Pulmonary Hypertension Treatments and Selected Indications of Prostanoids

Number: 0184

Commercial CPB  |  Medicare CPB

Policy

Note: REQUIRES PRECERTIFICATION

Precertification of Flolan and Veletri (epoprostenol sodium), Remodulin (treprostinil sodium), Tyvaso (treprostinil), and Ventavis (iloprost) is required of all Aetna participating providers and members in applicable plan designs. For precertification, call (866) 752-7021 (Commercial), (866) 503-0857 (Medicare), or fax (866) 267-3277.

Note: See Pharmacy CPB on Pulmonary Hypertension Agents for information on preferred agents for pulmonary hypertension: Formularies and Pharmacy Clinical Policy Bulletins.

1. Pulmonary Arterial Hypertension (PAH)

   Ambrisentan tablets (Letairis), bosentan tablets (Tracleer), epoprostenol for injection (Flolan, Veletri), iloprost inhalation (Ventavis), macitentan tablets (Opsumit), riociguat tablets (Adempas), selexipag tablets (Uptravi), sildenafil tablets (RevatioFootnotes for Revatio^**), tadalafil tablets (Adcirca, Alyq), treprostinil extended-release tablets (Orenitram), treprostinil inhalation (Tyvaso), treprostinil injection (Remodulin) are considered medically necessary for treatment of PAH when all of the following criteria are met:

   1. Member has PAH defined as WHO Group 1 class of pulmonary hypertension (including Eisenmenger's syndrome - for Tracleer only) (see Appendix);
   2. PAH was confirmed by either criterion below:
      

      1. Pretreatment right heart catheterization with all of the following results:

         1. mean pulmonary artery pressure (mPAP) greater than 20 mmHg
         2. pulmonary capillary wedge pressure (PCWP) less than or equal to 15 mmHg
         3. pulmonary vascular resistance (PVR) greater than or equal to 3 Wood units.

      2. In infants less than one year of age for bosentan (Tracleer), epoprostenol (Flolan, Veletri), iloprost (Ventavis), macitentan (Opsumit), selexipag (Uptravi), sildenafil (Revatio), tadalafil (Adcirca, Alyq), treprostinil (Orenitram, Remodulin, Tyvaso): PAH was confirmed by Doppler echocardiogram if right heart catheterization cannot be performed. 

   Aetna considers atrial septostomy and balloon pulmonary angioplasty medically necessary for the treatment of persons with refractory severe pulmonary arterial hypertension and right heart failure, despite aggressive advanced therapy and maximal diuretic therapy, and for persons with severe pulmonary artery hypertension who have signs of impaired systemic blood flow (such as syncope) due to reduced left heart filling.

2. Secondary Raynaud’s Phenomenon

   Sildenafil tablets (Revatio) and tadalafil tablets (Adcirca, Alyq) are considered medically necessary for treatment of secondary Raynaud’s phenomenon when the member has had an inadequate response to one of the following medications:

   1. Calcium channel blockers
   2. Angiotensin receptor blockers
   3. Selective serotonin reuptake inhibitors
   4. Alpha blockers
   5. Topical nitrates.
      

3. Chronic Thromboembolic Pulmonary Hypertension (CTEPH)

   Riociguat tablets (Adempas) are considered medically necessary for treatment of CTEPH when all of the following criteria are met:

   1. Member has CTEPH defined as WHO Group 4 class of pulmonary hypertension (See Appendix)
   2. Member meets either criterion (1) or criterion (2) below:
      
      
      1. Recurrent or persistent CTEPH after pulmonary endarterectomy (PEA)
      2. Inoperable CTEPH with diagnosis confirmed by both of the following:
         
         
         1. Computed tomography (CT)/magnetic resonance imaging (MRI) angiography or pulmonary angiography
         2. Pretreatment right heart catheterization with all of the following results:
            
            
            1. mean pulmonary artery pressure (mPAP) greater than 20 mmHg
            2. pulmonary capillary wedge pressure (PCWP) less than or equal to 15 mmHg
            3. pulmonary vascular resistance (PVR) greater than or equal to 3 Wood units.
               

4. Continuation of therapy

   Aetna considers continued therapy medically necessary for members with a medically necessary indication who are currently receiving the requested medication through a paid pharmacy or medical benefit, and who are experiencing benefit from therapy as evidenced by disease stability or disease improvement.

5. Experimental and investigational

   Aetna considers pulmonary artery hypertension agents 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. Asthma; or
   2. Chronic obstructive pulmonary disease; or
   3. Congestive heart failure; or
   4. Ischemic vascular diseases/Peripheral arterial disease; or
   5. Lung resection.  

   Aetna considers the following treatments experimental and investigational because the effectiveness of the requested treatment for the indication has not been established:

   1. Imatinib mesylate, simvastatin, and sorafenib for the treatment of pulmonary hypertension;
   2. Prostanoids (epoprostenol and treprostinil) for the treatment of chronic ulcers/limb-threatening ischemia and chronic inflammatory demyelinating polyneuritis;
   3. Ambrisentan and bosentan for the treatment of critical limb ischemia, exercise-induced pulmonary hypertension, peripheral arterial disease, and pulmonary hypertension secondary to histiocytosis X;
   4. Pulmonary artery denervation for the treatment of pulmonary arterial hypertension;
   5. Oral sildenafil for the treatment of pulmonary hypertension after heart transplantation;
   6. Implantable intravenous prostanoid pump for the treatment of  pulmonary hypertension;
   7. Tadalafil for the treatment of Duchenne muscular dystrophy.

Footnotes for Revatio^** Revatio tablets (sildenafil 20 mg) are only indicated for pulmonary arterial hypertension. Viagra tablets (sildenafil 25 mg, 50 mg or 100 mg) are only indicated for erectile dysfunction. Some plans exclude coverage of drugs for the treatment of erectile dysfunction, impotence or sexual dysfunction or inadequacy. Please check benefit plan descriptions.

Dosing Recommendations

Ambrisentan (Letairis)

Initiate treatment at 5 mg once daily. Titrate at 4-week intervals as needed and tolerated.

Source: Gilead 2019

Bosentan (Tracleer)

Initiate at 62.5 mg orally twice daily; for patients weighing greater than 40 kg, increase to 125 mg orally twice daily after 4 weeks. For patients 12 years of age and younger, dosage is based on weight.

Source: Actelion Pharmaceuticals 2019.

Epoprostenol for injection (Flolan, Veletri)

Initiate intravenous infusion through a central venous catheter at 2 ng/kg/min, then increase by 2 ng/kg/minute at intervals of ≥15 minutes until dose-limiting pharmacological effects are observed. See full prescribing information for dosing adjustment.

Source: GlaxoSmithKline 2018.

Iloprost Inhalation Solution (Ventavis)

Patients should receive 6 to 9 doses (inhalations) per day (minimum of 2 hours between doses during waking hours) as follows:

• Starting dose: 2.5 mcg
• Up-titrate to 5 mcg if 2.5 mcg is well tolerated
• Maintenance dose: 5 mcg.

Source: Actelion Pharmaceutials US 2019.

Macitentan (Opsumit)

10 mg once daily. Doses higher than 10 mg once daily have not been studied in patients with PAH and are not recommended.

Source: Actelion 2019.

Riociguat (Adempas)

Initiate treatment at 1 mg taken three times a day. For patients who may not tolerate the hypotensive effect of Adempas, consider a starting dose of 0.5 mg, three times a day. Increase dosage by 0.5 mg at intervals of no sooner than 2-weeks as tolerated to a maximum of 2.5 mg three times a day.

Source: Bayer HealthCare 2018.

Selexipag (Uptravi)

Starting dose: 200 mcg twice daily. Increase the dose by 200 mcg twice daily at weekly intervals to the highest tolerated dose up to 1600 mcg twice daily. Maintenance dose is determined by tolerability.

Source: Actelion Pharmaceuticals 2019.

Sildenafil (Revatio)

5 mg or 20 mg three times a day, 4–6 hours apart; see full prescribing information for reconstitution instructions for the Powder for Oral Suspension.

Injection: 2.5 mg or 10 mg three times a day administered as an intravenous bolus injection.

Source: Pfizer 2020.

Tadalafil (Adcirca, Alyq)

40 mg once daily, with or without food.

Source: Eli Lilly 2017.

Treprostinil extended-release tablets (Orenitram)

Starting dose: 0.125 mg TID or 0.25 mg BID. Titrate by 0.125 mg TID or by 0.25 mg or 0.5 mg BID, not more frequently than every 3 to 4 days as tolerated.

Source: United Therapeutics Corp. 2019.

Treprostinil Inhalation Solution (Tyvaso)

Initial dosage: 3 breaths (18 mcg) per treatment session. If 3 breaths are not tolerated, reduce to 1 or 2 breaths.

Source: United Therapeutics Corp. 2017.

Treprostinil injection (Remodulin)

Initial dose for patients new to prostacyclin infusion therapy:

1.25 ng/kg/min; increase based on clinical response (increments of 1.25 ng/kg/min per week for the first 4 weeks of treatment, later 2.5 ng/kg/min per week).

Source: United Therapeutics Corp. 2018.

Background

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 % to 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.

The American College of Cardiology/American Heart Association's expert consensus document on pulmonary hypertension (McLaughlin et al, 2009) stated that "[m]ultiple randomized controlled trials of combination therapy are currently ongoing, and to adequately study the safety and efficacy of combination therapy, we encourage enrollment into randomized controlled trials".

Prostacyclin Infusions

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.

Epoprostenol

Epoprostenol [Flolan, Velitri] has two major pharmacological actions: (i) direct vasodilation of pulmonary and/or systemic arterial vascular beds, and (ii) inhibition of platelet aggregation.

Epoprostenol [generic Flolan] is a naturally occurring prostaglandin synthesized by the blood vessel wall. It is a bicyclic enol‐ether derivative of the fatty acid precursor arachidonic acid, and is formed from unstable prostaglandin endoperoxide intermediates via actions of the enzyme epoprostenol synthetase located in vascular endothelial cells.

Epoprostenol [Flolan, Velitri] is indicated for the treatment of pulmonary arterial hypertension (WHO group I) to improve exercise capacity. Studies establishing effectiveness included predominantly patients with New York Heart Association (NYHA) Class III and Class IV symptoms and etiologies of idiopathic or heritable pulmonary arterial hypertension (PAH) or PAH associated with connective tissue diseases.

Flolan (epoprostenol) for Injection is supplied as a sterile freeze‐dried powder in 17‐mL vials containing epoprostenol sodium equivalent to 0.5 mg (500,000 ng), and 1.5 mg (1,500,000 ng). Veletri and Generic Epoprostenol for Injection is supplied as a sterile freeze‐dried powder in 10‐mL vials containing epoprostenol sodium equivalent to 0.5 mg (500,000 ng), and 1.5 mg (1,500,000 ng). Chronic infusion should be initiated at 2 ng/kg/min and increased in increments of 2 ng/kg/min every 15 minutes or longer until dose‐limiting pharmacologic effects are elicited or until a tolerance limit to the drug is established and further increases in the infusion rate are not clinically warranted.

Abrupt withdrawal (including interruptions in drug delivery) or sudden large reductions in dosage of epoprostenol may result in symptoms associated with rebound pulmonary hypertension, including dyspnea, dizziness, and asthenia.

Contraindications to treatment with epoprostenol include pulmonary edema and congestive heart failure due to severe left ventricular systolic dysfunction.

In clinical trials, the most common dose‐limiting adverse events were nausea, vomiting, hypotension, sepsis, headache, abdominal pain, or respiratory disorder (most treatment‐limiting adverse events were not serious). If the initial infusion rate of 2 ng/kg/min is not tolerated, a lower dose that is tolerated by the patient should be identified.

Iloprost

Venatvis (iloprost) is a self-administered inhalation solution for the treatment of pulmonary arterial hypertension in patients with New York Heart Association (NYHA) Class III or IV symptoms. Ventavis (iloprost) is a synthetic analogue of prostacyclin PGI2. Ventavis (iloprost) dilates systemic and pulmonary arterial vascular beds. It also affects platelet aggregation but the relevance of this effect to the treatment of pulmonary hypertension is unknown.

Ventavis (iloprost) is indicated for the treatment of pulmonary arterial hypertension, World Health Organization (WHO) Group I to improve a composite endpoint consisting of exercise tolerance, symptoms (NYHA Class), and lack of deterioration. Studies establishing effectiveness included predominantly patients with NYHA functional class III‐IV symptoms and etiologies of idiopathic or heritable PAH (65%) or PAH associated with connective tissue diseases (23%).

Ventavis (iloprost) is supplied in 1 mL single‐use ampules in two concentrations: 10 mcg/mL and 20 mcg/mL.  It is intended to be inhaled using either of 2 pulmonary drug delivery devices:

1. the I-neb AAD System, or
2. the Prodose AAD System. 

Accroding to the Food and Drug Administration (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 recommended first inhaled dose should be 2.5 mcg (as delivered at the mouthpiece). If this dose is well tolerated, dosing should be increased to 5 mcg and maintained at that dose. Ventavis (iloprost) should be taken six‐to‐nine times per day (no more than every two hours) during waking hours, according to individual need and tolerability. The maximum daily dose evaluated in clinical studies was 45 mcg (5 mcg nine times per day).

The 20 mcg/mL concentration is intended for members stabilized on 5 mcg dose and who have repeatedly experienced extended treatment times which could result in incomplete dosing. Transitioning to the 20 mcg/mL concentrations using the I‐neb AAD System will decrease treatment times to help maintain member compliance.

Ventavis (iloprost) inhalation can induce bronchospasm, especially in susceptible patient with hyperreactive airways. Ventavis iloprost) has not been evaluated in patients with chronic obstructive pulmonary disease (COPD), severe asthma, or with acute pulmonary infections. Such patient should be carefully monitored during therapy with Ventavis (iloprost).

Avoid oral ingestion of solution and contact with the skin or eyes.

Systolic blood pressure less than 85 mmHg, should not be initiated (risk of syncope).

Ventavis (iloprost) is contraindicated in persons with known hypersensitivity to Iloprost.

Remodulin

Remodulin (treprostinil), a tricyclic benzidine analog of epoprostenol, has two major pharmacological actions:

1. direct vasodilation of pulmonary and/or systemic arterial vascular beds, and
2. inhibition of platelet aggregation.

Epoprostenol is a naturally occurring prostaglandin synthesized by the blood vessel wall. It is a bicyclic enol‐ether derivative of the fatty acid precursor arachidonic acid, and is formed from unstable prostaglandin endoperoxide intermediates via actions of the enzyme epoprostenol synthetase located in vascular endothelial cells. Epoprostenol's action as an inhibitor of platelet aggregation is secondary to stimulation of adenylate cyclase, which results in increased platelet cyclic AMP.

Remodulin (treprostinil) is indicated for the treatment of pulmonary arterial hypertension (PAH) to diminish symptoms associated with exercise. Studies establishing effectiveness included patients with NYHA Functional Class II‐IV symptoms and etiologies of idiopathic or heritable PAH (58%), PAH associated with congenital systemic‐portopulmonary shunts (23%), or PAH associated with connective tissue diseases (19%).

It may be administered as a continuous subcutaneous infusion or continuous intravenous infusion; however, because of the risks associated with chronic indwelling central venous catheters, including serious blood stream infections, continuous intravenous infusion should be reserved for patients who are intolerant of the subcutaneous route, or in whom these risks are considered warranted.

Remodulin (treprostinil) is also indicated to diminish the rate of clinical deterioration in patients requiring transition from Flolan; the risks and benefits of each drug should be carefully considered prior to transition.

Treprostinil is available as Remodulin in 20 mL vials in concentrations of 1 mg/mL, 2.5 mg/mL, 5 mg/mL and 10 mg/mL.

Remodulin (treprostinil) is administered by continuous infusion. The recommended initial Infusion rate is initiated at 1.25ng/kg/min. If this initial dose cannot be tolerated because of systemic effects, the infusion rate should be reduced to 0.625 ng/kg/min.

Remodulin (treprostinil) is preferably infused subcutaneously, but can be administered by continuous intravenous infusion if the subcutaneous route is not tolerated, because of severe site pain or reaction.

Caution should be used in patients with hepatic or renal impairment.

No dosing adjustment is needed for warfarin when co‐administered with Remodulin (treprostinil).

The most common adverse events in clinical trials were infusion site pain and reactions, diarrhea, jaw pain, edema, vasodilatation and nausea.

Abrupt cessation of infusion or abrupt decrease in dose should be avoided.

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 of 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-min walking distance (6MWD) 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.

Tyvaso

Tyvaso (treprostinil) is a prostacyclin analogue. The major pharmacologic actions of treprostinil are direct vasodilation of pulmonary and systemic arterial vascular beds and inhibition of platelet aggregation.

Tyvaso (treprostinil) inhalation solution is indicated for the treatment of pulmonary arterial hypertension (PAH) (WHO Group 1) to improve exercise ability. Studies establishing effectiveness included predominately patients with New York Heart Association (NYHA) Class III symptoms and etiologies of idiopathic or heritable PAH (56%) or PAH associated with connective tissue diseases (33%).

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 sidenafil (a phosphodiesterast type 5 inhibitor).

Tyvaso (treprostinil) is a sterile formulation of treprostinil intended for administration by oral inhalation using the Optinep-ir Model ON-100/7 device.

Tyvaso is supplied in 2.9 mL low density polyethylene (LDPE) ampules, containing 1.74 mg treprostinil (0.6 mg/mL). One ampule contains a sufficient volume of medication for all 4 treatment sessions in a single day.

Tyvaso is dosed in four separate, equally spaced treatment sessions per day, during waking hours. The treatment should be approximately four hours apart. One ampule contains enough medicine for one day of treatment no matter how many breaths the doctor has prescribed.

Initial dosage: Therapy should begin with three breaths of Tyvaso per treatment session, four times a day.

Maintance dosage: Dosage should be increased by an additional three breathes at approximately one-to-two week intervals, if tolerated, until the target dose of nine breaths (54 mcg of treprostinil) is reached per treatment session, four times daily.

Maximum recommended dosage is nine breaths per treatment session, four times daily.

Caution shluld be used in patients with renal or hepatic impairment.

The most common adverse events in clinical trials were infusion site pain and reactions, diarrhea, jaw pain, edema, vasodilations and nausea. Angioedema is possible.

Tyvaso is intended for oral inhalation using the Tyvaso Inhalation System, which consists of the Optineb-ir Model ON-100/7 (an ultrasonic, pulsed-delivery device) and its accessories.

Concurrent use of Tyvaso with another prostanoid, Flolan (epoprostenol), Remodulin (treprostinol) and/or Ventavis (iloprost) is not necessary.

Orenitam

Orenitram is an extended‐release tablet for oral administration used to treat PAH. Orenitram is indicated for the treatment of PAH (WHO Group 1) to improve exercise capacity. The primary study that established efficacy (FREEDOM‐M) included predominately patients with WHO functional class II‐III symptoms and etiologies of idiopathic or heritable PAH (75%) or PAH associated with connective tissue disease (19%).

United States Food and Drug Administration (FDA) approved Orenitram (treprostinil) Extended-Release Tablets for the treatment of pulmonary arterial hypertension (PAH) in WHO Group I patients to improve exercise capacity. Orenitram contains the same active ingredient (treprostinil) as Remodulin (treprostinil) Injection and Tyvaso (treprostinil) Inhalation Solution. 

The primary efficacy study, FREEDOM-M, demonstrated that patients receiving Orenitram twice daily (BID) improved their median six-minute walk distance (6MWD) by +23 meters [p=0.013] as compared to patients receiving only placebo.  As the sole vasodilator, the effect of Orenitram on exercise is small and Orenitram has not been shown to add to other vasodilator therapy.  Two other Phase 3 studies (FREEDOM-C and FREEDOM-C2) did not demonstrate a benefit in exercise with median 6MWD at Week 16 (11 meters [p=0.072] and 10 meters [p=0.089], respectively).  

The primary study that established efficacy (FREEDOM-M) included predominately patients with WHO functional class II-III symptoms and etiologies of idiopathic or heritable PAH (75%) or PAH associated with connective tissue disease (19%).  When used as the sole vasodilator, the effect of Orenitram on exercise is about 10% of the deficit, and the effect, if any, on a background of another vasodilator is probably less than this.  The use of Orenitram to replace subcutaneous, intravenous, or inhaled treprostinil has not been studied. 

The most common side effects reported in the clinical studies with Orenitram (placebo-corrected incidence >10%) are headache, nausea, and diarrhea. In the 12-week placebo-controlled monotherapy study, adverse reactions with rates at least 5% higher on Orenitram than on placebo included headache, diarrhea, nausea, flushing, pain in jaw, pain in extremity, hypokalemia, and abdominal discomfort. 

Treprostinil is available as Orenitram in 0.125 mg, 0.25 mg, 1 mg, and 2.5 mg extended-release tablets. The dose of Orenitram should be increased as tolerated to achieve optimal clinical response. Orenitram is dosed twice a day with food, but the total daily dose can be divided and given three times daily with food. The recommended starting dose is 0.25 mg BID or 0.125mg TID with food. Orenitram dose must be titrated.  Titrate by 0.25 mg or 0.5 mg BID or 0.125 mg TID every 3‐4 days as tolerated. The maximum dose is determined by tolerability. In the Freedom M trial, the max dose of Orenitram allowed was 12 mg BID.

If transitioning from intravenous (IV) or subcutaneous (SC) Remodulin, the Orenitram dose should be increased while simutaneously decreasing the IV/SC infusion rate. The dose of Remodulin can be reduced up to 30 ng/kg/min per day and the dose of Orenitram simutaneously increased up to 6 mg per day (2 mg TID) if tolerated. The following equation can be usded to estimate a comparable total daily dose of Orenitram in mg using a patient's dose of IV/SC treprostinil (ng/kg/min) and weight (in kg): Orenitram total daily dose (mg) = 0.00072 X Remodulin dose (ng/kg/min) X weight (kg).

Orenitram is contraindicated for patients with severe hepatic impairment (Child Pugh Class C).  There is a marked increase in the systemic exposure to treprostinil in hepatically impaired patients. 

Abrupt discontinuation or sudden large reductions in dosage of Orenitram may result in worsening of PAH symptoms. Orenitram inhibits platelet aggregation and increases the risk of bleeding, particularly among patients receiving anticoagulants. Orenitram should not be taken with alcohol as release of treprostinil from the tablet may occur at a faster rate than intended. The Orenitram tablet shell does not dissolve.  In patients with diverticulosis (blind-end pouches), Orenitram tablets can lodge in a diverticulum. Concomitant administration of Orenitram with diuretics, antihypertensive agents or other vasodilators increases the risk of symptomatic hypotension. Co-administration of Orenitram and the CYP2C8 enzyme inhibitor gemfibrozil increases exposure to treprostinil, therefore, Orenitram dosage reduction may be necessary in these patients.

Sildenafil

Revatio (sildenafil citrate) is an inhibitor of cyclic guanosine monophosphate (cGMP) specific phosphodiesterase type‐5 (PDE5) in the smooth muscle of the pulmonary vasculature, where PDE5 is responsible for degradation of cGMP. Revatio, increases cGMP within pulmonary vascular smooth muscle cells resulting in relaxation. In patients with pulmonary arterial hypertension (PAH), this can lead to vasodilation of the pulmonary vascular bed and, to a lesser degree, vasodilatation in the systemic circulation.

Revatio (sildenafil citrate) is indicated for the treatment of PAH, World Health Organization (WHO) Group I to improve exercise ability and delay clinical worsening. Studies establishing effectiveness included predominantly patients with NYHA Functional Class II‐III symptoms and etiologies of primary pulmonary hypertension (71%) or pulmonary hypertension associated with connective tissue disease (25%).

Sildenafil citrate is available as Revatio in 20 mg tablets and 10 mg vials (12.5 mL) and 10mg/ml oral suspension. The recommended dose of Revatio (sildenafil citrate) tablet is 5 or 20 mg three times a day. Tablets should be taken approximately four‐to‐six hours apart, with or without food. In the clinical trial no greater efficacy was achieved with the use of higher doses. Treatment with doses higher than 20 mg three times a day is not recommended.

Caution is advised when PDE5 inhibitors are co‐administered with alpha‐blockers. PDE5 inhibitors, including sildenafil, concomitant use of these two drug classes can lower blood pressure significantly, leading to symptomatic hypotension. In the sildenafil interaction studies with alpha‐blockers, cases of symptomatic hypotension consisting of dizziness and lightheadedness were reported. No cases of syncope or fainting were reported during these interaction studies. Consideration should be given to the fact that safety of combined use of PDE5 inhibitors and alpha‐blockers may be affected by other variables, including intravascular volume depletion and concomitant use of anti‐hypertensive drugs.

Sildenafil should be used with caution in patients with anatomical deformation of the penis (such as angulation, cavernosal fibrosis or Peyronie’ disease) or in patients who have conditions, which may predispose them to priapism (such as sickle cell anemia, multiple myeloma or leukemia). If priapism (painful erections greater than 6 hours in duration) is not treated immediately, penile tissue damage and permanent loss of potency could result.

The most common adverse events in clinical trials were epistaxis, headache, dyspepsia, flushing, insomnia, erythema, dyspnea exacerbation, and rhinitis.

At doses higher than the recommended 20 mg three times a day, there was a greater incidence of some adverse events including flushing, diarrhea, myalgia and visual disturbances. Visual disturbances were identified as mild and transient, and were predominately color‐tinge to vision, but also increased sensitivity to light or blurred vision.

There is an increased risk of mortality with increasing doses of Revatio in pediatric patients. Revatio is not recommended for use in pediatric patients.

Use in pulmonary veno‐occlusive disease may cause pulmonary edema and is not recommended.

Revatio may cause serious vaso‐occlusive crises in patients with pulmonary hypertension secondary to sickle‐disease.

Patients should seek medical attention if a sudden decrease or loss of vision or hearing occurs.

Combination therapies: Efficacy of Revatio not been evaluated in patients currently on Tracleer/bosentan therapy.

Delay in clinical worsening demonstrated when Revatio added to background Flolan/epoprostenol therapy.

Revatio (sildenafil citrate) therapy should be avoided in persons with with the following concomitant conditions: concurrent use of nitrates (e.g., nitroglycerin); concurrent use of protease inhibitor Ritonavir; and concurrent use of another PDE5 inhibitor such as Adcirca (tadalafil).

In a randomized, double-blind, placebo-controlled, dose-ranging study, Barst et al (2012) examined the effects of oral sildenafil citrate in treatment-naive children with PAH.  Children (n = 235; weight greater than or equal to 8 kg) were randomized to low-, medium-, or high-dose sildenafil or placebo orally 3 times daily for 16 weeks in the Sildenafil in Treatment-Naive Children, Aged 1-17 Years, With Pulmonary Arterial Hypertension (STARTS-1) study.  The primary comparison was percent change from baseline in peak oxygen consumption (PVo(2)) for the 3 sildenafil doses combined versus placebo.  Exercise testing was performed in 115 children able to exercise reliably; the study was powered for this population.  Secondary end points (assessed in all patients) included hemodynamics and functional class.  The estimated mean ± SE percent change in PVo(2) for the 3 doses combined versus placebo was 7.7 ± 4.0 % (95 % confidence interval [CI]: -0.2 % to 15.6 %; p = 0.056).  PVo(2), functional class, and hemodynamics improved with medium- and high-doses versus placebo; low-dose sildenafil was ineffective.  Most adverse events were mild-to-moderate in severity.  STARTS-1 completers could enter the STARTS-2 extension study; patients who received sildenafil in STARTS-1 continued the same dose, whereas placebo-treated patients were randomized to low-, medium-, or high-dose sildenafil.  In STARTS-2 (ongoing), increased mortality was observed with higher doses.  The authors concluded that 16-week sildenafil monotherapy is well-tolerated in pediatric PAH.  Percent change in PVo(2) for the 3 sildenafil doses combined was only marginally significant; however, PVo(2), functional class, and hemodynamic improvements with medium- and high- doses suggest efficacy with these doses.  Combined with STARTS-2 data, the overall profile favors the medium dose.  The authors stated that further investigation is needed to determine optimal dosing based on age and weight.

Tadalafil

Adcirca (tadalafil) is an inhibitor of cyclic guanosine monophosphate (cGMP) specific phosphodiesterase type‐5 (PDE5) in the smooth muscle of the pulmonary vasculature, where PDE5 is responsible for degradation of cGMP. Adcirca (tadalafil) increases cGMP within pulmonary vascular smooth muscle cells resulting in relaxation. In patients with pulmonary arterial hypertension (PAH), this can lead to vasodilation of the pulmonary vascular bed and, to a lesser degree, vasodilatation in the systemic circulation.

Adcirca (tadalafil) is indicated for the treatment of PAH, World Health Organization (WHO) Group I to improve exercise ability. Studies establishing effectiveness included predominately patients with NYHA Functional Class II and III symptoms and etiologies of idiopathic or heritable PAH (61%) or PAH associated with connective tissue diseases (23%).

Tadalafil is available as Adcirca in 20mg tablets. The recommended dose of Adcirca (tadalafil) is 40 mg (two 20 mg tablets) once daily, with or without food. Dividing the dose (40 mg) over the course of the daily is not recommended. In mild (creatinine clearance (CrCl)=51‐80 mL/min) to moderate (CrCl=31‐50 mL/min) renal impairment, Adcirca should be initiated at 20mg once daily and titrated to 40mg once daily as tolerated.

Caution is advised when PDE5 inhibitors are co‐administered with alpha‐blockers. PDE5 inhibitors, including tadalafil, concomitant use of these two drug classes can lower blood pressure significantly, leading to symptomatic hypotension.

The most common adverse events in clinical trials were headache, myalgia, nasopharyngitis, flushing, upper and lower respiratory infection, pain in extremity, nausea, back pain, dyspepsia, and nasal congestion.

Concurrent use with Potent CYP3A Inhibitors or Inducers is not recommended.

Seek immediate medical attention in the event of sudden loss of vision or sudden decrease in hearing.

Prolonged erection may occur, use cautiously in patients at risk for priapism.

Dose adjustments are necessary with the co‐administration of ritonavir: Special dosing instructions are advised.

Coadministration of Adcirca in patients on ritonavir:

1. Start Adcirca at 20mg once daily in patients that have received ritonavir for at least one week
2. Increase to 40mg once daily based on individual tolerability.

Coadministration of ritonavir in patients on Adcirca:

1. Stop Adcirca at least 24 hours prior to starting ritonavir
2. Resume Adcirca at 20mg once daily following minimum of one week on ritonavir
3. Increase to 40mg once daily based on individual tolerability.

Adcirca (tadalafil) therapy should not be used concurrently with nitrates (e.g., nitroglycerin).

Concurrent use of another PDE5 inhibitor, sildenafil (Revatio), with Adcirca is not necessary.

Victor and colleagues (2017) performed a randomized trial to test the primary hypothesis that once-daily tadalafil, administered orally for 48 weeks, lessens the decline in ambulatory ability in boys with Duchenne muscular dystrophy (DMD).  A total of 331 participants with DMD 7 to 14 years of age taking glucocorticoids were randomized to tadalafil 0.3 mg/kg/day, tadalafil 0.6 mg/kg/day, or placebo.  The primary efficacy measure was 6-minute walk distance (6MWD) after 48 weeks.  Secondary efficacy measures included North Star Ambulatory Assessment and timed function tests.  Performance of upper limb (PUL) was a pre-specified exploratory outcome.  Tadalafil had no effect on the primary outcome: 48-week declines in 6MWD were 51.0 ± 9.3 m with placebo, 64.7 ± 9.8 m with low-dose tadalafil (p = 0.307 versus placebo), and 59.1 ± 9.4 m with high-dose tadalafil (p = 0.538 versus placebo).  Tadalafil also had no effect on secondary outcomes.  In boys greater than 10 years of age, total PUL score and shoulder sub-score declined less with low-dose tadalafil than placebo; AEs were consistent with the known safety profile of tadalafil and the DMD disease state.  The authors concluded that tadalafil did not lessen the decline in ambulatory ability in boys with DMD.  They stated that further studies should be considered to confirm the hypothesis-generating UL data and to determine whether ambulatory decline can be slowed by initiation of tadalafil before 7 years of age.

Bosentan

Tracleer (bosentan) is a mixed endothelin‐A‐ and endothelin‐B‐receptor antagonist (with higher affinity for the A‐receptor subtype) that blocks the vasoconstrictor effects of endothelin‐1 in peripheral vascular smooth muscle (with resultant peripheral vasodilation). Endothelin‐A is present in vascular smooth muscle and mediates vasoconstriction; endothelin‐B also mediates vasoconstriction in vascular smooth muscle, but is additionally found on endothelial cells where it mediates vasodilation.

Tracleer (bosentan) is indicated for the treatment of pulmonary arterial hypertension, World Health Organization (WHO) Group I (see table 1) to improve exercise ability and decrease clinical worsening. Studies establishing effectiveness included predominately patients with NYHA Functional Class II‐IV symptoms and etiologies of idiopathic or heritable PAH (60%), PAH associated with connective tissue diseases (21%), and PAH associated with congenital systemic‐to‐pulmonary shunts (18%).

Considerations for use: Patients with WHO Class II symptoms showed reduction in the rate of clinical deterioration and a trend for improvement in walk distance. Physician should consider whether these benefits are sufficient to offset the risk of liver injury in WHO Class II patients, which may preclude future use as their disease progresses.

Tracleer (bosentan) can be prescribed and dispensed only through a restricted distribution program (Tracleer Access Program).

Bosentan is available as Tracleer 62.5 mg and 125 mg tablets. Treatment should be initiated at a dose of 62.5 mg BID for four weeks and then increased to the maintenance dose of 125 mg BID. Doses above 125 mg BID did not appear to confer additional benefit sufficient to offset the increased risk of liver injury.

Dosage Adjustments: Dose adjustments are necessary with the co‐administration of sildenafil. No dose‐adjustment for renal impairment is required. Adjustments of warfarin dosing may be necessary in order to maintain the desired level of anticoagulation.

Liver function tests should be measured prior to initiation and monthly during treatment with bosentan.

Potential Liver Injury: Tracleer (bosentan) can cause elevation of liver aminotransferases. Serum aminotransferase levels (and bilirubin if aminotransferase levels are elevated) should be measured prior to initiation of treatment and then monthly.

Tracleer (bosentan) is should generally be avoided in patients with moderate or severe hepatic impairment. Caution should be used in patients with mild hepatic impairment.

Pregnancy: Contraindicated due to high likely of causing serious birth defects (Pregnancy Category X). Tracleer (bosentan) is very likely to produce major birth defects if used by pregnant women. Therefore, pregnancy must be excluded before the start of treatment with bosentan and prevented thereafter by the use of a reliable method of contraception. Hormonal contraceptives, including oral, injectable, transdermal, and implantable contraceptives should not be used as the sole means of contraception because these may not be effective in patients receiving bosentan. Therefore, effective contraception through additional forms of contraception must be practiced. Monthly pregnancy tests should be obtained.

Treatment with Tracleer (bosentan) caused a dose‐related decrease in hemoglobin and hematocrit. The overall mean decrease in hemoglobin concentration for bosentan‐treated patients was 0.9 g/dL (change to end of treatment). Most of this decrease of hemoglobin concentration was detected during the first few weeks of treatment and hemoglobin levels stabilized by four‐to‐12 weeks of treatment. In placebo‐controlled studies of all uses of bosentan, marked decreases in hemoglobin (> 15% decrease from baseline resulting in values < 11 g/dL) were observed in 6% of bosentan‐treated patients and 3% of placebo‐treated patients. Hemoglobin levels should be monitored after one and three months of treatment and then every three months.

Sperm count may be decreased.

If signs of pulmonary edema occur, consider the possibility of underlying pulmonary veno occlusive disease.Discontinuation of treatment with Tracleer (bosentan) may be necessary.

Concomitant use of cyclosporine‐A or glyburide with Tracleer should be avoided.

Kovacs et al (2012) noted that borderline PAH, characterized by a marked exercise-induced increase in pulmonary artery pressure (PAP) with normal resting values, may precede overt PAH in SSc.  In a pilot study, these investigators examined if PAH treatment is safe in these patients and might attenuate hemodynamic progression.  SSc patients with borderline PAH underwent right heart catheterization at baseline, after a 12-month observation period, and subsequently after 6 months of bosentan therapy.  Changes in mean PAP at 50W during the observation period versus during therapy were compared.  A total of 10 patients completed the study.  Mean PAP at rest, at 50W, and during maximal exercise increased significantly during the observation period (mean +/- SD increases of 2.5 +/- 3.0 mm Hg [p = 0.03], 4.0 +/- 2.9 mm Hg [p = 0.002], and 6.8 +/- 4.1 mm Hg [p = 0.0005], respectively) and tended to decrease during the treatment period (decreases of 2.5 +/- 3.9 mm Hg [p = 0.07], 1.5 +/- 4.5 mm Hg [p = 0.32], and 1.8 +/- 7.0 mm Hg [p = 0.43], respectively).  The changes during the observation period versus the therapy period were significantly different (p = 0.03 at rest, p = 0.01 at 50W [primary end point], and p = 0.02 during maximal exercise).  The changes in resting pulmonary vascular resistance (PVR) were also significantly different during the observation period (increase of 8 +/- 25 dynes · seconds · cm(-5) ) versus during the therapy period (decrease of 45 +/- 22 dynes · seconds · cm(-5) ) (p < 0.0005).  Changes in resting pulmonary arterial wedge pressure were not significantly different between the observation period and the treatment period, despite the significant increase during the observation period (2.6 +/- 2.5 mm Hg [p = 0.01]).  No relevant adverse effects were reported.  The authors concluded that in SSc patients with borderline abnormal pulmonary hemodynamics, resting and exercise PAP may increase significantly within 1 year of observation.  Bosentan might be safe and effective to attenuate these changes.  They stated that randomized controlled trials (RCTs) are needed to confirm the exploratory findings of this hypothesis-generating pilot study.

Ambrisentan

Letairis (ambrisentan) is a selective endothelin type‐A (ETA) receptor antagonist. The primary actions of ETA are vasoconstriction and cell proliferation.

Letairis (ambrisentan) is indicated for the treatment of pulmonary arterial hypertension, World Health Organization (WHO) Group 1 to improve exercise ability and delay clinical worsening. Studies establishing effectiveness include predominantly patients with WHO Functional Class II‐III symptoms and etiologies of idiopathic or heritable PAH (64%) or PAH associated with connective tissue diseases (32%). Letairis can be prescribed and dispensed only through a restricted distribution program (Letairis Education and Access Program‐LEAP).

Ambrisentan is available as Letairis in 5 mg and 10 mg tablets. The recommended initial dose is 5 mg once daily with or without food and titrated to 10 mg once daily if 5 mg is tolerated. Doses higher than 10 mg once daily have not been studied in members with PAH.

Embryo‐Fetal Toxicity: Letairis (ambrisentan) is very likely to produce serious birth defects if used by pregnant women. Pregnancy must be excluded before the initiation. Females of reproductive potential must use acceptable methods of contraception during treatment with Letairis and for one month after treatment. In addition, monthly pregnancy tests are required for women of child‐bearing potential taking ambrisentan. Letairis (ambrisentan) is Pregnancy Category X

The most common adverse events is clinical trials were peripheral edema, headache, and nasal congestion. Fluid retention was identified as an adverse reaction during postapproval use of Letairis.

Multiple dose co‐administration of ambrisentan and cyclosporine resulted in an approximately a 2‐fold increase in ambrisentan exposure. When co‐administered with cyclosporine, limit the dose of Letairis (ambrisentan) to 5 mg once daily.

Tablets should not be split, crushed, or chewed.

In a prospective single-center, open-label, pilot study, Saggar et al (2012) described the changes in hemodynamics and exercise capacity in patients with SSc spectrum-associated exercise-induced pulmonary hypertension (ePH) treated with daily ambrisentan.  Patients were treated with ambrisentan, 5 mg or 10 mg once-daily, for 24 weeks.  At baseline and 24 weeks, patients with SSc spectrum disorders exercised in a supine position, on a lower extremity cycle ergometer.  All patients had normal hemodynamics at rest.  Baseline ePH was defined as a mean pulmonary artery pressure of greater than 30 mm Hg with maximum exercise and a trans-pulmonary gradient (TPG) of greater than 15 mm Hg.  The primary end point was change in PVR with exercise.  Secondary end points included an improvement from baseline in 6-min walking distance, health-related quality of life assessments, and cardiopulmonary hemodynamics.  Of the 12 enrolled patients, 11 completed the study.  At 24 weeks, there were improvements in mean exercise PVR (85.8 dynes × second/cm(5) ; p = 0.003) and mean distance covered during 6-min walk (44.5 meters; p = 0.0007).  Improvements were also observed in mean exercise cardiac output (1.4 liters/min; p = 0.006), mean pulmonary artery pressure (-4.1 mm Hg; p = 0.02), and total pulmonary resistance (-93.0 dynes × seconds/cm(5) ; p = 0.0008).  Three patients developed resting pulmonary arterial hypertension during the 24 weeks.  The authors concluded that exercise hemodynamics and exercise capacity in patients with SSc spectrum-associated ePH improved over 24 weeks with exposure to ambrisentan.  Moreover, they stated that placebo-controlled studies are needed to confirm whether this is a drug-related effect and to determine optimal therapeutic regimens for patients with ePH.

Macitentan

Opsumit (macitentan) is an endothelial receptor antagonist (ERA). In pulmonary arterial hypertension (PAH), the local ET system is up regulated mediating a variety of effects such as vasoconstriction, fibrosis, proliferation, hypertrophy, and inflammation. Up regulation of these processes is ultimately responsible for vascular hypertrophy and organ damage seen in PAH.

Opsumit (macitentan) is approved for the treatment of PAH (WHO Group 1) to delay disease progression. Disease progression includes: death, initiation of intravenous (IV) or subcutaneous prostanoids, or clinical worsening of PAH (decreased 6‐minute walk distance, worsened PAH symptoms and need for additional PAH treatment). Studies establishing effectiveness included predominately patients with WHO functional class II‐III and etiologies of idiopathic or heritable PAH or PAH associated with connective tissue disease in monotherapy or in combination with PDE‐5 inhibitors or inhaled prostanoids.

Opsumit (macitentan) is available in 10mg tablets. The recommended dose of Opsumit is 10mg daily.

Opsumit may cause fetal harm when administered to pregnant women. Opsumit was consistently shown to have teratogenic effects when administered to animals. Initiate treatment with Opsumit in females of reproductive potential only after a negative pregnancy test.Obtain monthly pregnancy test during treatment. For all females, Opsumit is available only through a restricted program called to Opsumit REMS program.

Avoid concomitant use of strong CYP3A4 inducers and inhibitors with Opsumit. Use other PAH treatment options when strong CYP3A4 inhibitors are needed as part of HIV treatment.

Opsumit (macitentan) therapy is not necessary for members concomitantly taking endothelin receptor antagonist (e.g. Letairis, Tracleer).

Riociguat

Adempas (riociguat) stimulates soluble guanylate cyclase and increases the sensitivity of guanylate cyclase to nitric oxide. In pulmonary arterial hypertension (PAH), synthesis of nitric oxide and the nitric oxidesoluble guanylate cyclase‐cyclic guanosine monophosphate pathway are impaired. By increasing the level of cyclic guanosine monophosphate, riociguat causes vasorelaxation and can have antifibrotic effects.

Adempas (riociguat) is indicated for the treatment of adults with persistent/recurrent Chronic Thromboembolic Pulmonary Hypertension (CTEPH) World Health Organization (WHO) Group 4 after surgical treatment or inoperable CTEPH to improve exercise capacity and WHO functional class. In addition, Adempas is indicated for the treatment of adults with PAH (WHO Group 1) to improve exercise capacity, improve WHO functional class and to delay clinical worsening. Efficacy was shown in patients on Adempas monotherapy or in combination with endothelin receptor antagonists or prostanoids. Studies establishing effectiveness included predominately patients with WHO functional class II–II and etiologies of idiopathic or heritable PAH (61%) or PAH associated with connective tissue diseases (25%).

Riociguat is available as Adempas in 0.5mg, 1mg, 1.5mg, 2mg and 2.5mg tablets. Initiate treatment at 1mg three times a day.Increase dosage by 0.5mg at intervals of no sooner than 2 weeks as tolerated to a maximum of 2.5mg three times a day.

Adempas (riociguat) is Pregnancy Category X. Do not administer Adempas to a pregnant female because it may cause fetal harm. Exclude pregnancy before start of treatment, monthly during treatment, and one month after treatment discontinuation. Prevent pregnancy during treatment and for one month after treatment discontinuation by use of acceptable methods of contraception. For females, Adempas is available only through a restricted program called the Adempas REMS Program.

Persons on Adempas (riociguat) therapy should avoid use with nitrates or nitric oxide donors in any form.

During the clinical trials with Adempas (PATENT and CHEST), patients with HIV PAH were excluded from the trial.

Selexipag

Uptravi (selexipag) is an oral, selective prostacyclin receptor (IP receptor) agonist approved for treatment of adults with PAH. Prostacyclin synthase is reduced in patients with pulmonary arterial hypertension, resulting in reduced production of prostacyclin, a potent vasodilator with antiproliferative effects. Selexipag is an oral selective prostacyclin receptor (IP receptor) agonist that is structurally distinct from prostacyclin. Activation of the prostacyclin receptor produces cyclic adenosine monophosphate, which induces vascular smooth muscle relaxation and produces decreases in vascular pressure and pulmonary vascular resistance and an increase in cardiac index.

Uptravi (selexipag) is approved for the treatment of pulmonary arterial hypertension (PAH, WHO Group I) to delay disease progression and reduce the risk of hospitalization for PAH. Effectiveness was established in a long‐term study in PAH patients with WHO Functional Class II‐III symptoms. Patients had idiopathic and heritable PAH (58%), PAH associated with connective tissue disease (29%), PAH associated with congenital heart disease with repaired shunts (10%).

In a phase III, randomized, double-blind, placebo-controlled trial, Sitbon et al (2015) randomly assigned 1,156 patients with PAH to receive placebo or selexipag (a prostacyclin receptor agonist) in individualized doses (maximum dose, 1,600 μg twice-daily).  Patients were eligible for enrollment if they were not receiving treatment for PAH or if they were receiving a stable dose of an endothelin-receptor antagonist (ETRA), a phosphodiesterase type 5 inhibitor, or both.  The primary end-point was a composite of death from any cause or a complication related to PAH up to the end of the treatment period (defined for each patient as 7 days after the date of the last intake of selexipag or placebo).  A primary end-point event occurred in 397 patients -- 41.6 % of those in the placebo group and 27.0 % of those in the selexipag group (HR in the selexipag group as compared with the placebo group, 0.60; 99 % CI: 0.46 to 0.78; p < 0.001).  Disease progression and hospitalization accounted for 81.9 % of the events.  The effect of selexipag with respect to the primary end-point was similar in the subgroup of patients who were not receiving treatment for the disease at baseline and in the subgroup of patients who were already receiving treatment at baseline (including those who were receiving a combination of 2 therapies).  By the end of the study, 105 patients in the placebo group and 100 patients in the selexipag group had died from any cause.  Overall, 7.1 % of patients in the placebo group and 14.3 % of patients in the selexipag group discontinued their assigned regimen prematurely because of adverse events (AEs).  The most common AEs in the selexipag group were consistent with the known side effects of prostacyclin, including headache, diarrhea, nausea, and jaw pain.  The authors concluded that among patients with PAH, the risk of the primary composite end-point of death or a complication related to PAH was significantly lower with selexipag than with placebo.  There was no significant difference in mortality between the 2 study groups.

In the phase III trial used for FDA approval of Uptravi (GRIPHON) approximately 80% of patients were receiving an ERA and/or a PDE‐5 inhibitor at baseline.

Should signs of pulmonary edema occur the possibility of pulmonary veno‐occlusive should be considered, if confirmed Uptravi should be discontinued.

Selexipag is available as Uptravi in 200 mcg, 400 mcg, 600 mcg, 800 mcg, 1000 mcg, 1200 mcg, 1400 mcg, and 1600 mcg tablets. The recommended starting dose of UPTRAVI is 200 micrograms (mcg) given twice daily. Tolerability may be improved when taken with food. Increase the dose in increments of 200 mcg twice daily, usually at weekly intervals, to the highest tolerated dose up to 1600 mcg twice daily. If a patient reaches a dose that cannot be tolerated, the dose should be reduced to the previous tolerated dose.

Experimental Drugs for PAH

Imatinib

In a phase II study, Ghofrani et al (2010) evaluated safety, tolerability, and efficacy of the platelet-derived growth factor receptor (PDGFR) inhibitor imatinib in patients with PAH.  Patients with PAH in functional classes II to IV were enrolled in a 24-week randomized, double-blind, placebo-controlled pilot study.  Patients received imatinib 200 mg orally once-daily (or placebo), which was increased to 400 mg if the initial dose was well- tolerated.  The primary endpoints were safety and change from baseline in the 6MWD.  Secondary endpoints included hemodynamics and functional classification.  A total of 59 patients enrolled (imatinib [n = 28]; placebo [n = 31]); 42 completed the study.  Drop-outs were equally matched between the 2 groups.  In the intention-to-treat (ITT) population there was no significant change in the 6MWD (mean +/- SD) in the imatinib versus placebo group (+22 +/-  63 versus -1.0 +/- 53 m).  There was a significant decrease in pulmonary vascular resistance (imatinib -300 +/- 347 versus placebo -78 +/- 269 dynes/second/cm2, p < 0.01) and increase in cardiac output (imatinib +0.6 +/- 1.2 versus placebo -0.1 +/- 0.9 L/min, p = 0.02).  Serious adverse events occurred in 11 imatinib recipients (39 %) and 7 placebo recipients (23 %); 3 deaths occurred in each group.  Post-hoc subgroup analyses suggested that patients with greater hemodynamic impairment may respond better than patients with less impairment.  The authors concluded that these findings are consistent with imatinib being well-tolerated in patients with PAH, and provide proof of concept for further studies evaluating its safety, tolerability, and efficacy in PAH.

Chhina et al (2010) noted that various studies have implicated the PDGF pathway in the pathogenesis of PAH.  Inhibition with imatinib mesylate has shown efficacy in human case reports and experimental models of PAH.  Results from a phase II trial of imatinib mesylate in PAH did not meet the primary endpoint but showed improvement in several secondary endpoints and in a subgroup analysis.  As suggested by this study as well as a few case reports, imatinib may be effective in a subset of patients with more severe disease.  However, this remains to be further validated through a phase III study, which is already underway.

Simvastatin

Wikins et al (2010) evaluated the therapeutic value of simvastatin in patients with PAH.  A total of 42 patients with PAH were randomized to receive either simvastatin (80 mg/day) or placebo in addition to current care for 6 months, and thereafter offered open-label simvastatin.  The primary outcome was change in right ventricular (RV) mass, assessed by cardiac MRI.  At 6 months, RV mass decreased by 5.2 +/- 11 g in the statin group (p = 0.045) and increased 3.9 +/- 14 g in the placebo group.  The treatment effect was -9.1 g (p = 0.028).  N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels decreased significantly in the statin group (-75 +/- 167 fmol/ml; p = 0.02) but not the placebo group (49 +/- 224 fmol/ml; p = 0.43; overall treatment effect -124 fmol/ml; p = 0.041).  There were no significant changes in other outcome measures (including 6MWD, cardiac index, and circulating cytokines).  From 6 to 12 months, both RV mass and NT-proBNP increased toward baseline values in 16 patients on active treatment who continued with simvastatin but remained stable in 18 patients who switched from placebo to simvastatin.  Two patients required a reduction in dose but not cessation of simvastatin.  The authors concluded that simvastatin added to conventional therapy produces a small and transient early reduction in RV mass and NT-proBNP levels in patients with PAH, but this is not sustained over 12 months.

Sorafanib

Gomberg-Maitland and colleagues (2010) noted that PAH and cancer share elements of pathophysiology.  This provides an opportunity for the cross-development of anti-cancer agents that can be used in improving PAH care.  The adaptation of new drugs across these disease populations warrants a structured approach.  This study was a 16-week, phase Ib, single-center, open-label trial of the multi-kinase/angiogenesis inhibitor sorafenib.  In order to assess the safety of sorafenib in PAH, patients with advanced but stable disease on parenteral prostanoids (with or without oral sildenafil) were initiated on treatment at the lowest active dosage administered to cancer patients: 200 mg daily.  Patients underwent weekly clinical evaluations and monthly functional testing and dose escalations to a final dosage of 400 mg twice-daily.  Among 12 patients (10 of them women), sorafenib was well-tolerated at 200 mg twice-daily.  The most common adverse events were moderate skin reactions on the hands and feet and alopecia.  The authors concluded that this is a tolerable dosing regimen for testing the therapeutic activity of sorafenib in PAH patients.

Warfarin

Johnson et al (2012) stated that warfarin is recommended in systemic sclerosis-associated PAH (SSc-PAH) and idiopathic PAH (IPAH) to improve survival.  There is no evidence to support this in SSc-PAH and the evidence in IPAH is conflicting.  These researchers evaluated the ability of warfarin to improve survival using 2 large SSc-PAH and IPAH cohorts.  The effect of warfarin on all-cause mortality was evaluated.  Bayesian propensity scores (PS) were used to adjust for baseline differences between patients exposed and not exposed to warfarin, and to assemble a matched cohort.  Bayesian Cox proportional hazards models were constructed using informative priors based on international PAH expert elicitation.  Review of 1,138 charts identified 275 patients with SSc-PAH (n = 78; 28 % treated with warfarin) and 155 patients with IPAH (n = 91; 59 % treated with warfarin).  Baseline differences in PAH severity and medications were resolved using PS matching.  In the matched cohort of 98 patients with SSc-PAH (49 treated with warfarin), the posterior median hazard ratio (HR) was 1.06 [95 % credible interval (CrI): 0.70 to 1.63].  In the matched cohort of 66 patients with IPAH (33 treated with warfarin), the posterior median HR was 1.07 (95 % CrI: 0.57 to 1.98).  The probabilities that warfarin improves median survival by 6 months or more are 23.5 % in SSc-PAH and 27.7 % in IPAH.  Conversely, there is a greater than 70 % probability that warfarin provides no significant benefit or is harmful.  The authors concluded that there is a low probability that warfarin improves survival in SSc-PAH and IPAH.  Given the availability of other PAH therapies with demonstrable benefits, there is little reason to use warfarin to improve survival for these patients.

Prostanoids for Critical Limb Ischemia

Ruffolo et al (2010) noted that peripheral arterial occlusive disease (PAOD) is a common cause of morbidity and mortality due to cardiovascular diseases in the general population.  While numerous treatments have been adopted for different disease stages, there is no option other than amputation for patients presenting with critical limb ischemia (CLI), unsuitable for rescue or reconstructive intervention.  These researchers determined the safety and effectiveness of prostanoids in patients presenting with CLI.  The Cochrane Peripheral Vascular Diseases Group searched their trials register (last searched October 2009) and the Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library (last searched 2009, Issue 4) for publications describing RCTs of prostanoids for CLI.  These researchers ran additional searches in MEDLINE, EMBASE, LILACS, and SciSearch, and we also contacted pharmaceutical companies and experts, in order to identify unpublished data and trials still underway.  Randomized controlled trials describing the safety and efficacy of prostanoids compared with placebo or other pharmacological control treatments, in patients presenting with CLI, without chance of rescue or reconstructive intervention.  Two authors independently selected trials, assessed trials for eligibility and methodological quality, and extracted data.  Disagreements were resolved by consensus or by the 3rd author.  These investigators retrieved 532 citations which after the first screening resulted in 111 potential studies.  Finally, after exclusion of studies of poor quality and a lack of sufficient information, 20 trials were included in the review.  Prostanoids seem to have efficacy regarding rest-pain relief (risk ratio (RR) 1.32, 95 % confidence interval (CI): 1.10 to 1.57; p = 0.003), and ulcer healing (RR 1.54, 95 % CI: 1.22 to 1.96).  Iloprost also shows favorable results regarding major amputations (RR 0.69, 95 % CI: 0.52 to 0.93).  The more frequently reported adverse events when using prostanoids were headache, facial flushing, nausea, vomiting and diarrhea.  The authors concluded that despite some positive results regarding rest-pain relief, ulcer healing and amputations, there is no conclusive evidence based on this meta-analysis of the long-term effectiveness and safety of different prostanoids in patients with CLI.  They stated that further well-conducted, high quality randomized double-blinded trials should be performed.  Furthermore, the 2007 TASC II consensus document on the management of peripheral arterial disease (Norgren et al, 2007) does not recommend epoprostenol or any other prostanoids for the management of limb-threatening ischemia.

Prostanoids for Peripheral Arterial Diseases

In a meta-analysis, Vitale and colleagues (2016) verified the effects of prostanoids on amputation rate and ulcer healing in patients with lower limb peripheral arterial disease (PAD).  The review protocol was published on http://www.crd.york.ac.uk/prospero (CRD42015020258).  A comprehensive search for published and unpublished trials comparing iloprost, alprostadil, prostaglandin-E1, epoprostenol, or taprostene with placebo/no therapy on amputation rate in patients with PAD and ulcer healing rate in patients with concomitant foot ulcers.  Mantel-Haenzel odds ratio (MH-OR) was calculated with random effect models for the chosen end-points.  A total of 18 trials, enrolling 3,077 and 2,763 patients in the prostanoid and comparator groups, respectively were included in the analysis.  Only 11 and 10 of those trials reported data on total and major amputations, respectively.  Prostanoids were associated with a significantly lower risk of major (MH-OR [95 % CI: 0.77 [0.63 to 0.93], p = 0.007), but not total, amputations. Healing rate (available only in 7 trials) was not significantly augmented by prostanoid treatment.  The authors concluded that available data are not sufficient to support an extensive use of prostanoids in patients with critical limb ischemia, as an adjunct to re-vascularization or as an alternative to major amputation in cases which cannot undergo re-vascularization.

Prostanoids for Pulmonary Hypertension Secondary to Histiocytosis X

In a pilot study, Bendayan and colleagues (2008) examined the potential of combination therapy with prostacyclin and tadalafil for treatment of severe pulmonary arterial hypertension (PAH).  These researchers reported 4 cases of severe PAH that deteriorated despite prostacyclin therapy; 2 patients had Eisenmenger syndrome, 1 had pulmonary hypertension associated with scleroderma and 1 had histiocytosis X.  All were treated with tadalafil, 10 to 20 mg once-daily, in addition to prostacyclin.  After 3 months of treatment, all patients improved clinically, with an increase in mean 6MWD from 214 to 272 m.  In 3 patients, the New York Heart Association functional class decreased from IV to III.  Echocardiograms showed no significant changes in pulmonary arterial pressure.  The authors conclude that although this study was limited by the small sample size, it suggested that tadalafil in combination with prostacyclin is an effective treatment for severe PAH.  They stated that tadalafil may be beneficial for the treatment of patients with advanced disease.

Furthermore, an UpToDate review on “Pulmonary Langerhans cell histiocytosis” (King, 2016) does not mention prostanoid/epoprostenol as a therapeutic option.

Prostanoids and Analogs for the Treatment of Pulmonary Hypertension in Neonates

Shivanna and colleagues (2019) stated that persistent pulmonary hypertension of the newborn (PPHN) is a disease entity that describes a physiology in which there is persistence of increased PAP.  PPHN is characterized by failure to adapt to a functional postnatal circulation with a fall in PVR.  PPHN is responsible for impairment in oxygenation and significant neonatal mortality and morbidity.  Prostanoids and their analogs may be useful therapeutic interventions due to their pulmonary vasodilatory and immunomodulatory effects.  In a Cochrane review, these researchers examined the safety and efficacy of prostanoids and their analogs (beraprost, iloprost, and treprostinil) in decreasing mortality and the need for extra-corporeal membrane oxygenation (ECMO) among neonates with PH.  Secondary objective was to determine the safety and efficacy of prostanoids and their analogs (beraprost, iloprost, and treprostinil) in decreasing neonatal morbidity (necrotizing enterocolitis (NEC), chronic lung disease (CLD), retinopathy of prematurity (ROP), intra-ventricular hemorrhage (IVH), peri-ventricular leukomalacia (PVL), length of hospital stay, and duration of mechanical ventilation) and improving neurodevelopmental outcomes among neonates with PH.  These investigators also compared prostanoids and their analogs at any dosage or duration used to treat PPHN versus “standard treatment without these agents”, placebo, or inhaled nitric oxide (iNO) therapy.  Prostanoids and their analogs at any dosage or duration used to treat refractory PPHN as an “add-on” therapy to iNO versus iNO alone.  These investigators used the standard search strategy of Cochrane Neonatal to search the Cochrane Central Register of Controlled Trials (CENTRAL; 2018, Issue 9), Medline via PubMed (1966 to September 16, 2018), Embase (1980 to September 16, 2018), and the Cumulative Index to Nursing and Allied Health Literature (CINAHL; 1982 to September 16, 2018).  They also searched clinical trials databases, conference proceedings of the Pediatric Academic Societies (1990 to September 16, 2018), and the reference lists of retrieved articles for RCTs and quasi-randomized trials.  They contacted authors who have published in this field as discerned from the reference lists of identified clinical trials and reviewed authors' personal files; RCTs and quasi-RCTs evaluating prostanoids or their analogs (at any dose, route of administration, or duration) used in neonates at any gestational age less than 28 days' post-natal age for confirmed or suspected PPHN.  These researchers used the standard methods of Cochrane Neonatal to conduct a systematic review and to evaluate the methodological quality of included studies (neonatal.cochrane.org/en/index.html).  Three review authors independently assessed the titles and abstracts of studies identified by the search strategy and obtained full-text versions for assessment if necessary.  They designed forms for trial inclusion or exclusion and for data extraction.  They planned to use the GRADE approach to assess the quality of evidence.  These investigators did not identify any eligible neonatal trials evaluating prostanoids or their analogs as sole agents in the treatment of PPHN.  The authors concluded that currently, no evidence showed the use of prostanoids or their analogs as pulmonary vasodilators and sole therapeutic agents for the treatment of PPHN in neonates (aged 28 days or less).  These researchers stated that the safety and efficacy of different preparations and doses and routes of administration of prostacyclins and their analogs in neonates must be established; well-designed, adequately powered, randomized, multi-center trials are needed to address the safety and efficacy of prostanoids and their analogs in the treatment of PPHN.  These trials should evaluate long-term neurodevelopmental and pulmonary outcomes, in addition to short-term outcomes.

Oral Sildenafil for Pulmonary Hypertension after Heart Transplantation

Kulkarni et al (2004) stated that patients with increased pulmonary vascular resistance may experience acute pulmonary hypertension after heart transplantation.  Pulmonary vasodilator drugs usually are delivered by the intravenous or the endotracheal route during acute pulmonary hypertensive crisis.  Oral pulmonary vasodilators have a potential role in less acutely ill patients with increased pulmonary artery pressure after heart transplantation.  These researchers described the 1st successful post-operative use of oral sildenafil for pulmonary vasodilation in a patient after heart transplantation.

Sansone and Rinaldi (2010) noted that early right ventricular dysfunction after heart transplantation (HTx) is a major complication especially in patients with pre-transplant pulmonary arterial hypertension (PH).  The possibility to reverse secondary PH using sodium nitroprusside (NPS) or inhaled nitric oxide has been already established and there is a well-known stratification of the incidence of early death after HTx related to the reversibility of PH.  Despite this, in a group of patients with irreversible disorders of the pulmonary vascular bed, conventional therapy may not be useful.  However, the decision to disqualify non-responsive HTx candidates may be inappropriate, considering that PH unresponsiveness to NPS does not exclude the possibility to decrease pulmonary pressures with other medications.  In case of non-responsive patients, the debate regarding the role of new selective pulmonary vasodilators is still open and oral sildenafil use in cardiac transplant candidates and recipients is growing.  Despite this, there were many reports of the use of phosphodiesterase 5 inhibitors in patients with chronic heart failure and several studies described the positive effects of sildenafil in reducing pulmonary vascular resistance and pulmonary arterial pressure and in increasing cardiac output.  The authors concluded that oral sildenafil use in cardiac transplant candidates or recipients is still limited.

De Santo et al (2012) stated that unresponsive PH may contraindicate heart transplant since it implies poor early outcomes.  The present study reported the effectiveness of oral peri-operative sildenafil in allowing heart transplant candidacy and surgery in a selected group of patients initially deemed ineligible because of PH.  Between May 2005 and December 2009, a total of 31 consecutive patients (5 females, 9 with a history of idiopathic cardiomyopathy and 16 with a history of coronary artery disease, 10 with previous sternotomies, 71.42 ± 27.69 ml/min/m(2) mean pre-operative epidermal growth factor receptor) were qualified for oral sildenafil because of unresponsive PH at baseline right heart catheterization (RHC).  After a 12-week trial, RHC disclosed PH reversibility (mean pulmonary vascular resistance index: 9.57 ± 4.07 WU, mean trans-pulmonary gradient 14.47 ± 5.66 mmHg and mean systolic pulmonary artery pressure: 68.96 ± 15.15 mmHg), allowing listing despite a higher risk for early post-transplant RV failure.  Transplant protocol included donor/recipient size matching greater than or equal to 0.8 and inhaled nitric oxide in the early post-operative period followed by re-institution of oral sildenafil.  All patients underwent heart transplantation.  Mean overall graft ischemic time was 179 ± 47 mins; mean donor recipient weight ratio was 1.04 ± 0.17.  Right ventricular failure developed in 3 patients (9.6 %) and hospital mortality was 3.2 %.  Protocol RHC disclosed pulmonary hemodynamic profile normalization within the 3rd post-operative month allowing weaning from sildenafil in the 30 hospital survivors.  One-year RHC confirmed PH reversal (n = 29 patients, all who survived up to 1 year).  The authors concluded that the findings of this pilot prospective uncontrolled trial suggested that oral sildenafil is effective in allowing candidacy, safe transplantation and post-operative pulmonary profile normalization in potential recipients initially disqualified because of PH.

Singh et al (2014) noted that high pulmonary vascular resistance index (PVRI) can lead to right ventricular dysfunction and failure of the donor heart early after pediatric heart transplantation.  Oral pulmonary vasodilators such as sildenafil have been shown to be effective modifiers of pulmonary vascular tone.  These researchers performed a retrospective, observational study comparing patients treated with sildenafil ("sildenafil group") to those not treated with sildenafil ("non-sildenafil group") after heart transplantation from 2007 to 2012.  Pre- and post-transplant data were obtained, including hemodynamic data from right heart catheterizations; 24 of 97 (25 %) transplant recipients were transitioned to sildenafil from other systemic vasodilators.  Pre-transplant PVRI was higher in the sildenafil group (6.8 ± 3.9 indexed Woods units [WU]) as compared to the non-sildenafil group (2.5 ± 1.7 WU, p = 0.002).  In the sildenafil group post-transplant, there were significant decreases in systolic pulmonary artery pressure, mean pulmonary artery pressure, trans-pulmonary gradient and PVRI (4.7 ± 2.9 WU before sildenafil initiation to 2.7 ± 1 WU on sildenafil, p = 0.0007).  While intubation time, length of inotrope use and time to hospital discharge were longer in the sildenafil group, survival was similar between both groups.  Oral sildenafil was associated with a significant improvement in right ventricular dysfunction and invasive hemodynamic measurements in pediatric heart transplant recipients with high PVRI early after transplant.

An UpToDate review on “Prognosis after cardiac transplantation” (Pham, 2015) does not mention sildenafil as a management option.

Combination (Dual / Triple) Pharmacotherapy

Dual pharmacotherapy (agents with different mechanisms of action) for the treatment of members with WHO Class II to IV pulmonary arterial hypertension (PAH) should be considered when criteria listed above are met; triple pharmacotherapy (agents with different mechanisms of action) for the treatment of PAH should be reviewed on an individual case basis.

The American College of Chest Physicians (CHEST) guideline’s on “Pharmacologic therapy for pulmonary arterial hypertension in adults” (Taichman et al, 2014) stated that “For treatment naive pulmonary arterial hypertension (PAH) patients in World Health Organization [WHO] functional class [FC] IV who are unable or do not desire to manage parenteral prostanoid therapy, the panel advises treatment with an inhaled prostanoid in combination with an endothelin receptor antagonists (ETRA) (e.g., bosentan, ambrisentan, macitentan)”.

Zijlstra et al (2014) stated that in order to describe survival and treatment strategies in pediatric PAH in the current era of PAH-targeted drugs and to identify predictors of outcome, these investigators studied uniformly defined contemporary patient cohorts at 3 major referral centers for pediatric PAH (New York [NY], Denver, and the Netherlands [NL]).  According to uniform inclusion criteria, 275 recently diagnosed consecutive pediatric PAH patients who visited the 3 referral centers between 2000 and 2010 were included.  Un-adjusted survival rates differed between the center cohorts (1-, 3-, and 5-year transplantation-free survival rates: 100 %, 96 %, and 90 % for NY; 95 %, 87 %, and 78 % for Denver; and 84 %, 71 %, and 62 % for NL, respectively; p < 0.001).  Based on WHO FC and hemodynamic parameters, disease severity at diagnosis differed between the center cohorts.  Adjustment for diagnosis, WHO FC, indexed pulmonary vascular resistance, and pulmonary-to-systemic arterial pressure ratio resolved the observed survival differences.  Treatment with PAH-targeted dual and triple therapy during the study period was associated with better survival than treatment with PAH-targeted monotherapy.  The authors concluded that survival rates of pediatric PAH patients differed between 3 major referral centers.  This could be explained by differences between the center cohorts in patients' diagnoses and measures of disease severity, which were identified as important predictors of outcome.  They stated that in this study, treatment with PAH-targeted combination therapy during the study period was independently associated with improved survival.

Coeytaux et al (2014) conducted a systematic review to evaluate the comparative safety and effectiveness of monotherapy or combination therapy for PAH using ETRA, phosphodiesterase inhibitors, or prostanoids.  These investigators searched English-language publications of comparative studies that reported intermediate or long-term outcomes associated with drug therapy for PAH.  Two investigators abstracted data and rated study quality and applicability.  They identified 28 RCTs involving 3,613 patients.  They found no studies that randomized treatment-naive patients to monotherapy versus combination therapy.  There was insufficient statistical power to detect a mortality difference associated with treatment.  All drug classes demonstrated increases in 6MWD when compared with placebo, and combination therapy showed improved 6MWD compared with monotherapy.  For hospitalization, the odds ratio (OR) was lower in patients taking ETRA or phosphodiesterase-5 inhibitors compared with placebo (OR, 0.34 and 0.48, respectively).  The authors concluded that although no studies were powered to detect a mortality reduction, monotherapy was associated with improved 6MWD and reduced hospitalization rates.  They stated that these findings also suggested an improvement in 6MWD when a second drug is added to monotherapy.

Galie et al (2015) stated that data on the effect of initial combination therapy with ambrisentan and tadalafil on long-term outcomes in patients with PAH are scarce.  In this event-driven, double-blind study, these researchers randomly assigned, in a 2:1:1 ratio, participants with WHO FC II or III symptoms of PAH who had not previously received treatment to receive initial combination therapy with 10 mg of ambrisentan plus 40 mg of tadalafil (combination-therapy group), 10 mg of ambrisentan plus placebo (ambrisentan-monotherapy group), or 40 mg of tadalafil plus placebo (tadalafil-monotherapy group), all administered once-daily.  The primary end-point in a time-to-event analysis was the first event of clinical failure, which was defined as the first occurrence of a composite of death, hospitalization for worsening PAH, disease progression, or unsatisfactory long-term clinical response.  The primary analysis included 500 participants; 253 were assigned to the combination-therapy group, 126 to the ambrisentan-monotherapy group, and 121 to the tadalafil-monotherapy group.  A primary end-point event occurred in 18 %, 34 %, and 28 % of the participants in these groups, respectively, and in 31 % of the pooled-monotherapy group (the 2 monotherapy groups combined).  The HR for the primary end-point in the combination-therapy group versus the pooled-monotherapy group was 0.50 (95 % confidence interval [CI]: 0.35 to 0.72; p < 0.001).  At week 24, the combination-therapy group had greater reductions from baseline in N-terminal pro-brain natriuretic peptide levels than did the pooled-monotherapy group (mean change of -67.2 % versus -50.4 %; p < 0.001), as well as a higher percentage of patients with a satisfactory clinical response (39 % versus 29 %; OR of 1.56 [95 % CI: 1.05 to 2.32; p = 0.03) and a greater improvement in the 6MWD (median change from baseline, 48.98 m versus 23.80 m; p < 0.001).  The adverse events that occurred more frequently in the combination-therapy group than in either monotherapy group included peripheral edema, headache, nasal congestion, and anemia.  The authors concluded that among participants with PAH who had not received previous treatment, initial combination therapy with ambrisentan and tadalafil resulted in a significantly lower risk of clinical-failure events than the risk with ambrisentan or tadalafil monotherapy.

Hassoun and colleagues (2015) noted that scleroderma-associated PAH (SSc-PAH) is a rare disease characterized by very dismal response to therapy and poor survival.  These researchers assessed the effects of upfront, combined PAH therapy in SSc-PAH.  In this prospective, multi-center, open-label trial, 24 treatment naïve SSc-PAH patients received ambrisentan (10 mg) and tadalafil (40 mg) daily for 36 weeks.  Functional, hemodynamic and imaging (cardiac magnetic resonance and echocardiography) assessment at baseline and 36 weeks included changes in right ventricular mass and pulmonary vascular resistance (RV mass and PVR) as co-primary end-points, and stroke volume/pulmonary pulse pressure (SV/PP), tricuspid annular plane systolic excursion (TAPSE), 6MWD and N-terminal pro-brain natriuretic peptide (NT-proBNP), all secondary end-points.  Treatment resulted in significant reductions in median RV mass (28.0 IQR 20.6 to 32.9 versus 32.5 IQR 23.2 to 41.4 gm; p < 0.05) and PVR (3.1 IQR 2.0 to 5.7 versus 6.9 IQR 4.0 to 12.9 Wood Units; p < 0.0001), and improvements in SV/PP (2.6 IQR 1.8 to 3.5 versus 1.4 IQR 8.9 to 2.4 ml/mmHg; p < 0.0001), TAPSE (2.2 ± 0.12 versus 1.65 ± 0.11 cm; p < 0.0001), 6MWD (395 ± 99 versus 343 ± 131 m; p = 0.001) and serum NT-proBNP (647 ± 1,127 versus 1,578 ± 2,647 pg/ml; p < 0.05).  The authors concluded that upfront ambrisentan and tadalafil therapy significantly improved hemodynamics, RV structure and function, and functional status in treatment naïve SSc-PAH patients and may represent a very effective therapy for this patient population.

Tacoy et al (2015) noted that PAH is a progressive disease of the pulmonary vascular bed and causes right heart failure and death.  Combination therapy which targets 3 different pathways is necessary due to the progressive nature of the disease.  In patients with PAH, there are 2 approaches in combination therapy: "first-line, up-front" and "sequential add-on" treatment.  In "first-line, up-front" treatment, patients receive double or triple drug therapy from the start.  In the "sequential add-on" approach, a single drug is initially started and then according to the patient's requirements, a second or third drug is added.  There is insufficient evidence about the efficiency and safety of treatment approaches.  In this study, these researchers evaluated the treatment approach in patients with PAH at a tertiary center.  Pulmonary arterial hypertension was diagnosed according to clinical, echocardiographic and right heart catheterization findings.  The patients received bosentan, sildenafil and iloprost treatment in accordance with guidelines recommendations.  Clinical worsening in patients was defined as death, requirement of hospitalization for PAH, a 15 % decline in the 6MWD, deterioration in functional capacity, and symptoms and findings of right heart failure.  At the end of the follow-up period, clinical and echocardiographic findings, BNP levels and oxygen saturation were similar between patients who completed the study with monotherapy and with combination therapy.  The follow-up period was significantly longer in patients who required combination treatment.  Two patients (6.9 %) died and 4 patients (13.8 %) were hospitalized due to recurrent symptoms and findings of right heart failure.  At the end of follow-up, 10 patients (34.5 %) completed the study with a single drug, 15 patients (51.7 %) with 2 drugs and 4 patients (13.8 %) with 3 drugs.  The authors concluded that combination therapy was given to patients as "sequential add-on therapy".  At the end of the follow-up period, monotherapy was sufficient in 34.5 % of patients of the study group and in 8 patients, sildenafil or prostaglandin analogues are added; a total of 15 patients (48.4 %) completed the study under dual therapy; 4 patients (12.9 %) received combination therapy with 3 drugs.

Furthermore, an UpToDate review on “Treatment of pulmonary hypertension in adults” (Hopkins and Rubin, 2016) states that “Combination Therapy -- It has been proposed that combining pharmacologic agents with different mechanisms of action may produce an additive effect or may induce the same effect at lower doses of each agent.  Combination therapy may be administered as two agents initiated together or as "add-ons" (i.e., one followed by another).  The combination associated with the best efficacy is tadalafil and ambrisentan for patients with functional class II or III PAH.

• Tadalafil plus ambrisentan -- The combined oral regimen of tadalafil (phosphodiesterase-5 inhibitor) plus ambrisentan (endothelin receptor antagonist), improves outcomes in patients with WHO functional class II or III.  One randomized trial (AMBITION) of 500 newly diagnosed patients with group 1 PAH (mostly idiopathic and connective tissue disease-related) who had class II or III symptoms compared the combination of 10 mg of ambrisentan and 40 mg of tadalafil with either agent alone.  The combined regimen administered on average for 18 months resulted in a 50 % reduction in the rate of clinical failure (18 % versus 31 %) and improved exercise capacity (49 versus 24 meters).  The reduction in clinical failure rate was primarily driven by decreased hospitalizations for progressive PAH (which portends a poor prognosis), rather than by improved survival or WHO functional class.  Adverse events including edema, headache, nasal congestion, anemia, and syncope were reported more frequently in those receiving combination therapy (45 versus 30 percent), but rates of hypotension were similar.  This trial is the basis for recommending this particular combination in PAH patients with class II or III symptoms.  However, clinicians should be aware that substituting with other drugs within the same family (e.g., sildenafil plus bosentan) may not be associated with the same improved outcomes.  As an example the increased metabolism and consequent reduction in plasma concentration of sildenafil by bosentan may partly explain the contradictory outcomes associated with this combination.  In contrast, the lack of drug interaction between tadalafil and ambrisentan may also explain why the outcomes reported in AMBITION were more robust.
• Sildenafil plus bosentan -- Combining sildenafil and bosentan may be associated with improved outcomes but results from trials have been contradictory.  One prospective cohort study followed 25 patients with group 1 PAH who were initially treated with bosentan monotherapy, but developed clinical deterioration and had sildenafil added.  Clinical improvement occurred after the addition of sildenafil, as measured by symptoms, exercise capacity, and WHO functional classification. Improvement was more frequent and of greater magnitude in patients with IPAH, compared to patients with scleroderma-associated PAH.  In a second study of patients failing monotherapy with either bosentan or sildenafil, the addition of the other agent also resulted in improved functional class and survival in those with idiopathic PAH, when compared with those with connective tissue-associated PH.  In contrast, a larger placebo-controlled trial reported no benefit when bosentan was added to sildenafil in a similar population, although the inclusion of patients with repaired congenital heart disease may have impacted the outcome.
• Bosentan added to either epoprostenol or treprostinil -- Limited experience suggests that bosentan can be used safely and effectively added to epoprostenol or subcutaneous treprostinil therapy.  A trial (BREATHE-2 trial) randomly assigned 22 patients with group 1 PAH who were receiving epoprostenol to have either bosentan or placebo added for 16 weeks.  Epoprostenol improved hemodynamic parameters, exercise capacity, and functional class, compared to baseline.  The addition of bosentan improved these outcomes to a greater degree than the addition of placebo, although the difference was not statistically significant.
• Treprostinil added to either bosentan or sildenafil -- The addition of inhaled treprostinil may improve the exercise capacity and quality of life of patients with persistent symptoms despite bosentan or sildenafil therapy.  This was demonstrated by the Treprostinil Sodium Inhalation Used in the Management of Pulmonary Arterial Hypertension (TRIUMPH) trial.  In the trial, 235 patients with group 1 PAH, a WHO functional class III or IV, and a six minute walking distance (6MWD) of only 200 to 450 meters despite bosentan or sildenafil therapy were randomly assigned to receive either inhaled treprostinil or placebo for 12 weeks.  The treprostinil group had a larger improvement in their six minute walking distance and quality of life, but there were no differences in the time to clinical worsening, dyspnea, or WHO functional class.
• Oral treprostinil added to an endothelin receptor antagonist and/or a phosphodiesterase-5 inhibitor -- The addition of oral treprostinil in patients with group 1 PAH already on an endothelin receptor antagonist and/or a phosphodiesterase-5 inhibitor did not improve the 6MWD at 16 weeks (FREEDOM-C and FREEDOM C-2).  The 354 subjects were randomly assigned to oral treprostinil or placebo for 16 weeks.  The dose of treprostinil was increased at intervals according to protocol to a median dose of 3 mg twice daily.  A study drug discontinuation rate of 22 % was noted in the treprostinil group and was attributed to the high incidence (> 40 %) of side effects of headache, nausea, vomiting, diarrhea, flushing, and jaw pain.  Significant improvements were noted in the secondary end-points of median dyspnea fatigue index score and combined 6MWD and Borg dyspnea score.
• Sildenafil added to epoprostenol -- The addition of sildenafil to long-term epoprostenol therapy improves clinical outcomes.  A trial randomly assigned 267 patients with group 1 PAH who were receiving epoprostenol to have sildenafil or placebo added for 16 weeks.  Most patients were WHO functional class III at the beginning of the trial.  Sildenafil improved hemodynamic parameters, exercise capacity, quality of life, and time to clinical worsening, compared to placebo.  There was no difference in dyspnea.  Headache and dyspepsia were more common in the sildenafil group.
• Sildenafil added to iloprost -- The combination of iloprost plus sildenafil may improve outcomes compared to either agent alone.  This was illustrated by a prospective cohort study of 73 patients with group 1 PAH who were receiving long-term inhaled iloprost.  Clinical deterioration occurred in 14 patients, prompting the addition of sildenafil for 9 to 12 months.  Among those patients who had sildenafil added to their iloprost regimen, there was improvement in exercise capacity, WHO functional class, and hemodynamics.
• Bosentan plus iloprost -- The effect of combining bosentan with iloprost is less clear.  Early observational studies suggested that the combination was both safe and effective when bosentan was added to preexisting inhaled iloprost therapy.  However, a subsequent trial that randomly assigned 40 patients with IPAH to receive bosentan alone or bosentan plus iloprost for 12 weeks, demonstrated no difference in the six-minute walking distance, the trial's primary end-point.  The results of the trial may have been skewed by three outliers in the combination therapy group.  Thus, larger trials are needed to adequately evaluate the efficacy of bosentan and iloprost combination therapy.
• Riociguat added to sildenafil -- The safety of combining sildenafil and riociguat was examined in one trial (PATENT PLUS) where patients receiving sildenafil were randomized to placebo or riociguat (up to 2.5 mg 3 times daily) and treated for 12 weeks.  There were no differences observed in standing or supine blood pressure, pulmonary hemodynamics, or exercise capacity with riociguat plus sildenafil compared with sildenafil alone.  However, when the combination was administered in a small number of patients beyond the study period, high rates of discontinuation (due to hypotension) and three deaths (thought not to be study drug-related) were reported.  Due to the unfavorable safety profile, the US Food and Drug Administration issued a warning against combining PDE5 inhibitors and guanylate cyclase stimulants.  We agree that this combination is contraindicated and should not be administered in patients with PAH”.

Atrial Septostomy, Balloon pulmonary angioplasty, and Pulmonary Artery Denervation

In a single-center, prospective trial, Chen et al (2013) evaluated the safety and effectiveness of pulmonary artery (PA) denervation (PADN) for patients with idiopathic PAH (IPAH) not responding optimally to medical therapy.  Of a total of 21 patients with IPAH, 13 patients received the PADN procedure, and the other 8 patients who refused the PADN procedure were assigned to the control group.  Pulmonary artery denervation was performed at the bifurcation of the main PA, and at the ostial right and left PA.  Serial echocardiography, right heart catheterization, and a 6-min walk test (6MWT) were performed.  The primary end-points were the change of PAP, tricuspid excursion (Tei) index, and 6MWT at 3 months follow-up.  Compared with the control group, at 3 months follow-up, the patients who underwent the PADN procedure showed significant reduction of mean PAP (from 55 ± 5 mm Hg to 36 ± 5 mm Hg, p < 0.01), and significant improvement of the 6MWT (from 324 ± 21 m to 491 ± 38 m, p < 0.006) and of the Tei index (from 0.7 ± 0.04 to 0.50 ± 0.04, p < 0.001).  The authors reported for the first time the effect of PADN on functional capacity and hemodynamics in patients with IPAH not responding optimally to medical therapy.  They stated that further randomized study is needed to confirm the effectiveness of PADN.  The major drawbacks of the study were its small sample size, as well as its non-placebo-controlled and non-double-blinded design.

In an editorial that accompanied the afore-mentioned study, Galie and Manes (2013) stated that the study by Chen et al (2013) should be considered a very preliminary proof-of-principle study that requires a formal and large multi-center RCT to appropriately evaluate a possible new area for the treatment of PAH patients.

Chen et al (2015) analyzed the hemodynamic, functional, and clinical responses to PADN in patients with PAH of different causes.  Between April 2012 and April 2014, a total of 66 consecutive patients with a resting mPAP greater than or equal to 25 mm Hg treated with PADN were prospectively followed-up.  Target drugs were discontinued after the PADN procedure.  Hemodynamic response and 6MWD were repeatedly measured within the 1 year post-PADN follow-up.  The clinical end-point was the occurrence of PAH-related events at the 1-year follow-up.  There were no PADN-related complications.  Hemodynamic success (defined as the reduction in mPAP by a minimal 10 % post-PADN) was achieved in 94 % of all patients, with a mean absolute reduction in systolic PAP and mPAP within 24 hours of -10 mm Hg and -7 mm Hg, respectively.  The average increment in 6MWD after PADN was 94 m.  Worse PAH-related events occurred in 10 patients (15 %), mostly driven by the worsening of PAH (12 %).  There were 8 (12 %) all-cause deaths, with 6 (9 %) PAH-related deaths.  The authors concluded that PADN was safe and feasible for the treatment of PAH.  The PADN procedure was associated with significant improvements in hemodynamic function, exercise capacity, and cardiac function and with less frequent PAH-related events and death at 1 year after PADN treatment.  Moreover, they stated that further randomized studies are needed to confirm the effectiveness of PADN for PAH.

Muller and Liebetrau (2016) stated that chronic thrombo-embolic pulmonary hypertension (CTEPH) occurs as a consequence of a series of events that includes arterial obstruction by embolic material, secondary in-situ thrombosis, cytokine activation and inflammation, and small vessel angiopathy.  Medical therapies have a limited effectiveness.  Only the guanylate cyclase stimulator, riociguat, is approved for this condition.  Surgical pulmonary endarterectomy is the definitive treatment for patients with proximal disease, but 1/3 of patients with CTEPH are considered ineligible for surgery.  Another 1/3 have significant residual pulmonary hypertension post-operatively.  The authors noted that balloon pulmonary angioplasty is an option for these patients.  The procedure has a low procedural mortality and high effectiveness in experienced centers; but has not yet been subjected to rigorous evaluation in clinical trials.  They also stated that alternative options for percutaneous management include atrial septostomy and PADN; experience with these procedures is accumulating, but adequately powered, controlled trials have yet to be carried out.

Guidelines on the pulmonary hypertension from the European Society of Cardiology and the European Respiratory Society (Galie, et al., 2016) state that the recommended technique for creating an interatrial right-to-left shunt to decompress the right heart chambers and increase left ventricular preload and cardiac output is the graded balloon dilation atrial septostomy. Other techniques are considered experimental. Published reports suggest a benefit in patients who are in WHO functional class IV with right heart failure refractory to medical therapy or with severe syncopal symptoms. It may also be considered in patients awaiting lung transplantation with unsatisfactory clinical response on maximal medical therapy or when medical therapy is not available. Studies show improvements in cardiac index and decreases in right atrial pressure with improvement in 6-minute walk distance. The impact of balloon atrial septoplasty on long-term survival has not been established in randomized controlled trials. The guideliens state that balloon atrial septoplasty should be regarded as a palliative or bridging procedure to be performed only in centres with experience in the method.

Implantable Intravenous Prostanoid Pump for the Treatment of Pulmonary Hypertension

Waxman and associates (2017) noted that prostacyclins improve symptoms and survival in PAH.  In response to risks associated with external delivery systems, an implantable intravenous (IV) infusion system was developed.  In a multi-center, prospective, single-arm, clinical trial (DelIVery for PAH), these researchers evaluated this system for treprostinil in PAH.  This analysis described the findings related to the implantation procedure.  Patients (n = 64) with PAH (WHO group 1) receiving stable IV treprostinil were enrolled.  They were transitioned to a temporary peripheral IV infusion catheter prior to the procedure.  System implantation was performed at 10 centers under general anesthesia or deep IV sedation by clinicians from various specialties.  Central venous access was via the cephalic, subclavian, jugular, or axillary vein.  Using an introducer and fluoroscopic guidance, the distal tip of the infusion catheter was placed at the superior caval-atrial junction.  The catheter was tunneled from the venous access site to an abdominal subcutaneous pocket, where the pump was placed.  Of the 64 patients enrolled, 4 exited prior to implantation.  All 60 implant procedures were successful.  At baseline, all patients were receiving treprostinil via an external pump at a mean dose of 71.4 ± 27.8 ng/kg/min (range of 22 to 142 ng/kg/min).  The implantation procedure averaged 102 ± 32 mins (range of 47 to 184 mins).  Clinically significant implant procedure-related complications included 1 pneumothorax, 2 infections, and 1 episode of atrial fibrillation.  There were 3 post-implantation catheter dislocations in 2 patients.  Common implant-related events that were not complications included implant site pain (83 %) and bruising (17 %).  The authors concluded that the procedure for inserting a fully implantable system for treprostinil was successfully performed, with few complications.  Larger well-designed studies with long-term follow-up are needed to ascertain safety and effectiveness of this approach.

Richter and colleagues (2017) stated that in patients with severe PAH, subcutaneous or catheter-based intravenous application of prostanoids carries a risk of local side effects or systemic infections, which limits their use and acceptance.  Recently, a fully implantable pump for continuous application of intravenous treprostinil was approved in Germany.  However, surgery is a major risk for patients with severe PAH.  The investigators examined the safety of a fully implantable pump inserted under local or general anesthesia in patients with severe PAH.  All patients with PAH undergoing pump implantation for the continuous application of intravenous treprostinil were included from 2 German centers.  Surgery was performed under local or general anesthesia according to the protocol of the recruiting center.  Intra-operative safety and in-hospital complications were analyzed for the 2 different implantation regimens.  A total of 51 patients were included.  No major intra-operative complications were recorded.  During the observation period, 2 patients died of progressive right heart failure, and 2 patients required treatment in the intensive care unit (ICU) for acute right heart decompensation and respiratory failure.  In total, major complications occurred in 8 out of 51 patients.  The authors concluded that the findings of this observational study provided preliminary evidence supporting the procedural safety of a fully implantable pump inserted under local or general anesthesia for patients with severe PAH; and the observation of major complications in a subset of patients requires extensive pre- and post-operative assessments.  They stated that future trials are needed to provide further evidence for the long-term safety and efficacy of the pump using this approach.

Ambrisentan and Bosentan for Critical Limb Ischemia / Peripheral Arterial Disease

De Haro and associates (2016) stated that endothelin (ET) is involved in the etiopathogenesis of peripheral arterial disease (PAD).  These researchers hypothesized that ET antagonism might improve the endothelial function, inflammatory status, and symptoms in PAD.  In a pilot, proof-of-concept trial, these investigators examined the clinical efficacy, pleiotropic effects, and safety of dual ET-receptor antagonist bosentan in Hispanic patients with PAD presenting intermittent claudication.  The Bosentan Population-Based Randomized Trial for Clinical and Endothelial Function Assessment on Endothelin Antagonism Therapy was a 12-month, randomized, controlled, parallel-group, double-blind study evaluating the effect of bosentan on absolute claudication distance (primary efficacy end-point), flow-mediated arterial dilation, and C-reactive protein (CRP) levels (primary pleiotropic end-points) in patients with PAD with Rutherford category 1 to 2 of recent diagnosis.  Secondary end-points included ankle-brachial index (ABI), subjective claudication distance, and safety.  Of the 629 screened subjects, 56 patients were randomized 1:1 to receive bosentan for 12 weeks (n = 27) or placebo (n = 29).  Six months after the initiation, a significant treatment effect in flow-mediated arterial dilation of 2.43 ± 0.3 % (95 % CI: 1.75 to 3.12; p = 0.001), absolute claudication distance of 283 ± 23 m (95 % CI: 202 to 366; p = 0.01), ABI of 0.16 ± 0.03 (95 % CI: 0.09 to 0.23; p = 0.001), and a decrease in CRP levels of -2.0 ± 0.5 mg/L (95 % CI: -2.8 to -1.1; p = 0.02) were observed in the bosentan-treated group compared to the control group.  No severe adverse effects were found in the bosentan group.  The authors concluded that in Hispanic patients with intermittent claudication, bosentan was well-tolerated and improved endothelial function and claudication distance as well as inflammatory and hemodynamic states.  These preliminary findings from a proof-of-concept study need to be validated by well-designed studies.

Omarjee and colleagues (2017) noted that sildenafil and bosentan combined therapy could have beneficial effect in systemic sclerosis (SSc) patients with PAD.  These investigators reported a case of a 48-year old woman, who developed severe left limb claudication and walking limitation following a left femoro-popliteal bypass occlusion in 2014.  She was a heavy smoker and had a history of right middle cerebral artery ischemic stroke and bilateral Raynaud phenomenon.  According to the American College of Rheumatology/European League Against Rheumatism-2013 criteria, diagnosis of limited cutaneous SSc was retained with macrovascular lesions.  She was referred for investigation of left limb claudication on treadmill using transcutaneous oxygen pressure measurement during exercise to argue for the vascular origin of the walking impairment.  She had a severe left limb ischemia and the maximum walking distance (MWD) she reached was 118 m in March 2015 despite the medical optimal treatment and walking rehabilitation.  Sildenafil, 20 mg tid, was introduced due to active digital ulcers.  In July 2015, the MWD increased to 288 m, then to 452 m in December 2015.  The addition of bosentan to sildenafil to prevent recurrent digital ulcers resulted in an MWD of 1,576 m.  The authors concluded that with the combined therapy, the patient had no more pain during walking and her quality of life (QOL) has improved.  Moreover, they stated that further clinical trials are needed to confirm these preliminary findings.

The American Heart Association/American College of Cardiology’s guideline on “The Management of Patients With Lower Extremity Peripheral Artery Disease” (Gerhard-Herman et al, 2017) did not mention ambrisentan and bosentan as therapeutic options.

Furthermore, an UpToDate review on “Investigational therapies for treating symptoms of lower extremity peripheral artery disease” (Hess and Hiatt, 2018) does not mention ambrisentan and bosentan as therapeutic options.

Appendix

WHO Classification of Pulmonary Hypertension

1 PAH

1.1  Idiopathic (PAH)
1.2  Heritable PAH
1.3  Drug- and toxin-induced PAH
1.4  PAH associated with:

1.4.1  Connective tissue diseases
1.4.2  HIV infection
1.4.3  Portal hypertension
1.4.4  Congenital heart diseases, including Eisenmenger's syndrome
1.4.5  Schistosomiasis

1.5  PAH long-term responders to calcium channel blockers
1.6  PAH with overt features of venous/capillaries (PVOD/PCH) involvement
1.7  Persistent PH of the newborn syndrome

2 PH due to left heart disease

2.1  PH due to heart failure with preserved LVEF
2.2  PH due to heart failure with reduced LVEF
2.3  Valvular heart disease
2.4  Congenital/acquired cardiovascular conditions leading to post-capillary PH

3 PH due to lung diseases and/or hypoxia

3.1  Obstructive lung disease
3.2  Restrictive lung disease
3.3  Other lung disease with mixed restrictive/obstructive pattern
3.4  Hypoxia without lung disease
3.5  Developmental lung disorders

4 PH due to pulmonary artery obstruction

4.1  Chronic thromboembolic PH
4.2  Other pulmonary artery obstructions

4.2.1  Sarcoma (high or intermediate grade) or angiosarcoma
4.2.2  Other malignant tumors

Renal carcinoma
Uterine carcinoma
Germ cell tumours of the testis
Other tumours

4.2.3   Non-malignant tumours

Uterine leiomyoma

4.2.4  Arteritis without connective tissue disease
4.2.5  Congenital pulmonary artery stenosis
4.2.6  Parasites

Hydatidosis

5 PH with unclear and/or multifactorial mechanisms

Table:The World Health Organization (WHO) functional classification of pulmonary artery hypertension is as follows:

Classes	Functional Classification of Pulmonary Artery Hypertension
Class I	Persons with no symptoms, and for whom ordinary physical activity does not cause fatigue, palpitation, dyspnea, or anginal pain
Class II	Persons who are comfortable at rest but who have symptoms Footnotes for symptoms of PAH* with ordinary physical activity
Class III	Persons who are comfortable at rest but have symptoms Footnotes for symptoms of PAH* with less-than-ordinary effort
Class IV	Persons who have symptoms Footnotes for symptoms of PAH* at rest

Footnotes for symptoms of PAH^*Key symptoms of PAH include fatigue, dizziness and fainting (near syncope) 

Table:The World Health Organization classification of pulmonary hypertension (PH) is as follows:

Groups	Classification of Pulmonary Hypertension
Group 1	Patients that have PAH.  Most patients in this category have idiopathic PAH. However, others include inheritable, drug-related, and connective tissue disease-associated PAH.
Group 2	Patients who have pulmonary venous hypertension, which is usually due to left heart disease.
Group 3	Patients who have PH due to chronic lung disease and/or chronic hypoxemia.
Group 4	Patients with chronic thromboembolic disease causing PH.
Group 5	Patients who have PH that is of uncertain course and likely multifactorial.

Adapted from UpToDate, 2014.

Table: CPT Codes / HCPCS Codes / ICD-10 Codes

Code	Code Description
Information in the [brackets] below has been added for clarification purposes.   Codes requiring a 7th character are represented by "+":
Other CPT codes related to the CPB:
96365 - 96371	Intravenous and subcutaneous infusion, for prophylaxis, or diagnosis (specify substance or drug); initial, up to 1 hour
HCPCS codes covered if selection criteria are met:
J1325	Injection, epoprostenol, 0.5 mg
J3285	Injection, treprostinil, 1 mg
J7686	Treprostinil, inhalation solution, FDA-approved final product, non-compounded, administered through DME, unit dose form, 1.74 mg
Q4074	Iloprost, inhalation solution, FDA-approved final product, non-compounded, administered through DME, unit dose form, up to 20 micrograms
S0090	Sildenafil citrate, 25 mg [phosphodiesterase 5 inhibitor] [not covered in oral form for pulmonary hypertension after heart transplantation]
HCPCS codes not covered for indications listed in the CPB:
Ambrisentan, Bosentan, Alyq (tadalafil)- no specific code:
E0782	Infusion pump, implantable, nonprogrammable (includes all components, e.g., pump, catheter, connectors, etc.)
E0783	Infusion pump system, implantable, programmable (includes all components, e.g., pump, catheter, connectors, etc.)
S0088	Imatinib, 100 mg
ICD-10 codes covered if selection criteria are met:
I27.0	Primary pulmonary hypertension [not covered for pulmonary artery denervation]
I27.20 - I27.29	Other secondary pulmonary hypertension
I27.83	Eisenmenger's syndrome
I73.00 - I73.01	Raynaud’s syndrome
ICD-10 codes not covered for indications listed in the CPB (not all-inclusive):
C96.0	Multifocal and multisystemic (disseminated) Langerhans-cell histiocytosis
C96.5	Multifocal and unisystemic Langerhans-cell histiocytosis
C96.6	Unifocal Langerhans-cell histiocytosis
G61.81	Chronic inflammatory demyelinating polyneuritis
G71.00 - G71.09	Muscular dystrophy
I50.1 - I50.9	Heart failure
I70.0 - I70.92	Atherosclerosis
I73.1 - I73.9	Other peripheral vascular diseases [limb ischemia]
J44.0 - J44.9	Other chronic obstructive pulmonary disease
L97.101 - L97.929	Non-pressure chronic ulcer of lower limbs
M62.251 - M62.269	Nontraumatic ischemic infarction of muscle, lower extremity [peripheral arterial disease]
Z90.2	Acquired absence of lung [part of]
Z94.1	Heart transplant status
Atrial septostomy and balloon pulmonary angioplasty:
CPT codes covered if selection criteria are met:
33741	Transcatheter atrial septostomy (TAS) for congenital cardiac anomalies to create effective atrial flow, including all imaging guidance by the proceduralist, when performed, any method (eg, Rashkind, Sang-Park, balloon, cutting balloon, blade)
92997 - 92998	Percutaneous transluminal pulmonary artery balloon angioplasty

The above policy is based on the following references: