Prostacyclin Drug Class

[Video title: The Prostacyclin Pathway]

PAH and the Role of Prostacyclin

Pulmonary Arterial Hypertension, or PAH, is a serious and progressive disease that severely impairs patients’ functional abilities, ultimately leading to right heart failure. While the etiology of PAH is not fully understood, the pathophysiology of the disease is well-established.

The rate of progression can be rapid and unpredictable, underscoring the urgency to diagnose and treat quickly. In the absence of targeted drug treatment, median survival was shown to be less than 2.8 years.

Because of the poor prognosis, treatment guidelines emphasize achieving low risk status as a key treatment goal. Multiple registries tracking large patient cohorts have shown a distinct improvement in 5-year prognosis when patients improve their risk status, particularly when improvement is achieved in the first year of therapy.

Over the course of the disease, PAH manifests as remodeling of the small pulmonary arteries, resulting in vasoconstriction, smooth muscle cell proliferation, and platelet aggregation. These effects, together with inflammation and a host of other vascular changes, lead to increased resistance and pressure across the heart and lungs.

While the heart can initially compensate, the progressive increases in pulmonary vascular resistance (PVR) overloads the right ventricle, ultimately leading to decreases in cardiac output and right heart failure.

Fortunately, with decades of research and clinical experience, the role of various disease mediators has been elucidated, particularly the role of prostacyclin.

PAH is characterized by abnormally low levels of prostacyclin, or PGI2, an endogenous, naturally occurring metabolite of arachidonic acid.

Prostacyclin carries out several important actions to help improve heart and lung function. Prostacyclin deficiency, resulting from disease-mediated injury to vascular endothelial cells, has been linked with increased pulmonary arterial pressure, worse disease severity and higher risk of disease progression.

Complications in the lungs caused by inadequate levels of prostacyclin include constriction of the small pulmonary arteries, hypertrophy and proliferation of vascular smooth muscle cells, and heightened risk of blood clotting. Additionally, data suggests insufficient prostacyclin levels may be associated with pulmonary arterial inflammation.

While multiple classes of medications are now approved for the treatment of PAH, treating the Prostacyclin pathway has been a foundation of PAH care for over 25 years. Medications which aim to compensate for missing prostacyclin – known as prostacyclin replacement therapies – play a critical role in blood vessel dilation improving lung function and cardiac performance.

Prostacyclin replacement therapies have been shown to broadly improve right heart function by decreasing the burden on the right ventricle. For instance, prostacyclin reduces pulmonary artery pressure and resistance, leading to improved cardiac blood flow. Notably, these changes unload the right ventricle and decrease natriuretic peptide levels. These hemodynamic effects may lead to improved right heart function, which is predictive of better outcomes.

Additionally, in large-scale clinical trials, prostacyclin class therapies have been shown to delay clinical worsening while improving functional outcomes - such as 6-minute walk distance and Functional Class. These effects are key parameters considered in risk calculations. Improving these parameters may help patients improve their risk status.

Prostacyclin replacement therapies are formulated for multiple routes of administration including inhaled, oral, subcutaneous, and IV

Prostacyclin replacement therapies are most commonly used in combination with other classes of PAH therapy. With multiple administration forms available today, these therapies can be used earlier to adapt in a variety of patient lifestyles and used throughout all stages of PAH disease.

Prostacyclin replacement therapies have a well-characterized safety profile with side effects that are well-understood, including: headache, diarrhea, jaw pain, nausea, muscle pain, and flushing. Additional side effects may be specific to the drug and route of administration. Methods to help manage these expected effects can be personalized for each patient.

Part 3: Treatment considerations

Current treatment guidelines recommend multi-parameter risk assessment at baseline, with follow-up risk assessment as often as every 3 months. Prompt therapy adjustment is recommended when patients are not at low-risk status.

In addition, it is imperative to monitor the early or “leading” signs of disease changes. In PAH, changes in right heart function precede changes in other parameters such as exercise tests and functional class, the latter often referred to as “lagging” indicators. Treatment would be expected to benefit right heart function early, thereby improving overall patient function and reducing risk of disease worsening events.

Because changes in the right heart can be seen before clinical decline, the current treatment guidelines recommend echocardiography at baseline, with therapy changes and clinical worsening. Echos may also be completed every 3 to 6 months in stable patients.

Delaying therapy as little as 6 weeks – whether initial or sequential combination – can have a detrimental impact on your patient’s outcomes. Patients may experience early improvements in their condition, with noticeable improvements in function achieved in as few as 4-6 weeks of initiating Prostacyclin replacement therapy.

Visit PAHInitiaitive.com/HCP to find more PAH disease state education and resources for you, your practice and your patients.