Coverage Policy Manual
Policy #: 1998144
Category: Pharmacy
Initiated: August 1998
Last Review: June 2018
  Pulmonary Arterial Hypertension, Pharmacological Treatment with Prostacyclin Analogues, Endothelin Receptors Antagonists, or Phosphodiesterase Inhibitors

Description:
Pulmonary arterial hypertension (PAH) is defined by the National Institute of Health Registry on Primary Pulmonary Hypertension as a mean pulmonary artery pressure of 25 mm Hg or greater at rest, or 30 mm Hg or greater with exercise, and a pulmonary capillary wedge or left atrial pressure less then 15 mm Hg.  Prolonged increase in pulmonary artery pressure is associated with increasing shortness of breath and failure of pumping mechanism of the right ventricle and early death.
 
Elevated pulmonary artery pressure may result from a wide variety of conditions that affect either the heart, the chest/lungs, the liver, or the blood.  For some patients, pulmonary hypertension may be ameliorated by correcting the basic pathological problem; however, for patients with idiopathic pulmonary arterial hypertension or for pulmonary hypertension secondary to certain primary diseases of the heart or lungs, drugs have been developed which may reduce the pulmonary artery pressure without compromising the normal cardiac output.
 
In addition to older therapy with oxygen, anticoagulation, and calcium channel antagonists, prostacyclin (epoprostenol), prostacyclin analogues (treprostinil, iloprost), endothelin receptor antagonists (bosentan, ambrisentan), and phosphodiesterase inhibitors (sildenafil) have been proven to be effective and approved by the FDA for treatment of various stages of pulmonary arterial hypertension.  Despite the promise of these drugs, however, there is no level I evidence demonstrating a survival benefit from their use.  Essentially all trials to date have been based on relatively brief studies of 3 to 4 months (with the one exception of a trial of a prostacyclin analogue (beraprost) which was studied for 1 year; this trial showed benefit early, but not at one year [Barst, 2003]), and their primary end-point on the distance walked in 6 minutes.  Whether this is an appropriate measurement has been questioned (Farber, 2008).  A review of these new drugs (Rich, 2007) recommended that survival be used as the primary end point to determine effectiveness of drugs for the treatment of pulmonary hypertension.  Rich based his conclusions on a meta-analysis of randomized controlled trials published between January 1985 to January 2006, no association between the change in 6 minute walk distance and improved survival (Macchia, 2007).  Use of survival as a primary endpoint has been considered to be unethical by others (Olschewski, 2002)who have concluded that epoprostenol has shown to improve survival in the most severely ill patients with idiopathic pulmonary hypertension.  
 
The following describes Arkansas BCBS coverage of the various prostacyclin, prostacyclin analogues, endothelin receptor antagonists, and phosphodiesterase inhibitor drugs which are FDA approved for treatment of pulmonary hypertension.

Policy/
Coverage:
The following drugs meet primary coverage criteria for effectiveness and are covered for selected conditions listed as Category I causes of pulmonary hypertension (see “Rationale” section for the classification of pulmonary hypertension).  The category I conditions that are covered are (1.1) idiopathic pulmonary arterial hypertension; (1.2) familial idiopathic pulmonary arterial hypertension; (1.3.1) pulmonary hypertension associated with connective tissue disease (i.e., scleroderma, CRST, systemic lupus erythematosus), (1.3.2) pulmonary hypertension due to congenital systemic to pulmonary shunts (e.g., Eisenmenger syndrome; (1.3.4) pulmonary hypertension associated with AIDS, and (1.3.5) pulmonary hypertension associated with anorexigen use.
 
The category I conditions that are not covered include (1.3.3) portal hypertension; (1.3.5) drugs (other than anorexigenic) & toxins; (1.4.1) pulmonary veno-occlusive disease; (1.4.2) pulmonary capillary hemangiomatosis; (1.3.6) other (e.g., thyroid disorders; glycogen storage disease; Gaucher disease; hereditary hemorrhagic telangiectasia; hemoglobinopathies; myeloproliferative disorders; and post-splenectomy states.
 
These drugs are not covered for Category II, III, IV, or V conditions as some of the conditions have been studied and the drugs found not to be effective (e.g., left ventricular failure; chronic thromboembolic pulmonary hypertension); some of these conditions are presently being studied in clinical trials to determine effectiveness (e.g., interstitial fibrotic lung disease); some of these conditions are corrected or treated by other means (e.g., sleep disordered breathing, alveolar hypoventilation disorders, developmental disorders); and for some of these conditions there is no evidence of effectiveness or safety available.  
 
AMBRISENTAN (Letaris) is administered orally, and meets primary coverage criteria for effectiveness and is covered (Effective, June 2007) for treatment of patients with WHO/NYHA functional class II or III patients with Idiopathic pulmonary hypertension, idiopathic familial pulmonary hypertension, pulmonary hypertension associated with connective tissue disease, anorexigen use, or HIV infection.
 
AMBRISENTAN is not covered in combination with other endothelin antagonists, phosphodiesterase antagonists, prostacyclin, or prostacyclin analogue drugs as the safety and effectiveness of this use has not been established in appropriate trials.
 
AMBRISENTAN is not covered in combination with Tadalafil as this combination is currently being studied in clinical trials. (Effective, October 2011)
 
AMBRISENTAN is not covered in combination with sildenafil, as this combination is being studied in a randomized, double blind, placebo controlled trial to determine the safety and effectiveness of this combination. (Effective, October 2011)
 
BOSENTAN (Tracleer) is administered orally, and is covered (Effective, Nov 2001) for patients with pulmonary artery hypertension with NYHA class III-IV symptoms with idiopathic pulmonary hypertension, familial pulmonary hypertension, anorexigenic agent induced pulmonary hypertension, pulmonary hypertension associated with scleroderma or its variants, in patients with Eisenmenger Syndrome, and in PAH associated with AIDS.  Bosentan must be obtained through the manufacturer.
 
BOSENTAN is covered for patients with WHO/NYHA class II functional symptoms (Effective, Oct 2008).
 
BOSENTAN is not covered for the treatment of congestive heart failure with left ventricular dysfunction.  
 
BOSENTAN is not covered in conjunction with epoprostenol, treprostinil, or phosphodiesterase inhibitors (e.g., sildenafil) as these combinations are presently being studied in trials to determine safety and effectiveness.
 
BOSENTAN is not covered for patients with NYHA class I functional symptoms as this use of bosentan is not FDA approved and has not been studied to determine effectiveness.
 
BOSENTAN is not covered to treat pulmonary hypertension in patients with pulmonary fibrosis as this use of bosentan is under study in clinical trials to determine safety and effectiveness.
 
BOSENTAN is not covered to treat pulmonary hypertension in patients with chronic thromboembolic disease as this use has been found in a randomized controlled clinical trial to be ineffective.
 
EPOPROSTENOL (Flolan, Veletri)
Epoprostenol is covered for patients with idiopathic pulmonary arterial hypertension who are NYHA class III or IV (Effective, Sep 1995); and for patients with pulmonary arterial heart disease (PAH) and NYHA class III or IV symptoms secondary to (1) scleroderma or scleroderma variants (Effective, Apr 2000); (2) congenital heart disease with left to right shunts, left to right shunts that have reversed, and pulmonary hypertension that has developed following repair of left to right shunts; (Effective, Jun 1999); and (3) anorexigenic agents (Effective, Jun 2000).  Epoprostenol is usually not the initial drug of choice for these covered indications unless the patient is NYHA functional class IV.  Epoprostenol and the portable controlled infusion device used to administer the drug are available through restricted distribution programs and are not available through community pharmacies.
 
EPOPROSTENOL is covered (Effective, Jul 2003) for treatment of familial idiopathic pulmonary hypertension in patients who are WHO/NYHA functional class III or IV.
 
EPOPROSTENOL is covered for patients with pulmonary arterial hypertension associated with HIV disease (Effective, Sep 2003), in patients who are WHO/NYHA functional class III or IV, but there are concerns regarding the safety of long-term central venous catheter placement because of the potential for infectious complications, which are increased in patients with HIV disease (Barst, 2007).
 
EPOPROSTENOL is covered (Effective, Nov 2008) when used in combination with sildenafil in patients with pulmonary arterial hypertension idiopathic, associated anorexigen use, connective tissue disease, or corrected congenital heart disease) who are receiving long-term intravenous epoprostenol therapy.
 
EPOPROSTENOL is not covered for patients with NYHA functional class I or II symptoms, as this use is not FDA approved, has not been studied in appropriate trials, and is not recommended in position papers from national or international study groups on pulmonary hypertension.
 
EPOPROSTENOL is not covered for combination use with bosentan, iloprost, treprostinil, or ambrisentan (except when transitioning to these drugs) as there is lack of evidence of effectiveness.
 
ILOPROST (Ventavis) is administered by inhalation and is an FDA designated orphan drug and is covered (Effective, Dec 2004) to treat WHO group I pulmonary hypertension with WHO/NYHA class III or IV symptoms. Iloprost oral inhalation solution and the nebulizers used to administer the drug are available through a restricted distribution program and are not available through community pharmacies.
 
ILOPROST is covered as add-on therapy for patients receiving bosentan who have continued to be symptomatic (Effective, June 2007).
 
ILOPROST is not covered when used in conjunction with epoprostenol, treprostinil, ambrisentan, sildenafil or tadalafil (except when transitioning to these medications) as the safety and effectiveness of these combinations has not been demonstrated in appropriate clinical trials.
 
ILOPROST is not covered for patients with NYHA functional class I or II symptoms, as patients in these symptomatic classes have not been studied to determine effectiveness.
 
SILDENAFIL (Revatio, Viagra) is administered orally, and is FDA approved and  covered for patients with WHO/NYHA functional class II or III disease, due to pulmonary arterial hypertension categories of disease mentioned above (Effective, June 2005).  
 
SILDENAFIL is covered when used in combination with epoprostenol in patients with pulmonary arterial hypertension (idiopathic, associated anorexigen use or connective tissue disease, or corrected congenital heart disease) who are receiving long-term intravenous epoprostenol therapy (Effective, October, 2008).
 
SILDENAFIL is not covered in combination with endothelin antagonists or prostacyclin analogue drugs as the safety and effectiveness of this use has not been established in appropriate trials.
 
SILDENAFIL is not covered in combination with ambrisentan, as this combination is being studied in a randomized, double blind, placebo controlled trial to determine the safety and effectiveness of this combination. (Effective, October 2011)
 
SILDENAFIL is not covered for the treatment of PAH in children ages 1 through 17. This treatment is not recommended by the FDA to be used in this age group. (Effective, September 2012)
 
TADALAFIL (Adcirca, Cialis) is administered orally.  Adcirca was FDA approved in 2009 for the treatment of PAH (WHO GroupI) to improve exercise ability.  Tadalafil is covered (Effective June 2009) for patients who have symptomatic PAH due to categories of disease as mentioned above.
 
TADALAFIL is not covered in combination with Ambrisentan as this combination is currently being studied in clinical trials. (Effective, October 2011)
 
TADALAFIL is not covered in conjunction with other PDE inhibitors, endothelin antagonists, or other drugs for pulmonary hypertension because of lack of evidence for effectiveness of combination therapy.
  
TREPROSTINIL (Remodulin) is administered by chronic subcutaneous (Effective Nov 2001) or intravenous (Effective, Nov 2003) administration, and is covered in patients with pulmonary arterial hypertension with NYHA class III-IV symptoms due to 1) idiopathic pulmonary hypertension, 2) scleroderma and scleroderma variants, 3) congenital heart disease resulting in pulmonary hypertension, and 4) anorexigenic agents.    
 
TREPROSTINIL is not covered in conjunction with other prostacyclin analogues, endothelin receptor antagonists, or sildenafil as this combination therapy is presently under study to determine effectiveness and safety.
 
TREPROSTINIL (Tyvaso) is administered by oral inhalation, and meets primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes for the treatment of patients with pulmonary arterial hypertension (WHO Group I) with NYHA Class III symptoms, to increase walk distance. (Effective June, 2010)
 
Treprostinil does not meet primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes in for the treatment of patients with non-PAH PH conditions (WHO Groups 2-5). (Effective June, 2010)
 
For contracts without primary coverage criteria, treprostinil for the treatment of patients with non-PAH PH conditions (WHO Groups 2-5) is considered investigational.  Investigational services are an exclusion in most member benefit certificates of coverage. (Effective June, 2010)
 
TREPROSTINIL (Orenitram), oral tablet formulation, for the treatment of patients with pulmonary arterial hypertension does not meet member benefit certificate primary coverage criteria. (Effective April 2015)
 
For members with contracts without primary coverage criteria, treatment with treprostinil (Orenitram), oral tablet formulation, is considered not medically necessary. Services that are considered not medically necessary are specific contract exclusions in most member benefit certificates of coverage. (Effective April 2015)

Rationale:
 “Due to the detail of the rationale, the complete document is not online. If you would like a hardcopy print, please email: codespecificinquiry@arkbluecross.com”
 
The World Health Organization and the New York Heart Association have developed a classification of the functional status of patients with pulmonary hypertension:
 
Class I   Patients with pulmonary hypertension but without resulting limitation of physical activity. Ordinary physical activity does not cause dyspnoea or fatigue, chest pain or near syncope
 
Class II  Patients with pulmonary hypertension resulting in slight limitation of physical activity. They are comfortable at rest. Ordinary physical activity causes undue dyspnoea or fatigue, chest pain or near syncope
 
Class III  Patients with pulmonary hypertension resulting in marked limitation of physical activity. They are comfortable at rest.  Less than ordinary activity causes undue dyspnoea or fatigue, chest pain or near syncope
 
Class IV  Patients with pulmonary hypertension who are unable to perform any physical activity at rest and who may have signs of right ventricular failure.  Dyspnea and/or fatigue may be present at rest, and symptoms are increased by almost any physical activity
 
In 1998 the Second World Symposium on Pulmonary Hypertension developed a classification of pulmonary hypertension, which was last updated in 2003 (Simonneau, 2004; Haworth, 2008).  The purpose of this classification was to group individual categories of PAH with similar pathophysiological mechanisms, clinical presentations, and therapeutic options.  Previously, pulmonary hypertension was categorized as “primary pulmonary hypertension” and “secondary pulmonary hypertension”.  What had previously been known as “primary pulmonary hypertension” was renamed “idiopathic pulmonary hypertension”, and the category of “secondary” pulmonary hypertension was redefined into other subcategories of category I, plus 4 additional categories (II - V).  The subcategories of category I include familial pulmonary artery hypertension, pulmonary arterial hypertension associated with collagen vascular disease; congenital systemic-to-pulmonary shunts, portal hypertension, HIV infection, drugs and toxins (e.g., anorexigens, rapeseed oil, L-tryptophan, methamphetamine, and cocaine), other (e.g., thyroid disorders, glycogen storage disease, Gaucher disease, hereditary hemorrhagic telangiectasia, hemoglobinopathies, myeloproliferative disorders, or splenectomy); pulmonary artery hypertension associated with significant venous or capillary involvement (which includes pulmonary veno-occlusive disease and pulmonary capillary hemangiomatosis); and persistent pulmonary hypertension of the newborn.
Cat 1   Pulmonary arterial hypertension (PAH)
            1.1 Idiopathic
            1.2  Familial Idiopathic Pulmonary Hypertension
            1.3 Associated with pulmonary arterial hypertension
                  1.3.1 Connective tissue disease
                  1.3.2 Congenital systemic to pulmonary shunts
                  1.3.3 Portal hypertension
                  1.3.4 HIV
                  1.3.5 Drugs and toxins
                  1.3.6 Other
            1.4 Associated with significant venous or capillary involvement
                  1.4.1 Pulmonary veno-occlusive disease
                  1.4.2 Pulmonary capillary hemangiomatosis
            1.5 Persistent pulmonary hypertension of the newborn
Cat 2   Pulmonary Hypertension associated with left heart diseases
             2.1 Left sided atrial or ventricular disease
             2.2 Left sided valvular heart disease
Cat 3  Pulmonary hypertension associated with respiratory diseases and/or hypoxia
            3.1 Chronic obstructive pulmonary disease
            3.2 Interstitial lung disease
            3.3 Sleep disordered breathing
            3.4 Alveolar hypoventilation disorders
            3.5 High altitude
            3.6 Developmental abnormalities
Cat 4  Pulmonary hypertension due to chronic thrombotic/embolic disease
Cat 5  Miscellaneous pulmonary hypertension
           Tumor & Others
Coverage for prostacyclin, prostacyclin analogue, endothelin antagonist, and phosphodiesterase antagonist drugs is described for conditions listed in Category I.  There is no coverage for Category II, III, IV, or V conditions as 1) some of the conditions have been studied and the drugs found either ;not to be effective or not safe (e.g. left ventricular failure);  2) some of the conditions are presently being studied in clinical trials to determine effectiveness (e.g., chronic thromboembolic pulmonary disease, interstitial fibrotic lung disease); 3) some of the conditions are corrected or treated by other measures (e.g., sleep disordered breathing, alveolar hypoventilation disorders, developmental disorders); and 4) for some of the conditions there is no available evidence of effectiveness or safety (e.g. sickle cell disease, thalassemia, hereditary hemorrhagic telangiectasia, myeloproliferative disorders, splenectomy).
 
The coverage noted in the Policy/Coverage section does not include coverage of these drugs for treatment of persistent pulmonary hypertension of the newborn.  The accepted standard of care for persistent pulmonary hypertension in neonates is assisted ventilation and administration of nitric oxide (Donti, 2007).
 
The coverage noted in the Policy/Coverage section does not include coverage of these drugs for treatment of pulmonary hypertension associated with pulmonary veno-occlusive disease (Haworth, 2008; Montani, 2008) or pulmonary capillary telangiectasia (Humbert, 1998; Almagro, 2002) because the risk of pulmonary edema associated with this therapy has resulted in the recommendation that these drugs not be used in these conditions.
 
The coverage noted in the Policy/Coverage section does not include coverage of these drugs for treatment of pulmonary hypertension associated with chronic thromboembolic disease.  A number of uncontrolled case series and small prospective studies have evaluated the use of these drugs given either prior to pulmonary endarterectomy (Bresser, 2004), following pulmonary endarterectomy (Bonderman, 2005), or in patients with inoperable pulmonary thromboembolic disease (Ghofrani, 2002; Hughes, 2006; Lang, 2006; Cabrol, 2007; Skoro-Sajer, 2007; Seyfarth, 2007) for treatment of pulmonary hypertension associated with chronic thromboembolic disease (CTEPH). Some of these studies appear to report at least some of the same patients (e.g., Lang, 2006 & Skoro-Sajer, 2007).  The only randomized controlled trial to date, using inhaled iloprost, included 50 patients with distal CTEPH, but no benefit was found (Olschewski, 2002).  The BENEFIT trial (Xavier, 2008) was a prospective, randomized controlled, double blind multicenter trial of bosentan for patients with inoperable thromboembolic PAH and patients with persistent/recurrent PAH at least 6 months after pulmonary endarterectomy (PEA).  This study, involving 157 patients, demonstrated a significant benefit in the treatment group at 16 weeks in peripheral vascular resistance, total pulmonary resistance, and cardiac index; however, there was no improvement in exercise capacity or time to clinical worsening.  The patients will continue to be followed in a long-term, open-label extension study and those results will be reported separately.  Taken together these trials do not support use of PAH drugs for treatment of CTEPH.  Coverage of prostacyclin, prostacyclin analogue, endothelin receptor antagonist, and phosphodiesterase inhibitor will be determined following outcomes of these trials.
 
The American College of Chest Physicians most recent guidelines (2007) do not include studies on CTEPH and did not address the use of these drugs in treatment of pulmonary hypertension associated with CTEPH. The consensus statement on the management of pulmonary hypertensin in clinical practice in the UK and Ireland (National Pulmonary Hypertension Centres, 2008) concluded, "“While there is no doubt that most patients with CTEPH should undergo PEA, it is uncertain how to approach those with non-surgical distribution of disease and those with residual PH post-PEA.  Disease-targeted therapies for PAH are now being studied.  Intravenous epoprostenol has been used as a bridge before surgery resulting in some hemodynamic stabilization.  Uncontrolled studies suggest a role for both sildenafil and bosentan.  A randomized, placebo-controlled trial to establish safety and efficacy of bosentan is currently in progress...Current UK practice for medical treatment of CTEPH is to adopt the treatment algorithm as in IPAH until new evidence from randomized trials is available.  Patients with significant postoperative PH or late recurrence of PH are considered for disease-targeted therapies.”  The Bosentan Effects in iNopErable Forms of chronic Thromboembolic pulmonary hypertension (BENEFIT) was reported in December 2008 (Jais, 2008) and showed no benefit in 6-minute walk time although pulmonary artery pressure was reduced.  This is the second randomized controlled trial to show no exercise benefit from administration of a drug which reduced pulmonary artery pressure (Jais, 2008; Oleschewski, 2002).
 
