Pulmonary Hypertension Treatments and Selected Indications of Prostanoids

Number: 0184

Table Of Contents

Policy
Applicable CPT / HCPCS / ICD-10 Codes
Background
References

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Policy

Note: Requires Precertification:

Precertification of pulmonary arterial hypertension drugs is required of all Aetna participating providers and members in applicable plan designs. For precertification of pulmonary arterial hypertension drugs, call (866) 752-7021 (Commercial), (866) 503-0857 (Medicare), or fax (888) 267-3277.

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

Pulmonary Arterial Hypertension (PAH)

1. Criteria for Initial Approval

   Aetna considers epoprostenol for injection (Flolan, Veletri), iloprost inhalation (Ventavis), treprostinil inhalation (Tyvaso), treprostinil injection (Remodulin) medically necessary for treatment of PAH when all of the following criteria are met:

   1. Member has either of the following: 

      1. WHO Group 1 class of pulmonary hypertension (see Appendix); or
      2. Pulmonary hypertension associated with interstitial lung disease (WHO Group 3) - for Tyvaso only;

   2. PAH was confirmed by either criterion 1 or criterion 2 below:

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

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

      2. In infants less than one year of age for epoprostenol (Flolan, Veletri), iloprost (Ventavis), treprostinil (Remodulin, Tyvaso): PAH was confirmed by Doppler echocardiogram if right heart catheterization cannot be performed. 

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

   Aetna considers all other indications as experimental and investigational (for additional information, see Experimental and Investigational and Background sections).

2. Continuation of Therapy

   Aetna considers continuation of epoprostenol for injection (Flolan, Veletri), iloprost inhalation (Ventavis), treprostinil inhalation (Tyvaso), treprostinil injection (Remodulin) therapy medically necessary for members with an indication listed in Section I who are currently receiving the requested medication through a previously authorized pharmacy or medical benefit, and who are experiencing benefit from therapy as evidenced by disease stability or disease improvement.

3. Prescriber Specialties

   This medication must be prescribed by or in consultation with a pulmonologist or cardiologist.

For Adempas, ambrisentan-Letairis, bosentan-Tracleer, Opsumit, Orenitram, sildenafil-Revatio, Tadalafil Products, Tyvaso DPI inhalation powder, or Uptravi, see Pharmacy Clinical Policy Bulletins (PCPBs): Formularies and Pharmacy Clinical Policy Bulletins.

Dosage and Administration

Epoprostenol for injection (Flolan, Veletri)

Flolan is available as the following:

• Injection: 0.5 mg or 1.5 mg of epoprostenol freeze-dried powder in a single-dose vial for reconstitution with supplied diluent.

Veletri is available as the following:

• 10 mL vial with 0.5 mg (500,000 ng) or 1.5 mg (1,500,000 ng).

PAH WHO Group 1:

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

Source: GlaxoSmithKline 2021; Actelion Pharmaceuticals, 2020

Iloprost Inhalation Solution (Ventavis)

Iloprost inhalation solution (Ventavis) is available as the following:

• 1 mL ampules in two concentrations: 10 mcg/mL and 20 mcg/mL.

PAH WHO Group 1:

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

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

Source: Actelion Pharmaceutials,2022

Treprostinil Inhalation Solution (Tyvaso)

Treprostinil inhalation solution (Tyvaso) is available as the following:

• Sterile solution for oral inhalation: 2.9 mL ampule containing 1.74 mg treprostinil (0.6 mg per mL).

PAH WHO Group 1 and Pulmonary hypertension associated with interstitial lung disease (WHO Group 3):

Initial dosage: 3 breaths (18 mcg) per treatment session 4 times daily . If 3 breaths are not tolerated, reduce to 1 or 2 breaths and subsequently increase to 3 breaths, as tolerated.

Maintenance dosage: Dosage should be increased by an additional 3 breaths per treatment session, 4 times daily at approximately 1-to 2-week intervals. Studies have established target doses of 9 to 12 breaths pr treatment session, 4 times daily as being effective.

Source: United Therapeutics Corp., 2021

Treprostinil injection (Remodulin)

Treprostinil injection (Remodulin) is available as 20 mL vials containing 20, 50, 100, or 200 mg of treprostinil (1, 2.5, 5, 10, or 20 mg/mL).

PAH WHO Group 1:

Initial dose for patients new to prostacyclin infusion therapy:

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

Source: United Therapeutics Corp., 2021

Experimental and Investigational

Aetna considers pulmonary artery hypertension drugs experimental and investigational in the treatment of pulmonary hypertension secondary to other conditions including the following because they are not effective for these indications:

1. Asthma; or
2. Chronic obstructive pulmonary disease; or
3. Congestive heart failure; or
4. Ischemic vascular diseases/Peripheral arterial disease; or
5. Lung resection.  

