Medical Policy



Subject: Prostacyclin Infusion Therapy and Inhalation Therapy for Treatment of Pulmonary Arterial Hypertension
Document #: DRUG.00004 Current Effective Date:    10/01/2017
Status: Reviewed Last Review Date:    02/02/2017

Description/Scope

This document addresses intravenous, subcutaneous, and inhalation administration of prostacyclin analogues for the treatment of pulmonary arterial hypertension, (also referred to as idiopathic pulmonary arterial hypertension or IPAH), a life-threatening disease characterized by sustained elevations of pulmonary artery pressure with associated thickening of the pulmonary arteries and narrowing of the blood vessels.

The U.S. Food and Drug Administration (FDA) approved the following infusion and inhalation prostacyclin analogues for use in pulmonary arterial hypertension:

Position Statement

Diagnostic Criteria for Pulmonary Arterial Hypertension (PAH):

Criteria for Vasodilator Response:

Medically Necessary:

Continuous intravenous infusion of epoprostenol sodium (prostacyclin, PGI2 , Veletri, Flolan) is considered medically necessary as a treatment for individuals who meet all of the following criteria:

Continuous subcutaneous infusion of treprostinil sodium (Remodulin) is considered medically necessary as a treatment for individuals who meet all of the following criteria:

Continuous intravenous infusion of treprostinil sodium (Remodulin) is considered medically necessary for treatment of individuals who meet criteria for treprostinil treatment above when there is documented inability to tolerate treatment by subcutaneous infusion.

Inhalation therapy with iloprost (Ventavis) inhalation solution or Tyvaso inhalation solution* (treprostinil) is considered medically necessary as a treatment for individuals who meet all of the following criteria:

*FDA approved labeling for Tyvaso (treprostinil) inhalation solution states for use in the treatment of pulmonary arterial hypertension (WHO Group I) in individuals with NYHA Functional Class III symptoms to improve exercise ability (FDA, 2013).

Continuous infusion of epoprostenol or treprostinil is considered medically necessary for individuals with severe PAH refractory to medical therapy with calcium channel blockers.

Not Medically Necessary:

Use of epoprostenol, treprostinil or iloprost is considered not medically necessary as a treatment for individuals appropriate for treatment with calcium channel blockers:

Continuous intravenous infusion of treprostinil sodium (Remodulin) is considered not medically necessary for treatment of individuals when inability to tolerate treatment by subcutaneous infusion has not been documented.

Investigational and Not Medically Necessary:

The use of epoprostenol, treprostinil, or iloprost is considered investigational and not medically necessary for all other applications in the absence of WHO Group I PAH including those with WHO Group II to V* pulmonary hypertension and for other causes of pulmonary hypertension, including, but not limited to, left ventricular failure, left sided valvular heart disease, chronic pulmonary diseases, and alveolar hypoventilation syndromes.

*See the Definitions section of this document for a description of the WHO Classification System.

Rationale

The clinical effectiveness and safety of prostacyclin infusion therapy by continuous intravenous infusion of epoprostenol sodium (Flolan), continuous subcutaneous infusion of treprostinil sodium (Remodulin), and inhalation therapy with iloprost (Ventavis) inhalation solution for treatment of individuals with idiopathic pulmonary arterial hypertension (IPAH) or pulmonary hypertension associated with connective tissue disorders, such as scleroderma or congenital heart defects, is well documented in the peer-reviewed medical literature.  These therapies improve cardiopulmonary hemodynamics, exercise tolerance and quality of life in many individuals.  In addition, epoprostenol has been shown to enhance survival for individuals who have been unresponsive to conventional medical therapy. 

In a retrospective study of 557 consecutive subjects with IPAH, it was observed that 70 individuals demonstrated an acute hemodynamic response to vasodilators at cardiac catheterization, defined in this study as at least a 20% decrease in both mPAP and PVR (Sitbon, 2005).  Badesch and colleagues (2007) state:

Treatment with oral calcium channel blockers in this group of acute responders resulted in a long term response, (defined as subjects in NYHA Class I or II with a sustained hemodynamic improvement at one year without the addition of prostanoids or endothelin receptor antagonists) in only 54%, representing 6.8% of the total number of individuals studied.  It is strongly recommended, therefore, that individuals treated with calcium channel antagonists are followed closely with reassessment at three months to ensure they have improved to NYHA Functional Class I or II.  If this improvement is not observed, additional or alternative therapy should be instituted.

Prostacyclin Analogues as Monotherapy for PAH

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).  The authors searched the literature through July 2012 using broad inclusion criteria (diagnosis of PAH in individuals of any age; randomized controlled trials [RCTs], or observational studies; all sample sizes).  They identified 27 RCTs (3587 participants) and nine 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 (adult-only participants) compared a single drug (monotherapy) to placebo or standard therapy, defined as supportive treatment (diuretics, oxygen, digoxin, and/or oral anticoagulants) with or without calcium channel blockers; eight RCTs studied prostanoids, eight studied endothelin-receptor antagonists, and six studied PDE5 inhibitors.  The 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).  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) was 27.9 meters (95% CI: 10.3-45.4) for prostanoids.  There was insufficient evidence to form a conclusion concerning an association between use of prostanoids and rates of hospitalization.  Low strength of evidence for each drug class supported an association with improvements in most hemodynamic measures (pulmonary vascular resistance, 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.  Based on moderate strength of evidence, the incidence of flushing was greater with aerosolized prostanoids than with standard therapy/placebo.

