Continuing Education Activity

Treprostinil is a medication used in the management and treatment of pulmonary arterial hypertension (PH). This activity outlines and reviews the indications, action, and contraindications for treprostinil as a valuable agent in treating PH. This activity will highlight the mechanism of action, adverse event profile, and other key factors pertinent to members of the interprofessional team in the management of patients with PH.

Objectives:

• Describe the mechanism of action of treprostinil.
• Summarize the potential adverse effects of treprostinil.
• Review the side effects of treprostinil.
• Explain some interprofessional team strategies for improving care coordination and communication for patients with pulmonary hypertension (PH), where they could benefit from using treprostinil to improve outcomes.

Indications

Pulmonary hypertension (PH) is a progressive disease that, if left untreated, has very high morbidity and mortality due to right-sided heart failure. Pulmonary hypertension falls into five separate World Health Organization (WHO) groups based on the etiology, which has important ramifications for subsequent management. Group 1 is pulmonary arterial hypertension (PAH). PAH can be due to genetic causes, connective tissue diseases, HIV, schistosomiasis, portal hypertension, or drugs and toxins. Group 2 is PH due to left heart disease. Group 3 is PH due to chronic lung disease and/or hypoxemia. Group 4 is PH due to pulmonary artery obstruction, most commonly from venous thromboembolism (VTE). Group 5 is PH due to multifactorial mechanisms. The clinician can diagnose PH via a right heart catheterization (RHC) showing a mean pulmonary artery pressure (mPAP) of over 25 mm Hg or a pulmonary vascular resistance (PVR) greater than 3 Woods units. A normal pulmonary artery wedge pressure of under 15 mmHg is required to exclude group 2 PH. Currently, there are several pulmonary vasodilator agents with approval for the medical management of PAH, including endothelin receptor antagonists (ERA), phosphodiesterase-5 (PDE-5) inhibitors, and prostanoids.[1][2]

Treprostinil is a synthetic analog of prostacyclin approved for the treatment of Group 1 or PAH. It is a direct vasodilator of both pulmonary and systemic vascular beds, thereby reducing pulmonary artery pressure and improving systemic oxygenation.

The infusion form is for patients with PAH (WHO Group I) with New York Heart Association (NYHA) class II-IV. The inhaled form is used to treat PAH in patients with NYHA class III. The oral form is used to treat PAH in patients with NYHA class II-III.

Studies have also shown that in patients with severe chronic thromboembolic pulmonary hypertension (CTEPH) or WHO Group 4 PH, exercise capacity can improve with subcutaneous treprostinil.

The TRIUMPH-I trial (Treprostinil Sodium Inhalation Used in the Management of Pulmonary Arterial Hypertension) demonstrated that patients who were symptomatic despite dual treatment with bosentan (ERA) and sildenafil (PDE-5 inhibitor) improved clinically after the addition of treprostinil with improved quality of life and exercise capacity measured by an increased 6-minute walk distance (6MWD).[3]

This drug is available in multiple forms, inhaled, oral, and intravenous (IV). Treprostinil received approval from the Food and Drug Administration (FDA) in 2009 for the inhaled form, 2013 for the oral form, and 2017 for the infusion form.

Mechanism of Action

Treprostinil is a chemically stable prostacyclin analog. Its principal pharmacologic action is direct vasodilation, which causes reduction of pulmonary and systemic arterial pressure, reducing right and left ventricular afterload; therefore improves the cardiac output. It also has an antiplatelet effect.[4]

Administration

Treprostinil is available in three formulations: intravenous or continuous subcutaneous, oral, and inhaled. Each formulation is beneficial to patients with PAH. Different routes have different adverse effects, and the knowledge of these effects will facilitate transitioning between these formulations. For example, patients receiving the infusion form experienced infusion site pain, patients receiving the oral form experienced abdominal discomfort, which this activity will discuss in more detail in the “Adverse Effects” section. The subcutaneous (SQ) route is preferred as the drug will rapidly and completely absorb and is administered via an infusion pump. If the patient is not tolerant of the SQ infusion route, they can change to IV infusion. In this case, the solution must be diluted and administered through an indwelling central catheter, which can increase the risk of sepsis and bacteremia. Patients receiving inhaled treprostinil should be able to care for the system and the accessories. They should also have backup devices to avoid interruption of the treatment.