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

1. Imatinib mesylate, simvastatin, and sorafenib for the treatment of pulmonary hypertension;
2. Prostanoids (epoprostenol and treprostinil) for the treatment of chronic ulcers/limb-threatening ischemia and chronic inflammatory demyelinating polyneuritis;
3. Pulmonary artery denervation for the treatment of pulmonary arterial hypertension;
4. Implantable intravenous prostanoid pump for the treatment of  pulmonary hypertension.

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Table:

CPT Codes / HCPCS Codes / ICD-10 Codes

Code	Code Description
Information in the [brackets] below has been added for clarification purposes.   Codes requiring a 7th character are represented by "+":
Other CPT codes related to the CPB:
96365 - 96371	Intravenous and subcutaneous infusion, for prophylaxis, or diagnosis (specify substance or drug); initial, up to 1 hour
HCPCS codes covered if selection criteria are met:
J1325	Injection, epoprostenol, 0.5 mg
J3285	Injection, treprostinil, 1 mg
J7686	Treprostinil, inhalation solution, FDA-approved final product, non-compounded, administered through DME, unit dose form, 1.74 mg
Q4074	Iloprost, inhalation solution, FDA-approved final product, non-compounded, administered through DME, unit dose form, up to 20 micrograms
S0090	Sildenafil citrate, 25 mg [phosphodiesterase 5 inhibitor] [not covered in oral form for pulmonary hypertension after heart transplantation]
HCPCS codes not covered for indications listed in the CPB:
Ambrisentan, Bosentan, Alyq (tadalafil)- no specific code:
E0782	Infusion pump, implantable, nonprogrammable (includes all components, e.g., pump, catheter, connectors, etc.)
E0783	Infusion pump system, implantable, programmable (includes all components, e.g., pump, catheter, connectors, etc.)
S0088	Imatinib, 100 mg
ICD-10 codes covered if selection criteria are met:
I27.0	Primary pulmonary hypertension [not covered for pulmonary artery denervation]
I27.20 - I27.29	Other secondary pulmonary hypertension
I27.83	Eisenmenger's syndrome
I73.00 - I73.01	Raynaud’s syndrome
J84.111 - J84.113	Idiopathic interstitial pneumonia
ICD-10 codes not covered for indications listed in the CPB (not all-inclusive):
C96.0	Multifocal and multisystemic (disseminated) Langerhans-cell histiocytosis
C96.5	Multifocal and unisystemic Langerhans-cell histiocytosis
C96.6	Unifocal Langerhans-cell histiocytosis
G61.81	Chronic inflammatory demyelinating polyneuritis
G71.00 - G71.09	Muscular dystrophy
I50.1 - I50.9	Heart failure
I70.0 - I70.92	Atherosclerosis
I73.1 - I73.9	Other peripheral vascular diseases [limb ischemia]
J44.0 - J44.9	Other chronic obstructive pulmonary disease
L97.101 - L97.929	Non-pressure chronic ulcer of lower limbs
M62.251 - M62.269	Nontraumatic ischemic infarction of muscle, lower extremity [peripheral arterial disease]
Z90.2	Acquired absence of lung [part of]
Z94.1	Heart transplant status
Atrial septostomy and balloon pulmonary angioplasty:
CPT codes covered if selection criteria are met:
33741	Transcatheter atrial septostomy (TAS) for congenital cardiac anomalies to create effective atrial flow, including all imaging guidance by the proceduralist, when performed, any method (eg, Rashkind, Sang-Park, balloon, cutting balloon, blade)
92997 - 92998	Percutaneous transluminal pulmonary artery balloon angioplasty

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Background

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

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

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

The American College of Cardiology/American Heart Association's expert consensus document on pulmonary hypertension (McLaughlin et al, 2009) stated that "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".

Prostacyclin Infusions

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

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

Epoprostenol (Flolan and Veletri)

U.S. Food and Drug Administration (FDA)-Approved Indications for generic eproprostenol, Flolan, and Veletri

• Epoprostenol/Flolan/Veletri is indicated for the treatment of pulmonary arterial hypertension (PAH) (WHO Group I) to improve exercise capacity. Studies establishing effectiveness included predominantly patients with NYHA Functional Class III-IV symptoms and etiologies of idiopathic or heritable PAH or PAH associated with connective tissue diseases.

Epoprostenol is available as generic epoprostenol and as Flolan (GlaxoSmithKline) and Velitri (Actelion Pharmaceuticals US, Inc.) and has two major pharmacological actions: direct vasodilation of pulmonary and/or systemic arterial vascular beds, and inhibition of platelet aggregation. Epoprostenol is a naturally occurring prostaglandin synthesized by the blood vessel wall. It is a bicyclic enol‐ether derivative of the fatty acid precursor arachidonic acid, and is formed from unstable prostaglandin endoperoxide intermediates via actions of the enzyme epoprostenol synthetase located in vascular endothelial cells. Epoprostenol's action as an inhibitor of platelet aggregation is secondary to stimulation of adenylate cyclase, which results in increased platelet cyclic AMP.