Prostacyclin Analogues in Combination Therapy for PAH

In March 2009, the American College of Cardiology Foundation and the American Heart Association (ACCF/AHA) 2009 Expert Consensus Document on Pulmonary Hypertension was released.  This document includes the following information:

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…Caution is recommended against widespread treatment of non-PAH PH until patient benefit has been proven in clinical trials.  On the topic of combination therapy, while it is an attractive theoretical option in PAH, there are still ongoing trials investigating its safety and efficacy.  Benefit of combination therapy has been suggested in several smaller, open label observational studies but randomized controlled trials are needed and in process… (McLaughlin, 2009).

The safety and efficacy of combination therapy for PAH with various oral agents (vasodilators, endothelin-receptor antagonists, and phosphodiesterase type-5 [PDE-5] inhibitors) and with oral agents and prostacyclin analogues continues to be studied with some early results that suggest improved short-term clinical outcomes.  However, most authors acknowledge the need for further study to fully investigate the long-term efficacy and safety of combination therapy in PAH based on larger, well designed, controlled, clinical trials (Bai, 2011; Benza, 2008; Benza, 2011; Fox, 2011; Frantz, 2012; McLaughlin, 2010).

The 2013 AHRQ comparativeness effectiveness review also included five RCTs of combination therapies for PAH.  Treatments from different classes of drugs were combined in the meta-analyses of this review; 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 minimal important difference of 33 meters, the clinical significance of this finding is uncertain (McCrory, 2013).

Other Considerations

In 2013, the Fifth World Symposium on pulmonary hypertension (PH) (WSPH; Nice, France) reached consensus to maintain the general scheme of previous clinical classifications for PH, including some proposed modifications and updates related to pediatric PH.  The proposed change is to withdraw persistent PH of the newborn (PPHN) from Group 1 because the classification carries more differences than similarities with other PAH subgroups, thus designating PPHN as a separate number "1."  PH associated with chronic hemolytic anemia was moved from Group 1 PAH to Group 5, unclear/multifactorial mechanism.  In addition, specific items related to pediatric PH were added, in order to create a comprehensive, common classification for both adults and children, adding congenital or acquired left-heart inflow/outflow obstructive lesions and congenital cardiomyopathies to Group 2 and segmental pulmonary hypertension added to Group 5.  There were no changes to Groups 2, 3, and 4.  In summary, individuals in Group 1 are considered to have PAH, (including IPAH), and the remaining four groups are considered to have PH as follows:  PH due to left heart disease (Group 2), PH due to chronic lung disease and/or hypoxia (Group 3), chronic thromboembolic PH (Group 4), and PH due to unclear multifactorial mechanisms (Group 5) (Simonneau, 2013).  To date, the proposed modifications to the clinical classifications of PH in this 2013 consensus document differ from the earlier clinical classifications of PH (Simonneau, 2004); however, the latter remain in use by the ACCF/AHA in their 2009 expert consensus document on PH (McLaughlin, 2009).

The American College of Chest Physicians (ACCP) updated guidelines for the medical therapy of PAH clarify that an acute response to vasodilators is defined as a fall in mPAP of at least 10 mm Hg to 40 mm Hg or lower, with an unchanged or increased cardiac output when challenged with inhaled nitric oxide, intravenous epoprostenol or intravenous adenosine (Badesch, 2007).

For individuals with IPAH and a favorable response to acute vasodilator challenge, treatment with an appropriate oral calcium channel antagonist should be considered prior to the use of epoprostenol, treprostinil, or iloprost.  If a calcium channel antagonist is used, close follow-up is recommended with reassessment after three months to verify that the person has improved to NYHA Functional Class I or II (Badesch, 2007).

There is insufficient published evidence to support the use of epoprostenol, treprostinil, or iloprost for the treatment of PAH resulting from disorders other than those meeting the medical necessity criteria in this document.

Prostacyclin Analogues for the Treatment of PAH

Veletri (epoprostenol) received FDA approval on August 25, 2010 for continuous intravenous infusion for the treatment of PAH.  The current FDA-approved labeling includes indications and usage for Veletri for the treatment of PAH (WHO Group 1) to improve exercise capacity.  Studies establishing effectiveness included predominantly individuals with NYHA Functional Class III or IV symptoms and etiologies of idiopathic or heritable PAH or PAH associated with connective tissue diseases (Veletri Product Information, 2012).

Treprostinil (Remodulin) was originally approved as a subcutaneous infusion.  In 2004, the FDA approved intravenous use of treprostinil (Remodulin) "For those who are not able to tolerate a subcutaneous infusion for the treatment of PAH in patients with NYHA Class II, III, IV symptoms to diminish symptoms associated with exercise."  The current FDA-approved labeling indications and usage state:

In patients with pulmonary arterial hypertension requiring transition from Flolan (epoprostenol sodium), Remodulin is indicated to diminish the rate of clinical deterioration.  The risks and benefits of each drug should be carefully considered prior to transition (Remodulin Product Information, 2013).

While local site reactions may be lessened by continuous IV infusion of epoprostenol, this route exposes the individual to intravenous catheter-related complications, such as sepsis and venous thromboembolism and, due to the shorter half-life of treprostinil, when given intravenously as compared to subcutaneously, may increase the risks related to abrupt cessation in the delivery of the medication, as occurs with pump malfunction.  Accordingly, Remodulin is preferably infused subcutaneously, but can be administered by a central intravenous line if the subcutaneous route is not tolerated, due to severe site pain or reaction.  An uncontrolled study demonstrated that transition from IV epoprostenol to subcutaneous Remodulin can be successfully achieved without major adverse side effects.

