When standard therapy fails to improve outcomes in patients with pulmonary arterial hypertension (PAH), intravenous prostacyclin analogs are frequently administered. According to current guidelines, they are recommended in patients with functional class III or higher. However, the best time for initiation and many other questions remain up for debate.

To date, many prostacyclin analogs have been evaluated in the context of PAH therapeutics. These include epoprostenol (intravenous), iloprost (intravenous, oral, or aerosol), and treprostinil (intravenous and subcutaneous).

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Almost 2 decades ago, the role of intravenous prostacyclin analogs in the treatment of PAH patients was reassessed due to the introduction of new targeted drugs. At the time, epoprostenol was the only intravenous prostacyclin analog whose use was supported by the highest level of evidence, even in combination therapy. Since its approval in 1995 by the US Food and Drug Administration (FDA), it has been one of the most successful therapies used in PAH, showing a positive impact in reducing mortality rates and improving survival rates.

More recently, an increasing number of studies have been suggesting a switch from intravenous prostacyclin analogs to other routes of administration in specific groups of patients. “Even ‘upfront triple therapy’, including [
[intravenous or subcutaneous prostacyclin analogs], might be reasonable as preliminary data suggest a benefit in selected patients,” Ewert et al wrote. However, intravenous prostacyclin analogs remain the gold-standard choice since controlled studies are required to recommend such alternatives.

Different Prostacyclin Analogs Can Help Treat Pediatric PAH

In a recent article published in the journal Expert Review of Respiratory Medicine, experts from 3 German hospitals discussed strategies for optimizing therapy with intravenous prostacyclin analogs in patients with PAH. Here, we will address their recommendations as presented.

When Should Intravenous Prostacyclin Analogs Be Initiated?

Though current guidelines recommend the use of intravenous prostacyclin analogs in patients with functional class III onward, Ewert and colleagues believe it should be initiated earlier. “Intravenous therapy should be established whenever other therapies fail to improve patient status into the low-risk category,” they said.

The therapeutic approach in PAH is based on the patient’s individual risk. Therefore, an initial combination therapy including subcutaneous and intravenous prostacyclin analogs is highly recommended for patients at high risk, as studies suggest an improvement in the survival rate. For instance, patients treated upfront with progressively increasing doses of sildenafil, bosentan, and epoprostenol showed a survival rate of 100% after a mean follow-up of 41 ± 13 months.

Inhaled Treprostinil Palmitil Reduces PAH Pathology

On the other hand, the use of intravenous treprostinil showed only limited value when used in high-risk patients failing oral combination therapy. Only a small portion of these patients could be reverted to a lower risk group and only those reaching the low-risk group had an acceptable survival rate.

Hence, Ewert et al proposed the following:

  • Patients who have achieved low-risk status have a comparably good prognosis independently of how the low-risk status was achieved, ie, with or without intravenous prostacyclin analogs.
  • Achievement of low-risk status and clinical stabilization is sometimes impossible, even in the presence of intravenous prostacyclin analogs in a combination therapy.

Which Intravenous Prostacyclin Analog Should Be Used?

The different intravenous prostacyclin analogs have distinct features that might favor the choice of a particular one. These include differences in drug concentrations, half-lives, shelf-lives, and drug law licenses.

“When considering the clinical data and its long stability [treprostinil] has the advantage over the other medications,” Ewert et al said. Therefore, treprostinil is the drug of choice for fully implantable pumps with long
filling intervals, allowing for an average 47-day interval in the SynchroMed II pump (Medtronic) and a maximum
28-day interval in the Lenus Pro® pump (Tricumed GmbH).

Sildenafil and Beraprost Combination Can Increase Quality of Life in PAH Patients

Another aspect to consider is dose titration. Currently, there is no consensus regarding dose titration in daily practice. Studies on rapid uptitration have been published for intravenous treprostinil and epoprostenol. Recent evidence suggests that patients who received higher doses over time had better hemodynamics and improved survival.

Hence, Ewert et al recommended considering not only clinical data but also drug-specific characteristics (eg, drug stability) when selecting a treatment.

New Modes of Application of Intravenous Prostacyclin Analogs

Conventionally, intravenous prostacyclin analogs are dispensed from a drug reservoir through an external pump, and infused through right atrial catheters. This method of administration has been linked to life-threatening events, such as bloodstream infection and catheter-associated problems (eg, dislocation).

Novel fully implantable, constant flow infusion pumps for application of intravenous treprostinil became available in 2009. These devices improved the quality of life of PAH patients. However, at the time of Ewert et al’s publication, fully implantable pumps had been suspended in the US, while in Europe they were being evaluated to extend approval according to the new European Medical Device Regulation.

The optimization of these devices is imperative in the near future to improve intravenous prostacyclin analog therapy. “A combination with sensors distant from the pump system will integrate real-time hemodynamic data like right ventricular contractility, right atrial pressure or pulmonary vascular resistance and thereby adapt [prostacyclin analogs] application to the patients’ demand,” the authors wrote.

Reference

Ewert R, Habedank D, Halank M, Stubbe B, Opitz CF. Strategies for optimizing intravenous prostacyclin-analog therapy in patients with pulmonary arterial hypertension. Expert Rev Respir Med. 16(1):57-66. doi:10.1080/17476348.2022.2011220

Mohammadi A, Matos WF, Intriago C, et al. Use of epoprostenol in the treatment of pulmonary arterial hypertension. Cureus. 2021;13(9):e18191-e18191. doi:10.7759/cureus.18191