BlueCross and BlueShield of Montana Medical Policy/Codes
Pulmonary Arterial Hypertension (PAH) Drug Therapies
Chapter: Drugs - Medical Benefit
Current Effective Date: April 18, 2013
Original Effective Date: April 18, 2013
Publish Date: January 18, 2013
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 American College of Cardiology Foundation/American Heart Association (ACCF/AHA) 2009 Expert Consensus Task Force on Pulmonary Hypertension.  Patients in 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) Groups 1-5

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 condition 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.

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

Non-PAH Pulmonary 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.

In 2009, recommendations of an international group of experts who attended the 4th World Symposium on pulmonary hypertension were published; the symposium was held in 2008.  The group recommended some modifications to the nomenclature of pulmonary hypertension.  A key difference from the ACCF/AHA classification is the introduction of a new category of pulmonary hypertension, called “Group 1 prime” and defined as pulmonary veno-occlusive disease (PVOD) and/or pulmonary capillary hemangiomatosis (PCH).  The ACCF/AHA nomenclature lists these conditions as sub-categories of pulmonary arterial hypertension (Group 1).

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 PAH is determined by measuring exercising capacity and determining New York Heart Association (NYHA) or WHO functional class.  The WHO functional classification recognizes the importance of near syncope and syncope.  Syncope is thought to worsen the prognosis in patients with PAH.  Although not explicitly stated, PAH patients who have experienced a syncopal episode are generally assigned to WHO functional class IV.

The New York Heart 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 mm Hg and to a value less than 40 mm Hg, 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; 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; these include diuretics, oxygen therapy, anticoagulants, digoxin, and exercise.  Digoxin has been shown to have beneficial effects when used with caution (i.e., patients may be at higher risk for digitalis toxicity and require close monitoring).  Patients with a positive vasoreactivity test can be given a trial of CCBs.  Patients with a negative vasoreactivity test require advanced therapy with prostacyclin analogues, endothelin receptor antagonists, or phosphodiesterase type 5 (PDE5) inhibitors.  Various combinations of treatments have also been suggested.  Lung transplantation and combined heart-lung transplantation have been performed in patients refractory to medical management.  Objective assessments to measure treatment response include improvement in exercise capacity (6-minute walk distance [6MWD], cardiopulmonary exercise test, treadmill test), hemodynamics, and survival.

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.

Inhaled Nitric Oxide

Inhaled nitric oxide (NO) is a potent pulmonary vasodilator that is inhaled and delivered in the same manner as supplemental oxygen.  Researchers note that it can reduce pulmonary artery pressure in some patients with primary PAH.  Its use is being studied alone and in conjunction with other medications.

Policy

Each benefit plan, summary plan description or contract defines which services are covered, which services are excluded, and which services are subject to dollar caps or other limitations, conditions or exclusions.  Members and their providers have the responsibility for consulting the member's benefit plan, summary plan description or contract to determine if there are any exclusions or other benefit limitations applicable to this service or supply.  If there is a discrepancy between a Medical Policy and a member's benefit plan, summary plan description or contract, the benefit plan, summary plan description or contract will govern.

Coverage

The following drug therapies may be considered medically necessary for the treatment of patients who have World Health Organization (WHO) Group 1 pulmonary artery hypertension (PAH) (see Description section for classifications), when the drug is U.S. Food and Drug Administration (FDA) approved and is used according to the FDA labeled indications only, as indicated in the following table:

Drug Therapy:

Route Of Administration

FDA Indications:

PROSTACYCLIN ANALOGUES

A. epoprostenol sodium

1.       Flolan® 

 

 

  • Administered by continuous intravenous (IV) infusion with a portable infusion pump attached to a permanent indwelling central venous catheter is indicated.
  • Treatment of idiopathic or heritable PAH or PAH associated with connective tissue diseases in patients with NYHA (New York Heart Association) Class III or IV symptoms, and
  • When condition is refractory to conventional therapies (e.g., oxygen, diuretics, inotropics, anticoagulants, calcium channel blockers).

2.  Veletri®

 

  • Administered by continuous intravenous (IV) infusion with a portable infusion pump attached to a permanent indwelling central venous catheter is indicated

 

  • Treatment of idiopathic or heritable PAH or PAH associated with connective tissue diseases in patients with NYHA (New York Heart Association) Class III or IV symptoms, and
  • When condition is refractory to conventional therapies (e.g., oxygen, diuretics, inotropics, anticoagulants, calcium channel blockers).

B. trepostinol sodium

1.  Remodulin® (SQ) 

 

 

  • Continuous subcutaneous (SQ) infusion

  

 

 

  •  For treatment of PAH associated with NYHA Class II, III, or IV symptoms, to decrease symptoms associated with exercise, or
  • To decrease rate of clinical deterioration in patients requiring transition from Flolan®.