The coverage noted in the Policy/Coverage section does not include coverage of these drugs for treatment of portopulmonary hypertension.  Portopulmonary hypertension refers to the development of pulmonary arterial hypertension in patients with portal hypertension, an uncommon complication of cirrhosis.  The disease carries a poor prognosis with 1-year mortality rates ranging from 24% to 60%.  The few studies of these drugs in the treatment of portopulmonary hypertension (PPHT) are small case series, the largest being a retrospective multicenter report of 31 patients (Hoeper, 2007).  Use of these drugs in treatment of PPHT has never undergone study in randomized trials, and patients with PPHT have for the most part been excluded from RCTs of the various pulmonary artery hypertension therapeutic studies. The safety and effectiveness of these drugs in the treatment of PPHT are unknown.  The Hoeper, et al. report suggests an improved health outcome, at least from bosentan, in patients with PPHT, but there is no strong evidence that bosentan (or iloprost) is superior to placebo.  In a report from the Mayo Clinic (Findlay, 1999), 4 patients with PPHT developed progressive splenomegaly, thrombocytopenia, and leukopenia following epoprostenol treatment.
 
The coverage noted in the Policy/Coverage section does not include coverage of these drugs for treatment of pulmonary hypertension associated with Gaucher’s disease.  Intravenous epoprostenol has been reported in a few case reports (Bakst, 1999) and one case series (Mistry, 2002), and one case report of sildenafil in PAH associated with Gaucher’s disease (Fernandes, 2005) was identified.  The case series was of 9 patients, 6 of whom received epoprostenol.  Two of the 3 patients who did not receive epoprostenol received imiglucerase and had amelioration of their PAH.  The 6 who received epoprostenol also received imiglucerase, so it is difficult to determine if the epoprostenol was responsible for the improvement.  Both the epoprostenol and sildenafil single case reports described improvement thought by the authors to be related to the drugs.  PAH occurs rarely in Gaucher’s disease, hence it is unlikely that an appropriate trial will occur.  Coverage will be determined on a case-by-case basis.
 
The coverage noted in the Policy/Coverage section does not include coverage of these drugs for treatment of pulmonary hypertension associated with splenectomy.  The association of PAH post-splenectomy was originally reported in 1999 (Hoeper, 1999), but the cause remains unknown.  It has been postulated that PAH post splenectomy may result from microthrombi in pulmonary arterioles or small pulmonary arteries, or microemboli to these same vessels (Jais, 2005).  There is no data on the effectiveness of these drugs on PAH following splenectomy.
 
Agency for Healthcare Research and Quality (AHRQ) Comparative Effectiveness Review
In 2013, the Agency for Healthcare Research and Quality (AHRQ) published a comparative effectiveness review of the screening, management, and treatments of PAH (McCrory, 2013). 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 (3,587 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 (i.e., monotherapy) to placebo or standard therapy, defined as supportive treatment (diuretics, oxygen, digoxin, and/or oral anticoagulants) with or without calcium channel blockers; 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): 0.29-0.95]). 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 6-minute walk distance (6MWD); treatment effects (mean difference in distance walked, intervention – standard therapy/placebo) were 27.9 meters (95% CI: 10.3-45.4) for prostanoids, 39.9 meters (95% CI: 21.4-58.4) for endothelin receptor inhibitors, and 38.9 meters (95% CI: 22.0-55.9) 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- 0.69) and 38.9 (95% CI: 22.0- 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 (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.
 
The review included  5 RCTs of combination therapies. 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 to 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 to continued monotherapy (mean difference in distance walked 23.9 meters [95% CI: 8.0-39.9]). 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.
 
Cochrane Review
A 2013 Cochrane review by Liu et al. assessed the efficacy of endothelin receptor antagonists for the treatment of patients with PAH (Liu, 2013). A literature search through December 2011 identified 12 RCTs (1,471 patients), 11 of which were placebo controlled. The 12th  RCT was a head-to-head comparison of borsentan and sildenafil in 26 patients (Wilkins, 2005). 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 to placebo in 6MWD (mean difference 33.7 meters [95% CI: 24.9-42.5]), proportion of patients with improved WHO or NYHA functional class (OR 1.6 [95% CI: 1.2-2.1]), proportion of patients with deteriorated functional class (OR 0.3 [95% CI: 0.2-0.4]), and hemodynamic parameters (mean pulmonary artery pressure, pulmonary vascular resistance, and cardiac index). Based on 22 events in 1,201 patients, the reduction in mortality with endothelin receptor antagonists was not statistically significant (OR 0.57 [95% CI: 0.26, 1.24 ]).
 
AMBRISENTAN (Letaris)
AMBRISENTAN is a second generation endothelin antagonist, and the FDA orphan drug approval of ambrisentan is based on two 12-week randomized, double-blind placebo-controlled multicenter studies of patients with pulmonary hypertension due to idiopathic pulmonary hypertension, connective tissue disease, HIV infection, or anorexigen use (Galie, 2008-1).  The primary end-point of the study was the change from baseline to week 12 in exercise capacity as measured by the distance walked in 6-minutes.  A statistically significant increase in walk distance was observed in each ambrisentan dose group at week 4, and this effect was maintained at weeks 8 and 12, whereas in the placebo groups, it deteriorated by week 12.  In 280 patients completing 48 weeks of therapy, the improvement from baseline in 6-minute walk test at 48 weeks was 39 meters.  Secondary end-points of time to clinical worsening, World Health Organization functional class, Borg dyspnea score, and reduction in B-type natriuretic peptide concentration also improved, although not all of these secondary end-points had sufficient statistical power to be significant.  No elevation of serum amino-transferase concentrations greater than 3 times the upper normal limits was observed in any of the ambrisentan treated patients.   
 
AMBRISENTAN is not covered in combination with bosentan as both of these drugs are endothelin receptor antagonists, and there is no evidence of safety or improved effectiveness of this combination.  
 
AMBRISENTAN is not covered in combination with sildenafil, as this combination is being studied in a randomized, double blind, placebo controlled trial to determine the safety and effectiveness of this combination (NCT00617305).  This trial is listed on the clinicaltrials.gov website as completed with results but no publications have been identified.
 
AMBRISENTAN is not covered in combination with epoprostenol, treprostinil, or iloprost, due to the lack of evidence of safety and effectiveness.
 
AMBRISENTAN is not covered in combination with tadalafil, as this combination is currently being studied in clinical trials to determine the safety and effectiveness of this combination (NCT01042158) (NCT001178073).
 
BOSENTAN (Tracleer)
Endothelin-1 is an endogenous vasoconstrictor that is overproduced in the plasma and lung tissue of patients with PPH and scleroderma (Giaid, 1993).  Its actions are mediated by two receptors in the arterial vascular endothelium of the lung.  Bosentan is an oral antagonist of both endothelin receptors, and it decreases both pulmonary and systemic vascular resistance resulting in increased cardiac output without increasing the heart rate.  Efficacy of bosentan was established in 2 randomized, double-blind multicenter, placebo-controlled trials (Channick, 2001; Rubin, 2002) in a total of 245 patients with severe (NYHA Class III or IV) symptoms with 1) primary pulmonary hypertension, 2) scleroderma or scleroderma variants, and 3) autoimmune diseases.  (Patients with PAH secondary to portal hypertension and HIV were not evaluated in these 2 studies).  Bosentan significantly improves exercise capacity and increases the time to clinical worsening in patients with severe pulmonary arterial hypertension, but has not been studied to determine improvement in survival.  A Cochrane systematic analysis of endothelin receptor antagonists concluded, “ERAs in conjunction with conventional therapy over 12 to 16 weeks can improve exercise capacity, Borg dyspnea scores and several cardiopulmonary hemodynamics variables in patients mainly with idiopathic PAH.  The data on mortality due not currently show a benefit of this class of drugs on theis endpoint.  Additional assessment of this outcome is important in order to establish whether there is evidence that ERAs have an impact on the risk of death.  Studies with longer follow up are required (Liu, 2006)
 
Bosentan was studied in patients with functional WHO II symptom classification in a randomized, double-blind placebo-controlled trial of 168 patients over 6 months which showed that, if left untreated, mildly symptomatic pulmonary arterial hypertension can progressively deteriorate both clinically and in terms of hemodynamics, despite the maintenance of exercise capacity (Galie, 2008-2).  Bosentan treatment was associated with improvements in hemodynamics and prevention of clinical deterioration.  Bosentan and sildenafil are the only two drugs that have shown benefit in significant numbers of patients in treatment of patients in WHO/NYHA functional class II.
 
BOSENTAN is covered for the treatment of pulmonary hypertension related to Eisenmenger syndrome.  Eisenmenger syndrome is defined as a congenital heart defect that initially causes a major left to right shunt, induces severe pulmonary vascular disease and PAH, and finally results in reversal of the direction of shunting and development of cyanosis.  Bosentan has off-label recommendation for treatment of Eisenmenger syndrome, based on the results of a randomized controlled trial of 54 WHO functional Class III patients (Galie, 2006).   
 
BOSENTAN is covered in combination with inhaled iloprost based on a 3-month randomized, multicenter, double-blind trial of 67 patients with NYHA class III PAH, in which iloprost or placebo was added to the treatment regimen of patients previously treated for at least 4-months with bosentan, but were still symptomatic; (McLaughlin, 2006).  The 6-minute walk distance, NYHA functional class, right heart catheterization, and Borg dyspnea score were evaluated.  Approximately 50% of the patients had IPAH, with the remaining 50% had PAH due to scleroderma, other connective tissue diseases, HIV infection, repaired congenital heart disease, and anorexigen use.  The mean duration of bosentan therapy prior to addition of iloprost was 17.6 in the iloprost group, and 18.8 for the placebo patients.  The 6-minute walk test, NYHA functional class, the time to clinical worsening, the pulmonary artery pressure and pulmonary vascular resistance all improved significantly at the end of the 12-week period.
 
BOSENTAN is not covered in combination with epoprostenol.  This combination has been studied in a randomized trial (Humbert, 2004) which showed no benefit. Agagi et al. (2008) reported on 8 patients with IPAH treated initially with epoprostenol followed by the addition of bosentan, who showed a reduction in pulmonary artery systolic pressure at 2-days and 1-year, but the small number of patients, the lack of a comparator group, and the lack of long-term follow-up is of concern.
 
BOSENTAN is not covered in combination with treprostinil.  A study of treprostinil by Barst, et al. (2006) included some patients who were also treated with bosentan, but there was no difference in outcome.  A retrospective study by Benza (2008) of 19 patients who received treprostinil but had bosentan added if the patients remained in NYHA function class III or II.  The authors concluded that there was significant additional improvement.  Bosentan in combination with treprostinil has not been studied in appropriate trials.  
 
BOSENTAN is not covered for treatment of pulmonary hypertension in combination with sildenafil, as it is presently under study ClinicalTrials.gov/NCT00303459) in combination with sildenafil to determine the effectiveness of this combination in pulmonary hypertension.
 
BOSENTAN is not covered in combination with ambrisentan for treatment of pulmonary hypertension.  Both of these drugs are endothelin receptor antagonists, and there is no evidence of safety or effectiveness of this combination.  
 
BOSENTAN is not covered for treatment of pulmonary hypertension associated with idiopathic pulmonary fibrosis as this use is presently under study to determine its effectiveness and safety (ClinicalTrials.gov/NCT00625469).
 
BOSENTAN  is not covered for treatment of pulmonary hypertension associated with congestive heart failure as it is not effective in the treatment of congestive heart failure with left ventricular dysfunction.  The Endothelin Antagonist Bosentan for Lowering Cardiac Events in Heart Failure Study (Packer, 2002) randomized 1,613 patients with a left ventricular ejection fraction of less than 35% and NYHA class IIIb-IV to receive either bosentan or placebo.  The primary endpoint of all cause mortality or hospitalization for heart failure was reached in 321/808 patients on placebo and 312/805 receiving bosentan.  Treatment with bosentan appeared to confer an early risk of worsening heart failure necessitating hospitalization as a consequence of fluid retention.  Although this study was not reported in other than abstract form, Packer did report 370 patients with symptoms of heart failure at rest or on minimal exertion and a left ventricular ejection fraction less than 35% who were randomly assigned to placebo or bosentan.  Treatment with the study drug was to be maintained for 26 weeks, whereas background medications for heart failure were kept constant.  Bosentan exerted no apparent benefit when all randomized patients were analyzed (Packer, 2005).  A randomized controlled trial of bosentan in symptomatic heart failure patients (NYHA IIIb- IV) with an ejection fraction of less than 35% and systolic pulmonary artery pressure greater than 4o mm Hg failed to show any measurable hemodynamic benefit, and was associated with more adverse events, requiring drug discontinuation (Kaluski, 2008).
 
A Cochrane systematic review of endothelin receptor antagonists for pulmonary hypertension (Liu, 2006) concluded that ERAs can improve exercise capacity, lower Borg dyspnea score, and improve cardiopulmonary hemodynamics in patients with PAH.  All studies were short in duration and mortality data were limited.  Liver toxicity, as a main side effect of ERAs, was not a major problem.  Most participants in the studies were in the WHO or NYHA class III or IV.  Whether ERAs have more efficacy in patients with mild symptoms or mortality is a priority for additional studies which follow participants up for longer than four months.  Furthermore, whether ERAs in combination with prostacyclin or its analogues or phosphodiesterase inhibitors can further improve PAH prognosis still needs to be confirmed in larger studies.
 
 
EPOPROSTENOL (Flolan)
Epoprostenol (formerly called prostacyclin or prostaglandin I2) is administered by continuous intravenous (IV) infusion.  It is an FDA approved orphan drug, is administered by continuous intravenous infusion, and patients must reconstitute the medication at home and keep it continually cool once mixed.  It has a half-life of approximately 3-6 minutes, and sudden interruptions can be life threatening.  In patients with PAH it increases cardiac output and decreases pulmonary vascular resistance, mean systemic arterial pressure, and mean pulmonary artery pressure.  It is FDA approved for the long term treatment of idiopathic PAH resulting in WHO/NYHA functional class III or IV heart disease based on 2 randomized controlled trials of a total of 105 patients (Rubin, 1990; Barst, 1996), and for PAH secondary to scleroderma for those patients who also are WHO/NYHA class III or IV (Badesch, 2000).
 