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

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

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

Iloprost (Ventavis)

U.S. Food and Drug Administration (FDA)-Approved Indications for Ventavis

• Ventavis is indicated for the treatment of pulmonary arterial hypertension (PAH) (WHO Group 1) to improve a composite endpoint consisting of exercise tolerance, symptoms (NYHA Class), and lack of deterioration. Studies establishing effectiveness included predominately patients with NYHA Functional Class III-IV symptoms and etiologies of idiopathic or heritable PAH or PAH associated with connective tissue diseases.

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

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

Treprostinil injection (Remodulin)

U.S. Food and Drug Administration (FDA)-Approved Indications for Remodulin

• Treatment of pulmonary arterial hypertension (PAH; WHO Group 1) to diminish symptoms associated with exercise. Studies establishing effectiveness included patients with NYHA Functional Class II-IV symptoms and etiologies of idiopathic or heritable PAH , PAH associated with congenital systemic-to-pulmonary shunts, or PAH associated with connective tissue diseases.
• Patients with PAH requiring transition from epoprostenol, treprostinil/Remodulin to reduce the rate of clinical deterioration. The risks and benefits of each drug should be carefully considered prior to transition.

Treprostinil injection is available as Remodulin (United Therapeutics Corp.) and is a tricyclic benzidine analog of epoprostenol, has two major pharmacological actions:

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

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

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

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

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

Treprostinil inhalation solution (Tyvaso)

U.S. Food and Drug Administration (FDA)-Approved Indications for Tyvaso

• Treatment of pulmonary arterial hypertension (PAH; WHO Group 1) to improve exercise ability. Studies establishing effectiveness predominately included patients with NYHA Functional Class III symptoms and etiologies of idiopathic or heritable PAH or PAH associated with connective tissue diseases.
• Treatment of pulmonary hypertension associated with interstitial lung disease (PH-ILD; WHO Group 3) to improve exercise ability. The study establishing effectiveness predominately included patients with etiologies of idiopathic interstitial pneumonia (IIP) inclusive of idiopathic pulmonary fibrosis (IPF), combined pulmonary fibrosis and emphysema (CPFE), and WHO Group 3 connective tissue disease.

Treprostinil inhalation solution is available as Tyvaso (United Therapeutics Corp.) and is a prostacyclin analogue. The major pharmacologic actions of treprostinil are direct vasodilation of pulmonary and systemic arterial vascular beds and inhibition of platelet aggregation.

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

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

Experimental Drugs for PAH

Imatinib

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

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

Simvastatin

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

Sorafenib

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

Warfarin

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

Prostanoids for Critical Limb Ischemia

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

Prostanoids for Peripheral Arterial Diseases

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

Prostanoids for Pulmonary Hypertension Secondary to Histiocytosis X

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

Furthermore, an UpToDate review on “Pulmonary Langerhans cell histiocytosis” (King, 2021) does not mention epoprostenol as a therapeutic option.

Prostanoids and Analogs for the Treatment of Pulmonary Hypertension in Neonates

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

Oral Sildenafil for Pulmonary Hypertension after Heart Transplantation

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

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

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

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

An UpToDate review on “Heart transplantation in adults: Prognosis” (Pham, 2022) does not mention sildenafil as a management option.

Combination (Dual / Triple) Pharmacotherapy

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

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

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

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

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

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

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

Furthermore, an UpToDate review on “Treatment of pulmonary hypertension in adults” (Hopkins and Rubin, 2022) noted the following:

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

Atrial Septostomy, Balloon Pulmonary Angioplasty, and Pulmonary Artery Denervation

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

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

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

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

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

Implantable Intravenous Prostanoid Pump for the Treatment of Pulmonary Hypertension

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

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

Ambrisentan and Bosentan for Critical Limb Ischemia / Peripheral Arterial Disease

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

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

Appendix

WHO Classification of Pulmonary Hypertension

1 PAH

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

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

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

2 PH due to left heart disease

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

3 PH due to lung diseases and/or hypoxia

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

4 PH due to pulmonary artery obstruction

4.1  Chronic thromboembolic PH
4.2  Other pulmonary artery obstructions

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

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

4.2.3   Non-malignant tumours

Uterine leiomyoma

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

Hydatidosis

5 PH with unclear and/or multifactorial mechanisms

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

Classes	Functional Classification of Pulmonary Artery Hypertension
Class I	Persons with no symptoms, and for whom ordinary physical activity does not cause fatigue, palpitation, dyspnea, or anginal pain
Class II	Persons who are comfortable at rest but who have symptoms Footnote1* with ordinary physical activity
Class III	Persons who are comfortable at rest but have symptoms Footnote1* with less-than-ordinary effort
Class IV	Persons who have symptoms Footnote1* at rest

Footnote1* Key symptoms of PAH include fatigue, dizziness and fainting (near syncope) 

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

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

Source: Hopkins and Rubin, 2021

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References