2.  Remodulin® (IV)

 

  • Continuous intravenous (IV) infusion with a portable infusion pump attached to a permanent indwelling central venous catheter is indicated
  • For treatment of PAH associated with NYHA Class II, III, or IV symptoms, and
  • When patient cannot tolerate SQ infusion of trepostinol.

 

3.  Tyvasol®

 

  • Inhalation via nebulizer (using the Tyvaso Inhalation System, which consists of the Optineb-ir Model ON-100/7 [an ultrasonic, pulsed-delivery device] and its accessories)
  • Treatment of PAH in patients with NYHA Class III or IV symptoms, to increase walk distance.

C. iloprost

Ventavis®

 

  •  Inhalation via nebulizer (either of two devices, the I-neb™ AAD® System or the Prodose® AAD® System)
  •  For treatment of PAH in patients with NYHA Class III or IV symptoms, to improve exercise tolerance, symptoms (NYHA Class), and rate of deterioration.

ENDOTHELIN RECEPTOR ANTAGONISTS

bosentan

  • Tracleer®

 

  • Oral
  • Treatment of PAH in patients with WHO Class II, III or IV symptoms to improve exercise ability and decrease rate of clinical worsening.
  • NOTE: The FDA states that Tracleer should be given to patients with WHO Class II symptoms only when the physician deems the benefits are sufficient to offset the risk of liver injury or failure.

ambrisentan

  • Letairis®
  • Oral
  • Treatment of PAH in patients with WHO class II or III symptoms to improve exercise capacity and delay clinical worsening.

PHOSPHODIESTERASE (PDES) INHIBITORS

sildenafil citrate

  • Revatio®
  • Oral
  • For treatment of PAH to improve exercise ability.

tadalafil

  • Adcirca®
  • Oral
  • For treatment of PAH to improve exercise ability.

Combination therapy using medications from different therapeutic classes may be considered medically necessary for those patients who fail to demonstrate an adequate response to a single medication.  Combination therapy is considered experimental, investigational and unproven as a first-line treatment. 

The use of drug therapy that has not been FDA-approved is considered experimental, investigational and unproven, including but not limited to beraprost, vardenafil, and imatinib.

Drug Therapy:

Route Of Administration

FDA Indications:

Prostacyclin Analogues

 

 

beraprost

  • Dorner®
  • Oral
  • Not FDA approved.

Phosphodiesterase (PDES) Inhibitors

 

 

vardenafil

  • Levitra®
  • Oral
  • No FDA-approved indications for PAH.

Tyrosine Kinase Inhibitors

 

 

imatinib

  • Gleevec®
  • Oral
  • No FDA-approved indications for PAH.

The use of epoprostenol, treprostinil, iloprost, bosentan, ambrisentan, sildenafil, tadalafil, vardenafil, and imatinib is considered experimental, investigational and unproven for the treatment of non-PAH pulmonary hypertension (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; or
  • Miscellaneous group (i.e. sarcoidosis, histiocytosis X and lymphangiomatosis)

The use of inhaled Nitric Oxide for treatment of PAH is considered experimental, investigational, and unproven.

Policy Guidelines

  • While epoprostenol would be considered under the medical benefits, use of sildenafil, bosentan, beraprost, iloprost, and treprostinil may be considered under the pharmacy benefits.
  • Patients treated using 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.
  • Treatment with iloprost inhalation therapy requires the use of a specialized nebulizer.
  • Treatment with trepostinol sodium inhalation therapy requires a specialized nebulizer.
  • 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 20-mg tablet.  Viagra is available in 25-mg, 50-mg, 100-mg tablets.
  • Tadalafil is available as both Cialis and Adcirca.  Benefit or contract language describing the "least costly alternative" may be applicable to this choice.  Pricing differences may exist between alternatives.  Cialis is available as 2.5-mg, 5-mg, 10-mg, and 20-mg tablets.  Adcirca is available as a 20-mg tablet.  The recommended initial daily dose of Adcirca is 40-mg at once a day (two 20-mg tablets).

Rationale

Several meta-analyses that pool the findings of studies evaluating the efficacy of pulmonary artery hypertension (PAH) treatments have been published.  In 2009, Galie and colleagues in Italy published a meta-analysis of randomized controlled trials (RCTs) examining approved medications i.e., prostanoids, endothelin-receptor antagonists, and phosphodiesterase type-5 (PDE5) inhibitors for treating PAH.  The primary analysis included only studies with a placebo-comparator arm; a sensitivity analysis also included studies comparing two active treatment arms.  The main outcome measure was all-cause mortality.  Twenty-one trials were included in the primary analysis (n=3,140) and two 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 PAH.  The limitations of the meta-analysis include the prolonged period of time between the first and last RCT (about 18 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 that were eventually not approved because of lack of efficacy and different doses of approved therapies that were not approved because they were less effective or had increased adverse effects.

