineligible for pulmonary endarterectomy because of distal disease may be candidates for lung transplantation if functional status is adequate (eg, functional class IV decreases the likelihood of receiving a transplant). Patients who are eligible for pulmonary endarterectomy but are considered high risk due to poor functional status (Class IV) may have improved surgical outcomes if pretreated with intravenous epoprostenol(4)

Hemodynamic derangement: CTEPH is characterized by a mean pulmonary artery pressure greater than 25 mm Hg. European guidelines also require pulmonary capillary wedge pressure of 15 mm Hg or less and PVR greater than 2 Wood units.(6) In patients with poor hemodynamics (eg, pulmonary artery pressure greater than 50 mm Hg) who are eligible for pulmonary endarterectomy, pretreatment with intravenous epoprostenol is recommended to improve surgical outcomes.(4)

Medical Management of CTEPH

Patients with CTEPH are treated with diuretics and oxygen as needed and with extended or lifelong anticoagulant therapy. Eligible patients undergo pulmonary endarterectomy, which may be curative. Current guidelines recommend medical treatment using PAH therapies when pulmonary endarterectomy is contraindicated (due to significant distal disease or comorbidity) and when pulmonary artery pressures remain elevated after pulmonary endarterectomy (due to residual distal pathology).(4,7)

The only medication currently FDA-approved for treatment of CTEPH is riociguat. Riociguat is a first-in –class oral soluble guanylate cyclase stimulator. Riociguat stimulates soluble guanylate cyclase both directly and indirectly, by increasing sensitivity of the enzyme to nitric oxide. Thus, riociguat may be effective in conditions in which endogenous nitric oxide (a vasodilator) is depleted.(8)


Policy  

The following therapies may be considered medically necessary for the treatment of pulmonary arterial hypertension (PAH/ WHO Group 1):

  • epoprostenol sodium (eg, FLOLAN®) continuous IV infusion;
  • treprostinil sodium (REMODULIN®) Continuous SC infusion, IV infusion or (TYVASO®) inhalation via nebulizer;
  • iloprost (VENTAVIS®) Inhalation via nebulizer;
  • bosentan (TRACLEER®) oral;
  • ambrisentan (LETAIRIS®) oral;
  • sildenafil citrate (eg, REVATIO®) oral;
  • tadalafil (ADCIRCA®) oral;
  • vardenafil (LEVITRA®) oral;
  • riociguat (ADEMPAS®) oral;
  • macitentan (OPSUMIT®) oral.

Combination therapy for the treatment of pulmonary arterial hypertension (PAH/ WHO Group 1) may be considered medically necessary when all of the following conditions are met (see Policy Guidelines section):

  • Patients have failed to demonstrate an adequate response to a single medication;
  • Medications are from different therapeutic classes;
  • Each medication may be considered medically necessary for the treatment of PAH (see above statement).

Combination therapy as first-line treatment is considered investigational.

Use of other advanced therapies for the pharmacologic treatment of pulmonary arterial hypertension (PAH/ WHO Group 1), including but not limited to imatinib, simvastatin, and atorvastatin, is considered investigational.

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

  • Pulmonary hypertension associated with left heart diseases;
  • Pulmonary hypertension associated with lung diseases and/ or hypoxemia (including chronic obstructive pulmonary disease);
  • Pulmonary hypertension due to chronic thrombotic and/or embolic disease;
  • Miscellaneous group (ie, sarcoidosis, histiocytosis X and 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 pulmonary hypertension after surgical thrombectomy; or
  • Inoperable CTEPH.

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

The use of riociguat is considered investigational for the treatment of WHO Groups 2, 3, and 5 pulmonary hypertension, including but not limited to:

  • Pulmonary hypertension associated with left heart diseases;
  • Pulmonary hypertension associated with lung diseases and/ or hypoxemia (including chronic obstructive pulmonary disease);
  • Miscellaneous group (ie, sarcoidosis, histiocytosis X and lymphangiomatosis)

Policy Guidelines

Treatment with epoprostenol requires 3 steps as follows:

  • Initial dose-ranging study, which is typically performed as an inpatient. The pulmonary capillary wedge pressure is monitored, and the infusion rate of the drug is increased until 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. Since rebound pulmonary hypertension may recur if the drug is abruptly withdrawn, the drug labeling advises that all patients should have access to a backup infusion pump and intravenous infusion set.
  • Ongoing maintenance of portable infusion pump and treatment of complications related to the pump. Complications include catheter thrombosis, sepsis, and pump malfunction. In the 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.
For combination treatment, riociguat should not be combined with a phosphodiesterase type 5 inhibitor (sildenafil, tadalafil, or vardenafil).


Benefit Application
BlueCard/National Account Issues

While epoprostenol would generally be considered under medical benefits, use of bosentan, ambrisentan, macitentan, iloprost, treprostinil, sildenafil, and riociguat may be considered under pharmacy benefits, as determined by each individual Plan.

Benefit or contract language describing the “least costly alternative” may be applicable to the choice of therapy among epoprostenol, bosentan, ambrisentan, macitentan, iloprost, or treprostinil. A generic formulation of epoprostenol is available.

Patients treated with infusion pumps may require a back-up pump. However, the cost of a back-up pump may be included in the home infusion therapy charges or in the HCPCS code (see Codes section below).

Sildenafil citrate is available as both Revatio and Viagra. Benefit or contract language describing the "least costly alternative" may be applicable to this choice. Pricing differences may exist between alternatives. Revatio is available as a 20-mg tablet. Viagra is available in 25-mg, 50-mg, 100-mg tablets. Generic sildenafil is available.

Tadalafil is available as both Cialis and Adcirca. Benefit or contract language describing the "least costly alternative" may be applicable to this choice. Pricing differences may exist between alternatives. Cialis is available as 2.5-mg, 5-mg, 10-mg, and 20-mg tablets. Adcirca is available as a 20-mg tablet. The recommended initial daily dose of Adcirca is 40 mg once a day (two 20-mg tablets).


Rationale 

This policy was originally created in 1998 and was updated regularly with searches of the MEDLINE database. The most recent literature review was performed on October 28, 2013. Following is a summary of the key literature to date on agents that are approved by the U.S. Food and Drug Administration (FDA) for treatment of pulmonary arterial hypertension (PAH/WHO [World Health Organization] Group 1) and chronic thromboembolic pulmonary hypertension (CTEPH/WHO Group 4). Some off-label treatments also are discussed.

Research Issues

Editorial critiques of the available literature have raised questions about the study end points selected, which often are insufficient for addressing the mechanism of disease, optimizing treatment by patient population, and making meaningful comparisons between therapies. Studies are short in duration and compare outcomes that reflect symptomatic improvement (eg, 6-minute walk distance [6MWD] or functional class) but not disease status (such as vasculature remodeling) or survival. Studies also need to address the durability of these outcomes. However, designing long-term (≥1 year) studies with survival as an end point may raise additional issues, including potential ethical questions.

Additionally, some authors have questioned the utility of the 6MWD test as an intermediate clinical outcome in therapeutic PAH trials.(9,10) It is unclear whether change in 6MWD is associated with clinical outcomes (eg, death, lung transplantation, hospitalization due to worsening PAH, or worsening right heart failure), or whether there is a threshold above and below which risk for adverse outcomes substantially changes. Two groups attempted to validate the 6MWD and to define a minimal important difference (MID) using different methods. Gabler et al examined correlations between 6MWD and clinical events to establish a threshold that would indicate a significant change in the probability of such events.(11) A significant threshold effect was observed at 41.8 meters. However, the authors noted that “change in 6MWD does not explain a large proportion of the treatment effect, has only modest validity as a surrogate end point for clinical events, and may not be a sufficient surrogate end point.” Mathai et al used anchor- and distribution-based methods and reported MIDs of 38.6 meters and 25.1 to 38.5 meters, respectively.(12) The mean of these values was 33 meters, which the authors considered a consensus MID. A recent meta-analysis of 22 randomized controlled trials (RCTs) that assessed 6MWD in patients with PAH and reported clinical outcomes found no relationship between changes in 6WMD and clinical outcomes.(13) All 3 of these analyses were based on trials of short duration (eg, 12 weeks) and in treatment-naïve patients; it may be that the utility of the 6MWD is limited to such trials.

PAH Monotherapy using prostanoids, endothelin-receptor antagonists, PDE5 inhibitors, or a soluble guanylate cyclase stimulator (riociguat)

Several meta-analyses that pool the findings of studies evaluating the efficacy of PAH treatments have been published. In 2013, the Agency for Healthcare Research and Quality (AHRQ) published a comparative effectiveness review of the screening, management, and treatments of PAH.(14) McCrory et al searched the literature through July 2012 using broad inclusion criteria (diagnosis of PAH in patients of any age; RCTs or observational studies; all sample sizes). They identified 27 RCTs (3587 patients) and 9 observational studies that evaluated the comparative effectiveness and safety of monotherapy or combination therapy for PAH. Data from the observational studies was considered unusable. Twenty-two RCTs compared a single drug (ie, monotherapy) with placebo or standard therapy, defined as supportive treatment (diuretics, oxygen, digoxin, and/or oral anticoagulants) with or without calcium channel blockers (CCBs); 8 studied prostanoids, 8 studied endothelin-receptor antagonists, and 6 studied PDE5 inhibitors. All patients were adults. Median trial duration was 12 weeks (range, 4-24). Based on low strength of evidence, prostanoids were associated with lower mortality compared with standard therapy/placebo (odds ratio [OR], 0.52; 95% confidence interval [CI], 0.29 to 0.95). Evidence for endothelin receptor antagonists and PDE5 inhibitors was insufficient to form a conclusion for this outcome. Moderate strength of evidence for each drug class supported an association with improved 6MWD; treatment effects (mean difference in distance walked, intervention – standard therapy/placebo) were 27.9 meters (95% CI, 10.3 to 45.4) for prostanoids, 39.9 meters (95% CI, 21.4 to 58.4) for endothelin-receptor inhibitors, and 38.9 meters (95% CI, 22.0 to 55.9) for PDE5 inhibitors. Endothelin-receptor antagonists and PDE5 inhibitors were associated with lower incidences of hospitalization based on moderate strength of evidence for each drug class; ORs were 0.34 (95% CI, 0.17 to 0.69) and 38.9 (95% CI, 22.0 to 55.9). Evidence for prostanoids was insufficient to form a conclusion for this outcome. Low strength of evidence for each drug class supported an association with improvements in most hemodynamic measures (pulmonary vascular resistance [PVR], mean pulmonary artery pressure, and cardiac index). However, the clinical significance of the observed treatment effect magnitudes is unclear. Among commonly reported adverse events, high strength of evidence supported a greater incidence of jaw pain and cough with aerosolized prostanoid than with placebo. Moderate strength of evidence supported a greater incidence of headache and flushing with PDE5 inhibitors compared with standard therapy/placebo. The incidence of flushing was greater with aerosolized prostanoids than with standard therapy/placebo, based on moderate strength of evidence.

