SUBJECT: Pulmonary Arterial Hypertension (PAH) POLICY NUMBER: Pharmacy-42 Clinical criteria used to make utilization review decisions are based on credible scientific evidence published in peer reviewed medical literature generally recognized by the medical community. Guidelines take into account physician society recommendations, the views of the physicians practicing in relevant clinical areas, the needs of the members in consultation with their providers, and other relevant factors to the extent practicable. Clinical criteria is reviewed and approved for use on an annual basis. Criteria are accessible to network providers, members, and prospective members upon request. Criteria may be verbally requested by calling 1 (800) 683-3781, or submitting a fax request to 1 (888) 273-8296. Requests may also be submitted in writing to P.O. Box 240, Pittsford, N.Y. 14534. Providers may also submit feedback regarding criteria by visiting www.yourcarehealthplan.com DESCRIPTION: Pulmonary arterial hypertension (PAH) is characterized by sustained elevation of pulmonary artery pressure. The condition is uncommon but is associated with a high mortality rate. Some causes of pulmonary hypertension include congenital heart defects, connective tissue disease, HIV infection, blood clots, liver disease, and medication (ex. Fenphen). The disease can also have an unknown cause (primary pulmonary hypertension, PPH). The most common symptoms caused by PAH are unusual fatigue, SOB, chest pain, fainting, and peripheral edema. Careful invasive assessment of pulmonary hemodynamics is critical in the evaluation of any patient with suspected PAH. All patients that are suspected of having PAH after non-invasive evaluation (chest X-ray or echocardiogram) should undergo right heart catheterization (RHC) prior to initiating therapy. RHC can be performed safely even in patients with severe pulmonary hypertension and right heart failure. Treatment goals include improvement in patient symptoms such as dyspnea and exercise endurance, lowering pulmonary artery pressure, prevent progression of disease and improve survival. Medical management for PAH includes oral calcium-channel blockers, anticoagulants, oxygen therapy, endothelial-receptor antagonists (bosentan, ambrisentan, macitentan), phosphodiesterase-5 inhibitors (sildenafil, tadalafil) and prostacyclins (iloprost, treprostinil, epoprostonol) and the newer class of sgc inhibitors (riociguat). Lung and heart transplants have been performed in those patients that are refractory to medical management. Class 1 Class 2 Class 3 Class 4 New York Heart Association Functional Classification Ordinary physical activity does not cause symptoms Comfortable at rest, ordinary physical activity causes symptoms Comfortable at rest, less than ordinary activity (ADLs) causes symptoms Symptoms at rest This policy is applicable to the following drugs that are FDA approved for the treatment of PAH Adcirca Adempas Flolan (epoprostenol) 1
Letairis Orenitram Opsumit Remodulin Revatio (sildenafil) Tracleer Veletri Ventavis PAH Policy Criteria: 1. The patient must have a diagnosis of Pulmonary Arterial Hypertension which has been confirmed by a right heart catheterization. 2. The right heart catheterization must demonstrate the following: Mean pulmonary artery pressure (PAP) of to 25 mmhg at rest AND Pulmonary capillary wedge pressure to 15 mm Hg at rest 3. Patient must be followed by and drug therapy prescribed by a cardiologist or pulmonologist. 4. Adcirca and generic sildenafil will be approved as initial treatment for anyone with a confirmed diagnosis of PAH. 5. New starts for Letairis, Tracleer, Revatio or Opsumit will require a trial of generic sildenafil or Adcirca prior to approval of one of these agents. 6. New starts for Adempas for a diagnosis of PAH will require a trial of sildenafil or Adcirca and an endothelin receptor antagonist (Letairis, Tracleer or Opsumit) prior to approval. Past treatment with a prostacyclin (Flolan, Veletri, Tyvaso, Remodulin or Ventavis) will also be taken in to consideration if used as one of two previous therapies. 7. New starts for Orenitram will require a trial of sildenafil or Adcirca and an endothelin receptor antagonist (Letairis, Tracleer or Opsumit) prior to approval. Past treatment with a prostacyclin (Flolan, Veletri, Tyvaso, Remodulin or Ventavis) will also be taken in to consideration if used as one of two previous therapies. 8. New starts for Flolan (epoprostenol), Remodulin, Tyvaso, Veltri, and Ventavis will require a trial of sildenafil or Adcirca and an endothelin receptor antagonist (Letairis, Tracleer or Opsumit) prior to approval for lower risk individuals (typically WHO Class II and III). a. Patients at high risk (WHO Class IV) may require continuous treatment with IV prostacyclin as initial therapy. 9. Combination therapy has been studied for the treatment of PAH. The goal of combination therapy should be to maximize efficacy, while minimizing toxicity. For individuals who have inadequate response, combination therapy (with drugs with different mechanisms of action) can be considered. Combination therapy should only be attempted by those with the expertise to monitor such high risk individuals. Adempas specific criteria: 1. Can be used for the treatment of Chronic Thromboembolic Pulmonary Hypertension (CTEPH) (WHO Group 4) and have: a. Recurrent or persistent disease after surgical disease OR b. Inoperable disease determined by V/Q scan and/or pulmonary angiography 2
3 Exclusion Criteria: 1. Conditions considered investigational will not be covered. Conditions considered investigational due to lack of peer-reviewed literature for which efficacy or safety data is not yet available include, but are not limited to: Ischemic vascular diseases Congestive heart failure Chronic obstructive pulmonary disease 2. The use of Revatio or Adcirca and nitrates concurrently is contraindicated and therefore will not be covered. 3. Revatio (Sildenafil 20mg) and Adcirca will not be authorized for a diagnosis of erectile dysfunction as there are FDA approved medications for this diagnosis. POLICY GUIDELINES: 1. Prior authorization is contract dependent. 2. Patient must have a right heart catheterization to diagnose Pulmonary Arterial Hypertension 3. Patient must be followed by a cardiologist or pulmonologist 4. Adcirca, Adempas, Revatio (sildenafil), Opsumit, Orenitram, and Tracleer are covered under the pharmacy benefit. 5. Ventavis is covered under the medical benefit to coordinate care with the necessary supplies. Proper verification (based on Part B vs D determination) is necessary for Medicare requests. 6. Tyvaso is self-administered and therefore should be processed under the pharmacy benefit. Proper verification (based on Part B vs D determination) is necessary for Medicare requests. 7. Remodulin, Flolan (epoprostenol) and Veletri are covered under the medical benefit. 8. Sildenafil (Revatio) has been shown to be safe and effective up to a maximum dose of 80mg three times a day for the treatment of PAH. Doses above FDA approval will require documentation of a trial of the lower FDA approved dose which was shown to be ineffective. 9. Tadalafil (Adcirca) has been shown to be safe and effective up to a maximum dose of 40mg once a day. Doses above FDA approval will require documentation of a trial of the lower FDA approved dose which was shown to be ineffective. 10. Maximum dosing of bosentan (Tracleer) is 125mg twice a day. 11. Maximum dosing of ambrisentan (Letairis) is 10mg once a day. 12. Maximum dosing of riociguat (Adempas) is 2.5mg three times a day. 13. Maximum dosing of macitentan (Opsumit) is 10mg once a day. 14. There is no FDA approved maximum dose of oral treprostinil Orenitram, but the maximum dose allowed within the clinical trials was 16mg twice a day. 15. Surgery is the only definitive therapy for chronic thromboembolic pulmonary hypertension (CTEPH), with pulmonary thromboendarterectomy being the surgical procedure of choice
4 Please see YourCare PA list for related codes. REFERENCES: 1. Badesch D, et al. Medical therapy for pulmonary arterial hypertension. ACCP Evidence-Based Clinical Practice Guidelines. CHEST 2004; 126:35S-57S. 2. Sitbon O, et al. Inhaled nitric oxide as a screening vasodilator agent in primary pulmonary hypertension: a doseresponse study and comparison with prostacyclin. Am J Respir Crit Care Med 1995; 151:384-89. 3. Sitbon O, et al. Inhaled nitric oxide as a screening agent for safely identifying responders to oral calcium-channel blockers in primary pulmonary hypertension. Eur Respir J 1998; 12:265-70. 4. Opitz CF, 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; 24:356-65. 5. Barst RJ, et al. A comparison of continuous intravenous epoprostenol (prostacyclin) with conventional therapy for primary pulmonary hypertension. The Primary Pulmonary Hypertension Study Group. N Eng J Med 1996; 334:296-302. 6. Rich S, et al. The effects of chronic prostacyclin therapy on cardiac output and symptoms in primary pulmonary hypertension. J Am Coll Cardiol 1999; 34:1184-7. 7. Shapiro SM, et al. Primary pulmonary hypertension: improved long-term effects and survival with continuous intravenous epoprostenol infusion. J Am Coll Cardiol 1997; 30:343-9. 8. McLaughlin VV, et al. Efficacy and safety of treprostinil: an epoprostenol analog for primary pulmonary hypertension. J Cardiovasc Pharmacol 2003; 40:780-8. 9. Simonneau 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; 165:800-4. 10. Hoeper MM, et al. Long-term treatment of primary pulmonary hypertension with aerosolized iloprost, a prostacyclin analogue. N Eng J Med 2000; 342:1866-70. 11. Channick RN, et al. Effects of the dual endothelin-receptor antagonist bosentan in patients with pulmonary hypertension: a randomized placebo-controlled study. Lancet 2001; 358:1119-23. 12. Michelakis E, et al. Oral sildenafil is an effective and specific pulmonary vasodilator in patients with pulmonary arterial hypertension: comparison with inhaled nitric oxide. Circulation 2002; 105:2398-403. 13. Barst RJ, Galie N, Naeije R, et al. Long-term outcome in pulmonary arterial hypertension patients treated with subcutaneous treprostinil. Eur Respir J. 2006 Dec;28(6):1195-203. 14. 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):1672-81. 15. Rubenfire M, McLaughlin VV, Allen RP, et al. Transition from IV epoprostenol to subcutaneous treprostinil in pulmonary arterial hypertension: a controlled trial. Chest. 2007 Sep;132(3):757-63. 16. 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):1433-7.
17. Flolan package insert, GSK. September 2002. 18. Tracleer package insert, Actelion Inc. March 2007. 19. Remodulin package insert, Baxter. November 2004. 20. Ventavis package insert, CoTherix Inc. December 2004. 21. Revatio package insert, Pfizer, June 2005. 22. Letairis package insert, Gilead Sciences, Inc. June 2007 23. Adcirca package insert, Eli Lilly & Company marketed by United Therapeutics May 2009 24. McLaughlin VV 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 of American College of Cardiology. 53(17)2009. 25. Guidelines for the diagnosis and treatment of pulmonary hypertension. European Heart Journal. 2009:30:2493-2537. 5