1. Aetna considers continuous intravenous infusion of prostacyclin (epoprostenol, PGI2, [brand name: Flolan]) or continuous subcutaneous infusion of treprostinil (Remodulin) medically necessary for selected members with pulmonary hypertension that does not adequately respond to oral agents, and who meet all of the following selection criteria:

   1. Member has pulmonary hypertension with New York Heart Association Class II to IV heart failure and a mean pulmonary artery pressure greater than 50 mm Hg at rest, documented by right-heart catheterization; and
   2. Member's pulmonary artery pressure does not adequately decrease in response to oral agents; and
   3. Member has primary pulmonary hypertension, or has pulmonary hypertension secondary to any of the following conditions:
      
      
      1. Congenital heart disease with shunting; or
      2. Congenital diaphragmatic hernia; or
      3. Connective tissue diseases; or
      4. Anorectic agents (diet drugs); or
      5. Portopulmonary hypertension; or
      6. Chronic thromboembolic pulmonary hypertension; or
      7. HIV infection; or
      8. Sarcoidosis; or
      9. Familial pulmonary hypertension.
   For members with severe pulmonary vascular disease refractory to medical therapy, continuous infusion of prostacyclin or treprostinil may be considered medically necessary for use as a bridge to either lung or combined heart-lung transplantation (see CPB 597 - Heart-Lung Transplant and CPB 598 - Lung Transplantation).

2. Aetna considers epoprostenol and treprostinil experimental and investigational in the treatment of pulmonary hypertension secondary to other conditions including the following because they are not effective for these indications:
   
   
   1. Chronic obstructive pulmonary disease; or
   2. Asthma; or
   3. Congestive heart failure; or
   4. Ischemic vascular diseases; or
   5. Lung resection.

Note: The New York Heart Association (NYHA) functional classification of angina pectoris is provided in the background section.

See Pharmacy CPB on Pulmonary Hypertension Agents for information on Ventavis (Iloprost) inhalation solution. See also Pharmacy CPB on Tracleer (bosentan). http://www.aetna.com/products/rx/pcpb_menu.html

Primary pulmonary hypertension (PPH) is a rare but serious, life-threatening disease. As the disease progresses and right ventricular after-load increases, the heart’s ability to increase cardiac output with activity declines, resulting in exertional dyspnea, chest pain, or syncope. Eventually, progressive right heart dysfunction ensues, leading to right heart failure and death. In the National Institutes of Health's PPH registry, the median survival from diagnosis was less than 2.5 years. Medical management consists of anticoagulants, oral vasodilators (which are effective in 20% - 25% of cases), continuous intravenous infusions of prostacyclin, diuretics, and supplemental oxygen.

Initially, a hospital admission is required to evaluate the patient's pulmonary vascular responsiveness, as this determines selection of vasodilator treatment. Incremental doses of a short-acting pulmonary vasodilator are administered intravenously until a positive hemodynamic response or negative endpoint is observed (e.g., hypotension, headache, chest pain, etc). A decrease of 20 % or more in pulmonary vascular resistance and pulmonary arterial pressure, with no decrease in cardiac output, is considered a positive response.

Responders are usually treated with high doses of oral calcium antagonists (e.g., nifedipine, and diltiazem). Continuous intravenous prostacyclin infusions are reserved for those patients who fail to respond to oral calcium antagonists, and may be used either as long-term therapy or as a bridge to transplantation. Because of prostacyclin's very short half-life, it must be administered by continuous infusion by a portable, battery-operated syringe pump through a permanent central venous catheter.

Continuous prostacyclin infusion has been shown to improve hemodynamics, symptoms and survival time, and increase exercise tolerance in patients with pulmonary hypertension unresponsive to conventional therapy. Both “responders” and “non-responders” to conventional therapy (including short-acting vasodilators and/or calcium channel blockers) can be treated with continuous intravenous epoprostenol or treprostinil and manifest improvements in exercise tolerance, hemodynamics and survival.  Intravenously administered prostacyclin is similar to the prostacyclin that is produced by the cells lining blood vessels. Evidence suggests that pulmonary hypertension may be in part due to an abnormally low ratio of prostacyclin in relation to the endogenous vasoconstrictor thromboxane A2.

Secondary pulmonary hypertension is a complication of many pulmonary, cardiac and extra-thoracic conditions.  Chronic obstructive pulmonary diseases, left ventricular dysfunction and disorders associated with hypoxemia frequently result in pulmonary hypertension.  Regardless of the etiology, unrelieved pulmonary hypertension can lead to right-sided heart failure.  Secondary pulmonary hypertension can be treated with continuous intravenous infusion of prostacyclin or continuous subcutaneous infusion of treprostinil.

Continuous intravenous prostacyclin therapy may be limited by serious complications (e.g., sepsis, thromboembolism, or syncope) related to the need for an implanted central venous catheter.  Treprostinil sodium (Remodulin), a longer-acting, more chemically stable prostacyclin analog, can be administered by a continuous subcutaneous infusion, avoiding these risks.  In a 12-week, double-blind, placebo-controlled multi-center trial in 470 patients with pulmonary arterial hypertension (PAH), Simonneau and colleagues (2002) reported that exercise capacity improved with treprostinil and was unchanged with placebo.  The between treatment group difference in median 6-minute walking distance was 16 meters.  Improvement in exercise capacity was greater in the sicker patients and was dose-related, but independent of disease etiology.  Concomitantly, treprostinil significantly improved indices of dyspnea, signs and symptoms of PAH, and hemodynamics.  These investigators concluded that chronic subcutaneous infusion of treprostinil is an effective treatment in patients with PAH.  In addition, Vachiery and associates (2002) reported that patients with PAH could be safely transitioned from treatment with intravenous prostacyclin to subcutaneous treprostinil.

Venatvis (iloprost) is a self-administered inhalation solution for the treatment of pulmonary arterial hypertension in patients with NYHA Class III or IV symptoms.  It is intended to be inhaled using either of two pulmonary drug delivery devices: (i) the I-neb AAD System, or (ii) the Prodose AAD System.  Accroding to the FDA-approved labeling, Ventavis should be taken 6 to 9 times per day (no more than once every 2 hours) during waking hours, according to individual need and tolerability.

The New York Heart Association (NYHA) functional classification of angina pectoris is as follows: