What is the efficacy and safety of synthetic prostacyclin therapies or prostacyclin receptor agonists for managing pulmonary arterial hypertension?Pulmonary hypertension is defined as elevated mean pulmonary arterial pressure and increased pulmonary resistance. The World Health Organization (WHO) has divided pulmonary hypertension into 5 types on the basis of pathophysiology, clinical presentation, and treatment options.1 One of those types, pulmonary arterial hypertension (PAH), is characterized by narrowing or blockage of pulmonary blood vessels, causing decreased blood flow and elevated blood pressure within the pulmonary arteries. As a result, the heart has to pump harder, and eventually the heart muscle can weaken.2Millions of people are affected by PAH annually, and its prevalence has steadily increased over the last several years.3 Several treatment options for PAH are available, with the goals of relieving symptoms, improving exercise capacity, preventing or slowing progression, and improving overall quality of life. People with PAH may respond to a variety of pharmacological agents, including those that promote vasodilation and prevent platelet formation. Medications targeting the prostacyclin pathway have been effective in slowing the progression of PAH but are often associated with side effects and challenges related to safe administration.4Prostacyclin is a naturally occurring molecule in the body that is released by vascular endothelial cells, causing vasodilation and inhibition of platelet aggregation. Synthetic prostacyclins and prostacyclin receptor agonists have been developed to produce a similar effect. Currently, the main routes available for these therapies are intravenous, inhalation, and oral, each with its own benefits, risks, and side effects.5Barnes et al6 conducted a systematic review to summarize the available studies exploring the efficacy and safety of synthetic prostacyclin and prostacyclin agonist therapies for PAH. Specifically, they explored the effect of these therapies on changes in WHO or New York Heart Association functional class, exercise tolerance, and mortality compared with placebo or any other treatment.The systematic review conducted by Barnes et al6 included 17 randomized controlled trials comprising a total of 3765 participants. The trials examined prostacyclin treatment from all routes, including synthetic prostacyclins (prostaglandins, epoprostenol, iloprost, beraprost, and treprostinil) and prostacyclin receptor agonists (primarily selexipag). The included trials did not provide individual patient data, which prevented differentiation between adult and pediatric populations. The authors investigated several main primary outcomes: (1) change in WHO or New York Heart Association functional class, (2) 6-minute walk (6MW) distance, and (3) mortality.In addition to primary outcomes, several secondary outcomes were investigated, including hemodynamics, exercise capacity, dyspnea, quality of life, clinical worsening, adverse events, and costs. Of these secondary outcomes, adverse events and quality of life are included in this review summary. Barnes and colleagues6 independently assessed the risk of bias for each study, including selection, performance, detection, attrition, reporting, and publication biases. They resolved any disagreements by reviewing the data together and through discussion. To compare treatment effects, the review team used odds ratios (ORs) and risk differences (RDs) for dichotomous outcomes and mean differences (MDs) and standardized mean differences (SMDs) for continuous outcomes, with 95% CIs. They used the internationally approved GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach to determine the certainty of evidence—high, moderate, low, or very low—for each outcome7: Moderate-certainty evidence indicated that those who were taking synthetic prostacyclins were more likely to experience an improvement in their WHO functional class (239 per 1000) compared with those taking placebo or other treatment (116 per 1000) (OR, 2.39; 95% CI, 1.72-3.32; P < .001; 8 trials, 1066 participants). All routes showed improvement, with the greatest effect seen in the intravenous trials.Low-certainty evidence indicated that there was a small improvement in 6MW distance for those taking synthetic prostacyclins (MD, 19.50 m; 95% CI, 14.82-24.19; P < .001; 13 trials, 2283 participants). All routes indicated improvement, with the greatest effect seen in the intravenous trials, although none met the minimal clinically important difference of 41 m.Moderate-certainty evidence indicated that there was a significant improvement in overall mortality for those taking synthetic prostacyclins (24 per 1000) compared with placebo or other treatment (39 per 1000) (OR, 0.60; 95% CI, 0.38-0.94; P = .02; 15 trials, 2554 participants). This effect was seen mainly in the intravenous trials. These results were likely related to the fact that most studies were only about 12 weeks in duration and not sufficiently powered to assess mortality.Moderate-certainty evidence indicated that there was an increased risk of adverse events in the synthetic prostacyclin group, including excessive vasodilation, headache, pain, diarrhea, nausea and vomiting, upper respiratory tract infection, and infusion-site reactions.Moderate-certainty evidence indicated that there was a significant improvement in quality of life scores among those taking synthetic prostacyclins (SMD, 0.28; 95% CI, 0.04-0.52; P = .02).Moderate-certainty evidence indicated that there was no significant difference between selexipag and placebo in the number of participants who improved (OR, 1.61; 95% CI, 0.17-15.63; P = .68; 1 trial, 43 participants).High-certainty evidence indicated that selexipag treatment was associated with a small improvement in 6MW distance (MD, 12.62 m; 95% CI, 1.90-23.34; P = .02; 2 trials, 1199 participants). This value did not meet the minimal clinically important difference of 41 m.Moderate-certainty evidence indicated that there was no statistically significant difference in mortality between the selexipag and placebo groups (RD, 0.02; 95% CI, 0.00-0.04; P = .13; 2 trials, 1159 participants).Moderate-to high-certainty evidence indicated that there was an increased risk of adverse events with selexipag, including excessive vasodilation, headache, pain, diarrhea, nausea and vomiting, upper respiratory tract infection, and infusion-site reactions.Quality of life was not assessed as a metric in the included studies.The review of Barnes et al6 showed that there was a clinically and statistically significant benefit for the use of intravenous prostacyclin compared with placebo for patients with pulmonary hypertension in terms of improved WHO functional class, 6MW distance, quality of life, and mortality but that the treatment was accompanied by an increased risk of adverse events. In addition, it showed a small improvement with the use of inhaled prostacyclin and no clinically or statistically significant improvement with the use of oral prostacyclin. Selexipag, the oral selective prostacyclin receptor agonist that works similarly to prostacyclin, showed potentially similar efficacy, although all included trials compared selexipag only with placebo, not with synthetic prostacyclin.Intravenous prostacyclin showed the most benefit but was also associated with an increased incidence of side effects and adverse effects. Other factors to consider with intravenous prostacyclin are the requirements for a continuous infusion that cannot be stopped owing to a short half-life, specialty infusion pump operation, and a dedicated infusion catheter. Considerable attention and resources are needed to ensure adequate patient education, including troubleshooting steps, care and management of long-term intravenous catheters, and an escalation pathway for urgent or emergent situations. Thus, all administration routes and options should be carefully evaluated for each individual patient. This evidence may affect the health care team’s clinical decisions when they are considering treatment plans for patients in this population and discussing them with patients and their families.Advocating for the best evidence-based treatment remains an important part of the role of nurses caring for critically ill patients. We must always consider the best available evidence and understand the feasibility, appropriateness, meaningfulness, and effectiveness of any intervention considered to determine whether it is the most appropriate option in a particular case.