Treprostinil should not be mixed with any other medications. The oral form can be administered with food and should not be crushed or chewed. The absorption of the oral treprostinil increases when administered following a high-fat, high-calorie meal. Dosing requires adjustment in hepatic impairment due to decreased hepatic clearance and increased systemic exposure.

The metabolism of this medication is hepatic via CYP2C8 to form several inactive metabolites, which then get excreted through urine and feces.

It has not undergone testing in other types of PH.[5][2]

SQ absorption is almost immediate, whereas orally, the time to peak is 4 to 6 hours. The half-life is 4 hours. 

Adverse Effects

Local adverse effects are the most common side effects related to either the SQ or inhaled routes of administration:

• Skin manifestations such as infusion site reaction (83%), pain (85%), rash, and infection (seen with the SQ form)
• Respiratory manifestations such as cough, sore throat, and throat irritation (seen with inhaled form)

Systemic adverse effect:

• Central nervous system: Headache, syncope, paresthesia, jaw pain
• Cardiovascular: Flushing, hypotension, edema
• Gastrointestinal symptoms including nausea, abdominal discomfort, and diarrhea (mostly seen with oral form)

Long term adverse effects[6][7][2][3]:

• Epistaxis, hemoptysis, nasal discomfort, wheezing, and pneumonia

Contraindications

There are no contraindications to administering the SQ, IV, or inhaled route of medication. However, the dosage requires adjustment in mild, moderate, and severe hepatic dysfunction. Contraindications to the oral form of treprostinil include severe hepatic dysfunction (Child-Pugh class C).[8]

Monitoring

Treprostinil dosing must be carefully titrated slowly in an individualized manner, monitoring for symptom improvement with minimal adverse reactions at the current dosage.

Since treprostinil metabolism is via the liver, in patients with hepatic impairment, infusion and oral form of this medication can be initiated at a lower dose and titrated slowly.[7].

Researchers have not studied the safety of the inhaled form in patients with underlying pulmonary disease.

Toxicity

Researchers did encounter treprostinil overdose during the trials, which presented with signs and symptoms of vasodilatation such as flushing, hypotension, and headache. It can also result from pump dysfunction, accidental bolus administration, or prescribing the wrong dose. These symptoms are self-limited and will be resolved by temporarily discontinuing the medication or reducing the dosage.[6][9]

Enhancing Healthcare Team Outcomes

In patients with PAH (WHO group 1), treprostinil has been shown to improve the quality of life and the exercise capacity of patients who receive treatment. The effects of this drug have been the subject of study in multiple randomized controlled trials (RCT).

• TRUST trial showed that intravenous treprostinil improves the exercise capacity and dyspnea in treatment-naive patients with pulmonary artery hypertension.[10]
• TRIUMPH trial showed that inhaled treprostinil improved the quality of life and 6MWD in patients who were symptomatic on bosentan and sildenafil.[3]

However, patients with PAH will benefit from an interprofessional team approach to determine the optimal management. Patients with pulmonary hypertension, when treated with treprostinil, need close monitoring as adverse effects are common. Nursing will be at the front lines in this aspect since they have the first contact with the patient at each visit. They must report any suspected therapy failure or adverse effects to the prescribing physician immediately. Also, not all patients have the same response to the drug. Patients need to receive education from the pharmacist that medication compliance is critical for optimal response. Pharmacists must also perform medication reconciliation and verify dosing parameters. Only through interprofessional collaboration, as outlined above, can the patient achieve the best available results from treprostinil therapy. [Level 5]

However, the outcomes for most patients with pulmonary hypertension are guarded; to date, medications do improve the quality of life but offer no cure. The life expectancy of these patients is also markedly reduced.