The American College of Chest Physicians (ACCP) practice guidelines state that patients with NYHA functional class III who are not candidates for, or who have failed, oral calcium-channel blocker therapy are candidates for long-term therapy with an endothelin-receptor antagonist (bosentan), or prostacyclin (epoprostenol), or a prostacyclin analog (subcutaneous treprostinil, inhaled iloprost); and long-term epoprostenol therapy is considered the treatment of choice for patients with NYHA functional class IV pulmonary artery hypertension who are not candidates for, or who have failed, calcium channel blocker therapy (Badesch, 2007).  (The ACCP concensus panel that developed the 2007 practice guidelines restricted their analysis to articles conducted among patients with known or suspected idiopathic PAH, or PAH occurring in association with underlying collagen vascular disease, and congenital heart disease).
  
EPOPROSTENOL is covered as an off label treatment of PAH associated with congenital heart disease (CHD) with left to right shunt, PAH which develops following repair of a CHD defect, or PAH which develops following the prolonged presence of a left to right shunt which then reverses to a right to left shunt (Eisenmenger syndrome).  This use of epoprostenol was first reported and recommended based on a study of 20 patients with CHD and PAH.  Eleven of 20 patients had residual systemic to pulmonary shunts.  None of the patients acutely responded to epoprostenol administration, but mean pulmonary artery pressure decreased 21% on chronic therapy, and cardiac index and pulmonary vascular resistance also improved.  NYHA functional class improved from 3.2 to 2.0 (Rosenzweig, 1999). The ACCP guidelines, and the European Society of Cardiology (Galie, 2004) guidelines recommend epoprostenol for WHO/NYHA class III and IV patients with PAH associated with CHD.  
 
EPOPROSTENOL is covered for treatment of PAH associated with HIV disease. As patients with HIV has lived longer due to effective therapy, PAH has developed in a small subset of patients.  Epoprostenol is has been shown to be effective in HIV-associated PAH in case studies (Aguilar, 2000; Nunes, 2003), and the drug does not appear to have any adverse events when delivered to patients receiving highly active anti-retroactive viral therapy.  There are concerns regarding the safety of long-term central venous catheter placement because of the potential for infectious complications, which are increased in patients with HIV disease (Barst, 2007).
 
EPOPROSTENOL is covered in combination with sildenafil in patients with idiopathic pulmonary artery hypertension, pulmonary hypertension associated with anorexigen use, pulmonary hypertension due to connective tissue disease and pulmonary hypertension associated with corrected congenital heart disease as these uses were shown to improve exercise capacity, improve hemodynamic measurements (cardiac output, mean pulmonary artery pressure) and lengthened time to clinical worsening, but did not improve the Borg dyspnea score when compared to epoprostenol plus placebo (Simonneau G, 2008).
 
EPOPROSTENOL is not covered for WHO/NYHA class I or II patients.  The ACCP guidelines do not recommend epoprostenol for WHO/NYHA functional class I or II patients, and according to the 2008 AHFS Drug Compendia, “currently available clinical data are insufficient for evidence-based treatment recommendations for use of epoprostenol with NYHA functional class I or II patients” (McEvoy, 2008).
 
EPOPROSTENOL is not covered for treatment of PAH associated with congenital diaphragmatic hernia.  There are only case reports of this use of epoprostenol, and the advent of early operation and high frequency oscillatory ventilation has significantly reduced the utilization of epoprostenol for this indication (Kinsella, 2005; Shiyanagi, 2008).  
 
EPOPROSTENOL is not covered when used in combination with bosentan based on the results of a double-blind, placebo-controlled trial which showed no statistical difference in hemodynamics or clinical improvement (Humbert, 2004).
 
EPOPROSTENOL is not covered when used in combination with ambrisentan, iloprost, or treprostinil, because of lack of evidence of effectiveness.
 
A Cochrane systematic review (Paramothayan, 2005) of four IV epoprostenol studies concluded that there was significant improvement in exercise capacity of around 90 meters, cardiopulmonary hemodynamics and NYHA functional class over 3-days to 12 weeks of therapy.  Effects were consistent in idiopathic and secondary pulmonary hypertension.
 
ILOPROST (Ventavis)
Iloprost is a prostacyclin analogue designated an orphan drug by the FDA and approved by the FDA in December 2004.  It acts as a vasodilator of the pulmonary arterial vascular bed and is administered by inhalation multiple times a day.  Iloprost is covered by Arkansas BCBS for patients who are NYHA functional class III or IV, and who have certain conditions listed under the WHO group I PAH.  Iloprost is covered for IPAH; FIPH; PAH associated with scleroderma, mixed connective tissue disease, CRST, systemic lupus erythematosus; and PAH associated with anorexigenic drugs.  Coverage of iloprost is based principally on data from a 12-week, randomized, double-blind multicenter, placebo-controlled trial of patients with these conditions (Olschewski, 2002).  Long-term data on the effectiveness of iloprost is conflicting.  One uncontrolled study of 24 patients showed improvement of exercise capacity and pulmonary hemodynamics at 1 year (Hoeper, 2000), but a prospective study of 76 patients followed for an average of 1½ years showed that 60 of the 76 had not fared well (Opitz, 2005).  
 
ILOPROST is not covered for patients with NYHA functional class I symptoms, as this use of iloprost has not been studied, and is not FDA approved for this indication.
 
ILOPROST is covered in combination with bosentan based on a 3-month randomized, multicenter, double-blind trial of 67 patients with NYHA class III PAH, in which iloprost or placebo was added to the treatment regimen of patients previously treated for at least 4-months with bosentan, but were still symptomatic; (McLaughlin, 2006).  The 6-minute walk distance, NYHA functional class, right heart catheterization, and Borg dyspnea score were evaluated.  Approximately 50% of the patients had IPAH, with the remaining 50% had PAH due to scleroderma, other connective tissue diseases, HIV infection, repaired congenital heart disease, and anorexigen use.  The mean duration of bosentan therapy prior to addition of iloprost was 17.6 in the iloprost group, and 18.8 for the placebo patients.  The 6-minute walk test, NYHA functional class, the time to clinical worsening, the pulmonary artery pressure and pulmonary vascular resistance all improved significantly at the end of the 12-week period.  
 
ILOPROST is not covered in combination with epoprostenol, treprostinil, ambrisentan or sildenafil as there is no evidence of safety or effectiveness of these combinations. Iloprost was previously being studied in combination with sildenafil in a multicenter, randomized, double-blind placebo controlled trial but the trial was terminated due to slow enrollment (NCT00302211).
 
SILDENAFIL (Revatio, Viagra)
Sildenafil inhibits cGMP specific phosphodiesterase type-5 (PDES) in the smooth muscle of the pulmonary vasculature resulting in relaxation of smooth muscle cells.  This drug is taken orally three times daily.  It is indicated for treatment of WHO Class I pulmonary artery hypertension.  Efficacy of sildenafil was established in a randomized, double-blind, placebo-controlled trial in patients with PAH who were NYHA functional class II or III with primary pulmonary hypertension (idiopathic or familial), connective tissue disease, or with surgically repaired congenital systemic-to-pulmonary shunts (Galie, 2005).
 
A Cochrane systematic review (Kanthapillai, 2004) of 77patients reported in 4 randomized controlled trials of sildenafil for pulmonary hypertension concluded, “The validity of the observed effects is undermined by small participant numbers and inadequate exploration and inadequate exploration of the different disease etiologies.  The effects on long term outcome such as NYHA functional class, symptoms, mortality and exercise capacity require further validation.  More studies of adequate size are required before the long term effects of sildenafil on clinically important outcomes can be established.”  This review was done prior to the results of the Galie, et al. trial results, and is no longer applicable.
 
SILDENAFIL is covered in combination with epoprostenol, in patients with idiopathic pulmonary artery hypertension, or pulmonary hypertension associated with anorexigen use, or pulmonary hypertension due to connective tissue disease or corrected congenital heart disease as this combination has been shown to improve exercise capacity and hemodynamic measurements (cardiac output, mean pulmonary artery pressure), lengthened time to clinical worsening, but did not improve the Borg dyspnea score when compared to epoprostenol alone plus placebo (Simonneau G, 2008).
 
SILDENAFIL is not covered for treatment of persistent pulmonary hypertension of the neonate (PPHN), otherwise known as neonatal pulmonary hypertension.  A Cochrane systematic review (Shaw, 2007) on sildenafil for pulmonary hypertension in neonates concluded, “The safety and effectiveness of sildenafil in the treatment of PPHN has not yet been established and its use should be restricted within the context of randomized controlled trials.  Further randomized controlled trials of adequate power comparing sidenafil with other pulmonary vasodilators are needed in moderately ill infants with PPHN.”  
 
SILDENAFIL is not covered for treatment of pulmonary arterial hypertension secondary to idiopathic pulmonary fibrosis as this use of sildenafil is presently under study to determine its effectiveness and safety (ClinicalTrials.gov/NCT00625079).
 
SILDENAFIL is not covered in combination with bosentan as this combination is being studied in a multicenter, double-blind, randomized, placebo-controlled trial to determine effectiveness (ClinicalTrials.gov:NCT00303459).  Sildenafil has been added to bosentan monotherapy following failure of bosentan in an uncontrolled study (Mathal, 2007) with improvement in 6 MWD in IPAH, but failed to improve either parameter in scleroderma-associated pulmonary arterial hypertension patients.  The authors concluded that additional studies are needed to assess the tolerability and efficacy of this combination in patients with scleroderma-associated pulmonary arterial hypertension. Sildenafil is also currently being studied in combination with bosentan in two other trials; a randomized double-blind trial sponsored by Pfizer that is currently recruiting patients (NCT00323297) and a pilot study sponsored by the University of Calgary (NCT01247116) .
 
SIDENAFIL is not covered in combination with iloprost, as this combination was being studied in a multicenter randomized, double-blind, placebo-controlled trial to determine if the combination is better than sildenafil plus placebo (ClinicalTrials.gov:  NCT00302211), but this trial was terminated due to slow enrollment, and there is now  lack of data to determine the safety or effectiveness of this combination.
 
SILDENAFIL is not covered in combination with ambrisentan, as this combination is being studied in a randomized, double blind, placebo controlled trial to determine the safety and effectiveness of this combination (NCT00617305). This study is listed on clinicaltrials.gov website as completed with results but no publications were identified.
 
SILDENAFIL is not covered for treatment of PAH associated with pulmonary veno- occlusive disease.  Pulmonary vasodilators may worsen the cardiovascular states of  patients with pulmonary veno-occlusive disease (PVOD) and cause pulmonary edema.   Because there currently are no clinical data on the use of sildenafil in patients with  veno-occlusive disease, the manufacturer states that use of the drug in such patients  is not recommended.
 
SILDENFIL is not covered for treatment of PAH associated with severe diaphragmatic  hernia, as the use in this condition is presently being studied in a clinical trial  (ClinicalTrials.gov:NCT00133679).
 
SILDENAFIL is not covered for the treatment of PAH in children ages 1 through 17. An advisory was issued on August 30, 2012 by the U.S. Food and Drug Administration to notify healthcare providers not to prescribe sildenafil to children in this age group (www.fda.gov).  According to the FDA website this recommendation is based on the findings of a recent study where children taking a higher dose of Revatio had a higher risk of death than children taking a lower dose (www.fda.gov).
 
TADALAFIL
Tadalafil was approved in 2009 by the FDA for therapy of symptomatic PAH of WHO Category 1.  Approval was based on PHIRST, a randomized, double-blind trial (Galie, 2009) demonstrating a statistically significant increase in 6-minute walk distance in patients taking tadalafil 40 mg once daily.  In about ½ of the patients, tadalafil was added to a background of bosentan therapy.   At 16 weeks, there was a significant, 44 meter, increase in walk distance in patients taking tadalafil monotherapy; however, among the patients in whom tadalafil was added to bosentan, there was only a 23 meter increase in walk distance which did not meet statistical significance.  At 16 weeks, control patients were allowed to begin tadalafil therapy, and patients were followed for up to 6 months. There was improvement in hemodynamic data, again greater in the monotherapy patients than in the bosentan group.  Time to clinical worsening was prolonged in the tadalafil group.  Based on documented benefit for patients receiving tadalafil monotherapy and the lack of demonstrated benefit for tadalafil combined with bosentan, tadalafil is covered as monotherapy for certain categories of PAH but is not covered in combination with bosentan or other pulmonary hypertension medications.
 
In 2012, Oudiz et al. reported results from the 52-week, multicenter PHIRST extension study, PHIRST-2 (Oudiz, 2012). 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 who 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 who received 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.
  
TADALAFIL is not covered in combination with ambrisentan, as this combination is currently being studied in clinical trials to determine the safety and effectiveness of this combination (NCT01042158) (NCT01178073).
  
TADALAFIL in combination with inhaled treprostinil is currently being studied in randomized controlled trial (NCT01305252) to determine the safety and effectiveness of this combination. A clinical trial assessing the combination of tadalafil with treprostinil infusion (NCT01302444) enrolled only one patient and was terminated due to low enrollment.
 
TREPROSTINIL (Remodulin)
Treprostinil is a synthetic analog of prostacyclin (epoprostenol), and this drug has several advantages over epoprostenol, including a longer half-life (approximately 4 hours), and the ability to remain stable without refrigeration.  However, there are  concerns regarding the safety of long-term central venous catheter placement because  of the risk of blood stream infections, which appears to be more common with  treprostinil than epoprostenol (Barst, 2007).
 
