Clinical UM Guideline

 

Subject: Prostacyclin Infusion Therapy and Inhalation Therapy for Treatment of Pulmonary Arterial Hypertension
Guideline #: CG-DRUG-82 Publish Date:    05/01/2018
Status: New Last Review Date:    01/25/2018

Description

 

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:

Clinical Indications

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.

The use of epoprostenol, treprostinil, or iloprost is considered 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.

Coding

The following codes for treatments and procedures applicable to this guideline 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.

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

Discussion/General Information

PAH is a life-threatening disease characterized by sustained elevations of the 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 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.

The clinical effectiveness and safety of prostacyclin infusion therapy by continuous intravenous (IV) 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 arterial hypertension (PAH) 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.  Continuous IV 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 (CHF) 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, CHF), diseases of mitral or aortic valves, chronic obstructive pulmonary disease (COPD) or disorders of alveolar hypoventilation.

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 phosphodiesterase type 5 (PDE-5) 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) were 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 (PVR, mPAP, 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) 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 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.”  PAH associated with chronic hemolytic anemia was moved from Group 1 PAH to Group 5, (that is, 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 PAH 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 PAH as follows:  PAH due to left heart disease (Group 2), PAH due to chronic lung disease and/or hypoxia (Group 3), chronic thromboembolic PH (CTEPH - Group 4), and PAH 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, IV epoprostenol or IV 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 IV 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, 2016).

Treprostinil (Remodulin) was originally approved as a subcutaneous infusion.  In 2004, the FDA approved IV 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.”  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. 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 IV catheter-related complications, such as sepsis and venous thromboembolism.  Due to the shorter half-life of treprostinil, when given intravenously as compared to subcutaneously, the IV route 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 IV 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, 2017).

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, 2017).

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 for Tyvaso, 2017):

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).

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) and by updated specialty society guidelines for adults and children (ACCF/AHA Hoeper, 2013; Ivy, 2013; AHA/ATS Abman, 2015) as a:

  1. mean pulmonary artery pressure (mPAP) greater than 25 mm Hg (McLaughlin, 2009) or mPAP greater than or equal to 25 mm Hg at rest (Hoeper and Ivy, 2013; Abman, 2015); 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 (all guidelines); and
  3. pulmonary vascular resistance (PVR) greater than 3 Wood units (all guidelines).

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.

The World Health Organization (WHO) Classification System: Is used to describe IPAH and other causes of secondary 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 for the hypertension itself.

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).

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Government Agency, Medical Society, and Other Authoritative Publications:

  1. Abman SH, Hansmann G, Archer SL, et al. Pediatric pulmonary hypertension: guidelines from the American Heart Association and American Thoracic Society. Circulation. 2015; 132(21):2037-2099.
  2. American Hospital Formulary Service® (AHFS). AHFS Drug Information 2014®. Bethesda, MD: American Society of Health-Systems Pharmacists®, 2014.
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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.

History

Status

Date

Action

New

01/25/2018

Medical Policy & Technology Assessment Committee (MPTAC) review. Moved content of DRUG.00004 Prostacyclin Infusion Therapy and Inhalation Therapy for Treatment of Pulmonary Arterial Hypertension to new clinical utilization management guideline document with the same title. Revised the diagnostic criteria for adult and pediatric PAH in the Clinical Indications section, for clarification and consistency with updated specialty society guideline recommendations. The Discussion, Definitions and References sections were updated.