Two meta-analyses published in 2010, were similar in scope and design to the 2009 meta-analysis by Galie and colleagues.  All three were limited to RCTs in patients with PAH, had all-cause mortality as the primary outcome and evaluated the same classes of medications, prostanoids, endothelin receptor antagonists, and PDE5 inhibitors.  Ryerson and colleagues searched the literature through November 2009.  Their eligibility criteria included RCTs in adults with PAH, and they further required that studies have a follow-up of at least eight weeks, be double-blind, and be placebo-controlled (except for studies on intravenous [IV] medication use).  They included both studies that compared one medication to placebo (monotherapy), as well as studies that added a second medication versus placebo to a baseline medication (combined treatment); the latter were categorized by the class of the medication in the study that was under investigation.  Twenty-four trials met the inclusion criteria.  This included 11 on prostanoids, eight on endothelin-receptor antagonists, and three on PDE5 inhibitors.  The investigators did not pool studies across classes of medications.  There was a statistically significant reduction in all-cause mortality in a meta-analysis of the studies on prostanoids, but not studies on endothelin-receptor antagonists, or PDE5 inhibitors.  The pooled analysis of prostanoid trials found a 51% mortality reduction (95% confidence interval [CI]: 18-71%).  Meta-analyses of each of the three classes of medication found statistically significant improvement in exercise capacity, the primary outcome in most of the studies.  In pooled analyses, prostanoids were associated with a mean placebo-corrected improvement in 6-minute walk distance (6MWD) of 29 meters (95% CI: 18-41 meters), endothelin-receptor antagonists were associated with improvement of 38 meters (95% CI: 27 to 49 meters) and PDE5 inhibitors were associated with an improvement of 34 meters (95% CI: 23-49 meters).

The other 2010 meta-analysis, by Macchia and colleagues, searched the literature through April 2009 and, like the Ryerson et al. study, included RCTs on adults with PAH.  However, in this study, both open and blinded trials were included, and eligibility was not limited by type of control group (e.g., placebo).  Combination medication studies were treated in the same manner as in Ryerson et al., discussed above.  Twenty-six trials met eligibility criteria.  Of these, nine were on prostanoids, eight on endothelin receptor antagonists, and eight on PDE5 inhibitors.  In a meta-analysis of studies on all three classes of medications combined (23 studies), there was a statistically significant reduction in total mortality of 39% (2-62%) in the treatment group compared to controls.  However, when studies on each class of medication were examined separately, there were no significant reductions in mortality.  For example, the pooled analysis of studies on prostanoids found a nonsignificant 34% reduction in mortality; the 95% CI was consistent with a 64% decrease in mortality to a 21% increase.  The mortality reduction seemed confined to studies with more seriously ill study populations.  With all classes of medication combined, there was a significant reduction in all-cause mortality when findings from trials with a median mortality of above 2% were pooled; mortality reduction was 49% (95% CI: 12-70%).  There was no significant reduction in mortality in studies that had lower mortality rates.  In addition, there was a significant mortality reduction in studies that included patients with functional class IV (42%, 95% CI: 4-65%) but not studies that excluded these patients.  The authors also pooled study findings on change in exercise capacity and pulmonary vascular resistance (PVR).  They found small but statistically significant improvement in exercise capacity and PVR.  This was true for analyses pooling all studies, as well as those limited to one class of medication.  For example, a pooled analysis of endothelin receptor antagonists found a mean increase in the 6MWD of 46 meters (95% CI: 38-54 meters) with treatment versus control.  A meta-analysis of prostanoid studies found a mean fall in PVR of 4.24 mm Hg (95% CI: fall of 3.49-5.00 mm).

The all-cause mortality reduction with all medications combined in the Macchia et al. (2010) meta-analysis (39%) is similar to that found by Galie et al. (2009; 43%).  Macchia and colleagues, however, urge caution when interpreting this finding, since none of the individual classes of medication were found to reduce mortality.  Moreover, they question the validity of combining studies of pharmacologic treatments that have completely different modes of action and suggest that the finding of mortality reduction be tested in prospective clinical trials.

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., 6MWD 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.

Representative randomized trials and observational studies evaluating specific medications are described below.

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 PAH who were randomized to receive either epoprostenol or conventional medical management.  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 PAH.  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.  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.  A total of 162 consecutive patients diagnosed with primary PAH were treated with epoprostenol and followed up for a mean of 36.3 months.  Observed survival at one, two and three years was 87.8%, 76.3%, and 62.8%, significantly greater than the expected survival of 58.95, 46.3%, and 35.4%, respectively, based on historical controls.