Treprostinil is designated by the FDA as an orphan drug, and is approved for use in  patients with NYHA class II-IV pulmonary artery hypertension.  The FDA approval was  based on a randomized, placebo-controlled, double blind study of 470 patients with  Class II-IV primary or secondary pulmonary hypertension (Simonneau, 2002).  Pulmonary hypertension was due to IPAH, PH associated with connective tissue  diseases, or PH associated with congenital systemic to pulmonary shunts.  Patients with connective tissue disease had no pulmonary parenchymal disease as  evidenced by lung function tests and high resolution computed tomography.  Patients  with congenital heart disease (left-to-right shunts) had either pulmonary arterial  hypertension that developed a variable number of years after surgical correction, or  presented with an inversion of the shunt due to the development of pulmonary  hypertension and associated increase in pressures of the right heart (Eisenmenger  complex).  The primary endpoints were signs and symptoms of PH using a composite  score including 16 signs or symptoms; number of deaths, lung transplantations, or  drug discontinuations due to clinical deterioration.  Secondary  endpoints were  assessment of shortness of breath after the 6-minute walk test; cardiopulmonary  hemodynamics measured by right heart catheterization at baseline and week 12;  quality of life at baseline and Weeks 6 and 12.  The distance walked in 6 minutes  improved in the treprostinil group by 10 m, and remained unchanged in the placebo  group.  The signs and symptoms composite score improved in the treprostinil  group  but worsened in the placebo group.  The total number of deaths, transplantations, or  discontinuations due to clinical deterioration was 13 in the treprostinil group and 16 in  the placebo group.  Treprostinil treated patients had significant improvement in mean  right atrial pressure, mean pulmonary artery pressure, cardiac index, pulmonary  vascular resistance, mixed oxygen saturation, and quality of life.
 
TREPROSTINIL is covered for treatment of pulmonary hypertension associated with scleroderma, systemic lupus erythematosus, and mixed connective tissue disease based on a and colleagues published a subgroup analysis of the 90 patients in the  Simonneau (2002) study who had pulmonary hypertension associated with connective  tissue disease Oudiz (2004).  Twenty-five of these had SLE, 25 had diffuse  scleroderma, 20 had  limited scleroderma, and 20 had mixed connective tissue  disease.  All of these patients were said to have no pulmonary parenchymal disease  as determined by CT scan and pulmonary function studies.  This analysis showed  benefit similar to those patients with idiopathic pulmonary hypertension.
 
Treprostinil is not covered for WHO/NYHA functional class II patients.  Treprostinil is  FDA approved for treatment of NYHA/WHO class II patients, but the American College  of Chest Physicians Evidence-Based Clinical Practice Guidelines (Badesh, 2007) does  not recommend treprostinil for this class of patients.
 
There has been interest in combining treprostinil and oral therapy, but to date there  have been no randomized trials demonstrating effectiveness.  A retrospective, single center, open-label study designed to assess the efficacy of long-term, subcutaneously administered, treprostinil therapy alone or in combination with bosentan followed 38 patients for a mean duration of 984 days (range, 165 to 1,847 days) (Benza, 2008).  Oral bosentan was added to the treprostinil regimen if patients remained in New York Heart Association functional class III or II with intolerable prostacyclin side effects that limited therapy. Hemodynamic studies, Borg dyspnea score evaluations, 6-min walk (6MW) tests, and NYHA functional class determinations were performed at approximately 6-month intervals. Mean pulmonary artery pressure decreased from 59.7 to 50.5 mm Hg (p<0.001). Significant and sustained improvement in 6MW distance (p=0.022) and Borg dyspnea score (p=0.023) were observed.  At the final observation, the mean dose of treprostinil was 37.8 ng/kg/min (range, 7.5 to 115 ng/kg/min). At baseline, 5% of patients were in NYHA functional class 2 or lower vs 58% at the last follow-up. Bosentan was added to the regimens of 19 patients. In those patients, significant additional improvement occurred in the pulmonary arterial pressure (p<0.001), 6MW distance (p=0.001), and Borg dyspnea scale (p=0.020) compared to baseline. The authors concluded, “Long-term treatment with subcutaneous treprostinil-based therapy improved functional parameters and hemodynamics in patients with moderate-to-severe PAH. In patients requiring combination therapy, the addition of oral bosentan to treprostinil-based therapy was safe, well-tolerated, and associated with further clinical improvement.
 
Treprostinil was being studied in a randomized, placebo-controlled trial in combination with oral tadalafil (NCT01302444).  The trial enrolled one patient and was terminated due to low enrollment.
 
TREPROSTINIL (Tyvaso)
Tyvaso® (treprostinil inhalation solution), a prostacyclin vasodilator, was approved on July 30, 2009 for the treatment of pulmonary arterial hypertension (WHO Group I) in patients with NYHA Class III symptoms, to increase walk distance. TYVASO is dosed in 4 separate treatment sessions per day.  The effects diminish over time.  Treatment timing can be adjusted for planned activities.  Approval was based on the TRIUMPH I study which was a randomized, double-blind, placebo-controlled multi-center study of patients with PAH (McLaughlin, 2010). Two hundred thirty-five patients with NYHA Class III or IV symptoms being treated with bosentan or sildenafil were randomized to inhaled treprostinil or inhaled placebo four times daily.  The primary end point was the change in the six minute walk distance (6MWD) relative to baseline at 12 weeks.  Secondary endpoints included time to clinical worsening, Borg Dyspnea Score, NYHA Class, 12-week trough 6MWD, QOL, and PAH signs and symptoms.  The peak 6MWD within treatment median changes from baseline were 21.6m (interquartile range: -8.0 to 54.0m) and 3.0 (interquartile range:-26.0 to 31.5m) for inhaled treprostinil and placebo groups, respectively. The median difference between treatment groups was determined by the Hodges-Lehmann (H-L) between-treatment median difference.  The H-L between-treatment median difference in change in peak 6MWD was 19m at Week 6 and the change in trough 6MWD was 14m. QOL and proBNP both improved on active therapy.  No improvements were seen in any of the other secondary endpoints.  The authors conclude that Inhaled treprostinil was safe, well tolerated and improves exercise capacity in patients with PAH who remain symptomatic on bosentan or sildenafil.
 
One small uncontrolled series reported treatment of PAH in children. Krishnan and colleagues performed a retrospective cohort study of 29 children (median age 12 years, range 3.2-19) who received inhaled treprostinil for 6 weeks or longer.(Krishnan, 2012) Children were patients at one 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 mcg/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 4-8 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.
   
Treprostinil inhaled solution is currently being studied in a multicenter, randomized trial in combination with oral tadalafil. The trial is sponsored by Stanford University in collaboration with Northwestern University.  This trial was originally scheduled for completion in 2011, but is currently still recruiting subjects (NCT01305252).
 
2014 Update
 A literature search conducted through September 2014 did not reveal any new information that would prompt a change in the coverage statement.
 
 

CPT/HCPCS:
J1325Injection, epoprostenol, 0.5 mg
J3285Injection, treprostinil, 1 mg
J7686Treprostinil, inhalation solution, FDA-approved final product, noncompounded, administered through DME, unit dose form, 1.74 mg
Q4074Iloprost, inhalation solution, FDA-approved final product, noncompounded, administered through DME, unit dose form, up to 20 mcg

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