MP 5.01.09

Treatment of Pulmonary Arterial Hypertension with Prostacyclin Analogues, Endothelin Receptor Antagonists, or Phosphodiesterase Inhibitors

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Medical Policy
Section Prescription Drug	Original Policy Date 01/1998	Last Review Status/Date Reviewed with literature search/4:2009
Issue 4:2009		Return to Medical Policy Index

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Disclaimer

Our medical policies are designed for informational purposes only and are not an authorization, or an explanation of benefits, or a contract.  Receipt of benefits is subject to satisfaction of all terms and conditions of the coverage.  Medical technology is constantly changing, and we reserve the right to review and update our policies periodically.

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Description

Pulmonary Hypertension
Pulmonary hypertension (PH) refers to the presence of abnormally high pulmonary vascular pressure. The World Health Organization (WHO) classifies patients with PH into five groups based on etiology. These groups differ in their clinical presentation, diagnostic findings, and response to treatment. It is important to note the changes in defining and classifying pulmonary hypertension in the following revised WHO Classification of PH developed by the 2009 American College of Cardiology Foundation/American Heart Association (ACCF/AHA) 2009 Expert Consensus Task Force on Pulmonary Hypertension. Patients in the Group 1 are considered to have pulmonary arterial hypertension (PAH) and the remaining four groups are considered to have PH.
Revised WHO Classification of Pulmonary Hypertension (PH)

1. Pulmonary arterial hypertension (PAH)

1.1. Idiopathic (IPAH)
1.2. Familial (FPAH)
1.3. Associated with (APAH):

1.3.1. Connective tissue disorder
1.3.2. Congenital systemic-to-pulmonary shunts
1.3.3. Portal hypertension
1.3.4. HIV infection

1.3.5. Drugs and toxins
1.3.6. Other (thyroid disorders, glycogen storage disease, Gaucher’s disease, hereditary hemorrhagic telangiectasia, hemoglobinopathies, chronic myeloproliferative disorders, splenectomy)

1.4. Associated with significant venous or capillary involvement

1.4.1. Pulmonary veno-occlusive disease (PVOD)
1.4.2. Pulmonary capillary hemangiomatosis (PCH)

1.5. Persistent pulmonary hypertension of the newborn

2. Pulmonary hypertension with left heart disease

2.1. Left-sided atrial or ventricular heart disease
2.2. Left-sided valvular heart disease

3. Pulmonary hypertension associated with lung diseases and/or hypoxemia

3.1. Chronic obstructive pulmonary disease
3.2. Interstitial lung disease
3.3. Sleep disordered breathing
3.4. Alveolar hypoventilation disorders
3.5. Chronic exposure to high altitude
3.6. Developmental abnormalities

4. Pulmonary hypertension due to chronic thrombotic and/or embolic disease
(CTEPH)

4.1. Thromboembolic obstruction of proximal pulmonary arteries
4.2. Thromboembolic obstruction of distal pulmonary arteries
4.3. Nonthrombotic pulmonary embolism (tumor, parasites, foreign material)

5. Miscellaneous

Sarcoidosis, histiocytosis X, lymphangiomatosis, compression of pulmonary vessels (adenopathy, tumor, fibrosing mediastinitis)

Pulmonary Arterial Hypertension (WHO Group 1)
Pulmonary arterial hypertension (PAH) is a rare and debilitating disease characterized by abnormal proliferation and contraction of pulmonary artery smooth muscle cells. This causes a decrease in the size of the pulmonary artery lumen, a decreased reactivity of the vascular bed, increased pulmonary vascular resistance (PVR) and elevated pressure in the pulmonary circulation (initially with normal left-sided pressures) and leads to overload-induced progressive right ventricular dilation and low cardiac output.

Idiopathic pulmonary hypertension (IPAH) is more prevalent in women and the most common type of PAH. Familial PAH often results from a mutation in bone morphogenetic protein receptor-2 (BMPR2) and is inherited as an autosomal dominant disease. PAH is also associated with congenital heart disease (CHD), connective tissue diseases, drugs and toxins, human immunodeficiency virus (HIV), portal hypertension, hemoglobinopathies, and myeloproliferative disorders. The diagnosis of PAH requires confirmation with a complete right heart catheterization (RHC). The current hemodynamic definition of PAH is a mean pulmonary artery pressure (PAPm) greater than 25 mmHg; a pulmonary capillary wedge pressure (PCWP), or left ventricular end-diastolic pressure (LVEDP) less than or equal to 15 mm Hg; and a pulmonary vascular resistance (PVR) greater than 3 Wood units.

Non-Pulmonary Arterial Hypertension PH (WHO Groups 2-5)
PH associated with elevated left heart filling pressures are more prevalent than PAH. Treatment should be directed at the underlying left heart disease. Use of PAH-specific treatments for non-PAH PH has been suggested but there are no clinical trial data to support these hypotheses. There are potential adverse side effects of PAH-specific therapies in such patients including increased fluid retention, pulmonary edema and ventilation perfusion mismatch.

Baseline Assessment of PAH
A baseline assessment to determine severity of PAH is often performed before initiation of therapy.

This assessment includes the following measures as key determinants of disease severity;

Functional impairment- The functional significance of the PAH is determined by measuring exercising capacity and determining New York Heart Association (NYHA) or World Health Organization (WHO) functional class.

The New York Association (NYHA) Classification- functional classification

Class I	patients with no limitation of activities; they suffer no symptoms from ordinary activities.
Class II	patients with slight, mild limitation of activity; they are comfortable with rest or mild exertion.
Class III	patients with marked limitation of activity; they are comfortable only at rest
Class IV	patients who should be at complete rest, confined to bed or chair; any physical activity brings on discomfort and symptoms occur at rest

World Health Organization (WHO) - functional classification for pulmonary arterial hypertension

Class I	no limitation of clinical activity; ordinary physical activity does not cause dyspnea or fatigue
Class II	slight limitation in physical activity; ordinary physical activity produces dyspnea, fatigue, chest pain, or near-syncope; no symptoms at rest
Class III	marked limitation of physical activity; less than ordinary physical activity produces dyspnea, fatigue, chest pain, or near-syncope; no symptoms at rest
Class IV	unable to perform any physical activity without symptoms; dyspnea and/or fatigue present at rest; discomfort increased by any physical activity

Hemodynamic derangement- pulmonary artery systolic pressure and right ventricular function can be estimated by echocardiography. Right heart catheterization is performed to accurately measure the hemodynamic parameters and confirm PAH. Right heart catheterization is often deferred until advanced therapy is indicated because it is an invasive procedure. Patients with PAH typically undergo an invasive hemodynamic assessment and an acute vasoreactivity test prior to the initiation of advanced therapy.

The acute vasoreactivity test involves administration of a short-acting vasodilator, then measuring the hemodynamic response with a right heart catheter. Agents commonly used include epoprostenol, adenosine, and inhaled nitric oxide. An acute vasoreactivity test is considered positive if mean pulmonary artery pressure decreases at least 10 mmHg and to a value less than 40 mmHg, with an increased or unchanged cardiac output, and a minimally reduced or unchanged systemic blood pressure. Patients with a positive vasoreactivity test are candidates for a trial of calcium channel blocker therapy. In contrast, patients with a negative vasoreactivity test should be treated with alternative agents given calcium channel blockers (CCBs) have not shown to be beneficial in these patients and may be harmful.

Medical Management
Conventional therapies are considered in all patients with PAH regardless of the etiology; diuretics, oxygen therapy, anticoagulants, digoxin and exercise. Digoxin has been shown to have beneficial effects when used with caution (i.e. patients may be at higher risk for digitalis toxicity and require close monitoring). Patients with a positive vasoreactivity test can be given a trial of CCBs. Patients with a negative vasoreactivity test require advanced therapy with prostacyclin analogues, endothelin receptor antagonists, or phosphodiesterase type 5 (PDE5) inhibitors. Combination advanced therapy has been suggested and is under investigation, but the data is insufficient to draw conclusions. Lung transplantation and combined heart-lung transplantation have been performed in patients refractory to medical management. Objective assessments to measure treatment response include; improvement in exercise capacity (6 mile walk test, cardiopulmonary exercise test, treadmill test), hemodynamics and survival.

The following table summarizes the advanced therapies for treatment of PAH (WHO Group 1):

Advanced Therapy

Drug Brand Name Manufacturer FDA approval date

Route(s) of Administration Dose range

FDA Approval Indications

Prostaglandin Analogues

epoprostenol sodium (FLOLAN®) GlaxoSmithKline FDA approved 1995	continuous IV infusion via central venous catheter using an ambulatory infusion pump 1 to 20 ng/kg/min	Long-term treatment of primary pulmonary hypertension and pulmonary hypertension associated with the scleroderma spectrum of disease in NYHA Class III and Class IV patientswho do not respond adequately to conventional therapy
treprostinil sodium (REMODULIN®) United Therapeutics Corp. FDA approved 2002	Continuous SC infusion IV infusion 0.625 to 1.25 ng/kg/min	Treatment of PAH in patients with NYHA Class II-IV symptoms, to diminish symptoms associated with exercise Patients who require transition from Flolan, to reduce the rate of clinical deterioration.
iloprost (VENTAVIS®) Acetelion, Ltd. FDA approved 2004	Inhalation via nebulizer;either of two pulmonary drug delivery devices 2.5 to 5 mcg, 6-9 times/day	Treatment of pulmonary arterial hypertension (WHO Group I) in patients with NYHA Class II or IV symptoms.
beraprost NOT APPROVED IN US & EU Failed reviews APPROVED IN JAPAN Treatment of PAH	oral

Endothelin Receptor Antagonists

bosentan (TRACLEER®) Acetelion, Ltd. FDA approved 2001	oral 62.5 to 125 mg, 2 times/day	Treatment of pulmonary arterial hypertension (WHO Group I) in WHO Class III or IV symptoms to improve exercise ability and decrease rate of clinical worsening
ambrisentan (LETAIRIS®) Gilead Sciences, Inc. FDA approved 2007	oral 5-10 mg/day	Treatment of pulmonary arterial hypertension (WHO group i) in patients with WHO class II or III symptoms to improve exercise capacity and delay clinical worsening
sitaxsentan sodium NOT APPROVED IN US Reviewed & Rejected 3 times by the FDA Last: June 2007 APPROVED IN Canada- 2007 THELIN® Treatment of primary pulmonary arterial hypertension (PAH) and pulmonary hypertension secondary to connective tissue disease, in patients with WHO functional class III and patients with WHO functional class II who did not respond to conventional therapy Australia- 2007 EU-2006	oral

Phopshodiestrase (PDE5) Inhibitors

sildenafil citrate (REVATIO®) Pfizer Labs June 2005	oral 20mg three times/day	Treatment of pulmonary arterial hypertension (WHO Group I) to improve exercise ability
tadalafil CIALIS®) Eli Lilly FDA approved		No FDA approved indications for PAH or clinical evidence to support use for PAH
vardenafil (LEVITRA®) FDA approved		No FDA approved indications for PAH or clinical evidence to support use for PAH

It is important to emphasize that the approved treatments for pulmonary arterial disease (PAH; WHO Group 1) have serious side effects and have not shown to be effective in patients with other forms of pulmonary hypertension.

The use of bosentan and sildenafil is being investigated for the treatment of digital ulcers in patients with systemic sclerosis. The evidence is insufficient to permit conclusions concerning the impact on health outcome. Bosentan and sildenafil do not have FDA approval for this indication.

Policy

The following therapies may be considered medically necessary for the treatment of pulmonary arterial hypertension (PAH/ WHO Group 1):

• epoprostenol sodium (FLOLAN®) continuous IV infusion;
• treprostinil sodium (REMODULIN®) Continuous SC infusion, IV infusion;
• Iloprost (VENTAVIS®) Inhalation via nebulizer;
• bosentan (TRACLEER®) oral;
• ambrisentan (LETAIRIS®) oral;
• sildenafil citrate (REVATIO®) oral

Combination therapy is considered investigational for the treatment of pulmonary arterial hypertension, except when changing from one treatment to another.

The use of epoprostenol, treprostinil, iloprost, bosentan, ambrisentan, or sildenafil is considered investigational for the treatment of non-PAH PH conditions (WHO Groups 2-5), including but not limited to;

• Pulmonary hypertension associated with left heart diseases;
• Pulmonary hypertension associated with lung diseases and/ or hypoxemia (including chronic obstructive pulmonary disease);
• Pulmonary hypertension due to chronic thrombotic and/or embolic disease;
• Miscellaneous group (i.e. sarcoidosis, histiocytosis X and lymphangiomatosis)

The use of tadalafil (CIALIS®) and vardenafil (LEVITRA®) is considered investigational for the treatment of pulmonary arterial hypertension (WHO Group 1) and non-PAH PH conditions (WHO Groups 2-5).

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Policy Guidelines

• Initial dose-ranging study, which is typically performed as an inpatient. The pulmonary capillary wedge pressure is monitored, and the infusion rate of the drug is increased until dose-limiting pharmacologic effect such as nausea, vomiting, or headache is elicited. Some practitioners may consider the initial dose-ranging study optional.
• Insertion of central venous catheter and attachment to portable infusion pump. Since rebound pulmonary hypertension may recur if the drug is abruptly withdrawn, the drug labeling advises that all patients should have access to a backup infusion pump and intravenous infusion set.
• Ongoing maintenance of portable infusion pump and treatment of complications related to the pump. Complications include catheter thrombosis, sepsis, and pump malfunction. In the clinical trials, a cold pouch and frozen gel packs were used to facilitate extended use at ambient temperatures.

Treatment with lioprost requires the use of a specialized dispensing device.

Benefit Application

BlueCard/National Account Issues

• While epoprostenol would generally be considered under the medical benefits, use of bosentan, ambrisentan, iloprost, trepostinol, and sildenafil may be considered under the pharmacy benefits.
• Benefit or contract language describing the “least costly alternative” may be applicable to the choice of therapy among epoprostenol, bosentan, ambrisentan, iloprost, or trepostinil.
• Patients treated with infusion pumps may require a back-up pump. However, the cost of a back-up pump may be included in the home infusion therapy charges or in the HCPCS code. (See coding section, below.)

Sildenafil citrate is available as both Revatio and Viagra. Benefit or contract language describing the "least costly alternative" may be applicable to this choice. Pricing differences may exist between alternatives. Revatio is available as a 20mg tablet. Viagra is available in 25mg, 50mg, 100mg tablets.

Rationale

Studies included in updates and prior policy statements make reference to primary and secondary pulmonary hypertension. In March 2009, the ACCF/AHA Expert Consensus Task Force released a document that included a revised WHO classification for pulmonary hypertension. The 2009 update and policy statements reflect this change in nomenclature. The intent of the policy statements has not changed.

This section reviews data for the agents that are FDA-approved for treatment of pulmonary arterial hypertension. Most of the data are short-term results with measures such as the 6-minute walk distance. There are sparse data related to longer term outcomes (including survival), comparison among agents, and combination therapy. Editorial critiques of the available literature raise questions about the study endpoints selected. They comment that studies are short in duration, and compare outcomes that reflect symptomatic improvement, e.g., 6-minute walk distance or functional class, but not disease status such as vasculature remodeling or survival. (1)

Epoprostenol
The original approval of epoprostenol from the FDA was based on a 12-week trial of 81 patients with NYHA Class III or Class IV primary pulmonary hypertension who were randomized to receive either epoprostenol or conventional medical management. (2) As compared to conventional therapy, the continuous intravenous infusion of epoprostenol produced symptomatic and hemodynamic improvement, as well as improved survival in patients with severe primary pulmonary hypertension. In 1998, McLaughlin and colleagues reported on a case series of 27 patients treated with epoprostenol who were followed up for a mean of 16 months. (3) All patients had improvements in symptoms such as NYHA classification and exercise duration. While pulmonary vascular resistance declined only 23% acutely in response to a test dose of adenosine (another vasodilator), over long-term follow-up the vascular resistance fell by 53%. These results suggest that the beneficial effects of epoprostenol are not solely related to vasodilation, but perhaps are related to anticoagulant and endothelial cytoprotective effects. McLaughlin and colleagues subsequently reported survival data for those receiving epoprostenol. (4) A total of 162 consecutive patients diagnosed with primary PHTN were treated with epoprostenol and followed up for a mean of 36.3 months. Observed survival at 1, 2, and 3 years was 87.8%, 76.3%, and 62.8%, which were significantly greater than the expected survival of 58.95, 46.3%, and 35.4%, respectively, based on historical controls.

In 2000, epoprostenol received additional FDA approval as a treatment of pulmonary hypertension associated with the scleroderma spectrum of disease, based in part on the following data. Humbert and colleagues reported on an uncontrolled case series of epoprostenol in 17 patients with PHTN associated with either scleroderma, CREST syndrome, systemic lupus erythematosus (SLE), or Sjogren’s syndrome. (5) Patients were followed up from 14 to 154 weeks. After 6 weeks, exercise capacity improved in 15 of 17 patients; the remaining 2 patients died of pulmonary edema or sepsis. During the long-term follow-up, an additional 5 patients died, 2 patients underwent successful lung transplantation, and 7 of the remaining 8 patients had a persistent clinical improvement. Badesch and colleagues reported on a study that randomized 111 patients with pulmonary hypertension related to scleroderma to receive either conventional therapy or conventional therapy in addition to epoprostenol therapy. (6) The primary outcome measure was exercise capacity. A significant improvement in exercise capacity was noted in the epoprostenol group compared to the control group, for whom exercise capacity actually decreased. Cardiopulmonary hemodynamics also improved significantly in the treatment group compared to the control group. A total of 38% of patients in the treatment group reported improvements in NYHA classification, compared to none in the control group. Four deaths occurred in the epoprostenol group compared to 5 in the control group, although it should be noted that the study was not adequately powered to detect a significant difference in survival.

Rosenzweig and colleagues reported on a case series of 20 patients with pulmonary hypertension secondary to congenital heart disease who had failed to improve clinically with conventional therapy. (7) Although none of the patients experienced a decrease in pulmonary artery pressure in response to epoprostenol infusion, long-term therapy was associated with a 21% reduction in pulmonary artery pressure. In addition, NYHA classification improved from a mean of 3.2 to 2.0. A nonsignificant increase occurred in exercise capacity.

Treprostinil
The FDA approval of treprostinil (Remodulin) was based in part on 2 randomized, placebo-controlled double-blind studies of 470 patients with Class II–IV primary or secondary pulmonary hypertension. (8, 9) Endpoints, measured at 12 weeks, included exercise capacity (as measured by the 6-minute walk test), dyspnea, and hemodynamic effects. There was a median 16-meter improvement in the 6-minute walk test, which although statistically significant was not as great as that noted for epoprostenol. Patients who were more compromised at baseline had the greatest improvements, and thus the lower median improvement may be related to the inclusion of less severe patients (i.e., Class II) in this trial.

A cohort study of long-term survival was identified, which compared survival of patients treated with treprostinil (up to 4 years) with predicted survival using an NIH registry equation or untreated patients from registry data. Treprostinil survival among 860 patients was 87%– 68% over 1–4 years, noting that 59% of patients discontinued treatment due to adverse events (39%), death (27%), clinical deterioration (23%), and other (withdrew consent, transplantation, protocol violation, and loss to follow-up) reasons (11%). Sensitivity analyses found no differences between those discontinuing due to site pain reaction and patients who did not discontinue; however, selection bias due to censoring is possible, and could bias the results in favor of treprostinil survival. Among 332 patients for whom predicted survival could be calculated (using the NIH registry equation), treprostinil treatment resulted in 91% and 72% survival at 1 and 4 years compared to predicted survival of 69% and 38%, respectively. (10)

Ilosprost
The FDA approval of iloprost (i.e., Ventavis) was based in part on the results of a randomized, double- blind, multi-center placebo-controlled trial conducted in 203 adult patients with pulmonary arterial hypertension, including both patients with primary and secondary pulmonary hypertension. (11) The primary endpoint was a composite endpoint at 12 weeks defined by 1) improvement in exercise capacity (6-minute walk test) and 2) improvement by at least on NYHA class versus baseline; and no death or deterioration of pulmonary function. The response rate was 19% for the iloprost group compared to 4% for the placebo group. The use of iloprost requires a specialized dispensing device. One limitation of this delivery system is that drug may be lost in the device tubing.

Bosentan
The FDA approval of bosentan (Tracleer) was based in part on randomized, placebo-controlled double-blind studies of 213 patients with Class III–IV primary or secondary pulmonary hypertension. (12) The primary endpoint was degree of change in exercise capacity. At 16 weeks, a significant improvement was found in the 6-minute walk test in the treatment group compared to the placebo group. Other measures of symptoms and functional status also improved in the treatment group, including a composite measure of “clinical worsening,” which consisted of the outcomes of death, hospitalizations for PHTN, discontinuation of therapy, or need for epoprostenol. In addition, the treatment group had a significant increase in cardiac index associated with reduction in the pulmonary artery pressure. A review article detailed 2 randomized, controlled clinical trials (RCTs) (n =310) that evaluated the effect of bosentan for the treatment of systemic sclerosis-associated digital ulcers. In both trials, there was significant improvement in hand function, however, no differences seen in healing of established ulcers. (13)

Ambrisentan
The FDA approval of abrisentan (Letairis) was based on two 12-week randomized, double-blind, placebo-controlled multicenter studies of 393 patients with pulmonary arterial hypertension. (14) ARIES-1 compared once-daily doses of 5mg and 10 mg of Letairis to placebo, while ARIES-2 compared once-daily doses of 2.5 and 5 mg. Patients were not taking any of the other agents discussed in this policy during the study. Sixty-four percent had idiopathic PHTN and 32% had PHTN associated with connective tissue disease. Placebo-adjusted mean changes from baseline in the 6-minute walk distance were 51 meters in AIRES-1 and 59 meters in AIRES-2 (results for the higher dosages). For the two trials, clinical worsening was noted in 10% and 22% of the placebo patients compared to 3% and 6% of those receiving abrisentan.

Sildenafil citrate
The FDA approval of sildenafil citrate (Revatio, also marketed as Viagra) was based in part on the results of a study that randomized 278 patients with pulmonary hypertension to receive either placebo or sildenafil (20, 40, or 80 mg), orally 3 times daily for 12 weeks. (15) There was a significant improvement in primary endpoint, defined as the change in baseline to week 12 in the distance walked in 6 minutes. Of the 222 patients completing 1 year of treatment, the improvement in distance walked in 6 minutes was 51 meters. There was no significant difference among the 3 different doses of sildenafil given, and thus the recommended dose is 20 mg 3 times per day. At doses higher than the recommended dose, there was greater incidence of some adverse events including flushing, diarrhea, myalgia and visual disturbances. There have been a few case reports but no randomized controlled trials of sildenafil in the treatment of digital ulcers secondary to systemic sclerosis.

Other Drugs
Other prostacylin analogues that have been investigated for the treatment of PHTN but are not yet FDA approved include the oral drug beraprost (16, 17) and the oral drug terbogrel (a thromboxane A2 inhibitor). (18) There is also interest in combining therapies with different mechanisms of action (19); however, there have been no controlled trials of combination therapy.

Comparative Trials and Long-Term Outcomes
It should be noted that the randomized trials of epoprostenol, treprostinil, iloprost, bosentan, sidenafil, and abrisentan were all placebo controlled; no major trials have directly compared the efficacy of these agents. Wilkins and colleagues reported on a small trial of 26 patients who were randomized to receive either sildenafil or bosentan. There was no significant difference in the 6-minute walk test or other outcomes between the 2 groups. (20) A pilot study of 44 patients directly compared the 1-hour hemodynamic effects of inhaled iloprost to inhaled treprostinil (not FDA-approved); 1-hour effects cannot be used to broadly compare treatments. (21) An indirect comparison of 22 patients who were randomly transitioned from intravenous epoprostenol to either subcutaneous treprostinil or placebo was published.

(22) Although the study was not designed to compare the 2 medications directly, the treprostinil treated group maintained (decreased 6-minute walk distance, improved dyspnea score at 8 weeks) the exercise capacity obtained with optimal epoprostenol treatment (baseline values) with an average treprostinil dose approximately 1.5 times higher than epoprostenol. Only 1 of 14 treprostinil-treated patients was unable to transition from epoprostenol.

Also, the majority of trials have looked at short-term outcomes at 3 months only. Epoprostenol and treprostinil are the only drugs for which survival data are published. (4. 10)

Combination Therapy
Reports on the use of combination therapy are limited. Several small cohort and open-label pilot studies have been published. They provide preliminary data for the design of larger, more informative trials, such as the large multinational randomized trial of treprostinil as an adjunct to bosentan therapy (treprostinil inhalation used for the management of pulmonary hypertension [TRIUMPH I]) that is underway. (23)

Hoeper reported results from a small (n =40), 12-week, non-blinded randomized controlled trial comparing iloprost and bosentan to bosentan alone. (24) The study was terminated early because there appeared to be no benefit from the combined therapy: change was -10 m on 6-minute walking distance for the combination group and no difference in functional status, VO2 max, and time to clinical worsening. The study noted that these results may have been skewed by 3 patients in the iloprost group who presented with severe clinical worsening. McLaughlin et al (25) conducted a randomized double-blind trial of adding inhaled iloprost or placebo to bosentan monotherapy in 67 patients. After 12 weeks, treatment with iloprost resulted in a placebo-adjusted 6-minute walk distance improvement of 26 meters (p =0.05). Functional class, hemodynamic parameters (e.g., pulmonary arterial pressure, -6 mm Hg vs. +3 mm Hg in the treatment and placebo groups, respectively), and time to clinical worsening (p =0.02) were all improved at 12 weeks in the treatment group compared to the placebo group. This study provides promising results, but needs to be replicated in studies of longer duration involving more patients, given the conflicting results of these 2 studies.

Channick reported results for 12 patients in a 12-week open-label pilot study of add-on treprostinil (30 ug or 45 ug 4 times a day by inhalation added to bosentan. (23) (Note: Inhaled treprostinil is not FDA approved.) In this study, 6-minute walking distance increased by 67 m, and 75% of patients improved functional class from Class III to Class II; pulmonary arterial pressure and pulmonary vascular resistance also decreased.

Ruiz reported on the combined use of prostanoids and sildenafil. This European study described the combined use of these drugs in a small cohort of patients during a 2-year period. (26) Twenty patients (11 men, 9 women) with severe PHTN who showed clinical or functional worsening despite ongoing treatment with prostanoids (8 subcutaneous, 7 intravenous, 5 inhaled) were started on adjunct oral sildenafil. The NYHA functional class, 6-minute walking test, and signs of right ventricular failure on echocardiography were assessed before and after 1 and 2 years of combined therapy. Patients showed a mean increase in 6-minute walking distance of 79 m and 105 m after 1 and 2 years of adjunct sildenafil, respectively. Two patients died during follow-up. The echocardiographic parameters showed a reduction of right ventricular end-diastolic diameter. No serious side effects related to sildenafil were observed. These promising results should be followed up with a randomized clinical trial. Depending on the results of future studies, practice may evolve to more use of combination therapy as initial treatment instead of the current practice of changing or adding medications when patients exhibit clinical deterioration. (25)

As noted earlier, editorial critiques of the available literature raise questions about the study endpoints selected, which are often short-term measures that are insufficient for addressing the mechanism of disease, optimizing treatment by patient population, and making meaningful comparisons between therapies. Studies are short in duration, and compare outcomes that reflect symptomatic improvement (e.g., 6-minute walk distance or functional class) but not disease status (such as vasculature remodeling) or survival. Studies also need to address the durability of these outcomes. However, designing long-term (one year or more) studies with survival as an endpoint may raise additional issues, including potential ethical questions. (1)

2009 Update
A literature search using MEDLINE was performed for the period of February 2008 through February 2009. The search identified a systematic review, a meta-analysis of clinical trials of current therapies, guidelines, an expert consensus document, and review articles. No new high quality evidence was identified. Thus, the evidence base is unchanged.

In April 2009, The Canadian Agency for Drugs and Technologies in Health (CADTH) released a report, Drugs for Pulmonary Arterial Hypertension: A Systematic Review of the Clinical Effectiveness of Combination Therapy. (27) They identified 4 randomized controlled trials and 2 guidelines. No relevant meta-analyses, systematic reviews, or health technology assessment reports were identified. The authors concluded that “From the limited number of published RCTs, it appears that there may be some additional benefit from combinations of agents in PAH, but these studies have been relatively short in duration, and two of the three studies included only small numbers of patients. There are a number of RCTs of various combinations of agents underway that may help to clarify the clinical benefit of this treatment approach. Until these studies are completed, there is insufficient evidence to make broad policy decisions about combination therapy in PAH.”

Two RCTs were not included in previous policy updates; one RCT assessed the effect of adding oral sildenafil to long-term intravenous epoprostenol (n =267) with PAH. (28) After 16 weeks, the adjusted mean change in the 6-minute walk distance was 29.8 m for the sildenafil group and 1.0 m for the placebo group, a treatment difference of 28.8 m (13.9 to 43.8 m). In patients with IPAH, the difference between groups was 33.9 m in favor of the sildenafil group (P value and 95% CI not reported). Sildenafil also had a beneficial effect on hemodynamic measurements and health-related quality of life. The additional RCT evaluating bosentan in mildly symptomatic patients (29) also assessed the effect of combination therapy with bosentan and sildenafil. In this 6-month study, the impact of combination therapy with bosentan and sildenafil was assessed in a subgroup of patients as a secondary objective. The analysis presented in abstract assessed the effect of bosentan versus placebo and the effect of bosentan combined with sildenafil versus placebo. There was no direct comparison between the bosentan and bosentan combined with sildenafil groups. The sample size of this study was small. Additionally, patients with IPAH and those with PAH secondary to HIV, congenital heart disease, and connective tissue disease were included. It is not clear if the same results would be expected for only those with IPAH.

A meta-analysis of trials conducted in Italy (30) evaluated the treatment of pulmonary arterial hypertension with current approved treatment options; prostanoids, endothelin-receptor antagonists, and phosphodiesterase type-5 inhibitors and the effect on survival. The meta-analysis included all randomized controlled trials with drugs published in this condition. The primary analysis included only studies with a placebo-comparator arm, a sensitivity analysis also included studies comparing 2 active treatment arms. The main outcome measure was all-cause mortality. Twenty-one trials were included in the primary analysis (n =3140) and 2 additional studies (n =59) were included in the sensitivity analysis. Average duration of the trials was 14.3 weeks. All-cause mortality rate in the control group was 3.8%. Active treatments were associated with a reduction in mortality of 43%; the sensitivity analysis confirmed a reduction in mortality of 38%. The authors concluded that the results of this meta-analysis suggest an improvement of survival in the patients treated with the targeted therapies approved for pulmonary arterial hypertension. The limitations of the meta-analysis include the prolonged period of time between the first and last RCT (about eighteen years), the different duration of the trials (ranging from 8-36 weeks), the lack of blinding in some studies, the pooling of multiple active treatment arms and potential heterogeneity in the conduct of the trials. The meta-analysis included studies with compounds which were eventually not approved because of lack of efficacy, and different doses of approved therapies which were not approved because they were less effective or had increased side effects. Despite these results, current treatment options remain inadequate due to mortality rate continuing to be high, and the functional and hemodynamic impairments extensive in most patients. Additional efforts are needed to explore new treatment strategies including RCTs with combination therapy, new drug classes, study designs that include morbidity and mortality endpoints, and longer term studies.

In March 2009, the ACCF/AHA 2009 Expert Consensus Document on Pulmonary Hypertension was released. (31) The writing committee consisted of acknowledged experts in the field of PH. This is the first ACCF/AHA clinical expert consensus document on PH. The content of the document includes the following PH topics; pathology and pathogenesis; classification and epidemiology; natural history and survival; screening and diagnostic assessment; an evidence based treatment algorithm; reassessing patients; non-pulmonary arterial pulmonary hypertension; PAH in congenital heart disease and pediatric pulmonary arterial hypertension. The authors' discussion regarding an evidenced-based treatment algorithm stated that ”in general, patients with poor prognostic indexes should be initiated on parenteral therapy, while patients with class II or early II symptoms commonly commence therapy with either endothelin receptor antagonists or PDE-5 inhibitors.” The authors also stated that they "caution against widespread treatment of non-PAH PH" until patient benefit has been proven in clinical trials. On the topic of combination therapy, while it is an "attractive theoretical option in PAH," there are still ongoing trials investigating its safety and efficacy. Benefit of combination therapy has been suggested in "several smaller, open label observational studies" but RCTs are needed, in process and the authors "encourage enrollment" in them.

The available published evidence does not support the use of combination PAH specific therapies at this time.

Updated in 2007, American College of Chest Physicians (ACCP) developed guidelines for the diagnosis and treatment of PAH. (32) The AACP panel developed a treatment algorithm for PAH. The recommended therapies presented in this algorithm have been evaluated mainly in those with IPAH, or PAH associated with connective tissue disease or anorexigen use. “Extrapolation to other forms of PAH should be made with caution.” Country-specific regulatory agency approval status and functional class indications for PAH medications vary.

(1) Anticoagulation should be considered for patients with IPAH, and patients with an indwelling catheter for the administration of an IV prostanoid, in the absence of contraindications. Diuretics and oxygen should be added as necessary.
(2) A positive acute vasodilator response is defined as a fall in PAPm 10 mm Hg to 40 mm Hg, with an unchanged or increased cardiac output when challenged with inhaled nitric oxide, IV epoprostenol, or IV adenosine.
(3) Consideration should be given to using a PAH-specific medication such as a phosphodiesterase 5 inhibitor, endothelin receptor antagonist, or prostanoid as first-line treatment instead of a CCB in patients with PAH that is not IPAH or PAH associated with anorexigen use, or in those in an advanced functional class (FC) given the exceedingly low long-term response rate to CCB monotherapy in the former and poor prognosis in the latter.
(4) Sustained response to CCB therapy is defined as being in functional class I or II with normal or near-normal hemodynamics after several months of treatment.
(5) The risks and benefits of treatment in early PAH should be considered.
(6) First-line therapy for functional class III includes bosentan, sildenafil, epoprostenol, inhaled (inh) iloprost, and treprostinil.
(7) Most experts recommend IV epoprostenol as first-line treatment for unstable patients in functional class IV.
(8) RCTs studying add-on combination treatment regimens are underway.

Review articles (33, 34) discussed the impact of current treatments on PAH as modest. The authors note that proper selection and monitoring can improve symptoms, improve the quality and duration of life; newer agents may be better tolerated than older ones; however, improved efficacy has not yet been observed; and improved outcomes may rely on determining optimal combination strategies. Patients who respond to an acute trial of a vasodilator may be treated with an oral calcium channel blocker, whereas oral therapies such as sildenafil and bosentan have been effective in patients with mild to moderate symptoms. Infusions of the prostacyclin analogues epoprostenol and treprostinil appear to be the treatment of choice for moderate to severe PAH.

The PDE-5 inhibitor agents, tadalafil (CIALIS®) and vardenafil (LEVITRA®) are under investigation for the treatment of PAH. No published data are available. Other therapeutic classes that are under investigation in clinical trials include platelet-derived growth factor inhibitor (imatinib), vasoactive intenstinal peptide (VIP), bone-marrow derived endothelial progenitor cells (EPC), Rho kinase inhibitor (fasudil), soluble guanylate cyclase stimulator, autologous cell-based eNOS gene therapy and statins.

There is a need for conducting adequately powered randomized controlled trials comparing treatments approved for use in PAH. Future trials that focus on the long-term effects of currently available agents, as well as on combination therapy, are needed.

Summary
The policy statement has been reworded for clarification related to the agents used in the treatment of pulmonary arterial hypertension but the intent of the policy statements is unchanged. A new policy statement has been added stating that tadalafil (CIALIS®) and vardenafil (LEVITRA®) are considered investigational for treatment of pulmonary arterial hypertension.

Guidelines and Position Statements
In March 2009, the ACCF/AHA 2009 Expert Consensus Document on Pulmonary Hypertension was released. The authors’ discussion regarding evidenced-based treatment algorithm included the following statements: …”Given the availability of medications that target different pathologic processes, combination therapy is an attractive theoretical option in PAH…The safety and efficacy of combination therapy in PAH is a subject of active investigation.”

Updated in 2007, American College of Chest Physicians (ACCP) developed guidelines for the diagnosis and treatment of PAH. (32) The panel recommends that first-line therapy for functional class III includes bosentan, sildenafil, epoprostenol, inhaled iloprost, and treprostinil; and IV epoprostenol as first-line treatment for unstable patients in functional class IV.

 

References:

1. Rich S. The current treatment of pulmonary arterial hypertension: time to redefine success. Chest 2006; 130(4):1198-202.
2. Barst RJ, Rubin LJ, Long WA et al. A comparison of continuous intravenous epoprostenol (prostacyclin) with conventional therapy for primary pulmonary hypertension. The Primary Pulmonary Hypertension Study Group. N Engl J Med 1996; 334(5):296-302.
3. McLaughlin VV, Genthner DE, Panella MM et al. Reduction in pulmonary vascular resistance with long-term epoprostenol (prostacyclin) therapy in primary pulmonary hypertension. N Engl J Med 1998; 338(5):273-7.
4. McLaughlin VV, Shillington A, Rich S. Survival in primary pulmonary hypertension: the impact of epoprostenol therapy. Circulation 2002; 106(12):1477-82.
5. Humbert M, Sanchez O, Fartoukh M et al. Short-term and long-term epoprostenol (prostacyclin) therapy in pulmonary hypertension secondary to connective tissue diseases: results of a pilot study. Eur Respir J 1999; 13(6):1351-6.
6. Badesch DB, Tapson VF, McGoon MD et al. Continuous intravenous epoprostenol for pulmonary hypertension due to the scleroderma spectrum of disease. A randomized, controlled trial. Ann Intern Med 2000; 132(6):425-34.
7. Rosenzweig EB, Kerstein D, Barst RJ. Long-term prostacyclin for pulmonary hypertension with associated congenital heart defects. Circulation 1999; 99(14):1858-65.
8. Simonneau G, Barst RJ, Galie N et al. Continuous subcutaneous infusion of treprostinil, a prostacyclin analogue, in patients with pulmonary arterial hypertension: a double-blind, randomized placebo-controlled trial. Am J Respir Crit Care Med 2002; 165(6):800-4.
9. Oudiz RJ, Schilz RJ, Barst RJ et al. Treprostinil, a prostacyclin analogue, in pulmonary arterial hypertension associated with connective tissue disease. Chest 2004; 126(2):420-7.
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14.  www.fda.gov/cder/foi/label/2008/022081s002lbl.pdf
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16. Galie N, Humbert M, Vacheiry JL et al. Effects of beraprost sodium, an oral prostacyclin analogue, in patients with pulmonary arterial hypertension: a randomized, double-blind placebo-controlled trial. J Am Coll Cardiol 2002; 39(9):1496-502.
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18. Langleben D, Christman BW, Barst RJ et al. Effects of the thromboxane synthetase inhibitor and receptor antagonist terbogrel in patients with primary pulmonary hypertension. Am Heart J 2002; 143(5):E4.
19. Hoeper MM, Markevych I, Spiekerkoetter E et al. Goal-oriented treatment and combination therapy for pulmonary arterial hypertension. Eur Respir J 2005; 26(5):858-63.
20. Wilkins MR, Paul GA, Strange JW et al. Sildenafil versus endothelin receptor antagonists for pulmonary hypertension (SERAPH) study. Am J Respir Crit Care Med 2005; 171(11):1292-7.
21. Voswinckel R, Enke B, Reichenberger F et al. Favorable effects of inhaled treprostinil in severe pulmonary hypertension: results from randomized controlled pilot studies. J Am Coll Cardiol 2006; 48(8):1672-81.
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24. Hoeper MM, Leuchte H, Halank M et al. Combining inhaled iloprost with bosentan in patients with idiopathic pulmonary arterial hypertension. Eur Respir J. 2006 Oct; 28(4):683-6.
25. McLaughlin VV, Oudiz RJ, Frost A et al. Randomized study of adding inhaled iloprost to existing bosentan in pulmonary arterial hypertension. Am J Respir Crit Care Med 2006; 174(11):1257-63.
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Codes	Number	Description
CPT	93503	Insertion and placement of flow-directed catheter (e.g., Swan-Ganz) for monitoring purposes (i.e., as part of dose- ranging study)
ICD-9 Procedure
ICD-9 Diagnosis	416.0	Primary pulmonary hypertension
	416.8	Secondary pulmonary hypertension
HCPCS	J1325	Injection, epoprostenol, 0.5 mg
	J3285	Injection, treprostinil, 1 mg
	K0455	Infusion pump used for uninterrupted parenteral administration of medication (e.g., epoprostenol or treprostinil)
	K0730	Controlled-dose inhalation drug delivery system
	Q4080	Iloprost, inhalation solution, administered through durable medical equipment, 20 mcg
	S0090	Sildenafil citrate, 25 mg
	S0155	Sterile dilutant for epoprostenol, 50 ml
	S9347	Home infusion therapy, uninterrupted, long-term, controlled rate intravenous or subcutaneous infusion therapy (e.g., epoprostenol); administrative services, professional pharmacy services, care coordination, all necessary supplies and equipment (drugs and nursing visits coded separately), per diem
Type of Service	Drug Therapy
Place of Service	Inpatient, Home

Policy History