In 2000, epoprostenol received an additional FDA approval as a treatment of PAH 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 PAH associated with either scleroderma, CREST syndrome, systemic lupus erythematosus (SLE), or Sjogren’s syndrome.  Patients were followed up from 14 to 154 weeks.  After six weeks, exercise capacity improved in 15 of 17 patients; the remaining two patients died of pulmonary edema or sepsis.  During the long-term follow-up, an additional five patients died, two patients underwent successful lung transplantation, and seven of the remaining eight patients had a persistent clinical improvement.  Badesch and colleagues reported on a study that randomized 111 patients with PAH related to scleroderma to receive either conventional therapy or conventional therapy in addition to epoprostenol therapy.  The primary outcome measure was exercise capacity.  A significant improvement in exercise capacity was noted in the epoprostenol group compared to the control group, where 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 five 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 PAH secondary to congenital heart disease who had failed to improve clinically with conventional therapy.  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

FDA approval for treprostinil (Remodulin) was based in part on two randomized, placebo-controlled double-blind studies of 470 patients with PAH, either idiopathic or associated with connective tissue disease or congenital systemic-to-pulmonary shunts and a subgroup analysis of 90 patients with PAH associated with connective tissue disease.  Endpoints, measured at 12 weeks, included exercise capacity (as measured by the 6MWD), dyspnea, and hemodynamic effects.  There was a median 16-meter improvement in the 6MWD, 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.  There were no statistically significant differences in pretreatment and post-treatment hemodynamic variables between patients with different connective tissue diseases.

A cohort study of long-term survival was identified, which compared survival of patients (idiopathic PAH or associated with connective tissue, congenital heart disease, portal hypertension, or human immunodeficiency virus [HIV]) treated with treprostinil (up to four years) with predicted survival using an National Institutes of Health (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 reasons (withdrew consent, transplantation, protocol violation, and loss to follow-up; 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 one and four years compared to predicted survival of 69% and 38%, respectively.

Findings of a 12-week randomized placebo-controlled trial evaluating intravenous treprostinil in treatment-naïve patients with PAH were published in 2010 by Hiremath and colleagues.  The study, conducted in India, randomized 45 patients, one of whom died during catheter placement.  Due to safety concerns, recruitment was stopped early after these 45 patients had enrolled; an intention-to-treat analysis was performed on these patients’ outcomes data.  Forty-two of the 44 patients who received study medication had idiopathic PAH, and two had PAH associated with collagen vascular disease.  Forty-two of 44 patients had NYHA Class III disease and two had Class IV disease.  The initial dose of medication was 4 ng/kg/min treprostinil or an equivalent volume of placebo.  After the first week, dose increases up to 8 ng/kg/min weekly were allowed, up to a maximum of 100 ng/kg/min. Thirty-one of 45 (67%) randomized patients completed the study; six patients (two in each group) died during the 12-week follow-up period.  The mean treprostinil dose at 12 weeks was 72 ng/kg/min, and the mean placebo dose was 80 ng/kg/min.  The primary efficacy outcome was change in the 6MWD from baseline to 12 weeks.  The mean baseline 6MWD was 292 meters in the treprostinil group (n=30) and 231 in the placebo group (n=14).  The mean change was an increase of 67.2 meters in the treprostinil group and a decrease of 25.5 meters in the placebo group; the difference between groups was statistically significant, p=0.022.  This represents a placebo-corrected difference of a mean of 92.7 meters (standard error [SE]=42.0).  The median placebo-corrected difference between groups was 83 meters (95% confidence interval [CI]:7-187 meters, p=0.008) There were also statistically significant differences on other outcomes, favoring the treprostinil group.  For example, there was a mean decrease of 1.7 points on the Borg dyspnea scale in the treprostinil group and a mean increase of 0.4 points in the placebo group, p=0.009.  (A higher score on the Borg scale represents more dyspnea). 

Iloprost

The FDA approval for 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 PAH (WHO Group I); idiopathic (53%), associated with connective tissue disease including CREST and scleroderma (17%), or associated with anorexigen use (2%) or pulmonary hypertension related to chronic thromboembolic disease (WHO Group IV; 28%).  The primary endpoint was a composite endpoint at 12 weeks defined by one) improvement in exercise capacity (6MWD) and two) improvement by at least one 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.  There was inadequate evidence of benefit in patients with PH associated with chronic thromboembolic disease (WHO Group IV).  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 a randomized, placebo-controlled double-blind study of 213 patients with PAH (idiopathic (70%) or associated with connective tissue disease (30%); WHO Group I).  The primary endpoint was degree of change in exercise capacity.  At 16 weeks, a significant improvement was found in the 6MWD 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 PH, 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.

Ambrisentan

The FDA approval of ambrisentan (Letairis) was based on two 12-week randomized, double-blind, placebo-controlled multicenter studies of 393 patients with PAH.  ARIES-1 compared once-daily doses of 5 mg and 10 mg of ambrisentan 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 6MWD 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% - all respectively, of those receiving ambrisentan.  In 2010, Blalock published long-term outcomes in 12 of 14 patients who were enrolled in the AIRES-1 study at a single institution; these patients enrolled in an extension of the 12-week randomized period in which all participants received ambrisentan.  All of the 12 patients remained on ambrisentan monotherapy during the first two years of follow-up.  Two patients developed worsening symptoms requiring add-on IV therapy toward the end of the second year; two others developed worsening symptoms after two years and began IV therapy.  At last follow-up (3.5 to 5 years), 11 patients remained alive; three were on ambrisentan monotherapy, five on combinations of oral therapies and two on ambrisentan plus an IV prostacyclin.

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 (idiopathic [60%], connective tissue disease [40%] WHO Group 1) to receive either placebo or sildenafil (20, 40, or 80 mg) orally three times daily for 12 weeks.  There was a significant improvement in primary endpoint, defined as the change in baseline to week 12 in the 6MWD distance.  Of the 222 completing one year of treatment, the improvement in 6MWD was 51 meters.  There was no significant difference among the three different doses of sildenafil given, and thus the recommended dose is 20 mg three times per day.  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 6MWD or other outcomes between the two groups.  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 RCTs of sildenafil in the treatment of digital ulcers secondary to systemic sclerosis.

Tadalafil

The pivotal trial on tadalafil (ADCIRCA®), the Pulmonary Arterial Hypertension and Response to Tadalafil (PHIRST) study, was published by Galie and colleagues in 2009.  This was a double-blind multicenter study conducted in the United States, Canada, Europe, and Japan.  It included 406 patients who were at least 12-years old and had symptomatic PAH (Group 1) that was idiopathic/heritable or related to anorexigen use, connective tissue disease, HIV infection or congenital systemic-to-pulmonary shunts.  Randomization was stratified by type of PAH (idiopathic/heritable and anorexigen use versus other types), baseline bosentan use (53% were using bosentan), and baseline walking distance (less than 325 meters or at least 325 meters).  Patients were assigned to receive 16 weeks of treatment with placebo (n=82) or 1 of 4 doses of tadalafil: 2.5 mg (n=82), 10 mg (n=80), 20 mg (n=82), or 40 mg (n=79).  A total of 331 (82%) patients completed the 16-week study.  Discontinuation rates were similar across all treatment groups, about 16% in each.  The efficacy analysis was intention to treat and included 405 patients (all those randomized minus one patient who did not receive study medication).  The primary efficacy outcome was placebo-corrected change from baseline to 16 weeks in the 6MWD.  Compared to placebo, only the patients receiving 40 mg tadalafil significantly improved their 6MWD (i.e., the p-value was less than the prespecified cutoff of 0.01).  For the 392 participants who were assessed at 16 weeks, change in placebo-corrected 6MWD was as follows: 14 meters (95% CI: 6-33) for the 79 patients in the 2.5-mg group, 20 meters (95% CI: 1-39) for the 78 patients in the 10-mg group, 27 meters (95% CI: 11-44) for the 82 patients in the 20-mg group, and 33 meters (95% CI: 15-50) in the 79 patients in the 40-mg group.  The absolute 6MWDs for each of the four tadalafil groups and the placebo group were not reported.  The statistical significance cutoff for secondary outcomes was 0.05.  There were no statistically significant differences between any of the tadalafil groups and placebo in the proportion of patients with improved WHO functional class and change in the Borg dyspnea scales.  Time to clinical worsening, however, significantly improved in the tadalafil 40-mg group compared to placebo (p=0.041).  Moreover, the 40-mg group had significantly greater improvement than placebo in 6 of the 8 quality-of-life domains in the Medical Outcomes Study 36-item short form (SF-36); the total quality-of-life score was not reported.  Three deaths occurred during the 16-week study period; the study was not designed to evaluate differences in the mortality rate.  The study did not report long-term outcomes.

Vardenafil

Jing and colleagues published two studies from China evaluating vardenafil (LEVITRA®); a case series in 2009 and an RCT in 2011.  The case series included 45 patients with PAH who were admitted for treatment at one of the participating study centers.  Eligibility was limited to patients with idiopathic PAH, advanced pulmonary vasculopathy associated with connective tissue disease and congenital heart disease or portopulmonary hypertension.  Patients were treated with oral vardenafil 5 mg daily for one month, after which time the dose was increased to 10 mg daily (5 mg twice a day) if tolerated.  None of the patients had received other PAH-active drugs in the previous three months, but patients had been using vardenafil for a mean of 14 months before study entry.  The mean baseline 6MWD was 409 meters (standard deviation [SD]: 103).  All patients were evaluated after three months of treatment at which time the 6MWD had increased a mean of 71 meters (SD: 78).  The change in distance from baseline was statistically significant (p<0.001).  All patients were also evaluated after a mean of 14 months (SD: 3) of treatment.  At this longer-term follow-up, the mean 6MWD was 83 meters (SD: 92), which was significantly higher than baseline (p<0.001) but not higher than the distance walked at three months (p=0.36).  Change in functional improvement was seen at both three months and 14 months.  At baseline, 11 (24%) patients were in WHO functional class II, 29 (64%) were in class III, and five (12%) were in class IV.  At the end of the study, five (11%) were in functional class I, 31 (69%) in class II, eight (18%) in class III, and one (2%) in class IV.  No patients died during the study; two patients were admitted to the hospital for PAH-related symptoms after six and 11 months, respectively.  The study was limited in that there was no comparison group, the sample size was small, and most patients had previously received the study medication so they were more likely to continue to respond to it.

A double-blind RCT, published by Jing and colleagues in 2011, was conducted at eight centers in mainland China.  The study randomized 66 patients to receive 12 weeks of oral vardenafil monotherapy (n=44) compared to placebo (n=22).  Patients in the active treatment group received 5 mg vardenafil once daily for the first four weeks and then increased to the target dose of 5 mg twice daily, if tolerated.  Two patients dropped out before any follow-up data were recorded.  Thirty-nine of the remaining 64 patients (61%) had idiopathic PAH, 19 (30%) had connective tissue disease, and six (9%) had repaired right-to-left shunting.  WHO functional class at baseline was class II in 30 (47%) and class III in 34 (52%).  Baseline 6MWD (the primary efficacy outcome) was a mean of 388 meters in the placebo group and 395 in the vardenafil group.  A total of 59 patients (89% of those randomized) completed the 12-week randomized phase.  After 12 weeks, the median 6MWD increased by 59 meters in the vardenafil group and decreased by 10 meters in the placebo group.  The mean placebo-corrected treatment effect was 69 meters (95% CI: 41 to 98 meters, p<0.001).  During the 12-week follow-up period, 1 of 44 (2%) in the vardenafil group and 4 of 22 (18%) experienced clinical worsening; the difference between groups was statistically significant, p=0.044.  This includes two patients in the placebo group who died.  Other clinical outcomes favored the treatment group.  Ten of 44 (23%) patients treated with vardenafil improved at least one WHO functional class, compared to only 1 of 22 (5%) of patients in the placebo group.  In addition, the mean Borg dyspnea scale improved at week 12 (mean decrease of 0.4 point) in the vardenafil group, whereas the dyspnea score worsened (increase of 1.8 points) in the placebo group; the authors did not report a between-group p-value.  Fifty-eight patients completed a 12-week open-label extension of the study in which all patients received vardenafil 5 mg twice a day.  At the end of the extension phase, the mean improvement in the 6MWD in the group originally assigned to vardenafil was 69 meters.  In addition, patients who had been in the placebo group and then took vardenafil for 12 weeks had a mean increase of 59 meters in walk distance from week 12 (mean of 49 meters improvement from baseline).  This remains the only published RCT evaluating vardenafil for PAH; no major study was conducted in the United States; a limitation is that the analysis was not intention to treat.

Combination Therapy

No published meta-analyses have pooled findings of studies comparing the efficacy of a combination of two classes of medications to a single medication.  Several randomized trials have evaluated various combinations of medications; findings are summarized below by the classes of medications used.

Prostacyclin analogues and endothelin receptor antagonists

Two randomized trials evaluated the combination of inhaled iloprost and bosentan on clinical outcomes.  McLaughlin and colleagues conducted a randomized double-blind trial of adding iloprost or placebo to bosentan monotherapy in 67 patients with PAH (idiopathic, 55%, associated PAH, 45%).  After 12 weeks, treatment with iloprost resulted in a placebo-adjusted 6MWD 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.  Hoeper et al. reported results from a small (n=40), 12-week, non-blinded RCT evaluating the addition of iloprost to bosentan monotherapy in patients with idiopathic PAH (IPAH, WHO Group 1).  The study was terminated early because there appeared to be no benefit from the combined therapy: change was -10 meters on 6MWD 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 three patients in the iloprost group who presented with severe clinical worsening.

In 2010, McLaughlin and colleagues evaluated the addition of inhaled treprostinil to oral therapy in a double-blind RCT with 235 patients with PAH.  Patients had been on a stable dose of bosentan (n=165) or sildenafil (n=70) for at least three months.  They were randomized to receive inhaled treprostinil sodium (up to 54 ug) or placebo 4 times daily as add-on therapy.  A total of 212 (90%) patients completed the study; analysis was intention to treat.  The primary efficacy outcome was change in 6MWD over 12 weeks.  Mean baseline 6MWD was 346 meters in the inhaled treprostinil group and 351 in the placebo group.  After 12 weeks, the median change in peak 6MWD (10-60 minutes after nebulizer use) was 21.6 meters in the treprostinil group and 3.0 meters in the placebo group.  The median between-group difference was 20 meters (95% CI: 8.0 to 32.8), p=0.004.  When the analysis was limited to the patients taking bosentan at baseline, the median difference in change in 6MWD over 12 weeks was 25 meters, p=0.002.  There were no differences between groups in the secondary endpoints rate of clinical worsening, Borg dyspnea scores, change in NYHA functional classifications or PAH signs and symptoms.  For example, 4 of 115 (3%) patients in the treatment group and 6 of 120 (5%) in the placebo group experienced clinical worsening during the 12-week follow-up period.  Another secondary outcome was quality of life, measured by the Minnesota Living with Heart Failure questionnaire (MLWHF); the potential range of the total score is 0 to 105, with a higher score indicating a worse quality of life.  There was a median difference between groups of -4 points in the total score of the MLWHF; this difference was statistically significant, favoring the inhaled treprostinil group (p=0.027).  Differences between groups in the 6MWD and quality-of-life measure may not be clinically significant.

Prostacyclin analogues and phosphodiesterase inhibitors

In the 2010 McLaughlin et al. study, discussed above, patients on monotherapy were randomized to receive added inhaled treprostinil or placebo; 70 patients were taking sildenafil at baseline.  In this subgroup, the median placebo-corrected change in 6MWD at 12 weeks, the primary outcome, was 9 meters; the difference between groups was not statistically significant.  As previously noted, the groups did not differ significantly on secondary efficacy outcomes other than quality of life.

Simonneau and colleagues assessed the effect of adding oral sildenafil to long-term intravenous epoprostenol (n=267) with PAH in a 2008 RCT.  After 16 weeks, the adjusted mean change in the 6MWD was 29.8 meters for the sildenafil group and 1.0 meter for the placebo group, a treatment difference of 28.8 meters (13.9 to 43.8 meters).  In patients with IPAH, the difference between groups was 33.9 meters in favor of the sildenafil group (p value and 95% confidence interval [CI] not reported).  Sildenafil also had a beneficial effect on hemodynamic measurements and health-related quality of life.

Endothelin receptor antagonists and phosphodiesterase inhibitors

An RCT by Galie and colleagues evaluated bosentan in mildly symptomatic patients; the impact of combination therapy with bosentan and sildenafil was assessed in a subgroup of patients as a secondary objective.  The analysis 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 combination treatment groups.  The sample size of this study was small.  In addition, 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.

The Galie et al. study on tadalafil, discussed previously, included a predefined subgroup analysis comparing treatment effectiveness in patients who added tadalafil to baseline bosentan treatment and those taking only tadalafil.  For patients on tadalafil monotherapy, there was significantly greater change in the 6MWD in the groups taking 40 mg compared to placebo.  For example, the placebo-adjusted change in 6MWD in the 37 patients on 40-mg tadalafil monotherapy was 44 meters (95% CI: 20 to 69), p<0.01.  There was not a statistically significant change from baseline in the groups combining bosentan with any of the doses of tadalafil.  The placebo-adjusted change in 6MWD for the combined bosentan and 40-mg tadalafil group was 23 meters (95% CI: -2 to 52).

Tyrosine kinase inhibitors and any of three major classes of medications

In 2010, Ghofrani and colleagues published findings of a multisite double-blind Phase II randomized trial evaluating imatinib as an add-on treatment in patients with PAH; the study was conducted at sites in the United States and Europe.  Fifty-nine patients age 18 and older were enrolled; all had been on stable PAH medications for more than three months before enrollment but remained symptomatic.  Patients were taking a prostacyclin analogue, endothelin receptor antagonist, PDE5, or combinations of these medications.  Individuals in WHO functional class II-IV were eligible.  Participants were randomized to receive six months of treatment with imatinib or placebo.  Thirty-eight of 59 (64%) completed the study; two patients in each group died during the follow-up period.  Analysis was intention to treat.  In the treatment group, an initial dose of 200 mg oral imatinib was given for two weeks; if tolerated, the dose was increased to 400 mg.  The primary efficacy outcome was change in the 6MWD.  At six months, mean change in the 6MWD was an increase in 22 meters in the imatinib group and a decrease of 1 meter in the placebo group; this difference was not statistically significant, p=0.21.  Findings were similar regardless of the method used to impute missing data.

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.  They identified four RCTs and two 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.”

A 2010 review by O’Callaghan and colleagues discussed the published evidence on combination treatment for patients with PAH.  This review did not include the 2010 McLaughlin study evaluating the combination of inhaled treprostinil and oral medications.  The authors state that combination therapy for PAH is now widely accepted and note that several issues, such as which combinations are most effective, require further study.  They conclude: “Although many of the recently published studies have demonstrated statistically significant differences in parameters such as 6MWD after introduction of combination therapy, these changes often reflect only modest improvements in exercise capacity.  In this regard, it is likely that the design of future randomized clinical studies evaluating this approach will increasingly incorporate evaluation of more clinically relevant endpoints such as time to clinical worsening and mortality.  By this means, it should be possible to identify which, if any, of the various combination strategies can improve long-term disease control for patients.”

Summary

Several meta-analyses of randomized controlled trials have found that prostanoids, endothelin receptor antagonists, and phosphodiesterase type-5 inhibitors are all associated with small but statistically significant improvement in exercise capacity and hemodynamic parameters.  Findings on mortality reduction are mixed; in general, the evidence base on the effect of approved treatments on mortality is limited by the small size and short duration of most trials.  There are few randomized controlled trials on combination therapy and findings are mixed.  The evidence is inconclusive on whether any combination of classes of medications improves the net health outcome more than a single medication.  Additional trials on combination treatment are underway.

Practice Guidelines and Position Statements

In October 2009, the Health Technology Assessment Program in the U.K. published a systematic review of RCTs on medications for treatment of PAH.  The medications included epoprostenol sodium administered by IV infusion, inhaled iloprost, oral bosentan, oral sitaxentan and oral sildenafil; all are approved for use in the U.K.  The assessment concluded, “All of the five technologies, when added to supportive treatment and used at licensed dose(s), have been shown to be more effective than supportive treatment alone in patients of mixed FC (functional class) and other types of PAH.  The volume of evidence and patient populations included in the trials varied between the technologies.  Current evidence does not allow comparisons between the technologies nor for the use of combinations of the technologies.”

In March 2009, the ACCF/AHA 2009 Expert Consensus Document on Pulmonary Hypertension was released.  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 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, they state …”Given the availability of medications that target different pathologic processes, combination therapy is an attractive theoretical option in PAH…Multiple 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. “

In 2009, the Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS) published guidelines on the diagnosis and treatment of PH.  Regarding treatment of PAH (Group 1), the guidelines state that the results of clinical studies “support the efficacy of the currently approved pulmonary artery hypertension treatments.”  However, they note, “the medical and interventional treatments for more advanced cases are still invasive and prone to significant side effects.”  The guidelines also comment on combination therapy for PAH: “…There are many open questions regarding combination therapy, including the choice of combination agents, the optimal timing [initial combination (in naive patients) or sequential combination (according to the response to the first drug)], when to switch, and when to combine.  When combination therapy is considered, patients should be treated within clinical trials or registries whenever possible.  Combination therapy of established PAH drugs is recommended for patients not responding adequately to monotherapy, but combination therapy should be instituted by expert centers only.  Whether the response to monotherapy is sufficient or not can only be decided on an individual basis.  This is judged in an individual patient who, despite monotherapy and optimized background treatment, has an inadequate clinical response.”

Updated in 2007, American College of Chest Physicians (ACCP) developed guidelines for the diagnosis and treatment of PAH.  The ACCP 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.  The guideline statements include:

  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 mean pulmonary artery pressure 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 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. 

Ongoing Clinical Trials

A search of the online ClinicalTrials.gov database in April 2011 identified the following relevant randomized controlled trials that are underway:

NCT01042158: A 36-week trial comparing the combination of tadalafil and ambrisentan to ambrisentan monotherapy and tadalafil monotherapy and eligibility is limited to patients with PAH associated with systemic sclerosis.  The study is sponsored by the National Institutes of Health; the expected completion date is May 2013.

NCT01178073: A trial comparing the combination of tadalafil and ambrisentan as first-line therapy to first-line monotherapy with tadalafil or ambrisentan.  The study includes patients with PAH (unlike the trial described above; it is not limited to patients with PAH associated with systemic sclerosis).  The study will be terminated when a predefined number of events have occurred; the median study duration is expected to be 1.6 years.  The study is sponsored by GlaxoSmithKline; the expected date of completion is June 2013.

NCT00303459: A trial comparing the combination of bosentan and sildenafil to sildenafil monotherapy (Compass 2).  Patients will be treated with the study drug until the predefined number of morbidity/mortality events is reached.  The study is sponsored by Actelion and the expected study completion date is March 2013.

NCT00323297: A trial comparing the combination of bosentan and sildenafil 20 mg three times a day to bosentan and placebo in patients with PAH.  The study is sponsored by Pfizer and the expected date of completion is March 2012.

Coding

Disclaimer for coding information on Medical Policies           

Procedure and diagnosis codes on Medical Policy documents are included only as a general reference tool for each policy.  They may not be all-inclusive.           

The presence or absence of procedure, service, supply, device or diagnosis codes in a Medical Policy document has no relevance for determination of benefit coverage for members or reimbursement for providers.  Only the written coverage position in a medical policy should be used for such determinations.           

Benefit coverage determinations based on written Medical Policy coverage positions must include review of the member’s benefit contract or Summary Plan Description (SPD) for defined coverage vs. non-coverage, benefit exclusions, and benefit limitations such as dollar or duration caps. 

ICD-9 Codes
416.0, 416.8
ICD-10 Codes
I27.0, I27.2, I27.89, 3E013GC, 3E033GC
Procedural Codes: J1325, J3285, J7686, K0455, Q4074, S0088, S0090, S0155
References
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  2. McLaughlin, V.V., Genthner, D.E., et al.  Reduction in pulmonary vascular resistance with long-term epoprostenol (prostacyclin) therapy in primary pulmonary hypertension.  New England Journal of Medicine (1998 January 29) 338(5):273-7.
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History
November 2012  New 2013 BCBSMT medical policy.
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Pulmonary Arterial Hypertension (PAH) Drug Therapies