Iloprost (Ventavis) inhalation solution is a synthetic analogue of prostacyclin, which dilates systemic and pulmonary arterial vascular beds resulting in improvement in exercise capacity and the symptoms associated with PAH. Ventavis was FDA-approved on August 17, 2004 for, "The treatment of pulmonary arterial hypertension (WHO Group I) in patients with NYHA Class III or IV symptoms."  According to the FDA approval information, in controlled trials, it improved a composite endpoint consisting of exercise tolerance, symptoms (NYHA Class), and lack of deterioration (Olschewski, 2002).  Ventavis is intended for inhalation administration only via the pulmonary drug delivery device, the I-neb® AAD® System, and has not been studied with any other nebulizers. The current FDA-approved labeling includes the following warnings and precautions:

Ventavis inhalation can induce bronchospasm.  Bronchospasm may be more severe or frequent in patients with a history of hyperreactive airways.  Ventavis has not been evaluated in patients with chronic obstructive pulmonary disease (COPD), severe asthma, or with acute pulmonary infections.  Safety and efficacy in pediatric patients has not been established (Ventavis Product Information, 2013).

On July 30, 2009, the FDA approved another inhalation form of treprostinil, Tyvaso inhalation solution for the treatment of PAH.  The current FDA-approved labeling states:

Tyvaso is indicated for the treatment of pulmonary arterial hypertension (PAH) (WHO Group I) to improve exercise ability.  Studies establishing effectiveness included predominately patients with NYHA Functional Class III symptoms and etiologies of idiopathic or heritable PAH (56%) or PAH associated with connective tissue diseases (33%).  The effects diminish over the minimum recommended dosing interval of 4 hours; treatment can be adjusted for planned activities.  While there are long-term data on use of treprostinil by other routes of administration, nearly all controlled clinical experience with inhaled treprostinil has been on a background of bosentan (an endothelin receptor antagonist) or sildenafil (a phosphodiesterase type 5 inhibitor).  The controlled clinical experience was limited to 12 weeks in duration (Tyvaso Product Information, 2016).

In an updated supplemental approval letter from the FDA regarding Tyvaso, revisions were approved for the 'Use in Specific Populations' section of the labeling for pregnancy to remove the language, "Tyvaso should be used during pregnancy only if clearly needed."  Additional outcomes data was provided in this 2014 letter and in another update in 2016, both regarding animal study results and the following was also noted regarding long term results of the pivotal human trial with no change to the FDA approved labeling indications (FDA Prescribing Information, 2016):

In long-term follow-up of patients who were treated with Tyvaso in the pivotal study and the open-label extension (N=206), Kaplan-Meier estimates of survival at 1, 2, and 3 years were 97%, 91%, and 82%, respectively.  These uncontrolled observations do not allow comparison with a control group not given Tyvaso and cannot be used to determine the long-term effect of Tyvaso on mortality (FDA, August 2014).

Background/Overview

PAH is a life-threatening disease characterized by sustained elevations of the mean pulmonary arterial pressure (mPAP), thickening of the pulmonary arteries and narrowing of the blood vessels.  As the disease progresses, the right side of the heart becomes enlarged and may fail.

The World Health Organization (WHO) Classification System is used to describe idiopathic pulmonary arterial hypertension (IPAH) and other causes of secondary pulmonary hypertension (PH).  IPAH is characterized by a sustained level of mPAP without apparent cause.  The estimated incidence of IPAH is 1 to 2 cases per 1 million persons in the general population.  During childhood, the condition affects both genders equally; after puberty, it is more common in women than men and is most prevalent in persons 20 to 40 years of age.  If untreated, the median survival from time of diagnosis is less than 2.8 years.  Unexplained shortness of breath and fatigue are common early symptoms; angina and syncope are seen in advanced disease stages.  Secondary PH (WHO Groups 2 -5) occurs as a complication of pulmonary, cardiac and extrathoracic conditions.  Common causes include scleroderma and its variants (such as, the CREST syndrome), and various congenital heart defects.  In individuals with secondary PH, management is directed at early recognition and treatment of the underlying disease and may also include therapy of the hypertension itself.

The diagnosis and treatment of PAH is complex and continues to be refined.  Medical management consists of diuretics, supplemental oxygen, anticoagulants, calcium channel blockers, endothelin receptor antagonists (bosentan [Tracleer, Actelion Pharmaceuticals US, Inc., South San Francisco, CA]), and continuous infusion of prostacyclin (epoprostenol) or prostacyclin analog (treprostinil) or inhaled iloprost.  Lung or heart-lung transplantation has been performed in individuals who are refractory to medical management.

Epoprostenol sodium is a naturally occurring prostacyclin that decreases PVR and increases cardiac output.  Because of epoprostenol's short half-life, it must be administered intravenously with a portable infusion pump attached to a permanent indwelling central venous catheter.  Continuous intravenous epoprostenol infusions are reserved for those who are unresponsive to conventional therapy, and may be used either as long-term therapy or as a bridge to transplantation.  Epoprostenol is contraindicated in individuals with congestive heart failure due to severe left ventricular systolic dysfunction and those with hypersensitivity to epoprostenol or to structurally–related compounds.  It is not recommended for treatment in the following diagnoses: diseases of the left atrium or ventricle (for example, cardiomyopathy, congestive heart failure), diseases of mitral or aortic valves, chronic obstructive pulmonary disease (COPD) or disorders of alveolar hypoventilation.

Unlike epoprostenol, treprostinil (Remodulin) is administered by continuous subcutaneous infusion using an infusion pump designed for subcutaneous drug delivery.  Remodulin remains stable at room temperature, does not require reconstitution and is unlikely to cause serious infections, due to its subcutaneous method of delivery, (although continuous intravenous method of administering Remodulin is now FDA approved for those who are not able to tolerate the subcutaneous infusion of this drug).  Drugs, such as diuretics, antihypertensive agents, or vasodilators, that by themselves alter blood pressure, may exacerbate reductions in blood pressure caused by Remodulin.  Because Remodulin also inhibits platelet aggregation, there is potential for increased risk of bleeding, particularly among individuals maintained on anticoagulants.  During clinical trials, however, Remodulin was used concurrently with anticoagulants, diuretics, cardiac glycosides, calcium channel blockers, analgesics, antipyretics, nonsteroidal anti-inflammatories, opioids, corticosteroids, and other medications.

Definitions

New York Heart Association (NYHA) Functional Classification for Heart Failure symptoms:

Class I No limitation with ordinary physical activity;
Class II Slight limitation with fatigue, dyspnea, palpitations, or angina resulting from ordinary physical activity;
Class III Marked limitation; symptomatic with less than ordinary activity;
Class IV Symptoms present while at rest.

Pulmonary arterial hypertension (PAH): A class of diseases categorized by persistently increased blood pressure in the pulmonary artery, which transports blood from the right ventricle of the heart to the lungs.  This can lead to significant and potentially lethal damage to the heart, and may even require lung or heart-lung transplantation if not adequately controlled.  PAH is defined by the 2009 ACCF/AHA Expert Consensus document (McLaughlin, 2009) as a:

  1. mean pulmonary artery pressure (mPAP) greater than 25 mm Hg; and
  2. pulmonary capillary wedge pressure (PCWP), left atrial pressure, or left ventricular end-diastolic pressure (LVEDP) less than or equal to 15 mm Hg; and
  3. pulmonary vascular resistance (PVR) greater than 3 Wood units.

Pulmonary arterial hypertension (PAH) WHO Clinical Classification System: The changes in defining and classifying pulmonary hypertension were developed by the 2009 ACCF/AHA Expert Consensus Task Force on Pulmonary Hypertension (McLaughlin, 2009).  Persons in Group 1 are considered to have pulmonary arterial hypertension (PAH or idiopathic PAH/IPAH), and the remaining four groups are considered to have PH (secondary PH) (Simonneau, 2004).

Table 1. Revised WHO Classification of Pulmonary Hypertension (PH)

1.

Pulmonary arterial hypertension (PAH)
 

1.1.

Idiopathic (IPAH)
 

1.2.

Familial (FPAH)
 

1.3.

Associated with (APAH):
   

1.3.1.

Connective tissue disorder
   

1.3.2.

Congenital systemic-to-pulmonary shunts
   

1.3.3.

Portal hypertension
   

1.3.4.

HIV infection
   

1.3.5.

Drugs and toxins
   

1.3.6.

Other (thyroid disorders, glycogen storage disease, Gaucher's disease, hereditary hemorrhagic telangiectasia, hemoglobinopathies, chronic myeloproliferative disorders, splenectomy)

 

1.4.

Associated with significant venous or capillary involvement
   

1.4.1.

Pulmonary veno-occlusive disease (PVOD)
   

1.4.2.

Pulmonary capillary hemangiomatosis (PCH)
 

1.5.

Persistent pulmonary hypertension of the newborn (PPHN)

2.

Pulmonary hypertension associated with left heart diseases
 

2.1.

Left-sided atrial or ventricular heart disease
 

2.2.

Left-sided valvular heart disease

3.

Pulmonary hypertension associated with respiratory diseases and/or hypoxemia (including COPD)
 

3.1.

Chronic obstructive pulmonary disease
 

3.2.

Interstitial lung disease
 

3.3.

Sleep disordered breathing
 

3.4.

Alveolar hypoventilation disorders
 

3.5.

Chronic exposure to high altitude
 

3.6.

Developmental abnormalities

4.

Pulmonary hypertension due to chronic thrombotic and/or embolic disease (CTEPH)
 

4.1.

Thromboembolic obstruction of proximal pulmonary arteries
 

4.2.

Thromboembolic obstruction of distal pulmonary arteries
 

4.3.

Nonthrombotic pulmonary embolism (tumor, parasites, foreign material)

5.

Miscellaneous
  Sarcoidosis, histiocytosis X, lymphangiomatosis, compression of pulmonary vessels (adenopathy, tumor, fibrosing mediastinitis).

Scleroderma: A systemic disorder of connective tissue characterized by induration and thickening of the skin, abnormalities of the blood vessels, and fibrotic degenerative changes in various body organs.

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 (Rich, 1998).

 

Coding

The following codes for treatments and procedures applicable to this document are included below for informational purposes. Inclusion or exclusion of a procedure, diagnosis or device code(s) does not constitute or imply member coverage or provider reimbursement policy. Please refer to the member's contract benefits in effect at the time of service to determine coverage or non-coverage of these services as it applies to an individual member.

When services may be Medically Necessary when criteria are met: 

HCPCS  
J1325 Injection, epoprostenol; 0.5 mg [Flolan, Veletri]
J3285 Injection, treprostinil, 1 mg [Remodulin]
J7686 Treprostinil, inhalation solution, FDA-approved final product, non-compounded, administered through DME, unit dose form, 1.74 mg [TYVASO]
K0455 Infusion pump used for uninterrupted parenteral administration of medication (e.g., epoprostenol or treprostinil)
Q4074 Iloprost, inhalation solution, FDA-approved final product, non-compounded, administered through DME, unit dose form, up to 20 micrograms [Ventavis]
S0155 Sterile dilutant for epoprostenol, 50 ml [dilutant for Flolan]
S9347 Home infusion therapy, uninterrupted, long-term, controlled rate intravenous or subcutaneous infusion therapy (e.g., epoprostenol)
   
ICD-10 Diagnosis  
I27.0 Primary pulmonary hypertension
I27.20 Pulmonary hypertension, unspecified
I27.21 Secondary pulmonary arterial hypertension
I27.83 Eisenmenger's syndrome
I27.89 Other specified pulmonary heart diseases
I27.9 Pulmonary heart disease, unspecified
M34.0 Progressive systemic sclerosis
M34.81 Systemic sclerosis with lung involvement
M34.9 Systemic sclerosis, unspecified
Q20.0-Q24.9 Congenital malformations of heart

When services are Not Medically Necessary or Investigational and Not Medically Necessary:
For the procedure and diagnosis codes listed above when criteria are not met or for all other diagnoses not listed, or when the code describes a procedure indicated in the Position Statement section as not medically necessary or investigational and not medically necessary.

References

Peer Reviewed Publications:

  1. Adatia I. Recent advances in pulmonary vascular disease. Curr Opin Pediatr. 2002; 14(3):292-297.
  2. Bai Y, Sun L, Hu S, et al. Combination therapy in pulmonary arterial hypertension: a meta-analysis. Cardiology. 2011; 120(3):157-165.
  3. Barst RJ, Galie N, Naeije R, et al. Long-term outcome in pulmonary arterial hypertension patients treated with subcutaneous treprostinil. Eur Respir J. 2006; 28(6):1195-1203.
  4. Barst RJ, Rubin LJ, Long WA, et al. A comparison of continuous intravenous epoprostenol (prostacyclin) with conventional therapy for primary pulmonary hypertension. The Primary Pulmonary Hypertension Study Group. N Engl J Med. 1996; 334(5)296-302.
  5. Barst RJ, Rubin LJ, McGoon MD, et al. Survival in primary pulmonary hypertension with long-term continuous intravenous prostacyclin. Ann Intern Med. 1994; 121(6):409-415.
  6. Benza RL, Rayburn B, Tallaj J, et al. Treprostinil-based therapy in the treatment of moderate to severe pulmonary arterial hypertension: long-term efficacy and combination with bosentan. Chest. 2008; 134(1):139-145.
  7. Benza RL, Seeger W, McLaughlin VV, et al. Long-term effects of inhaled treprostinil in patients with pulmonary arterial hypertension: the Treprostinil Sodium Inhalation Used in the Management of Pulmonary Arterial Hypertension (TRIUMPH) study open-label extension. J Heart Lung Transplant. 2011; 30(12):1327-1333.
  8. Bing He, Zhang F, Li X, et al.  Meta-analysis of randomized controlled trials on treatment of pulmonary arterial hypertension. Circulation J. 2010; 74(7):1458-1464.
  9. Bos AP, Tibboel D, Koot VC, et al. Persistent pulmonary hypertension in high-risk congenital diaphragmatic hernia patients: incidence and vasodilator therapy. J Pediatr Surg. 1993; 28(11):1463-1465. 
  10. Budhiraja R, Hassoun PM. Portopulmonary hypertension: a tale of two circulations. Chest. 2003; 123(2):562-576.
  11. Channick RN, Olschewski H, Seeger W, et al. Safety and efficacy of inhaled treprostinil as add-on therapy to bosentan in pulmonary arterial hypertension. J Am Coll Cardiol. 2006; 48(7):1433-1437.
  12. Channick R, Williamson TL. Diagnosis and treatment of pulmonary arterial hypertension. Cardiol Clin. 2004; 22(3):441-452.
  13. Clapp LH, Finney P, Turcato S, et al. Differential effects of stable prostacyclin analogs on smooth muscles proliferation and cyclic AMP generation in human pulmonary artery. Am J Respir Cell Mol Biol. 2002; 26(2):194-202.
  14. Forrest IA, Small T, Corris PA. Effect of nebulized epoprostenol (prostacyclin) on exhaled nitric oxide in patients with pulmonary hypertension due to congenital heart disease and in normal controls. Clin Sci (Lond). 1999; 97(1):99-102.
  15. Fox BD, Shimony A, Langleben D. Meta-analysis of monotherapy versus combination therapy for pulmonary arterial hypertension. Am J Cardiol. 2011; 108(8):1177-1182.
  16. Frantz RP, McDevitt S, Walker S. Baseline NT-proBNP correlates with change in 6-minute walk distance in patients with pulmonary arterial hypertension in the pivotal inhaled treprostinil study TRIUMPH-1. J Heart Lung Transplant. 2012; 31(8):811-816.
  17. Galie N, Manes A, Negro L, et al. A meta-analysis of randomized controlled trials in pulmonary arterial hypertension. Eur Heart J. 2009; 30(4):394-403.
  18. Gall H, Sommer N, Milger K, et al. Survival with sildenafil and inhaled iloprost in a cohort with pulmonary hypertension: an observational study. BMC Pulm Med. 2016; 16:5.
  19. Hoeper MM. Drug treatment of pulmonary arterial hypertension: current and future agents. Drugs. 2005; 65(10):1337-1354.
  20. Hoeper MM, Leuchte H, Halank M, et al. Combining inhaled iloprost with bosentan in patients with idiopathic pulmonary arterial hypertension. Eur Respir J. 2006; 28(4):683-686.
  21. Hunbert M, Sitbon O, Simonneau G. Treatment of pulmonary arterial hypertension. N Engl J Med. 2004; 351(14):1425-1436.
  22. Lowson SM, Doctor A, Walsh BK, Doorley PA. Inhaled prostacyclin for the treatment of pulmonary hypertension after cardiac surgery. Crit Care Med. 2002; 30(12):2762-2764.
  23. Maloney JP. Advances in the treatment of secondary pulmonary hypertension. Curr Opin Pul Med. 2003; 9(2):139-143.
  24. McLaughlin VV, Benza RL, Rubin LJ, et al. Addition of inhaled treprostinil to oral therapy for pulmonary arterial hypertension: a randomized controlled clinical trial. J Am Coll Cardiol. 2010; 55(18):1915-1922.
  25. McLaughlin VV, Gaine SP, Barst RJ, et al. Efficacy and safety of treprostinil: an epoprostenol analog for primary pulmonary hypertension. J Cardiovasc Pharmacol. 2003; 41(2):293-299.
  26. McLaughlin VV, Genthner DE, Panella MM, et al. Compassionate use of continuous prostacycline in the management of secondary pulmonary hypertension: a case series. Ann Intern Med. 1999; 130(9):740-743.
  27. McLaughlin VV, Oudiz RJ, Frost A, et al. Randomized study of adding inhaled iloprost to existing bosentan in pulmonary arterial hypertension. Am J Respir Crit Care Med. 2006; 174(11):1257-1263.
  28. McLaughlin VV, Shillington A, Rich S. Survival in primary pulmonary hypertension: the impact of epoprostenol therapy. Circulation. 2002; 106(12):1477-1482.
  29. Nauser TD, Stites SW. Diagnosis and treatment of pulmonary hypertension. Am Fam Physician. 2001; 63(9):1789-1798.
  30. Olschewski H, Rohde B, Behr J, et al. Pharmacodynamics and pharmacokinetics of inhaled iloprost, aerosolized by three different devices, in severe pulmonary hypertension. Chest. 2003; 124(4):1294-1304.
  31. Olschewski H, Rose F, Grunig E, et al. Cellular pathophysiology and therapy of pulmonary hypertension. J Lab Clin Med. 2001; 138(6):367-377.
  32. Olschewski H, Simonneau G, Galie N, et al. Inhaled iloprost for severe pulmonary hypertension. N Engl J Med. 2002; 347(5):322-329.
  33. Opitz CF, Wensel R, Bettmann M, et al. Assessment of the vasodilator response in primary pulmonary hypertension. Comparing prostacyclin and iloprost administered by either infusion or inhalation. Eur Heart J. 2003; 24(4):356-365.
  34. Provencher S, Jais X, Yaici A, et al. Clinical challenges in pulmonary hypertension: Roger S. Mitchell Lecture.  Chest. 2005; 128(6 Suppl):622S-628S.
  35. Rich S. The current treatment of pulmonary arterial hypertension: time to redefine success. Chest. 2006; 130(4):1198-1202.
  36. Rosenzweig EB, Kerstein D, Barst RJ. Long-term prostacyclin for pulmonary hypertension with associated congenital heart defects. Circulation. 1999; 99(14):1858-1865.
  37. Rubenfire M, McLaughlin VV, Allen RP, et al. Transition from IV epoprostenol to subcutaneous treprostinil in pulmonary arterial hypertension: a controlled trial. Chest. 2007; 132(3):757-763.
  38. Rudarakanchana N, Trembath RC, Morrell NW. New insights into the pathogenesis and treatment of primary pulmonary hypertension. Thorax. 2001; 56(11):888-890.
  39. Ruiz MJ, Escribano P, Delgado JF, et al. Efficacy of sildenafil as a rescue therapy for patients with severe pulmonary arterial hypertension and given long-term treatment with prostanoids: 2-year experience. J Heart Lung Transplant. 2006; 25(11):1353-1357.
  40. Ryerson CJ, Nayer S, Swiston JR, Sin DD. Pharmacotherapy in pulmonary arterial hypertension: a systematic review and meta-analysis. Respir Res. 2010; 11:12.
  41. Simonneau G, Barst RJ, Nazzareno G, et al. Continuous subcutaneous infusion of treprostinil a prostacyclin analogue, in patients with pulmonary arterial hypertension: a double-blind, randomized, placebo-controlled trial. Am J Respir Crit Care Med. 2002; 165(6):800-804.
  42. Sitbon O, Humbert M, Jais X, et al. Long-term response to calcium channel blockers in idiopathic pulmonary arterial hypertension.  Circulation. 2005; 111(23):3105-3111.
  43. Tapson VF, Gomberg-Maitland M, McLaughlin VV, et al. Safety and efficacy of IV treprostinil for pulmonary arterial hypertension: a prospective, multicenter, open-label 12-week trial.  Chest. 2006; 129(3):683-688.
  44. Vachiery JL, Hill N, Zwicke D, et al. Transitioning from IV epoprostenol to subcutaneous treprostinil in pulmonary arterial hypertension. Chest. 2002; 121(5):1561-1565.
  45. Voswinckel R, Enke B, Reichenberger F, et al. Favorable effects of inhaled treprostinil in severe pulmonary hypertension: results from randomized controlled pilot studies. J Am Coll Cardiol. 2006; 48(8):1672-1681.

Government Agency, Medical Society, and Other Authoritative Publications:

  1. American Hospital Formulary Service® (AHFS). AHFS Drug Information 2014® . Bethesda, MD: American Society of Health-Systems Pharmacists® , 2014.
  2. Badesch BD, Abman SH, Simonneau G, et al. Medical therapy for pulmonary arterial hypertension: updated ACCP evidence-based clinical practice guidelines. Chest. 2007; 131(6):1917-1928.
  3. Barst RJ, Gibbs JS, Ghofrani HA, et al. Updated evidence based treatment algorithm in pulmonary arterial hypertension. J Am Coll Cardiol. 2009; 54(Suppl 1):S78-84. Available at: http://content.onlinejacc.org/article.aspx?articleid=1139844. Accessed on January 5, 2017.
  4. Epoprostenol sodium. In: DrugPoints® System (electronic version). Truven Health Analytics, Greenwood Village, CO. Updated August 14, 2014. Available at: http://www.micromedexsolutions.com.  Accessed on January 5, 2017.
  5. Fleming T, Lindenfeld J, Lipicky R, et al. Report from the 93rd Cardiovascular and Renal Drugs Advisory Committee Meeting, August 9-10, 2001. Circulation. 2001; 104(15):1742.
  6. Flolan [Product Information], Research Triangle Park, NC, GlaxoSmithKline; March 29, 2011. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/020444s018lbl.pdf. Accessed on January 5, 2017.
  7. Galie N, Corris PA, Frost A, et al. Updated treatment algorithm of pulmonary arterial hypertension. J Am Coll Cardiol. 2013; 62(25 Suppl):D60-72.
  8. Galiè N, Humbert M, Vachiery JL, et al. 2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension: The Joint Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS): Endorsed by: Association for European Pediatric and Congenital Cardiology (AEPC), International Society for Heart and Lung Transplantation (ISHLT). Eur Heart J. 2016; 37(1):67-119.
  9. Iloprost inhalation solution. In: DrugPoints System (electronic version). Truven Health Analytics, Greenwood Village, CO. Updated December 26, 2013. Available at: http://www.micromedexsolutions.com. Accessed on January 5, 2017.
  10. McCrory DC, Coeytaux RR, Schmit KM, et al. Pulmonary arterial hypertension: screening, management, and treatment [Internet]. Comparative Effectiveness Review No. 117. (Prepared by the Duke Evidence based Practice Center under Contract No. 290-2007-10066-I.). AHRQ Publication No. 13-EHC087-EF. Rockville (MD): Agency for Healthcare Research and Quality (US); 2013 April. Available at: http://effectivehealthcare.ahrq.gov/search-for-guides-reviews-and-reports/?pageaction=displayproduct&productid=1479. Accessed on January 5, 2017.
  11. McLaughlin VV, Archer SL, Badesch DB, et al. ACCF/AHA 2009 expert consensus document on pulmonary hypertension. A report of the American College of Cardiology Foundation Task Force on Expert Consensus Documents and the American Heart Association. J Am Coll Cardiol. 2009; 53:1573-1619. Available at: http://circ.ahajournals.org/content/119/16/2250.full.pdf+html. Accessed on January 6, 2017.
  12. National Institutes of Health (NIH). National Heart Lung and Blood. Patient Registry for Primary Pulmonary Hypertension (PPH Registry). Ann Intern Med. 1987; 107:216-223; Ann Intern Med. 1991; 115:343-349. Last updated June 23, 2005. Available at: https://biolincc.nhlbi.nih.gov/studies/pphreg/?q=Pulmonary%20hypertension . Accessed on January 5, 2017.
  13. Paramothayan NS, Lasserson TJ, Wells AU, Walters EH. Prostacyclin for pulmonary hypertension in adults. Cochrane Database Syst Rev. 2005;(2):CD002994.
  14. Pohar R, Clark M, Spry C. Drugs for pulmonary arterial hypertension: a systematic review of the clinical-effectiveness of combination therapy. Ottawa: Canadian Agency for Drugs and Technologies in Health; 2009.
  15. Rich S, Rubin LJ, Abenhaim L, et al. Executive summary from the World Health Organization world symposium on primary pulmonary hypertension 1998. World Health Organization. Evian, France: 1998; 6-10.
  16. Remodulin [Product Information], Research Triangle Park, NC. United Therapeutics Corporation; September 26, 2013. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/021272s020lbledt.pdf. Accessed on January 5, 2017.
  17. Simonneau G, Galie N, Rubin LJ, et al. Clinical classification of pulmonary hypertension. J Am Coll Cardiol. 2004; 43(12 Suppl S):5S-12S.
  18. Simonneau G, Gatzoulis MA, Adatia I, et al. Updated clinical classification of pulmonary hypertension. J Am Coll Cardiol. 2013; 62(25 Suppl):D34-41.
  19. Simonneau G, Robbins IM, Beghetti M, et al. Updated classification of pulmonary hypertension. J Am Coll Cardiol 2009; 54(1 suppl):S43-54.
  20. Taichman DB, Ornelas J, Chung L, et al. American College of Chest Physicians (ACCP). Pharmacologic therapy for pulmonary arterial hypertension in adults: CHEST Guideline and Expert Panel Report. Chest. 2014; 146 (2): 449-475.
  21. Treprostinil. In: DrugPoints System (electronic version). Truven Health Analytics, Greenwood Village, CO.  Updated January 9, 2014. Available at: http://www.micromedexsolutions.com. Accessed on January 5, 2017.
  22. Tyvaso [Product Information], Research Triangle Park, NC. United Therapeutics Corporation; Updated June 2016. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/022387s014lbl.pdf.Accessed on January 5, 2017.
  23. Veletri [Product Information], Actelion Pharmaceuticals US, Inc. South San Francisco, CA; June 28, 2012. Available at: https://www1.actelion.us/documents/us/product-documentation/veletri-(epoprostenol-for-injection)-prescribing-information.pdf .  Accessed on January 5, 2017.
  24. Ventavis [Product Information], Actelion Pharmaceuticals US, Inc. South San Francisco, CA; November 22, 2013. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/021779s014lbl.pdf. Accessed on January 5, 2017.
Index