A 2013 Cochrane review by Liu et al assessed the efficacy of endothelin receptor antagonists for the treatment of patients with PAH.(15) A literature search through December 2011 identified 12 RCTs (1471 patients), 11 of which were placebo controlled. The 12thRCT was a head-to-head comparison of bosentan and sildenafil in 26 patients.(16) Seven of 12 trials assessing bosentan comprised 38% of the total patient sample, 2 trials assessing ambrisentan comprised 27%, and 3 trials assessing sitaxsentan comprised 35%. Sitaxsentan is a selective endothelin receptor antagonist (like ambrisentan) that was withdrawn worldwide in 2010 due to fatal hepatotoxicity. Pooled results showed improved outcomes with endothelin-receptor antagonists compared with placebo in 6MWD (mean difference, 33.7 meters; 95% CI, 24.9 to 42.5), proportion of patients with improved WHO or NYHA functional class (OR=1.6; 95% CI, 1.2 to 2.1), proportion of patients with deteriorated functional class (OR=0.3; 95% CI, 0.2 to 0.4), and hemodynamic parameters (mean pulmonary artery pressure, PVR, and cardiac index). Based on 22 events in 1201 patients, the reduction in mortality with endothelin receptor antagonists was not statistically significant (OR=0.57; 95% CI, 0.26 to 1.24).

In 2009, Galie et al in Italy published a meta-analysis of RCTs examining approved medications ie, prostanoids, endothelin-receptor antagonists, and PDE5 inhibitors for treating PAH.(17) The primary analysis included only studies with a placebo-comparator arm; a sensitivity analysis also included studies comparing 2 active treatment arms. The main outcome measure was all-cause mortality. Twenty-one trials were included in the primary analysis (n=3140), and 2 additional studies (n=59) were included in the sensitivity analysis. Average duration of the trials was 14.3 weeks. All-cause mortality rate in the control group was 3.8%. Active treatments were associated with a reduction in mortality of 43%; the sensitivity analysis confirmed a reduction in mortality of 38%. The authors concluded that the results of this meta-analysis suggest an improvement of survival in the patients treated with the targeted therapies approved for PAH. The limitations of the meta-analysis include the prolonged period of time between the first and last RCT (about 18 years), the different duration of the trials (range, 8–36 weeks), the lack of blinding in some studies, the pooling of multiple active treatment arms, and potential heterogeneity in the conduct of the trials. The meta-analysis included studies with compounds that were eventually not approved because of lack of efficacy and different doses of approved therapies that were not approved because they were less effective or had increased adverse effects.

Two meta-analyses published in 2010, were similar in scope and design to the 2009 meta-analysis by Galie et al.(17) All 3 were limited to RCTs in patients with PAH, had all-cause mortality as the primary outcome and evaluated the same classes of medications, prostanoids, endothelin-receptor antagonists, and PDE5 inhibitors. Ryerson et al searched the literature through November 2009.(18) Their eligibility criteria included RCTs in adults with PAH, and they further required that studies have a follow-up of at least 8 weeks, be double-blind, and be placebo-controlled (except for studies on intravenous [IV] medication use). They included both studies that compared 1 medication with placebo (monotherapy), as well as studies that added a second medication versus placebo with a baseline medication (combined treatment); the latter were categorized by the class of the medication in the study that was under investigation. Twenty-four trials met the inclusion criteria. This included 11 on prostanoids, 8 on endothelin-receptor antagonists, and 3 on PDE5 inhibitors. The investigators did not pool studies across classes of medications. There was a statistically significant reduction in all-cause mortality in a meta-analysis of the studies on prostanoids, but not studies on endothelin-receptor antagonists, or PDE5 inhibitors. The pooled analysis of prostanoid trials found a 51% mortality reduction (95% CI, 18% to 71%). Meta-analyses of each of the 3 classes of medication found statistically significant improvement in exercise capacity, the primary outcome in most of the studies. In pooled analyses, prostanoids were associated with a mean placebo-corrected improvement in 6MWD of 29 meters (95% CI, 18 to 41 meters), endothelin-receptor antagonists were associated with improvement of 38 meters (95% CI, 27 to 49 meters), and PDE5 inhibitors were associated with an improvement of 34 meters (95% CI, 23 to 49 meters).

The other 2010 meta-analysis, by Macchia et , searched the literature through April 2009 and, like the Ryerson et al study, included RCTs on adults with PAH.(19) However, in this study, both open and blinded trials were included, and eligibility was not limited by type of control group (eg, placebo). Combination medication studies were treated in the same manner as in Ryerson et al, discussed earlier. Twenty-six trials met eligibility criteria. Of these, 9 were on prostanoids, 8 on endothelin-receptor antagonists, and 8 on PDE5 inhibitors. In a meta-analysis of studies on all 3 classes of medications combined (23 studies), there was a statistically significant reduction in total mortality of 39% (2%-62%) in the treatment group compared to controls. However, when studies on each class of medication were examined separately, there were no significant reductions in mortality. For example, the pooled analysis of studies on prostanoids found a nonsignificant 34% reduction in mortality; the 95% CI was consistent with a 64% decrease in mortality to a 21% increase. The mortality reduction seemed confined to studies with more seriously ill study populations. With all classes of medication combined, there was a significant reduction in all-cause mortality when findings from trials with a median mortality of above 2% were pooled; mortality reduction was 49% (95% CI, 12% to 70%). There was no significant reduction in mortality in studies that had lower mortality rates. In addition, there was a significant mortality reduction in studies that included patients with functional class IV (42%; 95% CI, 4% to 65%) but not studies that excluded these patients. The authors also pooled study findings on change in exercise capacity and PVR. They found small but statistically significant improvement in exercise capacity and PVR. This was true for analyses pooling all studies, as well as those limited to 1 class of medication. For example, a pooled analysis of endothelin-receptor antagonists found a mean increase in the 6MWD of 46 meters (95% CI, 38 to 54 meters) with treatment versus control. A meta-analysis of prostanoid studies found a mean fall in PVR of 4.24 mm Hg (95% CI, fall of 3.49 to 5.00 mm).

The all-cause mortality reduction with all medications combined in the Macchia et al (2010) meta-analysis, 39%, is similar to that found by Galie et al (2009), 43%. Macchia et al, however, urge caution when interpreting this finding, because none of the individual classes of medication were found to reduce mortality. Moreover, they question the validity of combining studies of pharmacologic treatments that have completely different modes of action and suggest that the finding of mortality reduction be tested in prospective clinical trials.

Representative randomized trials and observational studies evaluating specific medications are described next.

Epoprostenol

The original approval of epoprostenol from FDA was based on a 12-week trial of 81 patients with NYHA Class III or Class IV primary PH who were randomized to receive either epoprostenol or conventional medical management.(20) As compared with conventional therapy, the continuous intravenous infusion of epoprostenol produced symptomatic and hemodynamic improvement, as well as improved survival in patients with severe primary PH. In 1998, McLaughlin et al reported on a case series of 27 patients treated with epoprostenol who were followed up for a mean of 16 months.(21) All patients had improvements in symptoms such as NYHA classification and exercise duration. While PVR declined only 23% acutely in response to a test dose of adenosine (another vasodilator), over long-term follow-up the vascular resistance fell by 53%. These results suggest that the beneficial effects of epoprostenol are not solely related to vasodilation but perhaps are related to anticoagulant and endothelial cytoprotective effects. McLaughlin et al subsequently reported survival data for those receiving epoprostenol. (22) A total of 162 consecutive patients diagnosed with primary pulmonary hypertension (PHTN) were treated with epoprostenol and followed up for a mean of 36.3 months. Observed survival at 1, 2, and 3 years was 87.8%, 76.3%, and 62.8%, which was significantly greater than the expected survival of 58.9%, 46.3%, and 35.4%, all respectively, based on historical controls.

In 2000, epoprostenol received additional FDA approval as a treatment for PH associated with the scleroderma spectrum of disease, based in part on the following data. Humbert et al reported on an uncontrolled case series of epoprostenol in 17 patients with PHTN associated with either scleroderma, CREST syndrome, systemic lupus erythematosus (SLE), or Sjögren syndrome.(23) Patients were followed up from 14 to 154 weeks. After 6 weeks, exercise capacity improved in 15 of 17 patients; the remaining 2 patients died of pulmonary edema or sepsis. During the long-term follow-up, an additional 5 patients died, 2 patients underwent successful lung transplantation, and 7 of the remaining 8 patients had a persistent clinical improvement. Badesch et al reported on a study that randomized 111 patients with PH related to scleroderma to receive either conventional therapy or conventional therapy in addition to epoprostenol therapy.(24) The primary outcome measure was exercise capacity. A significant improvement in exercise capacity was noted in the epoprostenol group compared with the control group, for whom exercise capacity actually decreased. Cardiopulmonary hemodynamics also improved significantly in the treatment group compared with the control group. A total of 38% of patients in the treatment group reported improvements in NYHA classification, compared with none in the control group. Four deaths occurred in the epoprostenol group compared with 5 in the control group, although it should be noted that the study was not adequately powered to detect a significant difference in survival.

Rosenzweig et al reported on a case series of 20 patients with PH secondary to congenital heart disease who had failed to improve clinically with conventional therapy.(25) Although none of the patients experienced a decrease in pulmonary artery pressure in response to epoprostenol infusion, long-term therapy was associated with a 21% reduction in pulmonary artery pressure. In addition, NYHA classification improved from a mean of 3.2 to 2.0. A nonsignificant increase occurred in exercise capacity.

Treprostinil

FDA approval of treprostinil (Remodulin) was based in part on 2 randomized placebo-controlled double-blind studies of subcutaneous infusion of treprostinil in 470 patients with PAH, either idiopathic or associated with connective tissue disease or congenital systemic-to-pulmonary shunts and a subgroup analysis of 90 patients with PAH associated with connective tissue disease.(26,27) End points, measured at 12 weeks, included exercise capacity (as measured by 6MWT), dyspnea, and hemodynamic effects. There was a median 16-meter improvement in the 6MWT, which although statistically significant was not as great as that noted for epoprostenol. Patients who were more compromised at baseline had the greatest improvements, and thus the lower median improvement may be related to the inclusion of less severe patients (ie, Class II) in this trial. There were no statistically significant differences in pretreatment and posttreatment hemodynamic variables between patients with different connective tissue diseases.

A cohort study of long-term survival was identified, which compared survival of patients (idiopathic PAH or associated with connective tissue, congenital heart disease, portal hypertension, or HIV) treated with treprostinil (up to 4 years) with predicted survival using an National Institutes of Health (NIH) registry equation or untreated patients from registry data.(28) Treprostinil survival among 860 patients was 87% to 68% over 1 to 4 years, noting that 59% of patients discontinued treatment due to adverse events (39%), death (27%), clinical deterioration (23%), and other reasons (withdrew consent, transplantation, protocol violation, and loss to follow-up; 11%). Sensitivity analyses found no differences between those discontinuing due to site pain reaction and patients who did not discontinue; however, selection bias due to censoring is possible and could bias the results in favor of treprostinil survival. Among 332 patients for whom predicted survival could be calculated (using the NIH registry equation), treprostinil treatment resulted in 91% and 72% survival at 1 and 4 years compared with predicted survival of 69% and 38%, respectively.

Findings of a 12-week randomized placebo-controlled trial evaluating intravenous treprostinil in treatment-naïve patients with PAH were published in 2010 by Hiremath et al.(29) The study, conducted in India, randomized 45 patients, one of whom died during catheter placement. Due to safety concerns, recruitment was stopped early after these 45 patients had enrolled; an intention-to-treat analysis was performed on these patients’ outcomes data. Forty-two of the 44 patients who received study medication had I PAH, and 2 had PAH associated with collagen vascular disease. Forty-two of 44 patients had NYHA Class III disease and 2 had Class IV disease. The initial dose of medication was 4 ng/kg/min treprostinil or an equivalent volume of placebo. After the first week, dose increases up to 8 ng/kg/min weekly were allowed, up to a maximum of 100 ng/kg/min. Thirty-one of 45 (67%) randomized patients completed the study; 6 patients (3 in each group) died during the 12-week follow-up period. The mean treprostinil dose at 12 weeks was 72 ng/kg/min, and the mean placebo dose was 80 ng/kg/min. The primary efficacy outcome was change in the 6MWD from baseline to 12 weeks. The mean baseline 6MWD was 292 meters in the treprostinil group (n=30) and 231 in the placebo group (n=14). The mean change was an increase of 67.2 meters in the treprostinil group and a decrease of 25.5 meters in the placebo group; the difference between groups was statistically significant (p=0.022). This represents a placebo-corrected difference of a mean of 92.7 meters (SE=42.0). The median placebo-corrected difference between groups was 83 meters (95% CI, 7 to 187 meters; p=0.008) There were also statistically significant differences on other outcomes, favoring the treprostinil group. For example, there was a mean decrease of 1.7 points on the Borg dyspnea scale in the treprostinil group and a mean increase of 0.4 points in the placebo group (p=0.009). (A higher score on the Borg scale represents more dyspnea.)

One small uncontrolled series reported treatment of PAH in children. Krishnan et alperformed a retrospective cohort study of 29 children (median age, 12 years; range, 3.2-19) who received inhaled treprostinil for 6 weeks or longer.(30) Children were patients at 1 of 2 large pediatric pulmonary hypertension centers (Columbia University Medical Center, New York and Children’s Hospital, Colorado). Indications for initiation of inhaled treprostinil therapy included symptomatic PAH, despite background therapy or as a strategy to transition patients off parenteral prostanoids. Twenty-six patients were on PDE5 inhibitors, 22 were on endothelin-receptor antagonists, 12 were on prostanoids, 18 were on dual therapy, and 5 were on triple therapy. Treprostinil was started at 3 breaths (6 µg/breath) 4 times daily and titrated to a maximum of 9 breaths 4 times daily in 20 patients. Maximum dose for 9 younger children and patients experiencing side effects was 4 to 8 breaths 4 times daily. Mean treatment duration was 16 months. Four patients discontinued treatment after 4 months due to progressive pulmonary symptoms, and 1 patient each required dose reduction due to nausea and hypotension. Common adverse effects were cough, sore throat, headache, and nausea. In 13 patients for whom baseline and follow-up data were available, 6MWD improved from 456±72 meters to 498±70 meters. WHO functional class improved in 19 patients and was unchanged in 10. Improvements in hemodynamic parameters (right atrial pressure, pulmonary artery pressure, systemic arterial pressure, PVR, systemic vascular resistance) were observed in 8 patients for whom baseline and follow-up data were available.

Iloprost

FDA approval of iloprost (ie, Ventavis) was based in part on the results of a randomized double-blind, multicenter placebo-controlled trial conducted in 203 adult patients with PAH (WHO Group I); idiopathic (53%), associated with connective tissue disease including CREST and scleroderma (17%), or associated with anorexigen use (2%) or PH related to chronic thromboembolic disease (WHO Group IV; 28%).(31) The primary end point was a composite end point at 12 weeks defined by (1) improvement in exercise capacity (6MWT) and (2) improvement by at least 1 NYHA class versus baseline; and no death or deterioration of pulmonary function. The response rate was 19% for the iloprost group compared with 4% for the placebo group. There was inadequate evidence of benefit in patients with PH associated with chronic thromboembolic disease (WHO Group IV). The use of iloprost requires a specialized dispensing device. One limitation of this delivery system is that the drug may be lost in the device tubing.

Bosentan

FDA approval of bosentan (Tracleer) was based in part on a randomized placebo-controlled double-blind study of 213 patients with PAH (idiopathic (70%) or associated with connective tissue disease (30%); WHO Group I).(32) The primary end point was degree of change in exercise capacity. At 16 weeks, a significant improvement was found in the 6MWT in the treatment group compared with the placebo group. Other measures of symptoms and functional status also improved in the treatment group, including a composite measure of “clinical worsening,” which consisted of the outcomes of “death, hospitalizations for PAH, discontinuation of therapy, or need for epoprostenol.” In addition, the treatment group had a significant increase in cardiac index associated with reduction in the pulmonary artery pressure. A review article detailed 2 RCTs (n=310) that evaluated the effect of bosentan for the treatment of systemic sclerosis-associated digital ulcers. In both trials, there was significant improvement in hand function; however, no differences were seen in healing of established ulcers.(33)

Ambrisentan

FDA approval of ambrisentan (Letairis) was based on two 12-week randomized, double-blind, placebo-controlled multicenter studies of 393 patients with PAH. (34) ARIES-1 compared once-daily doses of 5 mg and 10 mg of ambrisentan with placebo, while ARIES-2 compared once-daily doses of 2.5 and 5 mg. Patients were not taking any of the other agents discussed in this policy during the study. Sixty-four percent had idiopathic PAH, and 32% had PAH associated with connective tissue disease. Placebo-adjusted mean changes from baseline in the 6MWD were 51 meters in AIRES-1 and 59 meters in AIRES-2 (results for the higher dosages). For the 2 trials, clinical worsening was noted in 10% and 22% of the placebo patients compared with 3% and 6%, all respectively, of those receiving ambrisentan. In 2010, Blalock published long-term outcomes in 12 of 14 patients who were enrolled in the AIRES-1 study at a single institution; these patients enrolled in an extension of the 12-week randomized period in which all participants received ambrisentan.(35) All of the 12 patients remained on ambrisentan monotherapy during the first 2 years of follow-up. Two patients developed worsening symptoms requiring add-on IV therapy toward the end of the second year; 2 others developed worsening symptoms after 2 years and began IV therapy. At last follow-up (3.5-5 years), 11 patients remained alive; 3 were on ambrisentan monotherapy, 5 on combinations of oral therapies and 2 on ambrisentan plus an IV prostacyclin.

Macitentan

The pivotal SERAPHIN trial (2013) assessed the efficacy and safety of macitentan to treat PAH.(36) SERAPHIN was an event-driven, double-blind RCT in 742 patients with PAH (55% idiopathic, 31% associated with connective tissue disease, 8% associated with congenital shunt). Both treated (excluding endothelin receptor antagonists) and untreated patients were enrolled. Patients were randomized to placebo or macitentan 3 mg or 10 mg once daily. Theprimary end point was a composite of morbidity (atrial septostomy, lung transplantation, or worsening of PAH) and all-cause mortality.

