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Pulmonary hypertension (PH) refers to the presence of abnormally high pulmonary vascular pressure. The World Health Organization (WHO) classifies patients with PH into the following five groups based on etiology:

• WHO Group 1: Pulmonary arterial hypertension (PAH) 
• WHO Group 2: Pulmonary hypertension due to left heart disease
• WHO Group 3: Pulmonary hypertension due to lung diseases and/or hypoxemia
• WHO Group 4: Chronic thromboembolic pulmonary hypertension (CTEPH)
• WHO Group 5: Pulmonary hypertension with unclear multifactorial mechanisms

Pulmonary Arterial Hypertension (PAH; WHO Group 1)

PAH is a rare and debilitating disease characterized by abnormal proliferation and contraction of pulmonary artery smooth muscle cells. This condition causes a decrease in the size of the pulmonary artery lumen, decreased reactivity of the vascular bed, increased pulmonary vascular resistance (PVR), elevated pressure in the pulmonary circulation (initially with normal left-sided pressures), and leads to overload-induced progressive right ventricular dilation and low cardiac output.

Idiopathic PAH is more prevalent in women, and is the most common type of PAH. Familial PAH often results from a mutation in bone morphogenetic protein receptor-2 (BMPR2) and is inherited as an autosomal dominant disease. PAH is also associated with congenital heart disease, connective tissue diseases, drugs and toxins, human immunodeficiency virus (HIV), portal hypertension, hemoglobinopathies, and myeloproliferative disorders.

Management of PAH

Conventional therapies are considered in all patients with PAH regardless of etiology. These therapies include diuretics, oxygen therapy, anticoagulants, digoxin, and exercise. Digoxin has been shown to have beneficial effects when used with caution (i.e., patients may be at higher risk for digitalis toxicity and require close monitoring). Patients with a positive vasoreactivity test can be given a trial of calcium channel blockers, whereas patients with a negative vasoreactivity test require advanced therapy.

Advanced therapies, according to therapeutic class, that are FDA-approved for the treatment of adults with PAH include:

• Prostacyclin analogues
  • Epoprestenol (Flolan^® or Veletri^®)
  • Treprostinil (Remodulin^®, Tyvaso^®, or Orenitram^™)
  • Iloprost (Ventavis^®)
• Non-prostanoid prostacyclin IP receptor agonist
  • Selexipag (Uptravi^®)
• Endothelin receptor antagonists
  • Bosentan (Tracleer^®)
  • Ambrisentan (Letairis^®)
  • Macitentan (Opsumit^®)
• Phosphodiesterase type 5 inhibitors
  • Sildenafil (Revatio^®)
  • Tadalafil (Adcirca^®)
• Soluble guanylate cyclase stimulator
  • Riociguat (Adempas^®) 

No advanced therapy is FDA-approved for pharmacological treatment of PAH in pediatric patients. Combination therapy with two or more advanced therapies has generally been reserved for patients who have failed monotherapy; however, first-line use is recommended in some clinical situations. Pulmonary endarterectomy, lung transplantation, and combined heart-lung transplantation have been performed in patients refractory to medical management. Objective assessments to measure treatment response include improvement in exercise capacity (6-minute walk test, cardiopulmonary exercise test, treadmill test), hemodynamics, and survival.

Definitions

WHO Functional Classification of patients with pulmonary hypertension (PH):

• Class I:  Patients with PH but without resulting limitation of physical activity. Ordinary physical activity does not cause dyspnea or fatigue, chest pain, or near syncope.
• Class II:  Patients with PH resulting in slight limitation of physical activity. They are comfortable at rest. Ordinary physical activity causes undue dyspnea or fatigue, chest pain, or near syncope.
• Class III:  Patients with PH resulting in marked limitation of physical activity. They are comfortable at rest. Less than ordinary activity causes undue dyspnea or fatigue, chest pain, or near syncope.
• Class IV:  Patients with PH with inability to carry out any physical activity without symptoms. These patients manifest signs of right-sided heart failure. Dyspnea and/or fatigue may even be present at rest. Discomfort is increased by any physical activity

NOTE:  For criteria on oral or inhaled advanced therapies for pulmonary arterial hypertension, please refer to applicable pharmacy benefit plan.