Epoprostenol Sodium
Flolan
Remodulin
Iloprost
Veletri
Ventavis
Treprostinil
Tyvaso

The use of specific product names is illustrative only.  It is not intended to be a recommendation of one product over another, and is not intended to represent a complete listing of all products available.

Document History
Status Date Action
  10/01/2017 Updated Coding section with 10/01/2017 ICD-10-CM diagnosis code changes.
Reviewed 02/02/2017 Medical Policy & Technology Assessment Committee (MPTAC) review. Updated the formatting in the Position Statement section. Updated Rationale and References sections.
Reviewed 02/04/2016 MPTAC review. References were updated. Removed ICD-9 codes from Coding section.
Reviewed 02/05/2015 MPTAC review. The Rationale and References sections were updated.
Reviewed 02/13/2014 MPTAC review. Format changes throughout document. Updated Description, FDA label information for Tyvaso in the Position Statement (with no change to criteria), Rationale, Background, References, and Index sections.
Reviewed 02/14/2013 MPTAC review. Rationale and References were updated.
Reviewed 02/16/2012 MPTAC review. References were updated.
Revised 02/17/2011 MPTAC review. Added the newly FDA approved epoprostenol agent, Veletri® to the medically necessary position statements. The title was revised to remove specific branded names of pharmaceutical agents. The Rationale and References were updated.
  01/01/2011 Updated Coding section with 01/01/2011 HCPCS changes.
Reviewed 08/19/2010 MPTAC review. The Rationale and References were updated.
  01/01/2010 Updated Coding section with 01/01/2010 HCPCS changes; removed HCPCS Q4080 deleted 12/31/2009.
Revised 08/27/2009 MPTAC review. The language of the medical necessity criteria has been reformatted and revised to refer to WHO Group I pulmonary arterial hypertension. Language referring to primary and secondary PAH has been removed. WHO Group II-V PAH has been added to the conditions considered investigational and not medically necessary. The definition of PAH has been revised to align with the 2009 ACCF/AHA Expert Consensus Document. The Description, Rationale, Background and Definitions sections have been updated with information from the 2009 ACCF/AHA Expert Consensus document on pulmonary hypertension, including the WHO Classification System for PAH. Information was also added to the Rationale section regarding a newly FDA approved inhalation form of treprostinil (TYVASO). TYVASO has also been added to the position statement regarding inhalation therapy as medically necessary when criteria are met. The title has been revised to add "Arterial" to pulmonary hypertension and to add TYVASO.
Revised 02/26/2009 MPTAC review. Ventavis® (iloprost) inhalation solution was added to the drugs considered medically necessary when criteria are met. The language of the not medically necessary criteria was also clarified. Document was re-titled to Prostacyclin Infusion Therapy and Inhalation Therapy for Treatment of Pulmonary Hypertension (epoprostenol [Flolanâ ], treprostinil [Remodulinâ ], iloprost [Ventavisâ ]). Rationale, Coding and References were also updated.
Revised 02/21/2008 MPTAC review. Language was revised to clarify the definition of what constitutes a favorable acute hemodynamic response to vasodilators within the medical necessity criteria based on newly updated ACCP guidelines. Rationale section was also updated.  The phrase "investigational/not medically necessary" was clarified to read "investigational and not medically necessary." This change was approved at the November 29, 2007 MPTAC meeting. References were updated including the change from USP DI to new DrugPoints compendia.
Reviewed 08/23/2007 MPTAC review. References and coding were updated.
Revised 09/14/2006 MPTAC review. The medical necessity criteria were revised to add reference to FDA-approved IV treprostinil when criteria are met. Rationale section was also updated with this information.  References were updated with recently published articles. Coding updated; removed HCPCS Q4077, S0114 deleted 12/31/05.
Reviewed 03/23/2006 MPTAC review. References were updated. 
  01/01/2006 Updated Coding section with 01/01/2006 CPT/HCPCS changes
Revised 04/28/2005 MPTAC review. Revision based on Pre-merger Anthem and Pre-merger WellPoint Harmonization. Updated coding: Removed HCPCS code S9210 deleted 01/01/2002; removed CPT code 99566 deleted 07/01/2003.
Pre-Merger Organizations Last Review Date Document Number Title
Anthem, Inc. 06/17/2003 DRUG.00004 Prostacyclin Infusion Therapy for Treatment of Pulmonary Hypertension (Epoprostenol [Flolan® ], treprostinil [Remodulin® ])
WellPoint Health Networks, Inc. 08/05/2004 Pharmacology Toolkit Prostacyclin, Flolan® , Epoprostenol
  08/05/2004 Pharmacology Toolkit Treprostinil Sodium Remodulin