Median treatment duration was 2 years 2 months. Primary end point events occurred in 46% of the placebo group, 38% in the 3 mg macitentan group (hazard ratio [HR] vs placebo, 0.70; 97.5% CI, 0.52 to 0.96; p=0.01), and 31% in the macitentan 10 mg group (HR vs placebo, 0.55; 97.5% CI, 0.39 to 0.76; p<0.001). Results were consistent across multiple sensitivity analyses and prespecified subgroups (eg, use or nonuse of concomitant PAH medication). The change from baseline in 6MWD at 6 months (a secondary outcome) was –9 meters in the placebo group, +7 meters in the 3 mg macitentan group (least squares mean difference vs placebo, 17 meters; 97.5% CI, -3 to 36; p=0.01), and +13 meters in the 10 mg macitentan group (least squares mean difference vs placebo, 22 meters; 97.5% CI, 3 to 41; p=0.008) from a baseline of 360 meters. Improvements in WHO functional class at month 6 in both macitentan groups were statistically significantly greater in both macitentan groups compared with placebo. Serious adverse events and discontinuations due to adverse events occurred with similar frequency in all 3 groups. Adverse events that occurred more commonly in macitentan-treated patients included headache (13% vs 9%), anemia (11% vs 3%), and bronchitis (10% vs 6%). Liver enzyme elevations, which are associated with bosentan (the parent drug of macitentan), occurred in approximately 4% of patients in all 3 groups.

Sildenafil citrate

FDA approval of sildenafil citrate (Revatio, also marketed as Viagra) was based in part on the results of a study that randomized 278 patients with PAH (idiopathic [60%], connective tissue disease [40%] WHO Group 1) to receive either placebo or sildenafil (20, 40, or 80 mg), orally, 3 times daily for 12 weeks.(37) The study is known as the SUPER-1 trial and findings were published by Galie et al in 2005. There was a significant improvement in primary end point, defined as the change in baseline to week 12 in the 6MWD. Of the 222 patients completing 1 year of treatment, the improvement in 6MWD was 51 meters. There was no significant difference among the 3 different doses of sildenafil given, and thus the recommended dose is 20 mg 3 times per day. At doses higher than the recommended dose, there was greater incidence of some adverse events including flushing, diarrhea, myalgia, and visual disturbances.

In 2011, Rubin et al published findings from an open-label extension study for which all patients who completed the initial trial were eligible (SUPER-2).(38) In the extension study, all patients titrated up to 80 mg sildenafil 3 times daily unless they could not tolerate this dose; there was no placebo group. A total of 259 of the 277 (93.5%) patients in the SUPER-1 trial entered the extension study. Compared with their SUPER-1 baseline value, at 3 years, 127 of 277 (46%) of patients had increased their 6MWD, 49 (18%) decreased their 6MWD, and 48 (17%) had missing data. A total of 81 patients (29%) had at least a 60-meter improvement in the 6MWD compared with the SUPER-1 baseline, and another 22 (8%) had a 30- to 60-meter improvement. Three years from SUPER-1 baseline, 187 patients were alive, 53 had died, and 37 were lost to follow-up. The Kaplan-Meier estimate of the survival rate, based on all randomized patients, was 79%. The estimate of survival was 68% if all censored patients were considered to have died. During the extension study, most adverse effects were mild or moderate in severity and were consistent with known side effects of sildenafil, eg, headache, diarrhea, and dyspepsia. Serious adverse events were reported by 153 of 277 (55%) patients. Serious events that were perceived to be treatment-related included grand mal seizure, hypotension, drug hypersensitivity, and gastroesophageal reflux disease (exact numbers of affected patients were not reported). Thirty-nine patients discontinued drug use due to adverse events. A major limitation of the extension study in terms of its ability to evaluate efficacy was that there was no comparison group of patients who were not taking sildenafil.

Tadalafil

The pivotal trial on tadalafil (ADCIRCA®), the Pulmonary Arterial Hypertension and Response to Tadalafil (PHIRST) study, was published by Galie et al in 2009.(39) This was a double-blind multicenter study conducted in the United States, Canada, Europe, and Japan. It included 406 patients who were at least 12 years-old and had symptomatic PAH (Group 1) that was idiopathic/heritable or related to anorexigen use, connective tissue disease, HIV infection or congenital systemic-to-pulmonary shunts. Randomization was stratified by type of PAH (idiopathic/heritable and anorexigen use versus other types), baseline bosentan use (53% were using bosentan), and baseline walking distance (less than 325 meters or at least 325 meters). Patients were assigned to receive 16 weeks of treatment with placebo (n=82) or 1 of 4 doses of tadalafil: 2.5 mg (n=82), 10 mg (n=80), 20 mg (n=82), or 40 mg (n=79). A total of 331 (82%) patients completed the 16-week study. Discontinuation rates were similar across all treatment groups, about 16% in each. The efficacy analysis was intention-to-treat and included 405 patients (all those randomized minus 1 patient who did not receive study medication). The primary efficacy outcome was placebo-corrected change from baseline to 16 weeks in the 6MWD. Compared with placebo, only the patients receiving 40 mg tadalafil significantly improved their 6MWD (ie, the p value was less than the prespecified cutoff of 0.01). For the 392 participants who were assessed at 16 weeks, change in placebo-corrected 6MWD was as follows: 14 meters (95% CI, 6 to 33) for the 79 patients in the 2.5-mg group, 20 meters (95% CI, 1 to 39) for the 78 patients in the 10-mg group, 27 meters (95% CI, 11 to 44) for the 82 patients in the 20-mg group, and 33 meters (95% CI, 15 to 50) in the 79 patients in the 40-mg group. The statistical significance cutoff for secondary outcomes was 0.05. There were no statistically significant differences between any of the tadalafil groups and placebo in the proportion of patients with improved WHO functional class and change in the Borg dyspnea scales. Time to clinical worsening, however, significantly improved in the tadalafil 40-mg group compared with placebo (p=0.041). Moreover, the 40-mg group had significantly greater improvement than placebo in 6 of the 8 quality-of-life domains in the Medical Outcomes Study 36-Item Short Form; the total quality-of-life score was not reported. Three deaths occurred during the 16-week study period; the study was not designed to evaluate differences in the mortality rate.

In 2012, Oudiz et al reported results from the 52-week, multicenter PHIRST extension study, PHIRST-2. (40) Of 364 eligible patients (PHIRST completers [n=341] or those who discontinued due to clinical worsening [n=23]), 357 (98%) continued in PHIRST-2. Patients were randomized in a double-blinded fashion to tadalafil 20 mg or 40 mg orally once daily. Sixty-three patients received tadalafil 20 mg in both PHIRST and PHIRST-2, and 69 received tadalafil 40 mg in both studies; all other patients (n=225) were randomized to receive tadalafil 40 mg in PHIRST-2. In the former groups, improvements in 6MWD achieved in PHIRST were maintained in PHIRST-2: In the group that received tadalafil 20 mg in both studies, 6MWD was 406±67 meters at the start and 415±80 meters at week 52 in PHIRST-2 (n=52). In the group that received tadalafil 40 mg in both studies, 6MWD was 413±81 meters at the start and 410±78 meters at week 52 in PHIRST-2 (n=59). In contrast, patients who had received lower tadalafil doses or placebo in PHIRST did not improve to similar levels after receiving 40 mg for 52 weeks. Headache was the most common adverse event, occurring in 14% and 16% of patients receiving tadalafil 20 mg or 40 mg in both studies, respectively; these incidences were less than those observed in PHIRST (32% and 42%, respectively), suggesting that headache may wane over time.

Vardenafil

Jing et al published 2 studies from China evaluating vardenafil (LEVITRA®); a case series in 2009 and an RCT in 2011. The case series included 45 patients with PAH who were admitted for treatment at one of the participating study centers.(41) Eligibility was limited to patients with IPAH, advanced pulmonary vasculopathy associated with connective tissue disease and congenital heart disease or portopulmonary hypertension. Patients were treated with oral vardenafil 5 mg daily for 1 month, after which time the dose was increased to 10 mg daily (5 mg twice a day) if tolerated. None of the patients had received other PAH-active drugs in the previous 3 months, but patients had been using vardenafil for a mean of 14 months before study entry. The mean baseline 6MWD was 409 meters (SD=103). All patients were evaluated after 3 months of treatment at which time the 6MWD had increased a mean of 71 meters (SD=78). The change in distance from baseline was statistically significant (p<0.001). All patients were also evaluated after a mean of 14 months (SD=3) of treatment. At this longer-term follow-up, the mean increase in 6MWD was 83 meters (SD=92), which was significantly higher than baseline (p<0.001) but not higher than the distance walked at 3 months (p=0.36). Change in functional improvement was seen at both 3 months and 14 months. At baseline, 11 (24%) patients were in WHO functional class II, 29 (64%) were in class III, and 5 (12%) were in class IV. At the end of the study, 5 (11%) were in functional class I, 31 (69%) in class II, 8 (18%) in class III, and 1 (2%) in class IV. No patients died during the study; 2 patients were admitted to the hospital for PAH-related symptoms after 6 and 11 months, respectively. The study was limited in that there was no comparison group, the sample size was small, and most patients had previously received the study medication so they were more likely to continue to respond to it.