I.   Initial Review

Epoprostenol (Flolan®, Veletri®), treprostinil (Remodulin®), sildenafil injection (Revatio®) or selexipag injection (Uptravi®) may be considered MEDICALLY NECESSARY AND APPROPRIATE when ALL of the following criteria are met:

• Diagnosis of pulmonary arterial hypertension (PAH), WHO Group 1, as determined by right heart catheterization AND ALL of the following:
  • Mean pulmonary artery pressure >20 mmHg; AND
    
  • Pulmonary capillary wedge pressure, left atrial pressure, or left ventricular end-diastolic pressure ≤ 15 mmHg; AND
  • Pulmonary vascular resistance ≥3 Wood units;
• AND
• ONE of the following:
  • Negative response to acute pulmonary vasodilator testing; OR
  • Inadequate response to a calcium-channel antagonist; OR
  • Documented intolerance, FDA labeled contraindication, or hypersensitivity to at least one calcium-channel antagonist;
• AND
• ONE of the following:
  • The requested agent will be used as monotherapy for PAH AND the patient is World Health Organization (WHO) functional class II or greater; OR
  • The requested agent will be used as add-on therapy to existing monotherapy for PAH AND ALL of the following:
    • WHO functional class II or greater; AND
    • Unacceptable or deteriorating clinical status despite established PAH pharmacotherapy; AND
    • Both advanced therapies for PAH are from different therapeutic classes.
  • OR
  • The requested agent will be used as add-on therapy to existing combination therapy for PAH AND ALL of the following:
    • WHO functional class III or IV; AND
    • Unacceptable or deteriorating clinical status despite established PAH pharmacotherapy; AND
    • All advanced therapies for PAH are from different therapeutic classes.

• AND
• For sildenafil (Revatio®) or selexipag (Uptravi®) injection requests only: Currently approved for oral Revatio or Uptravi, but temporarily unable to use oral formulation; AND
  
• No FDA labeled contraindications to therapy (see table below); AND
• For commercial health plan members only, step therapy supplement criteria may apply for select conditions (see policy II-242: Step Therapy Supplement).
  

II.   Renewal Review

Epoprostenol (Flolan®, Veletri®), treprostinil (Remodulin®), sildenafil injection (Revatio®), or selexipag injection (Uptravi®) may be considered MEDICALLY NECESSARY AND APPROPRIATE when ALL of the following criteria are met:

• Previously approved for therapy through the initial review process; AND
• Demonstrated positive clinical response (e.g., stabilization and/or slowing of disease progression or decrease in symptom severity and/or frequency); AND
• No FDA labeled contraindications to therapy (see table below).

III.  Experimental/Investigative Indications

All other uses of epoprostenol (Flolan®, Veletri®), treprostinil (Remodulin®), sildenafil injection (Revatio®), or selexipag injection (Uptravi®) are considered EXPERIMENTAL/INVESTIGATIVE, including but not limited to the following, due to the lack of clinical evidence demonstrating an impact on improved health outcomes:

• As part of combination therapy (i.e., two or more advanced therapies) for first-line treatment of PAH;
• Treatment of pulmonary hypertension conditions other than PAH, including but not limited to:
  • Pulmonary hypertension associated with left heart diseases (WHO Group 2);
  • Pulmonary hypertension associated with lung diseases and/or hypoxemia (including chronic obstructive pulmonary disease) (WHO Group 3);
  • Pulmonary hypertension due to chronic thrombotic and/or embolic disease (WHO Group 4);
  • Miscellaneous conditions (i.e., sarcoidosis, histocytosis X and lymphangiomatosis) (WHO Group 5).

Table 1. FDA Labeled Contraindications

Documentation Submission:
Documentation supporting the medical necessity criteria described in the policy must be included in the prior authorization. In addition, the following documentation must also be submitted:

Initial Review

1. Clinical notes describing confirmation of PAH by right heart catheterization and WHO functional class.
2. Clinical notes describing current and past medications for the diagnosis, including response to the medications.
3. For commercial health plan members only, when step therapy requirements apply for the requested indication, documentation for one or more of the step therapy supplement criteria MUST be provided (see policy II-242).
   

Renewal Review

1. Documentation of prior approval for the requested PAH agent through the initial review process.
2. Documentation supporting positive clinical response (e.g., slowing of disease progression or decrease in symptom severity and/or frequency).
3. Clinical notes describing current and past medications for the diagnosis, including response to the medications.