A double-blind RCT, published by Jing et al in 2011, was conducted at 8 centers in mainland China.(42) The study randomized 66 patients to receive 12 weeks of oral vardenafil monotherapy (n=44) compared with placebo (n=22). Patients in the active treatment group received 5 mg vardenafil once daily for the first 4 weeks and then increased to the target dose of 5 mg twice daily, if tolerated. Two patients dropped out before any follow-up data were recorded. Thirty-nine of the remaining 64 patients (61%) had idiopathic PAH, 19 (30%) had connective tissue disease, and 6 (9%) had repaired right-to-left shunting. WHO functional class at baseline was class II in 30 (47%) and class III in 34 (52%). Baseline 6MWD (the primary efficacy outcome) was a mean of 388 meters in the placebo group and 395 in the vardenafil group. A total of 59 patients (89% of those randomized) completed the 12-week randomized phase. After 12 weeks, the median 6MWD increased by 59 meters in the vardenafil group and decreased by 10 meters in the placebo group. The mean placebo-corrected treatment effect was 69 meters (95% CI, 41 to 98 meters; p<0.001). During the 12-week follow-up period, 1 of 44 (2%) in the vardenafil group and 4 of 22 (18%) in the placebo group experienced clinical worsening; the difference between groups was statistically significant (p=0.044). This includes 2 patients in the placebo group who died. Other clinical outcomes favored the treatment group. Ten of 44 (23%) patients treated with vardenafil improved at least 1 WHO functional class, compared with only 1 of 22 (5%) of patients in the placebo group. In addition, the mean Borg dyspnea scale improved at week 12 (mean decrease of 0.4 point) in the vardenafil group, whereas the dyspnea score worsened (increase of 1.8 points) in the placebo group; the authors did not report a between-group p value. Fifty-eight patients completed a 12-week open-label extension of the study in which all patients received vardenafil 5 mg twice a day. At the end of the extension phase, the mean improvement in the 6MWD in the group originally assigned to vardenafil was 69 meters. In addition, patients who had been in the placebo group and then took vardenafil for 12 weeks had a mean increase of 59 meters in walk distance from week 12 (mean of 49 meters improvement from baseline). This remains the only published RCT evaluating vardenafil for PAH; no major study was conducted in the United States; a limitation is that the analysis was not intention-to-treat.

Riociguat

The pivotal PATENT-1 trial (2013) assessed the efficacy and safety of riociguat to treat PAH.(43) PATENT-1 was a double-blind RCT in 443 adults who had symptomatic PAH (61% idiopathic, 25% associated with connective tissue disease, 8% associated with congenital heart disease). Both treated (excluding phosphodiesterase type 5 inhibitors) and untreated patients were enrolled. Patients were randomized to placebo or riociguat titrated to 0.5 to 2.5 mg 3 times daily. (A second riociguat group capped at 1.5 mg three times daily [63 patients] was excluded from efficacy analyses.) Dose was optimized during the first 8 weeks, and the optimized dose was continued for 4 additional weeks. The primary efficacy outcome was mean change in 6MWD at week 12.

Approximately 90% of patients in both groups completed the trial; 75% of completers in the riociguat group continued the maximum dose to week 12. Mean change in 6MWD was +30 meters in the riociguat group and –6 meters in the placebo group (least-squares mean difference, 36 meters; 95% CI, 20 to 52; p<0.001) from a baseline of 363 meters. Results were consistent across multiple sensitivity analyses and predefined subgroups (eg, use or nonuse of concomitant PAH medication). Improvements in PVR, N-terminal brain natriuretic peptide, WHO functional class, time to clinical worsening (defined as the first occurrence of death, transplantation, or other indicator of PAH worsening), and Borg dyspnea severity scale (a patient-reported outcome) also were statistically significantly greater in the riociguat group. Adverse events occurred with similar frequency across groups. Adverse events that occurred more commonly in riociguat-treated patients included stomach upset (19% vs 8%), hypotension (10% vs 2%), and anemia (8% vs 2%). Eight riociguat-treated patients (3%) and 9 placebo-treated patients (7%) discontinued study drug due to adverse events. Serious drug-related adverse events that led to riociguat discontinuation included increased hepatic enzyme levels, acute renal failure, and syncope.

Eighty-five percent of patients in the riociguat group enrolled in an extension study. The mean increase in 6MWD in this group was 36±54 meters at week 12 of PATENT-1. At week 12 of the extension study (week 24 of treatment), there was continued improvement reported with a mean increase of 53±62 meters on preliminary analysis.

Conclusions

RCTs and several meta-analyses of RCTs have found that prostanoids, endothelin receptor antagonists, PDE5, and the soluble guanylate cyclase stimulator, riociguat, are all associated with small but statistically significant improvement in exercise capacity and hemodynamic parameters in patients with PAH. Findings on mortality reduction are mixed; in general, the evidence base on the effect of approved treatments on mortality is limited by the small size and short duration of most trials.

Simvastatin

In 2011, Kawut et al published findings of a study evaluating simvastatin and aspirin, alone and together, for treating PAH.(44) The study used a 2´2 factorial design and was double-blind and placebo-controlled. After enrolling the first 65 patients, the Data Safety and Monitoring Board did an interim analysis. The analysis showed that it was highly unlikely that simvastatin would show improvement in the primary outcome, change in the 6MWD at 6 months, compared with aspirin or placebo and the study was terminated. No other RCTs were identified that studied any statin for treating PAH. This study represents insufficient evidence that simvastatin is an effective treatment for PAH.

Atorvastatin

In 2012, Zeng et al published a 6-month, randomized double-blind, placebo-controlled trial of 220 Chinese patients with PAH (83%) or CTEPH (6%) in WHO functional class II or III.(45) Patients received atorvastatin 10 mg orally daily or matching placebo in addition to supportive care (diuretics, digoxin, and warfarin). After 6 months, mean difference in 6MWD (atorvastatin – placebo) was 2.5 meters (95% CI, -33 to 38). 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 deaths in the atorvastatin group (8%) and 11 deaths in the placebo group (10%; p=0.31). The authors concluded, “Atorvastatin 10 mg daily has no beneficial effect on the natural history of PAH or CTEPH over 6 months.”

PAH Combination Therapy

RCTs have evaluated various combinations of medications for treating PAH. In addition, meta-analyses of RCTs have been published. The meta-analyses 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 second-line treatment, ie, patients were already taking 1 medication when they entered the trial.

A meta-analysis published by Fox et al in 2011 included 6 trials.(46) The review’s inclusion criteria included studies in which patients on 1 active treatment were randomized to receive a second medication or placebo. In addition, studies needed to have at least 12 weeks of follow-up and to include clinical outcomes. A pooled analysis of data from 4 trials found a statistically significant increase in the 6MWD with combination therapy versus monotherapy (weighted mean difference [WMD], 25.2 meters; 95% CI, 13.3 to 38.2). The clinical significance of this degree of difference between groups in the 6MWD is unclear. Other pooled analysis did not find significant differences between groups. A meta-analysis of data from 4 trials did not find a lower risk of mortality with combination versus monotherapy (risk ratio [RR] 0.42; 95% CI, 0.08 to 2.26). In addition, a meta-analysis of 4 trials did not find a significant difference between groups in the rate of clinical worsening (composite variable including death, hospital admission, transplantation and treatment escalation) (RR=0.42; 95% CI, 0.17 to 1.04).

Another meta-analysis was published by Bai et al in 2011 and also included 6 trials.(47) Inclusion criteria included RCTs on treatment of adults with PAH using combination therapy, follow-up of 8 weeks or more and reporting of clinical outcomes. Five of 6 of the included articles were the same in both meta-analyses. The meta-analyses differed on the 6th article they included; one included Galie et al (2009), (39) and the other included Barst et al 2011.(48) However, these 2 studies reported on data from the same randomized trial. A pooled analysis of data from 5 trials found significantly greater improvement in the 6MWD with combination therapy compared with monotherapy (WMD=22.2; 95% CI, 13.6 to 30.9). In addition, a pooled analysis of data from 5 trials found a significantly lower rate of clinical worsening with combination compared with monotherapy (RR=0.48; 95% CI, 0.26 to 0.91). Clinical worsening referred to death, hospitalization, symptomatic deterioration, lack of improvement, interatrial fistulization, transplantation or treatment escalation. A pooled analysis of data from 5 trials did not find a significant difference between groups in the risk of mortality (RR=0.44; 95% CI, 0.04 to 4.65).

The 2 meta-analyses both found that combination therapy resulted in significantly greater improvement in the 6MWD compared with monotherapy and both found no difference between groups in mortality. The Bai et al meta-analysis, but not the Fox et al meta-analysis, found a significantly lower rate of clinical worsening in the combination therapy group; clinical worsening was defined somewhat differently in the 2 meta-analyses.

The 2013 Agency for Healthcare Research and Quality comparative effectiveness review(14) previously described included 5 RCTs of combination therapies. As in the Fox et al(46) and Bai et al(47) meta-analyses, treatments from different classes were combined in the meta-analyses of the AHRQ review, and all treatment combinations were add-on therapies. Evidence was insufficient to form any conclusion about combination therapy in comparison with continuation of monotherapy for the outcomes of mortality or hospitalization. Low strength of evidence supported an association between greater improvement in the 6MWD with combination therapy compared with continued monotherapy (mean difference in distance walked, 23.9 meters; 95% CI, 8.0 to 39.9). Because the magnitude of the treatment effect is less than the commonly accepted MID of 33 meters, the clinical significance of this finding is uncertain.

A 2012 meta-analysis by Zhu et al(49) incorporated results from 5(39,50-53) of the 6 RCTs discussed next; the EARLY trial(54) evaluating sildenafil add-on therapy to bosentan in mildly symptomatic patients was excluded, and 1 small RCT (N=39) of sildenafil added to bosentan therapy(55) was included. In 3 trials, inhaled prostanoid was added to bosentan or sildenafil, and in 3 trials, a PDE5 inhibitor was added to bosentan or epoprostenol. A total of 735 patients were evaluated for the 6MWD outcome. The pooled treatment effect (weighted MD, combination - monotherapy) was 21.6 meters (95% CI, 13.3 to 29.9), less than the MID described above. For the outcome of clinical worsening (death, hospitalization, symptomatic deterioration, lack of improvement or the need for treatment escalation [such as additional drugs], the development of an interatrial fistula, or lung transplantation), 729 patients were evaluated. The incidence of clinical worsening was lower in the combination therapy group than in the monotherapy group (risk ratio, 0.43; 95% CI, 0.26 to 0.72). Results were primarily driven by 2 large trials(52,53) which together comprised 68% of the patient sample.

The key RCTs evaluating combination treatment for PAH are described next; studies are organized according to the classes of medications that were combined.

Prostacyclin analogues and endothelin receptor antagonists

Two randomized trials evaluated the combination of inhaled iloprost and bosentan on clinical outcomes. In 2006, McLaughlin et al conducted a randomized double-blind trial of adding iloprost or placebo to bosentan monotherapy in 67 patients with PAH (idiopathic, 55%, associated PAH, 45%).(50) After 12 weeks, treatment with iloprost resulted in a placebo-adjusted 6MWD improvement of 26 meters (p=0.05). Functional class, hemodynamic parameters (eg, pulmonary arterial pressure, -6 mm Hg vs +3 mm Hg in the treatment and placebo groups, respectively), and time to clinical worsening (p=0.02) were all improved at 12 weeks in the treatment group compared with the placebo group. Hoeper et al reported results from a small (n=40), 12-week, nonblinded RCT evaluating the addition of iloprost to bosentan monotherapy in patients with idiopathic PAH (IPAH, WHO Group 1).(51) The study was terminated early because there appeared to be no benefit from the combined therapy: change was -10 meters on 6MWD for the combination group and no difference in functional status, Vo max, and time to clinical worsening. The study noted that these results may have been skewed by 3 patients in the iloprost group who presented with severe clinical worsening.

In 2010, McLaughlin et al evaluated the addition of inhaled treprostinil to oral therapy in a double-blind RCT with 235 patients with PAH.(52) Patients had been on a stable dose of bosentan (n=165) or sildenafil (n=70) for at least 3 months. They were randomized to receive inhaled treprostinil sodium (up to 54 ug) or placebo 4 times daily as add-on therapy. A total of 212 (90%) patients completed the study; analysis was intention to treat. The primary efficacy outcome was change in 6MWD over 12 weeks. Mean baseline 6MWD was 346 meters in the inhaled treprostinil group and 351 in the placebo group. After 12 weeks, the median change in peak 6MWD (10-60 minutes after nebulizer use) was 21.6 meters in the treprostinil group and 3.0 meters in the placebo group. The median between-group difference was 20 meters (95% CI, 8.0 to 32.8; p=0.004). When the analysis was limited to the patients taking bosentan at baseline, the median difference in change in 6MWD over 12 weeks was 25 meters (p=0.002). There were no differences between groups in the secondary end points rate of clinical worsening, Borg dyspnea scores, change in NYHA functional classifications or PAH signs and symptoms. For example, 4 of 115 (3%) patients in the treatment group and 6 of 120 (5%) in the placebo group experienced clinical worsening during the 12-week follow-up period. Another secondary outcome was quality of life, measured by the Minnesota Living with Heart Failure questionnaire (MLWHF); the potential range of the total score is 0 to 105, with a higher score indicating a worse quality of life. There was a median difference between groups of -4 points in the total score of the MLWHF; this difference was statistically significant, favoring the inhaled treprostinil group (p=0.027). Differences between groups in the 6MWD and quality-of-life measure may not be clinically significant. Following the 12-week double-blind study, patients had the option of enrolling in an open-label extension study in which all patients received inhaled treprostinil. (56) A total of 206 of 235 (88%) patients participated in the extension study. Their mean 6MWD at baseline was 349 meters (SD=81). The median change in 6MWD was 31 meters (p<0.001, n=152) at 12 months and 18 meters (p=0.013, n=118) at 24 months. A limitation of this analysis was that there was no comparison with patients who were not taking inhaled treprostinil.

Prostacyclin analogs and phosphodiesterase inhibitors

In the 2010 McLaughlin et al study, previously discussed, patients on monotherapy were randomized to receive added inhaled treprostinil or placebo; 70 patients were taking sildenafil at baseline.(52) In this subgroup, the median placebo-corrected change in 6MWD at 12 weeks, the primary outcome, was 9 meters; the difference between groups was not statistically significant. As previously noted, the groups did not differ significantly on secondary efficacy outcomes other than quality of life.

Simonneau et al assessed the effect of adding oral sildenafil to long-term intravenous epoprostenol (n=267) with PAH in a 2008 RCT.(53) After 16 weeks, the adjusted mean change in the 6MWD was 29.8 meters for the sildenafil group and 1.0 meter for the placebo group, a treatment difference of 28.8 meters (13.9 to 43.8 meters). In patients with IPAH, the difference between groups was 33.9 meters in favor of the sildenafil group (p value and 95% CI not reported). Sildenafil also had a beneficial effect on hemodynamic measurements and health-related quality of life.

Endothelin-receptor antagonists and phosphodiesterase inhibitors

An RCT by Galie et al evaluated bosentan in mildly symptomatic patients; the impact of combination therapy with bosentan and sildenafil was assessed in a subgroup of patients as a secondary objective.(54) The analysis assessed the effect of bosentan versus placebo and the effect of bosentan combined with sildenafil versus placebo. There was no direct comparison between the bosentan and combination treatment groups. The sample size of this study was small. In addition, patients with (IPAH and those with PAH secondary to HIV, congenital heart disease, and connective tissue disease were included. It is not clear if the same results would be expected for only those with IPAH.

The Galie et al study on tadalafil, discussed previously,(39) included a predefined subgroup analysis comparing treatment effectiveness in patients who added tadalafil to baseline bosentan treatment and those taking only tadalafil. These findings were reported by Barst et al in 2011.(48) The analysis focused on the groups assigned to 40 mg tadalafil and placebo. At 16 weeks, there was statistically significant improvement in the 6MWD among patients taking tadalafil monotherapy but not in the group taking combination therapy. The placebo-corrected 6MWD was 44 meters (95% CI, 20 to 69) in the tadalafil-only group and 23 meters (95% CI, -2 to 48) in patients taking the combination of tadalafil and bosentan.

Tyrosine kinase inhibitors and any of 3 major classes of medications

In 2010, Ghofrani et al published findings of a multisite double-blind Phase II randomized trial evaluating imatinib as an add-on treatment in patients with PAH; the study was conducted at sites in the United States and Europe.(57) Fifty-nine patients age 18 and older were enrolled; all had been on stable PAH medications for more than 3 months before enrollment but remained symptomatic. Patients were taking a prostacyclin analog, endothelin-receptor antagonist, PDE5, or combinations of these medications. Individuals in WHO functional class II-IV were eligible. Participants were randomized to receive 6 months of treatment with imatinib or placebo. Thirty-eight of 59 (64%) completed the study; 2 patients in each group died during the follow-up period. Analysis was intention to treat. In the treatment group, an initial dose of 200 mg oral imatinib was given for 2 weeks; if tolerated, the dose was increased to 400 mg. The primary efficacy outcome was change in the 6MWD. At 6 months, mean change in the 6MWD was an increase in 22 meters in the imatinib group and a decrease of 1 meter in the placebo group; this difference was not statistically significant (p=0.21). Findings were similar regardless of the method used to impute missing data.

In 2013, Hoeper et al published a 6-month, international, randomized placebo-controlled trial of add-on imatinib 400 mg orally once daily (reduced to 200 mg if not tolerated) in 202 patients with advanced PAH who were receiving at least 2 PAH therapies.(58) Most patients (approximately 40% in each group) were receiving triple therapy with an endothelin-receptor antagonist, a PDE5 inhibitor, and a prostanoid. The trial was completed by 67% of imatinib-treated patients and 82% of placebo-treated patients; most discontinuations were due to adverse events in both groups (26% in the atorvastatin group, 7% in the placebo group). The mean between-group difference in 6MWD (imatinib-placebo) was 32 meters (95% CI:, 12 to 52), a finding that was robust to multiple modes of imputing missing data. Mortality, functional class, and time to clinical worsening (death, overnight hospitalization for worsening PAH, worsening of WHO functional class by at least 1 level, or a 15% or greater decrease from baseline 6MWD) did not differ between treatment groups. In a subset of 150 patients (approximately 70 imatinib-treated and 80 placebo-treated patients), statistically significant improvements in hemodynamic parameters (PVR, cardiac output, mean pulmonary artery pressure, and right atrial pressure) were observed with imatinib compared with placebo. Of 150 patients who completed the trial, 144 (66 imatinib-treated and 78 placebo-treated patients) entered an extension study of open-label imatinib. Among patients who received 48 weeks of imatinib therapy, mean increase in 6MWD from baseline was 45±46 meters; among placebo-treated patients who received imatinib in the extension study (24 weeks of imatinib therapy), mean increase in 6MWD from baseline was 19±72 meters (p=0.98). Serious adverse events occurred in 44% of the imatinib group and 30% of the placebo group; the most common serious adverse events in the imatinib group trial were anemia, dyspnea, peripheral edema, and presyncope. Subdural hematoma occurred in 8 patients cotreated with imatinib and anticoagulation and in no patients treated with placebo. Given the risk-benefit profile observed in the trial, the authors conclude that “the off-label use of imatinib for this indication is strongly discouraged.”

Conclusions

Meta-analyses of trials on combination therapy have included studies that use medications from different classes and evaluate the addition of a second medication in patients already taking medication. Two meta-analyses, which included data from the same 6 trials, have found small, statistically significant improvement in the 6MWD and have not found a significant benefit of combination therapy on mortality. Meta-analyses had mixed findings on the impact of combination therapy on clinical worsening, depending on how this variable was defined by the authors of the meta-analysis. There are few RCTs on any particular combination of therapies and findings of these studies are mixed. The evidence is sufficient to determine that combinations of classes of medications improve exercise capacity more than a single medication, although the impact on other outcome measures is not conclusive.

CTEPH Monotherapy

Riociguat

The pivotal CHEST-1 trial (2013) assessed the efficacy and safety of riociguat to treat CTEPH.(59) CHEST-1 was a double-blind RCT in 261 adults who had inoperable CTEPH (72%) or persistent PH after pulmonary endarterectomy (28%). Patients receiving PAH medications were excluded. Patients were randomized to placebo or riociguat titrated to 0.5 to 2.5 mg three times daily. Dose was 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.

Approximately 93% of patients in each group completed the trial; 77% of completers in the riociguat group continued the maximum dose to week 16. Mean change in 6MWD 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; p<0.001) from a baseline of 347 meters. Results were consistent across multiple sensitivity analyses and predefined subgroups (eg, baseline WHO functional class). Improvements in PVR, N-terminal brain natriuretic peptide, and WHO functional class also were statistically significantly greater in the riociguat group. Adverse events occurred in 92% of the riociguat group and 86% of the placebo group. Adverse events that occurred more commonly in the riociguat group 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%). 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.

Seventy-five percent of patients in the riociguat group enrolled in an extension study; mean increase in 6MWDin this group was 51±62 meters at week 16 of CHEST-1 and 63±64 meters in preliminary analysis at week 12 of the extension study (week 28 of treatment).

CTEPH Perioperative Therapy

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%. (60) Several studies have investigated the use of PAH-specific treatments to reduce elevated PVR preoperatively in patients with CTEPH who are candidates for pulmonary endarterectomy.

Bosentan

In 2010, Reesink et al reported results of a single-blind RCT in 26 patients with CTEPH who were eligible for pulmonary endarterectomy.(61) 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 to 6 times the upper limit of normal and was excluded from efficacy analyses. Eleven patients in the bosentan group and 10 patients in the no-bosentan group underwent pulmonary endarterectomy. Mortality rates within 30 days after surgery were 9% and 30%, respectively.

Epoprostenol

Nagaya et al (2003) retrospectively examined the effect of preoperative intravenous prostacyclin analog (epoprostenol).(60) Of 33 consecutive patients with CTEPH who underwent pulmonary endarterectomy, 12 patients with preoperative PVR greater than 1200 Wood units received preoperative epoprostenol for a mean of 6±2 weeks. Statistically significant reductions in PVR before surgery and further reductions after surgery led to a statistically nonsignificant difference between groups 1 month after surgery (mean PVR approximately 300 Wood units in both groups). The only patient who died within 30 days after surgery was in the epoprostenol group for an overall mortality rate of 3.0% (8.3% mortality rate in the epoprostenol group; 0% in the comparator group).

In a similar study, Bresser et al (2004) retrospectively reviewed 9 patients who had received IV epoprostenol for a median of 4 months (range, 2-26) before pulmonary endarterectomy.(62) Median baseline total pulmonary resistance was 1432 Wood units, and median baseline PVR was 1031 Wood units. (Baseline PVR could not be calculated in 1 patient.) Preoperatively, median total PVR decreased to 1000 Wood units, and median PVR decreased to 760 Wood units. Median total pulmonary resistance on postoperative day 1 or 2 was 350 Wood units.

Iloprost

In 2003, Kramm et al reported on the effect of inhaled iloprost in the perioperative period.(63) Ten patients with mean PVR of 972 Woods units received inhaled iloprost at 3 time points: immediately before surgery, upon admission to the intensive care unit after surgery, and at 12 or more hours after surgery. 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 pulmonary hypertension (10% mortality rate).

Riociguat

There are no trials evaluating riociguat for preoperative therapy. Because of the different mechanism of action for the different drugs, results from the studies previously described cannot be extrapolated to riociguat.

Clinical Input Received Through 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.

2011

In response to requests, input was received through 4 academic medical centers while this policy was under review in 2011. The input focused on the issue of combination therapy. Two of the 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 academic medical centers had mixed input; both thought there were situations in which combination therapy is medically necessary.

2014

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

  • The use of riociguat and PAH-specific medications to reduce PVR preoperatively in patients with CTEPH who are candidates for pulmonary endarterectomy: There was consensus among reviewers that riociguat is investigational in this setting, and there also was consensus that PAH-specific medications are investigational in this setting.
  • The use of riociguat in patients with CTEPH who are candidates for pulmonary endarterectomy but prefer medical treatment: Results of vetting were mixed on this question.

Summary

There is evidence from multiple randomized controlled trials (RCTs) and meta-analyses of RCTs that monotherapy using prostanoids, endothelin-receptor antagonists, phosphodiesterase type-5 (PDE5) inhibitors, or the soluble guanylate cyclase stimulator, riociguat, improves health outcomes in patients with WHO Group 1 PAH. Thus, FDA-approved medications in these classes may be considered medically necessary for the treatment of patients with pulmonary arterial hypertension (PAH). Evidence on the comparative efficacy of these individual agents is lacking; therefore it is not possible to determine which one is preferable as first-line choice for treatment. There is insufficient evidence that simvastatin, atorvastatin, or imatinib are effective for treating patients with PAH, and these medications do not have FDA-approved PAH indications. Thus, simvastatin, atorvastatin, and imatinib are considered investigational.

There is evidence from 6 trials on combination therapy and meta-analyses of these trials that combination therapy as second-line treatment using medications from different classes results in improvement in exercise capacity; evidence on mortality and clinical worsening is inconclusive. In addition, the evidence is lacking on which particular combination of medications is optimal. Clinical input in 2011 uniformly thought that at least some therapy combinations were beneficial. Therefore, combination therapy as second-line treatment may be considered medically necessary when certain conditions are met. Additional trials on combination treatment are underway, including at least 1 evaluating combination therapy as first-line treatment. Riociguat is contraindicated with PDE5 inhibitors.

There is evidence from 1 RCT that riociguat improves health outcomes in patients with chronic thromboembolic pulmonary hypertension (CTEPH/WHO Group 4 PH) who are ineligible for pulmonary endarterectomy or have persistent pulmonary hypertension after pulmonary endarterectomy. Riociguat is therefore considered medically necessary in these patient groups. Riociguat has not been studied to reduce elevated preoperative pulmonary vascular resistance in patients eligible for pulmonary endarterectomy. There is insufficient evidence for the use of any PAH-specific medication in this setting. Clinical input did not support medical necessity of riociguat or PAH-specific medications for this use. Due to lack of evidence and lack of support from clinical vetting, PAH-specific medications and riociguat are considered investigational for this indication.

Practice Guidelines and Position Statements

PAH

In October 2009, the Health Technology Assessment Program in the U.K. published a systematic review of RCTs on medications for treatment of PAH.(64) The medications included epoprostenol sodium administered by IV infusion, inhaled iloprost, oral bosentan, oral sitaxsentan and oral sildenafil; all are approved for use in the U.K. The assessment concluded, “All of the five technologies, when added to supportive treatment and used at licensed dose(s), have been shown to be more effective than supportive treatment alone in patients of mixed FC (functional class) and other types of PAH. The volume of evidence and patient populations included in the trials varied between the technologies. Current evidence does not allow comparisons between the technologies nor for the use of combinations of the technologies.”

In March 2009, the ACCF/AHA 2009 Expert Consensus Document on Pulmonary Hypertension was released.(4) The writing committee consisted of acknowledged experts in the field of PH. This is the first ACCF/AHA clinical expert consensus document on PH. The authors' discussion regarding an 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 PDE-5 inhibitors.” The authors also cautioned “against widespread treatment of non-PAH PH" until patient benefit has been proven in clinical trials. On the topic of combination therapy, they state, “Given the availability of medications that target different pathologic processes, combination therapy is an attractive theoretical option in PAH…Multiple randomized controlled trials of combination therapy are currently ongoing, and to adequately study the safety and efficacy of combination therapy, we encourage enrollment into randomized controlled trials.”

In 2009, the Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS) published guidelines on the diagnosis and treatment of pulmonary hypertension.(6) Regarding treatment of pulmonary arterial hypertension (Group 1), the guidelines state that the results of clinical studies “support the efficacy of the currently approved PAH treatments.” However, they note, “the medical and interventional treatments for more advanced cases are still invasive and prone to significant side effects.” The guidelines also comment on combination therapy for PAH:

“…There are many open questions regarding combination therapy, including the choice of combination agents, the optimal timing [initial combination (in naive patients) or sequential combination (according to the response to the first drug)], when to switch, and when to combine. When combination therapy is considered, patients should be treated within clinical trials or registries whenever possible. Combination therapy of established PAH drugs is recommended for patients not responding adequately to monotherapy, but combination therapy should be instituted by expert centers only. Whether the response to monotherapy is sufficient or not can only be decided on an individual basis. This is judged in an individual patient who, despite monotherapy and optimized background treatment, has an inadequate clinical response.”

Updated in 2007, American College of Chest Physicians (ACCP) developed guidelines for the diagnosis and treatment of PAH.(65) The ACCP panel developed a treatment algorithm for PAH. The recommended therapies presented in this algorithm have been evaluated mainly in those with IPAH, or PAH associated with connective tissue disease or anorexigen use. “Extrapolation to other forms of PAH should be made with caution.” Country-specific regulatory agency approval status and functional class indications for PAH medications vary. The guideline statements include:

(1) Anticoagulation should be considered for patients with IPAH, and patients with an indwelling catheter for the administration of an intravenous (IV) prostanoid, in the absence of contraindications. Diuretics and oxygen should be added as necessary.

(2) A positive acute vasodilator response is defined as a fall in mean pulmonary artery pressure 10 mm Hg to 40 mm Hg, with an unchanged or increased cardiac output when challenged with inhaled nitric oxide, IV epoprostenol, or IV adenosine.

(3) Consideration should be given to using a PAH-specific medication such as a phosphodiesterase 5 inhibitor, endothelin receptor antagonist, or prostanoid as first-line treatment instead of a CCB in patients with PAH that is not IPAH or PAH associated with anorexigen use, or in those in an advanced functional class (FC) given the exceedingly low long-term response rate to CCB monotherapy in the former and poor prognosis in the latter.

(4) Sustained response to CCB therapy is defined as being in functional class I or II with normal or near-normal hemodynamics after several months of treatment.

(5) The risks and benefits of treatment in early PAH should be considered.

(6) First-line therapy for functional class III includes bosentan, sildenafil, epoprostenol, inhaled iloprost, and treprostinil.

(7) Most experts recommend IV epoprostenol as first-line treatment for unstable patients in functional class IV.

(8) RCTs studying add-on combination treatment regimens are underway.

CTEPH

The 2009 ACCF/AHA Expert Consensus Document on Pulmonary Hypertension recommended pulmonary endarterectomy for eligible patients with CTEPH.(4) 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 pulmonary hypertension 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.”

The 2009 European Society of Cardiology/European Respiratory Society (ESC/ERS) guideline also recommends pulmonary endarterectomy for patients with CTEPH.(6) Like the ACCF/AHA consensus document, PAH-specific drug therapy is recommended for “selected CTEPH patients such as patients not candidates for surgery or patients with residual pulmonary hypertension after pulmonary endarterectomy.”

Ongoing Clinical Trials

A search of the online ClinicalTrials.gov database in November 2013 identified the following relevant randomized controlled trials (RCTs) that are underway:

PAH

NCT01178073: A trial comparing the combination of tadalafil and ambrisentan as first-line therapy with first-line monotherapy with tadalafil or ambrisentan in patients with PAH. The study will be terminated when a predefined number of clinical failure events has occurred; the median study duration is expected to be 2.0 years. The trial is sponsored by GlaxoSmithKline, and the expected completion date is June 2013.

NCT01305252: This is a randomized, double-blind, active controlled trial in 30 treatment-naïve adults with PAH who are starting tadalafil. One group will receive combination therapy with inhaled treprostinil. The trial is sponsored by Stanford University, and the estimated completion date is July 2014.

NCT00303459: A trial comparing the combination of bosentan and sildenafil with sildenafil monotherapy (Compass 2). Patients will be treated with the study drug until the predefined number of morbidity/mortality events is reached. The trial is sponsored by Actelion, and the expected completion date is September 2014.

NCT01712997: This open-label, randomized trial will compare first-line combination therapy with bosentan and inhaled iloprost to bosentan monotherapy in treatment-naïve patients with PAH (target enrollment 90 patients). The trial is sponsored by a Chinese military academy, and the expected completion date is September 2014.

NCT01558466: In this randomized, placebo-controlled, double-blind trial, inhaled nitric oxide will be combined with sildenafil or placebo to treat 200 newborns with persistent PH and or hypoxemic respiratory failure. Effect on oxygenation, duration of mechanical ventilation, and rebound hypoxic episodes will be observed. The trial is sponsored by Hamad Medical Corporation, and the expected completion date is June 2015.

NCT01560624: This double-blind trial compares the addition of oral treprostinil or placebo in patients with PAH who have been taking a phosphodiesterase inhibitor or endothelin receptor antagonist for 31 to 90 days. The trial is sponsored by United Therapeutics, and the expected completion date is August 2016.

CTEPH

NCT01884675: This Phase 3, placebo-controlled, double-blind RCT assesses the endothelin receptor antagonist, ambrisentan, in 160 patients with inoperable CTEPH. Treatment duration is 16 weeks. The trial is sponsored by GlaxoSmithKline, and the expected completion date is June 2015.

NCT01416636: This Phase 3, double-blind RCT compares low and high doses of subcutaneous treprostinil in patients with severe, inoperable CTEPH. Treatment duration is 24 weeks. The trial is sponsored by SciPharm SàRL, and the expected completion date is December 2014.

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 Codes  Number  Description
CPT 93503 Insertion and placement of flow-directed catheter (e.g., Swan-Ganz) for monitoring purposes (i.e., as part of dose- ranging study)
ICD-9 Procedure    
HCPCS J1325 Injection, epeprostenol. 0.5mg
  J3285 Injection, treprostinil, 1mg
  K0455 Infusion pump used for uninterrupted parenteral administration of medication (e.g., epoprostenol or treprostinil)
  K0730 Controlled does inhalation drug delivery system
  Q4074 Iloprost, inhalation solution, FDA-approved final product, noncompounded, administered through DME, up to 20 mcg
  S0088 Imatinib, 100mg
   S0090 Sildenafil citrate, 25mg
   S0155 Sterile dilutant for rpoprostenol, 50ml
   S9347 Home infusion therapy, uninterrupted, long-term, controlled rate intravenous or subcutaneous infusion therapy (e.g., epoprostenol); administrative services, professional pharmacy services, care coordination, all necessary supplies and equipment (drugs and nursing visits coded separately), per diem
ICD-9 diagnosis 416.0 Primary pulmonary hypertension
  416.8 Secondary pulmnary hypertension
ICD-10-CM (effective 10/1/15) I27.0 Primary pulmonary hypertension
  I27.2 Other secondary pulmonary hypertension
  I27.89 Other specified pulmonary heart diseases
ICD-10-PCS (effective 10/1/15)    ICD-10-PCS codes are only used for inpatient services. There is no specific ICD-10-PCS code for the initiation of this therapy. 
   3E013GC, 3E033GC Administration, physiological systems and anatomical regions, introduction, percutaneous, other therapeutic substance, code by body part (subcutaneous tissue or peripheral vein) 
Type of service Drug Therapy    
Place of service Inpatient, Home   

Index
Bosentan
Epoprostenol Sodium
Flolan
Primary Pulmonary Hypertension, Treatment of
Remodulin
Revatio
Scleroderma, Flolan (epoprostenol)
Sildenafil, Primary Pulmonary Hypertension
Tracleer
Treprostinil

Policy History

Date Action Reason
01/30/98 Add to Prescription section New policy
08/18/00 Replace policy Policy updated; policy statement revised to include new FDA-approved indication for treatment of secondary pulmonary hypertension
10/08/02 Replace policy Policy reviewed and updated with literature review; discussion of new drugs trepoprostinol and bosentan added. Policy retitled to reflect discussion of new drug
12/17/03 Replace policy Policy reviewed and updated with literature review References added. No change in policy statement
04/01/05 Replace policy Policy updated and policy statement revised to state that iloprost may be considered medically necessary reflecting FDA approval; reference numbers 9 and 15 added; HCPCS codes updated
04/25/06 Replace policy Policy updated and policy statement revised to state that sildenafil may be considered medically necessary reflecting FDA approval, and combination therapy is considered investigational; reference numbers 12, 13, and 16 added. Code table updated
03/13/08 Replace policy Policy updated with literature review through MEDLINE in February 2008. Policy statement on combination therapy changed to state that combination therapy is investigational (drug-specific information removed). Rationale updated; new reference numbers 1, 10, 13, and 20 to 25 added; prior references renumbered. Information about new FDA-approved agent (ambrisentan) added.
04/24/09 Replace policy Policy reviewed with literature search from February 2008 through February 2009. Title change from “Treatments of Pulmonary Hypertension with…” to “Treatments of Pulmonary Arterial Hypertension with…” The policy statement has been re-worded for clarification related to the agents used in the treatment of pulmonary arterial hypertension but the intent of policy statements are unchanged. The policy statement has been modified to include; tadalafil (CIALIS®) and vardenafil (LEVITRA®) is considered investigational for treatment of pulmonary arterial hypertension; Description updated to clarify PH and PAH by new WHO classification; new reference numbers 13, 27-34 added; prior references renumbered.
8/11/11 Replace policy Policy updated with literature search through March 2011. Rationale extensively rewritten. References 15, 20, 24, 27, 30, 32, 34, 37 and 39 added; other references renumbered or removed. Vardenafil added as medically necessary for PAH (WHO group 1); policy statement on combination therapy changed to “Combination therapy as first-line treatment is considered investigational. Combination therapy using medications from different therapeutic classes may be considered medically necessary for patients who fail to demonstrate an adequate response to a single medication.”
9/13/12 Replace policy statement added that “use of other advanced therapies for the treatment of pulmonary arterial hypertension (PAH/ WHO Group 1), including but not limited to imatinib and simvastatin, is considered investigational.” Policy statement on combination therapy reformatted as bulleted list; statement that each medication needs to be considered medically necessary was added. Title changed to “Advanced Therapies for Pharmacological Treatment of Pulmonary Arterial Hypertension”. References 21, 25-27, 28, 32 and 46 added; other references renumbered or removed.
9/12/13 Replace policy Policy updated with literature search through July 2013. References 2-9, 23, 32, 36, 40, 46, and 49 added; references 40-44 removed. Policy statement modified with “eg” to indicate availability of epoprostenol and sildenafil generic formulations. “Atorvastatin” added to policy statement on investigational drugs (“including but not limited to simvastatin, atorvastatin, and imatinib”).
12/12/13 Replace policy Policy updated with literature search through October 28, 2013. References 1, 3, 5, 7-8, 36, 43, and 59-63 added. Title changed to “Advanced Therapies for Pharmacological Treatment of Pulmonary Hypertension” due to addition of chronic thromboembolic pulmonary hypertension (CTEPH). Policy statement on treatment of PAH/WHO Group 1 updated to include riociguat and macitentan as medically necessary. Policy statement added that riociguat is medically necessary for treatment of chronic thromboembolic PH (CTEPH/WHO Group 4). Policy statement added that use of PAH-specific medications is investigational for preoperative treatment of CTEPH.
3/13/14 Replace policy Policy updated with input from clinical reviewers. The investigational policy statement on preoperative reduction of pulmonary vascular resistance in patients with CTEPH who are candidates for pulmonary endarterectomy modified to include riociguat. PAH classification and references 2, 14, and 42 updated.