Prostaciclina para la hipertensión arterial pulmonar
Resumen
Antecedentes
La hipertensión arterial pulmonar (HAP) se caracteriza por cambios vasculares pulmonares que dan lugar a presión elevada de la arteria pulmonar, disnea, una reducción de la tolerancia al ejercicio, insuficiencia cardíaca del lado derecho, y en último término la muerte.
Los fármacos análogos de prostaciclina imitan la prostaciclina endógena que da lugar a la vasodilatación, la inhibición de la agregación plaquetaria y la reversión de la remodelación vascular. La vida media corta de la prostaciclina mejora teóricamente la selectividad para el lecho vascular pulmonar mediante la administración directa (vía un catéter venoso central). Las prostaciclinas administradas mediante infusión continua inicial fueron eficaces, aunque el uso del acceso intravenoso aumenta el riesgo de eventos adversos. Ahora hay disponibilidad de preparaciones subcutáneas, orales e inhaladas más nuevas y más seguras, aunque posiblemente menos potentes.
El selexipag es un agonista selectivo del receptor de prostaciclina oral (receptor de IP) que funciona de manera similar a la prostaciclina, es potencialmente más estable, y su administración y ajuste de la dosis son menos complejos.
Objetivos
Determinar la eficacia y la seguridad de la prostaciclina, los análogos de prostaciclina o los agonistas de receptores de prostaciclina para la HAP en adultos y niños.
Métodos de búsqueda
Se realizaron búsquedas en CENTRAL, MEDLINE y Embase hasta el 16 de septiembre de 2018. Se hicieron búsquedas manuales en artículos de revisión, registros de ensayos clínicos y listas de referencias de artículos recuperados.
Criterios de selección
Se incluyó cualquier ensayo controlado aleatorizado (ECA) que comparara prostaciclina, análogos de prostaciclina o agonistas de receptores de prostaciclina versus control (placebo, cualquier otro tratamiento o atención habitual) durante al menos seis semanas.
Obtención y análisis de los datos
Se utilizaron los métodos estándar previstos por Cochrane. Los resultados primarios incluyeron el cambio en la clase funcional de la Organización Mundial de la Salud (OMS), la distancia caminada en seis minutos (DC6M) y la mortalidad.
Resultados principales
Se incluyeron 17 ensayos con 3765 participantes, en su mayoría adultos; la duración media del ensayo fue de 12 semanas. Quince ensayos utilizaron análogos de prostaciclina: intravenosos (N = 4); subcutáneos (N = 1); orales (N = 5); inhalados (N = 5); dos utilizaron agonistas del receptor de prostaciclina oral. Tres ensayos que utilizaron la vía intravenosa y dos la vía inhalada fueron no enmascarados.
Los participantes que recibieron prostaciclina tuvieron 2,39 veces más probabilidades de mejorar en al menos una clase funcional de la OMS (intervalo de confianza [IC] del 95%: 1,72 a 3,32; 24 por 100 [IC del 95%: 18,5 a 30,4] con prostaciclina en comparación con 12 por 100 con el control; ocho ensayos, 1066 participantes; evidencia de certeza moderada). Se observó una mejoría con las preparaciones intravenosas (odds ratio [OR] 14,96; IC del 95%: 4,76 a 47,04) e inhaladas (OR 2,94; IC del 95%: 1,53 a 5,66), pero no con las preparaciones orales. Los participantes que utilizaron prostaciclina aumentaron su DC6M en 19,50 metros (IC del 95%: 14,82 a 24,19; 13 ensayos, 2283 participantes; evidencia de certeza baja), lo que fue clínicamente significativo con la administración intravenosa (diferencia de medias [DM] 91,76 metros; IC del 95%: 58,97 a 124,55), pero no con las preparaciones no intravenosas (subcutáneas: DM 16,00 metros, IC del 95%: 7,38 a 24,62; oral: DM 14,76 metros, IC del 95%: 7,81 a 21,70; inhalado: DM 26,97 metros; IC del 95%: 17,21 a 36,73). La mortalidad se redujo en los estudios de la administración intravenosa (OR 0,29; IC del 95%: 0,12 a 0,69; riesgo de muerte 6 por 100 [IC del 95%: 2,38 a 12,31] con prostaciclina en comparación con 17 por 100 con el control; cuatro ensayos, 255 participantes), pero no en los estudios de la administración no intravenosa (OR 0,82; IC del 95%: 0,48 a 1,40; riesgo de muerte 21 por 1000 [IC del 95%: 12,00 a 34,20] con prostaciclina en comparación con 25 por 1000 con el control; evidencia de certeza moderada; 12 ensayos, 2299 participantes). Se redujo la certeza de la evidencia debido a que hubo pocos estudios por subgrupo y al uso de ensayos no enmascarados.
Las prostaciclinas mejoraron la hemodinámica cardiopulmonar (reducción de la presión de la arteria pulmonar media de 3,60 mmHg (IC del 95%: ‐4,73 a ‐2,48); la resistencia vascular pulmonar en 2,81 WU (IC del 95%: ‐3,80 a ‐1,82); presión auricular derecha en 1,90 mmHg (IC del 95%: ‐2,58 a ‐1,22), y aumento del índice cardíaco en 0,31 L/min/m2 (IC del 95%: 0,23 a 0,38); evidencia de certeza baja), mejoría de la disnea (evidencia de certeza baja y mejor calidad de vida (evidencia de certeza moderada), en comparación con el control. Cuando se incluyeron sólo los ensayos de la administración subcutánea/inhalada el efecto aún fue significativo, aunque la magnitud fue más pequeña. No hubo diferencias en los ensayos de la administración oral.
Los eventos adversos aumentaron en todas las preparaciones de prostaciclina, incluida la vasodilatación (OR 5,03; IC del 95%: 3,84 a 6,58), la cefalea (OR 3,16; IC del 95%: 2,62 a 3,80), el dolor de mandíbula (OR 5,25; IC del 95%: 3,96 a 6,98), la diarrea (OR 2,81; IC del 95%: 2,29 a 3,46), las náuseas/vómitos (OR 2,39; IC del 95%: 1,98 a 2,88), las mialgias (OR 2,75; IC del 95%: 1,65 a 4,58), los eventos de las vías respiratorias superiores (OR 1,61; IC del 95%: 1,22 a 2,13), el dolor de la extremidad (OR 3,36; IC del 95%: 2,32 a 4,85) y las reacciones en el sitio de infusión (OR 14,41; IC del 95%: 9,16 a 22,66). En los ensayos de la administración intravenosa, hubo un riesgo del 12%‐25% de eventos graves no mortales incluida la sepsis, la hemorragia, el neumotórax y la embolia pulmonar.
Dos ensayos (1199 participantes) compararon el selexipag oral con placebo; ningún ensayo comparó el selexipag con la prostaciclina. Hubo una pequeña mejoría de 12,62 metros en la DC6M (IC del 95%: 1,90 a 23,34; evidencia de certeza alta) y evidencia débil para la hemodinámica. El efecto fue incierto para la clase funcional de la OMS. El riesgo de muerte con selexipag fue de cinco por 100 en comparación con tres por 100 con placebo, aunque el IC cruzó cero por lo cual se desconoce el efecto verdadero (diferencia de riesgos [DR] 0,02; IC del 95%: ‐0,00 a 0,04). Hubo menos empeoramiento clínico con selexipag (OR 0,47; IC del 95%: 0,37 a 0,60), aunque hubo más efectos secundarios, incluida la vasodilatación (OR 2,67; IC del 95%: 1,72 a 4,17), la cefalea (OR 3,91; IC del 95%: 3,07 a 4,98), el dolor de mandíbula (OR 5,33; IC del 95%: 3,64 a 7,81), la diarrea (OR 3,11; IC del 95%: 2,39 a 4,05), las náuseas/vómitos (OR 2,92; IC del 95%: 2,29 a 3,73), el dolor en las extremidades (OR 2,44; IC del 95%: 1,69 a 3,52) y las mialgias (OR 3,05; IC del 95%: 2,02 a 4,58).
Conclusiones de los autores
Esta revisión demuestra el beneficio clínico y estadístico de la prostaciclina intravenosa (en comparación con el control) con una mejoría en la clase funcional, la DC6M, la mortalidad, las puntuaciones de los síntomas y la hemodinámica cardiopulmonar, aunque a costa de eventos adversos. Lo anterior puede deberse a un efecto verdadero, o puede ser sobrestimado debido a la inclusión de estudios pequeños, cortos o no enmascarados. Hubo un beneficio clínico estadístico y pequeño en la función y la hemodinámica para la prostaciclina inhalada, aunque el efecto es incierto para la mortalidad. Existe menos certeza en cuanto al efecto de las prostaciclinas orales. El selexipag demostró menos empeoramiento clínico sin una repercusión discernible sobre la supervivencia, aumentó los eventos adversos; y el efecto sobre otros resultados es menos seguro. Los datos del registro del mundo real pueden proporcionar mayor información acerca del efecto clínico.
PICO
Resumen en términos sencillos
Prostaciclina en la hipertensión arterial pulmonar
Pregunta de la revisión
Se deseaba examinar si un grupo de fármacos llamados análogos de prostaciclina ayudan a los pacientes con hipertensión pulmonar. Los investigadores Cochrane recopilaron y analizaron todos los estudios relevantes para responder esta pregunta.
Por qué es importante esta revisión
La hipertensión pulmonar puede causar disnea, tolerancia reducida al ejercicio, reducción en la calidad de vida, hospitalizaciones y muerte prematura. Los análogos de prostaciclina pueden mejorar la circulación sanguínea en la parte derecha del corazón y los pulmones. El objetivo era asegurarse de que si se utilizan estos fármacos haya evidencia de efectos beneficiosos y poco o ningún daño.
Principales hallazgos
Se incluyeron 17 ensayos en que participaron 3765 personas. La mayoría de los estudios duraron 12 semanas. Algunos ensayos tuvieron una duración de hasta 52 semanas. La mayoría de los ensayos incluyeron adultos. Los pacientes que recibieron análogos de prostaciclina se compararon con los pacientes que no recibieron prostaciclina. Los pacientes de cuatro ensayos recibieron los fármacos mediante un goteo continuo (24 horas/día) en una vena (vía intravenosa) y en un ensayo a través de una inyección continua bajo la piel (vía subcutánea). En cinco ensayos los pacientes inhalaron los fármacos a través de un nebulizador y en cinco ensayos recibieron comprimidos (vía oral). Los pacientes de dos estudios recibieron comprimidos de selexipag. El selexipag es un agonista del receptor de prostaciclina y los ensayos del selexipag se analizaron por separado.
Los pacientes que recibieron prostaciclinas vía un goteo intravenoso mostraron mejor supervivencia (menor perspectiva de muerte). También pudieron caminar en promedio 92 metros más en seis minutos que los pacientes que no recibieron el goteo de prostaciclina. También tuvieron una probabilidad mayor de mejorar su clase funcional (lo que se puede y no se puede hacer diariamente). Los pacientes con prostaciclinas intravenosas tuvieron una mejor función cardíaca en promedio que los que no recibieron ningún tratamiento.
En términos generales, los resultados estuvieron menos claros para los pacientes que recibieron prostaciclinas orales, inhaladas o subcutáneas. No estuvo claro si la administración del fármaco de estas formas dio lugar a una mejoría en la supervivencia. Los pacientes que recibieron prostaciclinas inhaladas (nebulizador) mejoraron su clase funcional, caminaron en promedio 27 metros más en seis minutos y tuvieron una mejor función cardíaca. También hubo alguna evidencia de que las prostaciclinas subcutáneas mejoraron la función cardíaca. No estuvo claro si la administración de comprimidos mejoró la clase funcional o la función cardíaca. Los pacientes que recibieron este tratamiento sólo caminaron 15 metros más en seis minutos que los que no recibieron comprimidos de prostaciclina.
Aunque esta revisión halló que la evidencia fue mejor para la prostaciclina vía goteo continuo, puede ser inconveniente y podría aumentar los riesgos como las infecciones relacionadas con la línea intravenosa. Además, casi todos los pacientes que recibieron las dosis recomendadas en cualquier forma tienen efectos secundarios importantes relacionados con los fármacos (que incluyen enrojecimiento, cefalea, dolor de mandíbula, diarrea, dolor en las extremidades, efectos secundarios en las vías respiratorias superiores, náuseas y vómitos).
Los pacientes que recibieron selexipag tuvieron un menor empeoramiento clínico, y una diferencia pequeña de 13 metros en la prueba de caminata de seis minutos en comparación con los pacientes que recibieron placebo. Los pacientes que usaron selexipag también presentaron una mayor probabilidad de tener efectos secundarios que incluyeron enrojecimiento, dolor de mandíbula, diarrea, náuseas/vómitos y dolor en los músculos/extremidades.
Limitaciones
Hay evidencia de certeza moderada de que la prostaciclina ayuda a los pacientes en comparación con los que no la usan. El beneficio es mejor para los que reciben el fármaco vía un goteo continuo, aunque los riesgos son mayores. Además, en promedio, los estudios sólo duraron tres meses (algunos hasta un año), y este periodo puede no ser suficiente para observar el beneficio o los riesgos.
Esta revisión sólo consideró a los pacientes con diagnóstico de hipertensión arterial pulmonar, no a los que presentan hipertensión pulmonar asociada con cardiopatía del lado izquierdo, enfermedad pulmonar o hipertensión pulmonar causada por coágulos sanguíneos.
Esta revisión está actualizada hasta septiembre de 2018.
Authors' conclusions
Summary of findings
| Prostacyclin compared to control for pulmonary arterial hypertension | ||||||
| Patient or population: pulmonary arterial hypertension | ||||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect | № of participants | Certainty of evidence | Comments | |
| Risk with control | Risk with prostacyclin | |||||
| Improvement in WHO functional class Mean follow‐up 16 weeks | Study population | OR 2.39 | 1066 | ⊕⊕⊕⊝ | ||
| 116 per 1000 | 239 per 1000 | |||||
| 6MWD Mean follow‐up 15 weeks | The mean 6MWD was 257 m* | MD 19.50 m higher | ‐ | 2283 | ⊕⊕⊝⊝ Low1,2 | 6MWD in PAH MCID is 41 m |
| Mortality Mean follow‐up 15 weeks | Study population | OR 0.60 | 2554 | ⊕⊕⊕⊝ | ||
| 39 per 1000 | 24 per 1000 | |||||
| mPAP (the higher the mPAP, the worse the pulmonary hypertension) Mean follow‐up 11 weeks | The mPAP ranged from 56 to 66 mmHg# | MD 3.60 mmHg lower | ‐ | 1132 | ⊕⊕⊝⊝ Low1,2 | |
| PVR (the higher the PVR, the Mean follow‐up 11 weeks | The mean PVR ranged from 26 to 29 units/m2# | MD 2.81 WU lower | ‐ | 658 | ⊕⊕⊕⊝ | |
| Cardiac index (the lower the cardiac index, Mean follow‐up 11 weeks | The mean cardiac Index ranged from 2 to 2.4 L/min/m2# | MD 0.31 L/min/m 2 higher | ‐ | 868 | ⊕⊕⊝⊝ Low1,2 | |
| RAP (the lower the RAP, Mean follow‐up 11 weeks | The mean RAP ranged from 8 to 13 mmHg# | MD 1.90 mmHg lower | ‐ | 1060 | ⊕⊕⊕⊝ | The higher the RAP, the |
| Dyspnoea (lower scores indicates more severe breathlessness) Mean follow‐up 17 weeks | ‐ | SMD 0.21 lower | ‐ | 1521 | ⊕⊕⊝⊝ Low1,2 | Using an illustrative SD, this converts to a difference of 0.64 units on the Borg scale. MCID in PAH is 0.9 units |
| Quality of life Mean follow‐up 12 weeks | ‐ | SMD 0.28 better | ‐ | 271 | ⊕⊕⊕⊝ | |
| Headache+ Mean follow‐up 12 weeks | 277 per 1000 | 529 per 1000 (95% CI 501 to 593) | 3.16 (2.62 to 3.80) | 2351 (12 RCTs) | ⊕⊕⊕⊝ | |
| *The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence | ||||||
| 1Downgraded due to the risk of bias with open‐label studies. | ||||||
| Selexipag compared to placebo for pulmonary arterial hypertension | ||||||
| Patient or population: pulmonary arterial hypertension | ||||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect | № of participants | Certainty of evidence | Comments | |
| Risk with placebo | Risk with selexipag | |||||
| Improvement in WHO functional class Mean follow‐up 17 weeks | Study population | OR 1.61 | 43 | ⊕⊕⊕⊝ | ||
| 100 per 1000 | 152 per 1000 | |||||
| 6MWD Mean follow‐up 40 weeks | The mean 6MWD ranged from 348 to 396 m | MD 12.62 m higher | ‐ | 1199 | ⊕⊕⊕⊕ | 6MWD in PAH MCID is 41 m |
| Mortality Mean follow‐up 40 weeks | Study population | Risk difference 0.02 (‐0.00 to 0.04) | 1199 | ⊕⊕⊕⊝ | ||
| 30 per 1000 | 48 per 1000 (27 to 84) | |||||
| mPAP the higher the mPAP, the worse the pulmonary hypertension) Mean follow‐up 17 weeks | The mPAP was 60 mmHg | MD 7.4 mmHg lower | ‐ | 43 | ⊕⊕⊕⊝ | |
| PVR (the higher the PVR, the Mean follow‐up 17 weeks | The mean PVR was 1687 dyn/sec/m2 | MD 33 dyn/sec/m2 lower | ‐ | 43 | ⊕⊕⊕⊝ | |
| Cardiac index (the lower the cardiac index, Mean follow‐up 17 weeks | The mean cardiac index was 2.3 L/min/m2 | MD 0.5 L/min/m2 higher | ‐ | 43 | ⊕⊕⊕⊝ | |
| RAP (the lower the RAP, Mean follow‐up 17 weeks | The mean RAP was 8.3 mmHg | MD 3.2 mmHg higher | ‐ | 43 | ⊕⊕⊕⊝ | |
| Dyspnoea (lower scores indicates more severe breathlessness) Mean follow‐up 17 weeks | ‐ | MD 0.1 lower | ‐ | 43 | ⊕⊕⊕⊝ | MCID in PAH is 0.9 units |
| Headache+ Mean follow‐up 40 weeks | Study population | 3.91 (3.07 to 4.98) | 1199 | ⊕⊕⊕⊕ | ||
| 325 per 1000 | 653 per 1000 | |||||
| *The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence | ||||||
| 1Downgraded due to imprecision with confidence intervals including no difference. | ||||||
Background
Description of the condition
Pulmonary hypertension is defined as a mean pulmonary arterial pressure (mPAP) exceeding 25 mmHg measured by right heart catheterisation (Galiè 2016). More than 50 diseases across five main categories (World Health Organization (WHO) type 1 to 5) are reported as potential aetiologies (Simonneau 2013). Many cause progressive disease, with associated right ventricular strain, hypertrophy, remodelling within the pulmonary vasculature and premature death. In the later stages of the disease, cardiopulmonary dysfunction leads to burdensome symptoms, such as exercise intolerance, syncope, oedema and breathlessness. The development of several specific therapies for WHO Group 1 pulmonary arterial hypertension (PAH) has led to heightened interest in the condition. Unfortunately, most people presenting with PAH have progressed to advanced disease at the time of specialist referral (Humbert 2006; Thenappan 2007); and the true prevalence of pulmonary hypertension is likely under‐recognised (Galiè 2016). Modern therapies have reduced morbidity and improved survival (Thenappan 2007); however the risks and side effects warrant their careful selection. Prostaglandins have an unusual spectrum of side effects and almost all patients on an effective dose will have significant prostaglandin‐related side effects.
The WHO classification system for pulmonary hypertension is widely used, grouping disorders based on underlying mechanisms (Simonneau 2013). This provides a framework for treatment, as pathophysiology varies greatly between groups. Group 1 comprises PAH, formerly termed "primary pulmonary hypertension", which refers to precapillary flow obstruction, independent of venous thromboembolism or hypoxaemic lung disease (Badesch 2009). PAH is a rare disease, with an estimated prevalence of 10 to 52 cases per million (Ling 2012; Peacock 2007).
The gold standard diagnostic tool in pulmonary hypertension is right heart catheterisation, which determines a diagnosis of pulmonary hypertension, and further characterises the aetiology according to the WHO classification (Galiè 2016). PAH is determined as pulmonary hypertension (mean pulmonary arterial pressure (mPAP) equal to or higher than 25 mmHg) with a normal back pressure from the heart (a pulmonary arterial wedge pressure equal to or less than 15 mmHg) and a pulmonary vascular resistance (PVR) more than 3 Wood units measured during right heart catheterisation. A pulmonary arterial wedge pressure higher than 15 mmHg indicates contributing left heart dysfunction. Other baseline evaluation includes high‐resolution computed tomography (HRCT) and ventilation‒perfusion (VQ) scanning to rule out other causes (non‐WHO Group 1); and exercise testing such as six‐minute walk distance (6MWD) (Galiè 2016) for baseline evaluation and prognostication.
Beyond confirmation of the diagnosis, right heart catheterisation and other baseline tests assist to stratify risk of progression which assists in directing treatment. Goals of therapy are relief of symptoms, improved exercise capacity, improved quality of life, arresting progression and reducing mortality. People with PAH often respond to disease‐specific modifying therapies, including calcium channel blockers, prostacyclin analogues, endothelin receptor antagonists and phosphodiesterase‐5 inhibitors. In contrast, indications for advanced therapies in other groups of pulmonary hypertension are less clear cut and treatment of underlying conditions is first line (Galiè 2016).
Description of the intervention
Prostacyclin is endogenously synthesised by endothelial cells using the cyclo‐oxygenase arachidonic pathway. Prostacyclin exerts vasodilatory, antithrombotic and antiproliferative effects that are essential for endothelial function (Mitchell 2014). The principal target of prostacyclin is the IP G protein‐coupled receptor in the smooth muscle of arterioles. Its activation triggers intracellular cyclic adenosine monophosphate formation, activating protein kinase A, which mediates vasodilation of the pulmonary arteries, inhibition of platelet aggregation, and relaxation of the smooth muscle (Humbert 2015). Disequilibrium between vasodilating mediators, such as a reduction in the normal release of prostacyclin, and increased release of vasoconstricting mediators, such as thromboxane A2, plays a causative role in PAH (Christman 1992; Sitbon 2016). Currently there are three prostacyclin analogues available ‐ epoprostenol, iloprost and treprostinil. Selexipag is a selective IP prostacyclin receptor agonist that is structurally distinct from prostacyclin. It is rapidly hydrolysed to a long‐acting metabolite that binds to IP receptors, resulting in the same actions as prostacyclin ‐ vasodilation, inhibition of platelet aggregation, and anti‐inflammatory effects (Noel 2017).
How the intervention might work
Epoprostenol directly vasodilates the pulmonary and systemic arterial vasculature, and has been demonstrated in previous trials to reduce ventricular afterload, pulmonary vascular resistance (PVR) and platelet aggregation, and to increase cardiac output (Sitbon 2016).
The key attributes of synthetic prostacyclin agents are prostacyclin's short half‐life at room temperature (minutes) and that it mainly only exerts local effects (Mitchell 2014). The first synthetic agent (epoprostenol) demonstrated significant efficacy as a therapeutic agent in the improvement of haemodynamic parameters, exercise capacity, and mortality (Barst 1996). However it is not without drawbacks. Its short half‐life requires continuous intravenous infusion, via a central venous catheter and continuous pump, requiring central line placement, and potentially introducing the risk of central line‐associated blood stream infection (Kallen 2008). Initial preparations were required to be refrigerated or kept on ice; however newer preparations have a more stable half‐life of 24 hours (Sitbon 2012).
Iloprost is a prostacyclin analogue that is most frequently used via inhalation. It has a slightly longer half‐life of 20 to 30 minutes, but still requires 5 to 10 inhalation doses throughout the day. Treprostinil has a much more stable half‐life of four hours, and can be administrated at much lower infusion rates via a subcutaneous or intravenous pump (Tapson 2006). However, treprostinil is metabolised by cytochrome P450 (CYP)2C8 in the liver and its metabolites are renally excreted, so clearance may be affected by hepatic impairment. Cumulative effects of treprostinil can occur if used with antihypertensives or anticoagulants (Simonneau 2002).
Beraprost is also available as an orally active prostacyclin analogue, theorised to maintain a stable structure due to its cyclopenta benzofuranyl skeleton. It acts by binding to prostacyclin membrane receptors to inhibit the release of calcium, leading to relaxation of smooth muscle cells and vasodilation, and inhibiting platelet aggregation. Given three times a day, it has previously exhibited improved outcomes in those with intermittent claudication due to peripheral arterial disease (Melian 2002).
For all prostacyclin agents, dose titration is individualised according to the individual patient. A characteristic pattern of adverse effects, particularly systemic hypotension, but also including flushing, diarrhoea, and muscle pains (Barst 1996; Sitbon 2016), may limit dose escalation. Indeed the dose is often up‐titrated until side effects are evident. This makes patient and investigator concealment (blinding) somewhat problematic in clinical trials. The method of delivery and the drug itself are expensive. Furthermore, therapy must be continuous, as abrupt withdrawal may precipitate rebound pulmonary hypertension, which can be fatal.
Selexipag is an oral selective prostacyclin receptor (IP receptor) agonist that works similarly to prostacyclin. It is postulated that the density of prostacyclin receptors varies between patients, therefore requiring complex personally tailored dosing of prostacyclin analogues, however, clinical trials in selexipag indicates patients respond similarly to the low‐, medium‐ and high‐dose regiments, therefore it offers a potentially more stable drug, with less complex administration and titration (GRIPHON).
Why it is important to do this review
Evidence in the literature suggests that prostacyclin analogues are efficacious in the treatment of PAH; however the treatment may come with considerable risks and side effects. The purpose of this review is to summarise the available published data regarding the relative efficacy and safety of prostacyclin analogues, in particular on haemodynamic response, and on participant‐centred outcomes, such as exercise tolerance, adverse effects, and quality of life.
Unfortunately, patients with PAH usually have advanced disease at presentation. Early diagnosis and management of this progressive condition offers a greater scope to delay or prevent onset of end‐stage symptoms. Recognising the presence of pulmonary hypertension as well as the underlying cause allows early initiation of appropriate treatment and potentially avoidance of end‐stage disease states.
Objectives
To determine the efficacy and safety of prostacyclin, prostacyclin analogues or prostacyclin receptor agonists, compared to placebo or any other treatment, for pulmonary arterial hypertension (PAH) in adults and children.
Methods
Criteria for considering studies for this review
Types of studies
We included any randomised controlled trials (RCTs) which compared prostacyclin or analogues to control (placebo, any other treatment or usual care) for at least six weeks. We defined 'randomised' as studies which are described by the author as 'randomised' anywhere in the manuscript. All defined trials, published or unpublished, in any language, were potentially eligible for inclusion.
Types of participants
We included any individual with a diagnosis of World Health Organization (WHO) Group 1 pulmonary hypertension, referred to as pulmonary arterial hypertension (PAH), as per the present definition of a mean pulmonary arterial pressure (mPAP) higher than 25 mmHg by right heart catheterisation (Galiè 2016). We did not include other WHO diagnostic groups (2 to 5) of pulmonary hypertension. We planned to specify subgroups of adults older than 18 years and a paediatric population younger than 18 years, however, no trials reported separate outcome data or individual patient data to make these subgroup comparisons.
Types of interventions
We included studies comparing any type of prostacyclin treatment by any route of administration with placebo or any other treatment for at least six weeks. This included, but was not limited to, prostaglandins, epoprostenol, iloprost, beraprost, treprostinil, prostacyclin receptor agonist and selexipag, via the intravenous, subcutaneous, inhaled, and oral route. We separated comparisons into prostacyclin versus control and selexipag versus control. We included studies with co‐interventions, provided they were not part of the randomised treatment, by any route of administration, with placebo or any other treatment used for pulmonary hypertension. Where multiple doses were used, we planned to perform subgroup analyses by dose, however, in the included studies, doses were titrated per individual participant. Where studies were too heterogeneous for meta‐analyses, or where only descriptive data were available, we described them in narrative form.
Types of outcome measures
Primary outcomes
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Change in WHO or New York Heart Association (NYHA) functional class (Badesch 2009)
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Six‐minute walk distance (6MWD) test (Badesch 2009)
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Mortality
Secondary outcomes
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Cardiopulmonary haemodynamics: including mean pulmonary artery pressure (mPAP), pulmonary vascular resistance (PVR), cardiac index, cardiac output, systemic arterial oxygen saturation and systemic oxygen transport
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Exercise capacity tests other than 6MWD test
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Symptom scales: Borg dyspnoea score (Badesch 2009), dyspnoea‐fatigue ratings (Badesch 2009)
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Quality of life
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Clinical worsening
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Adverse events
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Cost analysis
Reporting of one or more outcomes was not a criterion for inclusion of a study in the review. We only included trials which have treated participants for at least six weeks. We did not find any studies which reported multiple time points, nor did we find any studies which reported post‐intervention follow‐up separate to the initial trial results. We are aware that some included trials may use composite outcomes. Where these were presented, we re‐analysed data to report only outcomes specified above.
Search methods for identification of studies
Electronic searches
We identified studies from searches of the following databases up to 16 September 2018.
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Cochrane Airways Register of Trials through the Cochrane Register of Studies (CRS Web).
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Cochrane Central Register of Controlled Trials (CENTRAL), through the Cochrane Register of Studies (CRS Web).
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MEDLINE Ovid SP 1946 to 16 September 2018.
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Embase Ovid SP 1974 to 16 September 2018.
In addition, we searched the CENTRAL database in the Cochrane Library for conference abstracts and grey literature. The database search strategies are listed in Appendix 1. We did not apply any restrictions for language, date or type of publication.
We also searched the following trials registries for additional trials for inclusion and for additional data for included trials.
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US National Institutes of Health Ongoing Trials Register ClinicalTrials.gov (www.ClinicalTrials.gov).
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World Health Organization (WHO) International Clinical Trials Registry Platform (apps.who.int/trialsearch).
Searching other resources
We checked the reference lists of all primary studies and review articles for additional references. We handsearched reference lists of included studies, relevant chapters and review articles. We used Google to search for grey literature and conference abstracts. We planned to translate any relevant article into English for potential inclusion, however we did not identify any other language papers. Where data were missing, we checked on trial registries and attempted to contact the trial investigators. We searched for errata or retractions from included studies published in full text on PubMed and reported the date this was done within the review.
Data collection and analysis
Selection of studies
Two independent review authors (HB, HLY) independently screened all abstracts to determine if they met the accepted inclusion criteria using Covidence. We obtained full‐text publications for those papers which definitely or may meet inclusion criteria. Two independent review authors (HB, HLY) then reviewed all full‐text articles to determine eligibility, and recorded reasons for any that are ineligible. We resolved any concerns or disagreement through discussion with other review authors (AB, TW, MH). We included a PRISMA study flow diagram in the full review to document the screening process and included a 'Characteristics of excluded studies' table (Moher 2009).
Data extraction and management
Two review authors (HB and HLY) independently extracted data from included studies, and where appropriate, pooled data in Cochrane’s statistical software Review Manager 5 (RevMan 5) (Review Manager 2014), for further analysis. Following, both review authors met to check consistency of data entered into RevMan 5 prior to meta‐analyses being performed. The Cochrane Airways group methodologist (Christopher Cates) assisted with generic inverse variance analysis. We planned to resolve disagreements by consensus or by involving a third review author (AB). We used a data collection form which was piloted for inclusion in the review, containing the following data.
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Methods: study design, duration, study setting, date of study
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Participants: number, mean age and age range, gender, inclusion and exclusion criteria, and differences in baseline characteristics
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Intervention: type of prostacyclin analogue, dose, mode of administration, control drug, co‐interventions and exclusions
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Outcomes: primary and secondary outcomes as specified, type of scale used, time points collected
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'Risk of bias' summary
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Other: funding for trial, any conflicts of interest for trial authors
Assessment of risk of bias in included studies
Two independent authors (HB, HLY) assessed the included studies for risk of bias using Cochrane's tool for assessment of risk of bias according to the following domains (Higgins 2011).
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Random sequence generation
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Allocation concealment
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Blinding of participants and personnel
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Blinding of outcome assessment
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Incomplete outcome data
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Selective outcome reporting
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Other bias
We judged each potential source of bias as low, unclear risk (insufficient information to form a judgement), or high risk, and provided justification with evidence from each trial in the 'Risk of bias' table. When considering treatment effects, we took into account the risk of bias for the studies that contribute to that outcome. We provided a quote from the study report together with justification for our judgement in the 'Risk of bias' table.
Assessment of bias in conducting the systematic review
We conducted the review according to our previously published protocol and justified any deviations from it in the 'Differences between protocol and review' section of the systematic review.
Measures of treatment effect
Where possible, we pooled and presented results from dichotomous data as odds ratios (ORs). Where zero totals were obtained, we presented these data as risk differences (RDs). Where possible, we presented results from continuous variables using a fixed‐effect model and calculated the mean differences (MDs) or standardised mean differences (SMDs) where scales are combined, with the 95% confidence intervals (95% CIs). If data from rating scales are combined in a meta‐analysis, we ensured that they are entered with a consistent direction of effect (e.g. lower scores always indicate improvement). Where both change from baseline and endpoint scores were available for continuous data, we used change from baseline scores where possible. We only combined data reported at different time points if this is clinically appropriate. We described skewed data narratively (e.g. as medians and interquartile ranges for each group).
We used intention‐to‐treat or 'full analysis set' analyses where they are reported (i.e. those where data have been imputed for participants who were randomly assigned but did not complete the study) instead of 'completer' or 'per‐protocol' analyses.
Unit of analysis issues
For dichotomous outcomes, we used participants, rather than events, as the unit of analysis (i.e. number of children admitted to hospital, rather than number of admissions per child). However, where rate ratios are reported in a study, we analysed them on this basis. No cluster‐randomised trials were included, however if cluster‐randomised trials are included in future versions of the review, we will only use data which has been, or can be, adjusted to account for the clustering.
Dealing with missing data
We contacted investigators or study sponsors in order to verify key study characteristics and obtain missing numerical outcome data where possible (e.g. Han 2017 to obtain individual data). Where this was not possible, and the missing data are thought to introduce serious bias, we took this into consideration in the GRADE rating for affected outcomes.
Assessment of heterogeneity
For pooled analyses, we quantified statistical heterogeneity using the I² statistic, which describes the percentage of total variation across trials due to heterogeneity rather than sampling error. Significant statistical heterogeneity was considered to be present if the I² is greater than 50%. Where significant heterogeneity was identified, we planned to explore possible causes using prespecified subgroup analyses.
Assessment of reporting biases
We were unable to pool more than 10 studies using the same intervention, so we did not explore further possible small‐study and publication biases as stated a priori.
Data synthesis
We performed pooled quantitative meta‐analysis where trials were considered clinically homogenous. We used a fixed‐effect model to synthesise and report mean difference (MD) and 95% CIs. We synthesised and report dichotomous and continuous data separately for each outcome.
Where there was substantial heterogeneity (> 50%), we also reported outcomes in the text, including the direction and size of the effect along with the strength of the evidence (risk of bias).
'Summary of findings' table
We created a 'Summary of findings' table using the methods and recommendations described in Section 8.5 and Chapter 12 of the Cochrane Handbook for Systematic Reviews of Interventions along with GRADEPro GDT software (GRADEpro GDT; Higgins 2011). The outcomes included:
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WHO functional class status;
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mortality;
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change in haemodynamics;
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6MWD;
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dyspnoea;
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quality of life;
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adverse events.
We used the five GRADE considerations (risk of bias, consistency of effect, imprecision, indirectness, and publication bias) to assess the certainty of a body of evidence as it relates to the studies that contribute data for the prespecified outcomes. We justified all decisions to downgrade the quality of studies using footnotes and made comments to aid the reader’s understanding of the review where necessary.
Subgroup analysis and investigation of heterogeneity
We performed subgroup analyses comparing the different routes of administration, and presented these results under each outcome. We planned to compare different prostacyclin analogues, but assessed there were too few studies (one to two per type) to draw meaningful comparisons. We planned to compare children versus adults, but separate data were not available. We planned to compare the effect of WHO functional class at baseline, however almost all trials included functional class III/IV.
Sensitivity analysis
We included a fixed‐effect versus random‐effect sensitivity analysis in a tabular format.
We included open‐label versus blinded trials sensitivity analysis under each per‐protocol specified outcomes (functional class, 6MWD, mortality, and cardiopulmonary haemodynamics).
Results
Description of studies
Results of the search
We identified 3031 citations in the initial search as described in the methods, and after two review authors (HB and HLY) independently screened abstracts, we selected 74 articles for full‐text review. After further assessment, we included 17 trials with 3765 participants in the final meta‐analysis, which included 30 separate citations (see Figure 1). We also noted three ongoing studies (see Characteristics of ongoing studies). The search was run on 16 September 2018.
Study flow diagram
Included studies
We included 17 trials with 3765 participants in the final meta‐analysis (see Characteristics of included studies; Table 1). All included studies were randomised, parallel‐group trials involving people with World Health Organization (WHO) Group 1 pulmonary arterial hypertension (PAH) (confirmed on right heart catheterisation). Five studies were open‐label (Badesch 2000; Barst 1996; Han 2017; Olschewski 2010; Rubin 1990), where participants were randomised to prostacyclin or conventional treatment.
| Study | N | Intervention | Comparator | Blinded | Duration |
| 203 | Inhaled iloprost | Placebo | Blinded | 12 weeks | |
| 130 | Oral beraprost | Placebo | Blinded | 12 weeks | |
| 111 | Intravenous epoprostenol | Usual treatment | Open‐label | 12 weeks | |
| 81 | Intravenous epoprostenol | Conventional treatment | Open‐label | 12 weeks | |
| 116 | Oral beraprost | Placebo | Blinded | 12 months | |
| 349 | Oral treprostinil | Placebo | Blinded | 16 weeks | |
| 310 | Oral treprostinil | Placebo | Blinded | 16 weeks | |
| 349 | Oral treprostinil | Placebo | Blinded | 12 weeks | |
| 1156 | Selexipag | Placebo | Blinded | Median 63 weeks | |
| 27 | Inhaled iloprost | Other treatment* | Open‐label | 12 weeks | |
| 67 | Inhaled iloprost | Placebo | Blinded | 12 weeks | |
| 63 | Inhaled iloprost | Placebo | Open‐label | 2 years | |
| 19 | Intravenous epoprostenol | Conventional treatment | Open‐label | 8 weeks | |
| 470 | Subcutaneous treprostinil | Placebo | Blinded | 12 weeks | |
| 43 | Selexipag | Placebo | Blinded | 17 weeks | |
| 235 | Inhaled treprostinil | Placebo | Blinded | 12 weeks | |
| 44 | Intravenous treprostinil | Placebo | Blinded | 12 weeks |
N = number of participants
*Inhaled iloprost + bosentan versus inhaled iloprost alone versus bosentan alone
Fifteen trials compared a prostacyclin analogue with placebo/conventional treatment, and two trials compared selexipag (an oral selective IP prostacyclin receptor agonist) to placebo (GRIPHON; Simonneau 2012).
In those trials which studied prostacyclin, three used intravenous epoprostenol (Badesch 2000; Barst 1996; Rubin 1990), and one used intravenous treprostinil (TRUST). All of these studies recruited mostly or exclusively NYHA functional class III and IV. Three studies were open‐label (Badesch 2000; Barst 1996; Rubin 1990), and one was placebo‐controlled (TRUST). Badesch 2000 recruited people with scleroderma‐associated PAH, and all other trials recruited people with Group 1 PAH.
One trial used subcutaneous treprostinil compared to placebo (Simonneau 2002). Most (80%) participants were functional class III, and 10% were functional class II and 10% functional class IV.
Five trials used oral prostacyclin compared to placebo, including treprostinil (FREEDOM‐C; FREEDOM‐C2; FREEDOM‐M), and beraprost (ALPHABET; Barst 2003). In the FREEDOM studies, the participants were mostly functional class III, but in Barst 2003 50% were functional class II and 50% functional class III.
Five trials used inhaled preparations, including iloprost (AIR; Han 2017; McLaughlin 2006; Olschewski 2010), and treprostinil (TRIUMPH). Participants were all functional class III/IV.
Prostacyclin in any form is usually up‐titrated in a dose‐dependent manner, initially limited by side effects, but as the patient develops tolerance the dose is able to be increased. In most studies, both the intervention and control group were given opportunity to up‐titrate, and final doses in each group were provided.
Some trials enrolled participants already on PAH‐specific disease modifying therapy (PDE‐5 inhibitor or ERA) (AIR; FREEDOM‐C; FREEDOM‐C2; McLaughlin 2006; Simonneau 2002; Simonneau 2012; TRIUMPH), but some trials specifically excluded these participants and studied prostacyclin as initial therapy (FREEDOM‐M; GRIPHON).
Trial duration was a mean of 19 weeks (median 12 weeks), and most included an initial titration phase, prior to commencement.
Excluded studies
We excluded 41 studies for the following reasons: wrong study design (n = 24); wrong participant population (n = 2); duration of study did not meet prespecified criteria (n = 6); study was withdrawn before participants were enrolled (n = 4); wrong intervention (compared different doses or delivery devices) (n = 5); see Characteristics of excluded studies.
Risk of bias in included studies
We assessed risk of bias in the included studies using the Cochrane 'Risk of bias' assessment tool (Higgins 2011), including the domains of allocation, blinding, incomplete outcome data, and selective reporting. Please see Figure 2 and Figure 3 for a summary of the 'Risk of bias' findings.
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
Allocation
Although all studies were reported as randomised, few studies reported methods of randomisation or allocation concealment. Badesch 2000, GRIPHON, McLaughlin 2006 and Rubin 1990 clearly reported both domains, and Barst 1996, Simonneau 2002 and Simonneau 2012 clearly reported methods of randomisation and we judged them to be at low risk of bias. All other studies were probably randomised appropriately, but methods were not clearly stated.
Blinding
Twelve studies were placebo‐controlled (judged to be at low risk of bias) and five studies were open‐label (Badesch 2000; Barst 1996; Han 2017; Olschewski 2010; Rubin 1990), with participants randomised to an intervention group or conventional treatment. We judged the latter to be at high risk of bias.
In those with a placebo arm, saline infusions or inhalational preparations were utilised. In TRUST, a central venous catheter was placed in participants from both arms of the study. Given this was an up‐titration study, most studies (except FREEDOM‐M and TRUST), reported the final cumulative prostacyclin and equivalent placebo doses, as a method to confirm blinding. We noted in FREEDOM‐C, FREEDOM‐C2 and Simonneau 2002, the placebo dose was twice as high as the prostacyclin cumulative dose.
Blinding of outcome assessment was only explicitly reported in three studies (GRIPHON; McLaughlin 2006; Simonneau 2012), which we judged to be at low risk of bias. Simonneau 2002 explicitly reported blinding for six‐minute walk distance (6MWD) only. Outcome assessment for other placebo‐controlled studies were probably blinded, but methods were not clearly stated, and so we assigned these studies an unclear risk in this domain.
Incomplete outcome data
AIR, ALPHABET, Badesch 2000, Rubin 1990, and Simonneau 2002 did not report dropouts or withdrawals, so we judged these to be at unclear risk of bias. The remaining studies were at low risk of bias.
Selective reporting
Rubin 1990 reported data as post‐treatment scores but reported confidence intervals (CIs) for the mean difference (MD). Badesch 2000 did not report CIs or error bars for some reported outcomes. Olschewski 2010 randomised participants to inhaled prostacyclin or conventional treatment for three months, at which point all participants were on prostacyclin, and then reported results at the end of two years. We assessed selective reporting bias as low risk for all other studies.
Other potential sources of bias
We assessed Han 2017 as a high risk of bias as analysis reported as standard deviation (SD) were re‐analysed using individual patient data as standard error. It is unclear if there are other methodological issues with this paper. No other issues were identified for the remaining studies.
Effects of interventions
See: Summary of findings for the main comparison Prostacyclin compared to control for pulmonary arterial hypertension; Summary of findings 2 Selexipag compared to placebo for pulmonary arterial hypertension
Prostacyclin versus control
Change in World Health Organization (WHO) functional class
Those who were using prostacyclin were more likely to improve their WHO functional class (239 per 1000) compared to those who did not (116 per 1000); (odds ratio (OR) 2.39, 95% confidence interval (CI) 1.72 to 3.32; P < 0.00001; 8 trials, 1066 participants; Analysis 1.1). Using the Chi2 test for subgroup differences, there was a significant difference between route of administration (P = 0.0003), with the greatest effect seen in the intravenous prostacyclin arm.
When excluding open‐label trials, there was still a significant difference, though the effect size was smaller: OR 2.39 (95% CI 1.72 to 3.32) for all trials compared to OR 1.77 (95% CI 1.24 to 2.52) when open‐label trials were excluded, and there was no significant difference between fixed‐ and random‐effects (see Table 2; Table 3). A post hoc sensitivity analysis was carried out whereby the TRUST trial was excluded due to its premature termination following safety concerns. The removal of this study had a minimal impact on the pooled effect estimates.
| Outcome | Number of studies | Effect measure | Fixed‐effect size (95% CI) | Random‐effect size (95% CI) |
| Functional class ‐ improvement | 8 | OR | 2.39 (1.72 to 3.32) | 2.66 (1.37 to 5.19) |
| Functional class ‐ worsening | 5 | OR | 0.88 (0.57 to 1.37) | 0.88 (0.56 to 1.40) |
| Six‐minute walk distance | 13 | MD | 19.50 (14.82 to 24.19)* | 29.55 (18.63 to 40.48)* |
| Mortality | 15 | OR | 0.60 (0.38 to 0.94) | 0.68 (0.42 to 1.10) |
| mPAP | 8 | MD | ‐3.60 (‐4.73 to ‐2.48)* | ‐4.10 (‐6.22 to ‐1.99)* |
| PVR | 7 | MD | ‐2.81 (‐3.80 to ‐1.82)* | ‐2.40 (‐4.44 to ‐0.35)* |
| Cardiac index | 6 | MD | 0.31 (0.23 to 0.38)* | 0.34 (0.17 to 0.52)* |
| Cardiac output | 2 | MD | 0.57 (0.32 to 0.81) | 0.41 (‐0.34 to 1.15) |
| RAP | 6 | MD | ‐1.90 (‐2.58 to ‐1.22) | ‐1.90 (‐2.58 to ‐1.22) |
| Dyspnoea | 8 | SMD | ‐0.21 (‐0.32 to ‐0.11)* | ‐0.29 (‐0.50 to ‐0.08)* |
| Quality of life | 3 | SMD | 0.28 (0.04 to 0.52)* | 0.48 (‐0.11 to 1.08)* |
*High heterogeneity
Abbreviations: MD ‐ mean difference; SMD ‐ standardised mean difference; CI ‐ confidence interval; mPAP ‐ mean pulmonary arterial pressure; PVR ‐ pulmonary vascular resistance; RAP ‐ right atrial pressure
| Outcome | All studies effect size (95% CI) | Blinded studies only effect size (95% CI) |
| Functional class ‐ improvement | 2.39 (1.72 to 3.32)+ | 1.77 (1.24 to 2.52)+ |
| Functional class ‐ worsening | 0.88 (0.57 to 1.37) | 0.85 (0.54 to 1.35) |
| Six‐minute walk test distance | 19.50 (14.82 to 24.19)+ | 17.55 (12.82 to 22.29)+ |
| Mortality | 0.60 (0.38 to 0.94)+ | 0.76 (0.45 to 1.29)* |
| PAP | ‐3.60 (‐4.73 to ‐2.48)+ | ‐2.58 (‐3.86 to ‐1.30)+ |
| PVR | ‐2.81 (‐3.80 to ‐1.82)+ | ‐1.32 (‐2.95 to 0.32)* |
| Cardiac index | 0.31 (0.23 to 0.38)+ | 0.18 (0.08 to 0.27)+ |
| Cardiac output | 0.57 (0.32 to 0.81)+ | 0.57 (0.32 to 0.81)+ |
| RAP | ‐1.90 (‐2.58 to ‐1.22)+ | ‐1.80 (‐2.55 to ‐1.06)+ |
| Dyspnoea | ‐0.21 (‐0.32 to ‐0.11)+ | ‐0.18 (‐0.29 to ‐0.08)+ |
| Quality of life | 0.28 (0.04 to 0.52)+ | 0.07 (‐0.22 to 0.36)* |
+Statistically significant; *no longer statistically significant
Abbreviations: CI ‐ confidence interval; PAP ‐ pulmonary arterial pressure; PVR ‐ pulmonary vascular resistance; RAP ‐ right atrial pressure
There was no difference in the proportion of those worsening across the two arms (OR 0.88, 95% CI 0.57 to 1.37; P = 0.7; 5 trials, 805 participants; Analysis 1.2), and no difference across subgroups.
Six‐minute walk distance (6MWD)
There was a small, statistically significant improvement in 6MWD (mean difference (MD) 19.50 metres, 95% CI 14.82 to 24.19; P < 0.00001; 13 trials, 2283 participants; Analysis 1.3; Figure 4), though it did not meet the minimum clinically important threshold of 41 metres (Khair 2016). Although all modes of administration produced a significant improvement, there was a statistically significant difference across subgroups (P < 0.0001), with the greatest effect seen in the intravenous trials: MD 91.76 metres compared to 16.00 metres in the subcutaneous trial, 14.76 metres in the oral trials, and 26.97 metres in the inhaled trials.
Forest plot of comparison: 1 Prostacyclin versus control, outcome: 1.3 6MWD.
When excluding open‐label trials, there was still a significant difference, though the effect size was slightly smaller (MD 19.50 metres, 95% CI 14.82 to 24.19) for all trials compared to MD 17.55 metres (95% CI 12.82 to 22.29) when open‐label trials were excluded, and there was no significant difference between fixed‐ and random‐effects (see Table 2; Table 3). Exclusion of the TRUST trial had a minimal impact on the pooled effect estimates.
Mortality
There was a significant difference in mortality overall (OR 0.60, 95% CI 0.38 to 0.94; P = 0.02; 15 trials, 2554 participants; Analysis 1.4; Figure 5), whereby the risk of death over 12 weeks was two per 100 participants in the prostacyclin group compared to four per 100 in the control group (95% CI 1.50 to 4.12). This effect was largely due to the intravenous trials, and when the intravenous trials were excluded, this effect was lost (OR 0.82, 95% CI 0.48 to 1.40; P = 0.46). However, most studies were only approximately 12 weeks duration and most were not powered to assess mortality.
Forest plot of comparison: 1 Prostacyclin versus control, outcome: 1.4 Mortality.
When intravenous trials are analysed separately, the risk of death was 17 per 100 in the control group, compared to six (95% CI 2.38 to 12.31) per 100 for the prostacyclin group. There is, however, higher baseline mortality in these trials compared to the other included studies.
There was no significant difference between fixed‐ and random‐effects (see Table 2). When open‐label studies were excluded (which were almost all intravenous studies), the effect on mortality was lost (OR 0.76, 95% CI 0.45 to 1.29; P = 0.32) (see Table 3). However, it is less likely that the outcome of mortality would be affected by the degree of blinding of the studies. This was a post hoc sensitivity analysis whereby the TRUST trial was excluded due to its premature termination following safety concerns. The removal of this study had a minimal impact on the pooled effect estimates of mortality.
Cardiopulmonary haemodynamics
Only eight trials assessed change in haemodynamic parameters over the trial duration (AIR; ALPHABET; Badesch 2000; Barst 1996; Barst 2003; Han 2017; McLaughlin 2006; Simonneau 2002).
There was a significant improvement in mean pulmonary arterial pressure (mPAP) (MD ‐3.60 mmHg, 95% CI ‐4.73 to ‐2.48; P < 0.00001; Analysis 1.5); pulmonary vascular resistance (PVR) (MD ‐2.81 WU, 95% CI ‐3.80 to ‐1.82; P < 0.00001; Analysis 1.6), (Simonneau 2002 measured PVR as a geometric mean, so was not included in the meta‐analysis, but demonstrated a similar effect, whereby the change from baseline for treprostinil was ‐3.5 WU, standard error (SE) 0.6, and change from baseline for control was 1.2 WU, SE 0.06, P = 0.0001); cardiac index (MD 0.31 L/min/m2, 95% CI 0.23 to 0.38; P < 0.00001; Analysis 1.7); cardiac output (MD 0.57 L/min, 95% CI 0.32 to 0.81; P < 0.00001; Analysis 1.8); and right atrial pressure (RAP) (MD ‐1.90 mmHg, 95% CI ‐2.58 to ‐1.22; P < 0.00001; Analysis 1.9). There was a significant difference across route of administration subgroups for mPAP (P = 0.006), cardiac index (P < 0.0001), and cardiac output (P < 0.0001), however some of these differences may be accounted for by other differences between studies rather than route of administration.
Comparing fixed‐effect to random‐effects, there was a difference in PVR and cardiac index (see Table 2). There was also substantial heterogeneity in these outcomes, suggesting that small‐study effects may be influencing the overall effect size. When open‐label studies were excluded, the effects were still significant (see Table 3).
Although no minimum clinically relevant data currently exists for pulmonary haemodynamics, the clinical impact may be contextualised by applying these MDs to the risk stratification data, which correlates with mortality. A RAP < 8 mm Hg is classified as low risk, and > 14 mmHg as high risk. The overall reduction in RAP in all prostacyclin preparations was ‐1.90 mmHg (95% CI ‐2.58 to ‐1.22), and the intravenous preparations demonstrated a reduction in RAP of ‐2.41 (95% CI ‐4.10 to ‐0.72) compared to control. A cardiac index > 2.5 L/min/m2 is classified as low risk and < 2.0 L/min/m2 as high risk. Overall all prostacyclin preparations improved cardiac index by 0.31 L/min/m2 (95% CI 0.23 to 0.38) and intravenous preparations by 0.57 L/min/m2 (95% CI 0.40 to 0.74).
Exercise capacity tests
Only Barst 2003 reported additional exercise capacity tests. Using cardiopulmonary exercise testing and measuring peak VO2 with cycle ergometry, there was a trend towards improvement in favour of beraprost (Hodges Lehmann estimate MD between groups at 12 months of 66 mL/min), though this did not reach statistical significance.
Symptom scales including dyspnoea and fatigue
Five studies (ALPHABET; FREEDOM‐C2; FREEDOM‐M; McLaughlin 2006; TRUST) assessed dyspnoea using the Borg dyspnoea scale, AIR used the Mahler Transition Dyspnoea Index, and Barst 1996 and Simonneau 2002 used the Dyspnoea Fatigue Rating. For all scales lower scores indicate more severe breathlessness (Badesch 2009). These results were pooled in a standardised mean difference (SMD) to account for the different scales used, and the direction of effect was imputed to be consistent across scales. There was a significant improvement in dyspnoea (SMD ‐0.21, 95% CI ‐0.32 to ‐0.11; P < 0.00001; Analysis 1.10). Significant heterogeneity was noted (I2 = 72%; P = 0.0007). Using the calculated SD from the largest study (Simonneau 2002), an illustrative Borg score of ‐0.64 was determined. This is less than the minimum clinically important difference of 0.9 (Khair 2016).
When open‐labelled studies were excluded, there was still a significant difference (SMD ‐0.18, 95% CI ‐0.29 to ‐0.08; P = 0.0007; 7 trials, 1449 participants).
Badesch 2000 provided dyspnoea data using the Borg dyspnoea scale and Dyspnoea Fatigue Rating, but did not provide CIs, so we were unable to combine these data into the meta‐analysis. The post‐treatment score for Borg at 12 weeks was 1 in the conventional group and ‐2 in the epoprostenol group, and the post‐treatment score for Dyspnoea Fatigue Rating at 12 weeks was ‐1 in the conventional group and 1 in the epoprostenol group (lower scores indicate more breathlessness in both scales).
Quality of life
Three studies provided quality of life data suitable for meta‐analyses: Barst 1996 using the Chronic Heart Failure Questionnaire (Mastery) (Guyatt 1989) (lower scores indicate worse quality of life), FREEDOM‐C2 used the Cambridge Pulmonary Hypertension Outcome Review (McKenna 2006) (lower scores indicate better quality of life), and Han 2017 used the Minnesota Living with Heart Failure Questionnaire (Cenedese 2006) (lower scores indicate better quality of life). These results were pooled in a SMD to account for the different scales used, and the direction of effect was imputed to be consistent across scales. When data were pooled, there was a significant difference in quality of life scores (SMD 0.28, 95% CI 0.04 to 0.52; P = 0.02; Analysis 1.11). There was significant heterogeneity across trials (I2 = 72%; P = 0.03). When open‐labelled studies were excluded, results were no longer significant (MD 0.07, 95% CI ‐0.22 to 0.36; P = 0.65), however this only included one trial with 187 participants.
A further three studies provided descriptive data. Barst 2003 (using the Minnesota Living with Heart Failure Questionnaire) reported beraprost did not result in significant improvement relative to control in global, physical, or emotional indices of quality of life. TRIUMPH (using the Minnesota Living with Heart Failure Questionnaire) reported a between‐treatment median difference of 4 in the global score (P = 0.027) and 2 in the physical score (P = 0.037), for participants receiving inhaled treprostinil. Simonneau 2002 (also using the Minnesota Living with Heart Failure Questionnaire reported that participants treated with treprostinil experienced a significant improvement in their physical dimension score at Week 12 (P = 0.0064) with a trend toward improvement in the global dimension score (P = 0.17) as compared with the control group.
Clinical worsening
There was a significant difference in clinical worsening favouring prostacyclins (OR 0.67, 95% CI 0.48 to 0.92; P = 0.001; 12 trials, 2238 participants; Analysis 1.12). In the control group, seven out of 100 participants experienced clinical worsening, compared to five participants (95% CI 4.50 to 8.27) in the prostacyclin group. The definition of clinical worsening varied across studies (see Characteristics of included studies), but this did not affect heterogeneity of results.
Adverse events
There was an increased risk of adverse events in the prostacyclin group including vasodilation (OR 5.03, 95% CI 3.84 to 6.58; P < 0.00001; 11 trials, 2277 participants; Analysis 1.15), headache (OR 3.16, 95% CI 2.62 to 3.80; P < 0.00001; 12 trials, 2351 participants; Analysis 1.16), jaw pain (OR 5.25, 95% CI 3.96 to 6.98; P < 0.00001; 10 trials, 2149 participants; Analysis 1.17), diarrhoea (OR 2.81, 95% CI 2.29 to 3.46; P < 0.00001; 10 trials, 2317 participants; Analysis 1.18), nausea or vomiting (OR 2.39, 95% CI 1.98 to 2.88; P < 0.00001; 11 trials, 2399 participants; Analysis 1.20), pain in the extremities (OR 3.36, 95% CI 2.32 to 4.85; P < 0.00001; 6 trials, 1236 participants; Analysis 1.22), myalgias (OR 2.75, 95% CI 1.65 to 4.58; P = 0.00001; 3 trials, 1009 participants; Analysis 1.23), upper respiratory tract events (OR 1.61, 95% CI 1.22 to 2.13; P = 0.0009; 7 trials, 1038 participants; Analysis 1.24), and infusion site reactions (OR 14.41, 95% CI 9.16 to 22.66; P < 0.00001; 2 trials, 580 participants; Analysis 1.26).
There was no significant difference in the incidence of syncope (OR 0.77, 95% CI 0.42 to 1.42; P = 0.41; 4 trials, 560 participants; Analysis 1.13), dizziness (OR 1.09, 95% CI 0.84 to 1.42; P = 0.52; 7 trials, 1939 participants; Analysis 1.14), leg pain (OR 2.96, 95% CI 1.02 to 8.62; P = 0.05; 2 trials, 246 participants; Analysis 1.19), abdominal pain (OR 1.35, 95% CI 0.75 to 2.42; P = 0.32; 2 trials, 465 participants; Analysis 1.21), or peripheral oedema (OR 1.46, 95% CI 0.98 to 2.17; P = 0.06; 6 trials, 1228 participants; Analysis 1.25); see Table 4 for all adverse events and their corresponding risks.
| Outcome | Anticipated absolute effects* (95% CI) | Relative effect | № of participants | |
| Risk with placebo | Risk with selexipag | |||
| Syncope | 90 per 1000 | 71 per 1000 (40 to 123) | OR 0.77 | 560 |
| Dizziness | 126 per 1000 | 136 per 1000 (108 to 170) | OR 1.09 | 1939 |
| Vasodilation | 80 per 1000 | 305 per 1000 (251 to 365) | OR 5.03 | 2277 |
| Headache | 227 per 1000 | 548 per 1000 (502 to 593) | OR 3.16 | 2351 |
| Jaw pain | 67 per 1000 | 273 per 1000 (220 to 333) | OR 5.25 | 2149 |
| Diarrhoea | 167 per 1000 | 361 per 1000 (315 to 410) | OR 2.81 | 2317 |
| Leg pain | 41 per 1000 | 113 per 1000 (42 to 271) | OR 2.96 | 246 |
| Nausea and vomiting | 244 per 1000 | 435 per 1000 (390 to 481) | OR 2.39 | 2399 |
| Abdominal pain | 116 per 1000 | 151 per 1000 (90 to 242) | OR 1.35 | 465 |
| Pain in extremities | 77 per 1000 | 218 per 1000 (162 to 287) | OR 3.36 | 1236 |
| Myalgia | 47 per 1000 | 120 per 1000 (76 to 185) | OR 2.75 | 1009 |
| Upper respiratory tract events | 255 per 1000 | 355 per 1000 (294 to 422) | OR 1.61 | 1038 |
| Peripheral oedema | 75 per 1000 | 106 per 1000 (74 to 150) | OR 1.46 | 1228 |
| Infusion site reactions | 213 per 1000 | 796 per 1000 (713 to 860) | OR 14.41 | 580 |
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: confidence interval; OR: odds ratio
In the intravenous studies, three of four trials adequately reported line‐related side effects. There was a 12% to 25% risk of serious non‐fatal events attributed to the catheter, including sepsis, haemorrhage, pneumothorax and pulmonary embolism (Barst 1996: 5/41; Badesch 2000: 8/56; TRUST: 11/44; Rubin 1990: not reported), and two participants in TRUST died due to catheter‐related events on control in the double‐blind phase. Pump failure resulting in a temporary discontinuation in drug delivery occurred on five occasions (total 10 participants) in Rubin 1990 and on 26 occasions (total 41 participants) in Barst 1996. (Badesch 2000 and TRUST not reported).
Cost analysis
No trials reported cost analysis.
Selexipag versus placebo
Two studies (1199 participants) compared selexipag (a selective IP prostacyclin receptor antagonist) with placebo (GRIPHON; Simonneau 2012).
Change in WHO functional class
There was no significant difference in the number of participants who improved (OR 1.61, 95% CI 0.17 to 15.63; P = 0.68; 1 trial, 43 participants; Analysis 2.1), but the CI is wide. One per 100 participants in the placebo group had an improvement compared to 15 per 100 (95% CI 1.90 to 63.50) participants in the selexipag group.
There was a benefit of selexipag compared to placebo for worsening in WHO functional class (OR 0.79, 95% CI 0.60 to 1.04; P = 0.09; 2 trials, 1199 participants; Analysis 2.2), but the CI includes no difference. Twenty‐one participants per 100 in the prostacyclin group experienced worsening in WHO functional status compared to 25 per 100 (95% CI 17.48 to 26.13) in the placebo group.
Six‐minute walk distance (6MWD)
There was a small significant improvement in 6MWD (MD 12.62 metres, 95% CI 1.90 to 23.34; P = 0.02; 2 trials, 1199 participants; Analysis 2.3), though it did not meet the minimum clinically important threshold of 41 metres (Khair 2016).
Mortality
There was no statistically significant difference in mortality (risk difference (RD) 0.02 (95% CI ‐0.00 to 0.04); P = 0.13; 2 trials, 1159 participants; Analysis 2.4). Risk of death was increased as five per 100 participants in the selexipag group died compared to three per 100 participants in the placebo group, though the CI crossed zero, so the true effect is uncertain.
Cardiopulmonary haemodynamics
Only one trial assessed change in haemodynamic parameters (Simonneau 2012; 43 participants), and found an improvement in PVR (MD ‐33.00 dyn/s/cm‐5, 95% CI ‐47.00 to ‐19.00; P < 0.00001; Analysis 2.6), cardiac index (MD 0.50 L/min/m2, 95% CI 0.13 to 0.87; P = 0.008; Analysis 2.7), and RAP (MD 3.20 mmHg, 95% CI 0.80 to 5.60; P = 0.009; Analysis 2.8), but no significant difference in mPAP (MD ‐7.40 mmHg, 95% CI ‐15.90 to 1.10; Analysis 2.5).
Exercise capacity tests
Neither study assessed exercise capacity tests.
Symptom scales including dyspnoea and fatigue
There was no significant difference in dyspnoea, as assessed with the Borg dyspnoea scale (MD ‐0.10, 95% CI ‐1.40 to 1.20; P = 0.88; 1 trial, 43 participants; Analysis 2.9) (lower scores indicate better control of dyspnoea; minimum clinically important difference in PAH is 0.9 units).
Quality of life
Neither study assessed quality of life.
Clinical worsening
Both studies (1199 participants) assessed clinical worsening. There was a significant difference in clinical worsening (OR 0.47, 95% CI 0.37 to 0.60; P < 0.00001; Analysis 2.10), favouring selexipag. In the placebo group, 38 out of 100 people experienced clinical worsening compared to 22 (95% CI 18 to 27) in the selexipag group.
Adverse events
There was a significant increase in incidence of headache (OR 3.91, 95% CI 3.07 to 4.98; P < 0.00001; Analysis 2.12), vasodilation (OR 2.67, 95% CI 1.72 to 4.17; P < 0.0001; Analysis 2.13), jaw pain (OR 5.33, 95% CI 3.64 to 7.81; P < 0.00001; Analysis 2.14), diarrhoea (OR 3.11, 95% CI 2.39 to 4.05; P < 0.00001; Analysis 2.15), nausea and vomiting (OR 2.92, 95% CI 2.29 to 3.73; P < 0.00001; Analysis 2.16), pain in extremities (OR 2.44, 95% CI 1.69 to 3.52; P < 0.00001; Analysis 2.17), or myalgias (OR 3.05, 95% CI 2.02 to 4.58; P < 0.00001; Analysis 2.18). There was no difference in dizziness (OR 1.04, 95% CI 0.76 to 1.44; P = 0.79; Analysis 2.11), or upper respiratory tract infections (OR 0.99, 95% CI 0.78 to 1.26; P = 0.96; Analysis 2.19), see Table 5 for all adverse events and their corresponding risks.
| Outcome | Anticipated absolute effects* (95% CI) | Relative effect | № of participants | |
| Risk with placebo | Risk with selexipag | |||
| Dizziness | 145 per 1000 | 150 per 1000 | OR 1.04 | 1195 |
| Headache | 325 per 1000 | 653 per 1000 | OR 3.91 | 1195 |
| Vasodilation | 49 per 1000 | 122 per 1000 | OR 2.67 | 1195 |
| Jaw pain | 61 per 1000 | 258 per 1000 | OR 5.33 | 1195 |
| Diarrhoea | 189 per 1000 | 420 per 1000 | OR 3.11 | 1195 |
| Nausea or vomiting | 266 per 1000 | 514 per 1000 | OR 2.92 | 1195 |
| Pain in extremity | 78 per 1000 | 172 per 1000 | OR 2.44 | 1195 |
| Myalgias | 58 per 1000 | 158 per 1000 | OR 3.05 | 1195 |
| Upper respiratory tract infection | 361 per 1000 | 359 per 1000 | OR 0.99 | 1195 |
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: confidence interval; OR: odds ratio
Cost analysis
No studies assessed cost analysis.
Discussion
Summary of main results
This review demonstrates clinical and statistical benefit for the use of intravenous prostacyclin compared to control in terms of improved functional class, six‐minute walk distance (6MWD), mortality, symptoms scores, and cardiopulmonary haemodynamics, but at a cost of increased risk of adverse events.
This review also demonstrates a statistical and small benefit for inhaled prostacyclin compared to placebo in terms of improvement in functional class, symptoms scores, and cardiopulmonary haemodynamics, a statistical benefit for 6MWD, but the effect is uncertain for mortality. The use of oral prostacyclin did not demonstrate a statistical or clinical benefit for improvement in functional class, symptoms scores, cardiopulmonary haemodynamics, or mortality.
In these trials, there was only demonstrably significant mortality benefit using intravenous preparations; but not in subcutaneous, oral or inhaled preparations. This may be due to a true effect, or the inclusion of unblinded trials using intravenous preparations that may have over estimated the result, the low participant numbers, and relatively short trial duration.
Selexipag is a selective IP prostacyclin receptor agonist that works similarly to prostacyclin, offering a potentially more stable drug, with oral administration and titration, with potentially similar efficacy. We assessed two trials comparing selexipag to placebo; no trials compared selexipag with prostacyclin. When compared to placebo in large, long‐term trials, selexipag had less clinical worsening, but increased adverse events; the effect on other clinical outcomes is less certain. The rate of death was increased in the selexipag group, though the confidence interval crossed zero, so the true effect is uncertain.
Overall completeness and applicability of evidence
In the included trials comparing prostacyclin with control, there was demonstrable mortality benefit using intravenous preparations; but not in subcutaneous, oral or inhaled preparations. The certainty of evidence for mortality benefit was reduced as three out of four of these included trials were open‐label. It is unclear in other studies if using non‐intravenous preparations did not confer a mortality benefit due to their short (median 12 weeks) duration, or that they were under‐powered to detect a mortality difference, or if this is a true signal of no benefit.
When prostacyclin was first developed for PAH, it was delivered intravenously due to the short half‐life and potent local effects of the drug. Given the risks of rebound effects if the continuous infusion was suddenly stopped, the drug was administered by a central venous catheter ‐ a direct and reliable access. Invasive central catheter placement is associated with increased risk of adverse events, including infection, bleeding, and damage to surrounding structures. Of concern, these included studies demonstrated a 12% to 25% risk of non‐fatal serious line‐related events and two line‐related deaths. Although efficacious, the decision to commence intravenous prostacyclin must be weighed against the increased risk of serious side effects. The heterogeneity of line‐related events between these included trials likely reflects real‐world heterogeneity between clinical centres, and catheter placement should only be considered in experienced centres.
The decision to commence continuous intravenous therapy should also be weighed by the patient's ability to reliably control the pump device; several participants in these studies were not randomised because of their inability to work the device. Particular consideration should be given to people with connective tissue disease‐related PAH, who may have reduced dexterity.
In recent years, research has been undertaken to develop a safer, more convenient preparation of prostacyclin ‐ including via the inhaled, subcutaneous and oral routes. One subcutaneous trial (Simonneau 2002), five oral trials (ALPHABET; Barst 2003; FREEDOM‐C; FREEDOM‐C2; FREEDOM‐M), and four inhaled trials (AIR; Han 2017; McLaughlin 2006; TRIUMPH), were included in this review. Subgroup analyses suggest that these preparations did not result in the same mortality benefit as intravenous preparations and the overall effect on 6MWD and improvement in World Health Organization (WHO) functional class was less, though it still provided some benefit. However, these trials were not powered for mortality and median duration was only 12 weeks. No randomised controlled trials (RCTs) have compared different preparations head to head. One small study compared inhaled to continuous infusion prostacyclin in 16 participants for 12 weeks (and 4 participants up to 1 year) (Pepke‐Zaba 2000). They reported no difference in effect between groups, though data were limited. Another retrospective study reported the safe transition from intravenous or subcutaneous to inhaled treprostinil, with no immediate significant change in function (Enderby 2014).
Certainty of the evidence
We included several open‐label studies, which reduced the certainty of the evidence. When these studies were excluded, the differences were still significant, and the direction of effect was still the same, but the magnitude of the effect was smaller. Using subgroup analyses to draw these conclusions, however, relies on a smaller sample size which reduced confidence in these conclusions.
We found the evidence for 6MWD, some haemodynamics, and quality of life scores to be of moderate or low certainty due to imprecision of results from significant heterogeneity. We found that the Chi² test for subgroup difference was also significant, indicating that this heterogeneity is in part explained by the difference between the different drugs used.
Although there was statistical significance in the difference in 6MWD with the use of prostacyclins, the overall effect did not meet the minimum clinically important threshold of 41 metres. In addition, although there was a statistically significant difference in the level of dyspnoea reduction, the illustrative Borg score did not meet the clinically important threshold of 0.9 units.
Potential biases in the review process
We conducted this review in accordance with established Cochrane standards. Two review authors independently screened search results and resolved discrepancies by discussion and consensus. We did not restrict the literature search by language. Publication bias is possible, whereby failure to identify unpublished negative trials could have led to an overestimation of effect.
Agreements and disagreements with other studies or reviews
The data from this review are limited by the short follow‐up duration. At least two further real‐world long‐term registry studies have assessed the longer‐term use of intravenous epoprostenol in PAH patients (McLaughlin 2002; Sitbon 2002). McLaughlin 2002 followed patients for at least three years, and found observed survival with epoprostenol therapy at one, two, and three years was 87.8%, 76.3%, and 62.8% respectively. Sitbon 2002 followed patients for five years and observed an overall survival rate at one, two, three, and five years of 85%, 70%, 63%, and 55%, respectively. These data are compared to historical cohort data with no therapy, where the expected survival was 58.9%, 46.3%, and 35.4% at one, two, and three years, respectively (D’Alonzo 1991). Our data for intravenous‐only studies (duration of 12 weeks only) found a survival rate of 94% for intravenous epoprostenol at 12 weeks compared to an 83% survival rate without intravenous epoprostenol. While there are limitations to observational registry data, it supports the findings in this review that intravenous prostacyclin analogues do suggest a mortality benefit.
The European Society of Cardiology (ESC) guidelines (Galiè 2016), and further registry studies (McLaughlin 2002; Sitbon 2002), have derived and validated clinical and investigational parameters to stratify risk of mortality in PAH patients. They found that WHO functional class, 6MWD, and pro‐brain natriuretic peptide (BNP), as well as cardiopulmonary parameters including right atrial pressure (RAP) and cardiac index, were the most reliable predictors of survival. Whilst this review had short duration of follow‐up, which limits the conclusions regarding overall mortality, it did find that use of prostacyclin significantly improved WHO functional class, 6MWD, RAP, and cardiac index. These effects were largest using intravenous prostacyclin, but changes were also present across other preparations.
Study flow diagram
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
Forest plot of comparison: 1 Prostacyclin versus control, outcome: 1.3 6MWD.
Forest plot of comparison: 1 Prostacyclin versus control, outcome: 1.4 Mortality.
Comparison 1 Prostacyclin versus control, Outcome 1 Improvement in WHO functional class.
Comparison 1 Prostacyclin versus control, Outcome 2 Worsening of WHO functional class.
Comparison 1 Prostacyclin versus control, Outcome 3 6MWD.
Comparison 1 Prostacyclin versus control, Outcome 4 Mortality.
Comparison 1 Prostacyclin versus control, Outcome 5 mPAP.
Comparison 1 Prostacyclin versus control, Outcome 6 PVR.
Comparison 1 Prostacyclin versus control, Outcome 7 Cardiac index.
Comparison 1 Prostacyclin versus control, Outcome 8 Cardiac output.
Comparison 1 Prostacyclin versus control, Outcome 9 RAP.
Comparison 1 Prostacyclin versus control, Outcome 10 Dyspnoea.
Comparison 1 Prostacyclin versus control, Outcome 11 Quality of life.
Comparison 1 Prostacyclin versus control, Outcome 12 Clincal worsening.
Comparison 1 Prostacyclin versus control, Outcome 13 Adverse events ‐ syncope.
Comparison 1 Prostacyclin versus control, Outcome 14 Adverse events ‐ dizziness.
Comparison 1 Prostacyclin versus control, Outcome 15 Adverse events ‐ vasodilation.
Comparison 1 Prostacyclin versus control, Outcome 16 Adverse events ‐ headache.
Comparison 1 Prostacyclin versus control, Outcome 17 Adverse events ‐ jaw pain.
Comparison 1 Prostacyclin versus control, Outcome 18 Adverse events ‐ diarrhoea.
Comparison 1 Prostacyclin versus control, Outcome 19 Adverse events ‐ leg pain.
Comparison 1 Prostacyclin versus control, Outcome 20 Adverse events ‐ nausea and vomiting.
Comparison 1 Prostacyclin versus control, Outcome 21 Adverse events ‐ abdominal pain.
Comparison 1 Prostacyclin versus control, Outcome 22 Adverse events ‐ pain in extremity.
Comparison 1 Prostacyclin versus control, Outcome 23 Adverse events ‐ myalgia.
Comparison 1 Prostacyclin versus control, Outcome 24 Adverse events ‐ upper respiratory tract events.
Comparison 1 Prostacyclin versus control, Outcome 25 Adverse events ‐ peripheral oedema.
Comparison 1 Prostacyclin versus control, Outcome 26 Adverse events ‐ infusion site reaction.
Comparison 2 Selexipag versus placebo, Outcome 1 Improvement in WHO FC.
Comparison 2 Selexipag versus placebo, Outcome 2 Worsening in WHO FC.
Comparison 2 Selexipag versus placebo, Outcome 3 6MWD.
Comparison 2 Selexipag versus placebo, Outcome 4 Mortality.
Comparison 2 Selexipag versus placebo, Outcome 5 mPAP.
Comparison 2 Selexipag versus placebo, Outcome 6 PVR.
Comparison 2 Selexipag versus placebo, Outcome 7 Cardiac index.
Comparison 2 Selexipag versus placebo, Outcome 8 RAP.
Comparison 2 Selexipag versus placebo, Outcome 9 Dyspnoea.
Comparison 2 Selexipag versus placebo, Outcome 10 Clinical worsening.
Comparison 2 Selexipag versus placebo, Outcome 11 Adverse events‐ dizziness.
Comparison 2 Selexipag versus placebo, Outcome 12 Adverse events ‐ headache.
Comparison 2 Selexipag versus placebo, Outcome 13 Adverse events ‐ vasodilation.
Comparison 2 Selexipag versus placebo, Outcome 14 Adverse events ‐ jaw pain.
Comparison 2 Selexipag versus placebo, Outcome 15 Adverse events ‐ diarrhoea.
Comparison 2 Selexipag versus placebo, Outcome 16 Adverse events ‐ nausea or vomiting.
Comparison 2 Selexipag versus placebo, Outcome 17 Adverse events ‐ pain in extremity.
Comparison 2 Selexipag versus placebo, Outcome 18 Adverse events ‐ myalgias.
Comparison 2 Selexipag versus placebo, Outcome 19 Adverse events ‐ upper respiratory tract infection.
| Prostacyclin compared to control for pulmonary arterial hypertension | ||||||
| Patient or population: pulmonary arterial hypertension | ||||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect | № of participants | Certainty of evidence | Comments | |
| Risk with control | Risk with prostacyclin | |||||
| Improvement in WHO functional class Mean follow‐up 16 weeks | Study population | OR 2.39 | 1066 | ⊕⊕⊕⊝ | ||
| 116 per 1000 | 239 per 1000 | |||||
| 6MWD Mean follow‐up 15 weeks | The mean 6MWD was 257 m* | MD 19.50 m higher | ‐ | 2283 | ⊕⊕⊝⊝ Low1,2 | 6MWD in PAH MCID is 41 m |
| Mortality Mean follow‐up 15 weeks | Study population | OR 0.60 | 2554 | ⊕⊕⊕⊝ | ||
| 39 per 1000 | 24 per 1000 | |||||
| mPAP (the higher the mPAP, the worse the pulmonary hypertension) Mean follow‐up 11 weeks | The mPAP ranged from 56 to 66 mmHg# | MD 3.60 mmHg lower | ‐ | 1132 | ⊕⊕⊝⊝ Low1,2 | |
| PVR (the higher the PVR, the Mean follow‐up 11 weeks | The mean PVR ranged from 26 to 29 units/m2# | MD 2.81 WU lower | ‐ | 658 | ⊕⊕⊕⊝ | |
| Cardiac index (the lower the cardiac index, Mean follow‐up 11 weeks | The mean cardiac Index ranged from 2 to 2.4 L/min/m2# | MD 0.31 L/min/m 2 higher | ‐ | 868 | ⊕⊕⊝⊝ Low1,2 | |
| RAP (the lower the RAP, Mean follow‐up 11 weeks | The mean RAP ranged from 8 to 13 mmHg# | MD 1.90 mmHg lower | ‐ | 1060 | ⊕⊕⊕⊝ | The higher the RAP, the |
| Dyspnoea (lower scores indicates more severe breathlessness) Mean follow‐up 17 weeks | ‐ | SMD 0.21 lower | ‐ | 1521 | ⊕⊕⊝⊝ Low1,2 | Using an illustrative SD, this converts to a difference of 0.64 units on the Borg scale. MCID in PAH is 0.9 units |
| Quality of life Mean follow‐up 12 weeks | ‐ | SMD 0.28 better | ‐ | 271 | ⊕⊕⊕⊝ | |
| Headache+ Mean follow‐up 12 weeks | 277 per 1000 | 529 per 1000 (95% CI 501 to 593) | 3.16 (2.62 to 3.80) | 2351 (12 RCTs) | ⊕⊕⊕⊝ | |
| *The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence | ||||||
| 1Downgraded due to the risk of bias with open‐label studies. | ||||||
| Selexipag compared to placebo for pulmonary arterial hypertension | ||||||
| Patient or population: pulmonary arterial hypertension | ||||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect | № of participants | Certainty of evidence | Comments | |
| Risk with placebo | Risk with selexipag | |||||
| Improvement in WHO functional class Mean follow‐up 17 weeks | Study population | OR 1.61 | 43 | ⊕⊕⊕⊝ | ||
| 100 per 1000 | 152 per 1000 | |||||
| 6MWD Mean follow‐up 40 weeks | The mean 6MWD ranged from 348 to 396 m | MD 12.62 m higher | ‐ | 1199 | ⊕⊕⊕⊕ | 6MWD in PAH MCID is 41 m |
| Mortality Mean follow‐up 40 weeks | Study population | Risk difference 0.02 (‐0.00 to 0.04) | 1199 | ⊕⊕⊕⊝ | ||
| 30 per 1000 | 48 per 1000 (27 to 84) | |||||
| mPAP the higher the mPAP, the worse the pulmonary hypertension) Mean follow‐up 17 weeks | The mPAP was 60 mmHg | MD 7.4 mmHg lower | ‐ | 43 | ⊕⊕⊕⊝ | |
| PVR (the higher the PVR, the Mean follow‐up 17 weeks | The mean PVR was 1687 dyn/sec/m2 | MD 33 dyn/sec/m2 lower | ‐ | 43 | ⊕⊕⊕⊝ | |
| Cardiac index (the lower the cardiac index, Mean follow‐up 17 weeks | The mean cardiac index was 2.3 L/min/m2 | MD 0.5 L/min/m2 higher | ‐ | 43 | ⊕⊕⊕⊝ | |
| RAP (the lower the RAP, Mean follow‐up 17 weeks | The mean RAP was 8.3 mmHg | MD 3.2 mmHg higher | ‐ | 43 | ⊕⊕⊕⊝ | |
| Dyspnoea (lower scores indicates more severe breathlessness) Mean follow‐up 17 weeks | ‐ | MD 0.1 lower | ‐ | 43 | ⊕⊕⊕⊝ | MCID in PAH is 0.9 units |
| Headache+ Mean follow‐up 40 weeks | Study population | 3.91 (3.07 to 4.98) | 1199 | ⊕⊕⊕⊕ | ||
| 325 per 1000 | 653 per 1000 | |||||
| *The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence | ||||||
| 1Downgraded due to imprecision with confidence intervals including no difference. | ||||||
| Study | N | Intervention | Comparator | Blinded | Duration |
| 203 | Inhaled iloprost | Placebo | Blinded | 12 weeks | |
| 130 | Oral beraprost | Placebo | Blinded | 12 weeks | |
| 111 | Intravenous epoprostenol | Usual treatment | Open‐label | 12 weeks | |
| 81 | Intravenous epoprostenol | Conventional treatment | Open‐label | 12 weeks | |
| 116 | Oral beraprost | Placebo | Blinded | 12 months | |
| 349 | Oral treprostinil | Placebo | Blinded | 16 weeks | |
| 310 | Oral treprostinil | Placebo | Blinded | 16 weeks | |
| 349 | Oral treprostinil | Placebo | Blinded | 12 weeks | |
| 1156 | Selexipag | Placebo | Blinded | Median 63 weeks | |
| 27 | Inhaled iloprost | Other treatment* | Open‐label | 12 weeks | |
| 67 | Inhaled iloprost | Placebo | Blinded | 12 weeks | |
| 63 | Inhaled iloprost | Placebo | Open‐label | 2 years | |
| 19 | Intravenous epoprostenol | Conventional treatment | Open‐label | 8 weeks | |
| 470 | Subcutaneous treprostinil | Placebo | Blinded | 12 weeks | |
| 43 | Selexipag | Placebo | Blinded | 17 weeks | |
| 235 | Inhaled treprostinil | Placebo | Blinded | 12 weeks | |
| 44 | Intravenous treprostinil | Placebo | Blinded | 12 weeks | |
| N = number of participants *Inhaled iloprost + bosentan versus inhaled iloprost alone versus bosentan alone | |||||
| Outcome | Number of studies | Effect measure | Fixed‐effect size (95% CI) | Random‐effect size (95% CI) |
| Functional class ‐ improvement | 8 | OR | 2.39 (1.72 to 3.32) | 2.66 (1.37 to 5.19) |
| Functional class ‐ worsening | 5 | OR | 0.88 (0.57 to 1.37) | 0.88 (0.56 to 1.40) |
| Six‐minute walk distance | 13 | MD | 19.50 (14.82 to 24.19)* | 29.55 (18.63 to 40.48)* |
| Mortality | 15 | OR | 0.60 (0.38 to 0.94) | 0.68 (0.42 to 1.10) |
| mPAP | 8 | MD | ‐3.60 (‐4.73 to ‐2.48)* | ‐4.10 (‐6.22 to ‐1.99)* |
| PVR | 7 | MD | ‐2.81 (‐3.80 to ‐1.82)* | ‐2.40 (‐4.44 to ‐0.35)* |
| Cardiac index | 6 | MD | 0.31 (0.23 to 0.38)* | 0.34 (0.17 to 0.52)* |
| Cardiac output | 2 | MD | 0.57 (0.32 to 0.81) | 0.41 (‐0.34 to 1.15) |
| RAP | 6 | MD | ‐1.90 (‐2.58 to ‐1.22) | ‐1.90 (‐2.58 to ‐1.22) |
| Dyspnoea | 8 | SMD | ‐0.21 (‐0.32 to ‐0.11)* | ‐0.29 (‐0.50 to ‐0.08)* |
| Quality of life | 3 | SMD | 0.28 (0.04 to 0.52)* | 0.48 (‐0.11 to 1.08)* |
| *High heterogeneity Abbreviations: MD ‐ mean difference; SMD ‐ standardised mean difference; CI ‐ confidence interval; mPAP ‐ mean pulmonary arterial pressure; PVR ‐ pulmonary vascular resistance; RAP ‐ right atrial pressure | ||||
| Outcome | All studies effect size (95% CI) | Blinded studies only effect size (95% CI) |
| Functional class ‐ improvement | 2.39 (1.72 to 3.32)+ | 1.77 (1.24 to 2.52)+ |
| Functional class ‐ worsening | 0.88 (0.57 to 1.37) | 0.85 (0.54 to 1.35) |
| Six‐minute walk test distance | 19.50 (14.82 to 24.19)+ | 17.55 (12.82 to 22.29)+ |
| Mortality | 0.60 (0.38 to 0.94)+ | 0.76 (0.45 to 1.29)* |
| PAP | ‐3.60 (‐4.73 to ‐2.48)+ | ‐2.58 (‐3.86 to ‐1.30)+ |
| PVR | ‐2.81 (‐3.80 to ‐1.82)+ | ‐1.32 (‐2.95 to 0.32)* |
| Cardiac index | 0.31 (0.23 to 0.38)+ | 0.18 (0.08 to 0.27)+ |
| Cardiac output | 0.57 (0.32 to 0.81)+ | 0.57 (0.32 to 0.81)+ |
| RAP | ‐1.90 (‐2.58 to ‐1.22)+ | ‐1.80 (‐2.55 to ‐1.06)+ |
| Dyspnoea | ‐0.21 (‐0.32 to ‐0.11)+ | ‐0.18 (‐0.29 to ‐0.08)+ |
| Quality of life | 0.28 (0.04 to 0.52)+ | 0.07 (‐0.22 to 0.36)* |
| +Statistically significant; *no longer statistically significant Abbreviations: CI ‐ confidence interval; PAP ‐ pulmonary arterial pressure; PVR ‐ pulmonary vascular resistance; RAP ‐ right atrial pressure | ||
| Outcome | Anticipated absolute effects* (95% CI) | Relative effect | № of participants | |
| Risk with placebo | Risk with selexipag | |||
| Syncope | 90 per 1000 | 71 per 1000 (40 to 123) | OR 0.77 | 560 |
| Dizziness | 126 per 1000 | 136 per 1000 (108 to 170) | OR 1.09 | 1939 |
| Vasodilation | 80 per 1000 | 305 per 1000 (251 to 365) | OR 5.03 | 2277 |
| Headache | 227 per 1000 | 548 per 1000 (502 to 593) | OR 3.16 | 2351 |
| Jaw pain | 67 per 1000 | 273 per 1000 (220 to 333) | OR 5.25 | 2149 |
| Diarrhoea | 167 per 1000 | 361 per 1000 (315 to 410) | OR 2.81 | 2317 |
| Leg pain | 41 per 1000 | 113 per 1000 (42 to 271) | OR 2.96 | 246 |
| Nausea and vomiting | 244 per 1000 | 435 per 1000 (390 to 481) | OR 2.39 | 2399 |
| Abdominal pain | 116 per 1000 | 151 per 1000 (90 to 242) | OR 1.35 | 465 |
| Pain in extremities | 77 per 1000 | 218 per 1000 (162 to 287) | OR 3.36 | 1236 |
| Myalgia | 47 per 1000 | 120 per 1000 (76 to 185) | OR 2.75 | 1009 |
| Upper respiratory tract events | 255 per 1000 | 355 per 1000 (294 to 422) | OR 1.61 | 1038 |
| Peripheral oedema | 75 per 1000 | 106 per 1000 (74 to 150) | OR 1.46 | 1228 |
| Infusion site reactions | 213 per 1000 | 796 per 1000 (713 to 860) | OR 14.41 | 580 |
| *The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||
| Outcome | Anticipated absolute effects* (95% CI) | Relative effect | № of participants | |
| Risk with placebo | Risk with selexipag | |||
| Dizziness | 145 per 1000 | 150 per 1000 | OR 1.04 | 1195 |
| Headache | 325 per 1000 | 653 per 1000 | OR 3.91 | 1195 |
| Vasodilation | 49 per 1000 | 122 per 1000 | OR 2.67 | 1195 |
| Jaw pain | 61 per 1000 | 258 per 1000 | OR 5.33 | 1195 |
| Diarrhoea | 189 per 1000 | 420 per 1000 | OR 3.11 | 1195 |
| Nausea or vomiting | 266 per 1000 | 514 per 1000 | OR 2.92 | 1195 |
| Pain in extremity | 78 per 1000 | 172 per 1000 | OR 2.44 | 1195 |
| Myalgias | 58 per 1000 | 158 per 1000 | OR 3.05 | 1195 |
| Upper respiratory tract infection | 361 per 1000 | 359 per 1000 | OR 0.99 | 1195 |
| *The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Improvement in WHO functional class Show forest plot | 8 | 1066 | Odds Ratio (M‐H, Fixed, 95% CI) | 2.39 [1.72, 3.32] |
| 1.1 Intravenous | 3 | 202 | Odds Ratio (M‐H, Fixed, 95% CI) | 14.96 [4.76, 47.04] |
| 1.2 Oral | 3 | 596 | Odds Ratio (M‐H, Fixed, 95% CI) | 1.32 [0.85, 2.05] |
| 1.3 Inhaled | 2 | 268 | Odds Ratio (M‐H, Fixed, 95% CI) | 2.94 [1.53, 5.66] |
| 2 Worsening of WHO functional class Show forest plot | 5 | 805 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.88 [0.57, 1.37] |
| 2.1 Intravenous | 1 | 71 | Odds Ratio (M‐H, Fixed, 95% CI) | 1.33 [0.29, 6.07] |
| 2.2 Oral | 2 | 466 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.90 [0.54, 1.51] |
| 2.3 Inhaled | 2 | 268 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.68 [0.24, 1.89] |
| 3 6MWD Show forest plot | 13 | 2302 | Mean Difference (Fixed, 95% CI) | 19.50 [14.82, 24.19] |
| 3.1 Intravenous | 4 | 245 | Mean Difference (Fixed, 95% CI) | 91.76 [58.97, 124.55] |
| 3.2 Subcutaneous | 1 | 469 | Mean Difference (Fixed, 95% CI) | 16.0 [7.38, 24.62] |
| 3.3 Oral | 4 | 1070 | Mean Difference (Fixed, 95% CI) | 14.76 [7.81, 21.70] |
| 3.4 Inhaled | 4 | 518 | Mean Difference (Fixed, 95% CI) | 26.97 [17.21, 36.73] |
| 4 Mortality Show forest plot | 15 | 2554 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.60 [0.38, 0.94] |
| 4.1 Intravenous | 4 | 255 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.29 [0.12, 0.69] |
| 4.2 Subcutaneous | 1 | 469 | Odds Ratio (M‐H, Fixed, 95% CI) | 1.01 [0.35, 2.94] |
| 4.3 Oral | 5 | 1247 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.90 [0.44, 1.83] |
| 4.4 Inhaled | 5 | 583 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.39 [0.09, 1.71] |
| 5 mPAP Show forest plot | 8 | 1132 | Mean Difference (Fixed, 95% CI) | ‐3.60 [‐4.73, ‐2.48] |
| 5.1 Intravenous | 2 | 192 | Mean Difference (Fixed, 95% CI) | ‐6.23 [‐8.64, ‐3.83] |
| 5.2 Subcutaneous | 1 | 469 | Mean Difference (Fixed, 95% CI) | ‐0.7 [‐3.19, 1.79] |
| 5.3 Oral | 2 | 196 | Mean Difference (Fixed, 95% CI) | ‐1.71 [‐4.06, 0.63] |
| 5.4 Inhaled | 3 | 275 | Mean Difference (Fixed, 95% CI) | ‐4.88 [‐6.77, ‐2.99] |
| 6 PVR Show forest plot | 7 | 658 | Mean Difference (Fixed, 95% CI) | ‐2.81 [‐3.80, ‐1.82] |
| 6.1 Intravenous | 2 | 192 | Mean Difference (Fixed, 95% CI) | ‐5.31 [‐6.83, ‐3.80] |
| 6.2 Oral | 2 | 191 | Mean Difference (Fixed, 95% CI) | ‐1.51 [‐3.20, 0.18] |
| 6.3 Inhaled | 3 | 275 | Mean Difference (Fixed, 95% CI) | ‐0.10 [‐2.16, 1.96] |
| 7 Cardiac index Show forest plot | 6 | 868 | Mean Difference (Fixed, 95% CI) | 0.31 [0.23, 0.38] |
| 7.1 Intravenous | 2 | 192 | Mean Difference (Fixed, 95% CI) | 0.57 [0.40, 0.74] |
| 7.2 Subcutaneous | 1 | 469 | Mean Difference (Fixed, 95% CI) | 0.18 [0.07, 0.29] |
| 7.3 Oral | 2 | 192 | Mean Difference (Fixed, 95% CI) | 0.16 [‐0.04, 0.36] |
| 7.4 Inhaled | 1 | 15 | Mean Difference (Fixed, 95% CI) | 0.48 [0.30, 0.66] |
| 8 Cardiac output Show forest plot | 2 | 260 | Mean Difference (Fixed, 95% CI) | 0.57 [0.32, 0.81] |
| 8.1 Inhaled | 2 | 260 | Mean Difference (Fixed, 95% CI) | 0.57 [0.32, 0.81] |
| 9 RAP Show forest plot | 6 | 1060 | Mean Difference (Fixed, 95% CI) | ‐1.90 [‐2.58, ‐1.22] |
| 9.1 Intravenous | 2 | 192 | Mean Difference (Fixed, 95% CI) | ‐2.41 [‐4.10, ‐0.72] |
| 9.2 Subcutaneous | 1 | 469 | Mean Difference (Fixed, 95% CI) | ‐1.90 [‐3.01, ‐0.79] |
| 9.3 Oral | 2 | 196 | Mean Difference (Fixed, 95% CI) | ‐1.0 [‐2.60, 0.60] |
| 9.4 Inhaled | 1 | 203 | Mean Difference (Fixed, 95% CI) | ‐2.2 [‐3.49, ‐0.91] |
| 10 Dyspnoea Show forest plot | 8 | 1521 | Std. Mean Difference (Fixed, 95% CI) | ‐0.21 [‐0.32, ‐0.11] |
| 10.1 Intravenous | 2 | 116 | Std. Mean Difference (Fixed, 95% CI) | ‐0.92 [‐1.31, ‐0.52] |
| 10.2 Subcutaneous | 1 | 469 | Std. Mean Difference (Fixed, 95% CI) | ‐0.33 [‐0.51, ‐0.14] |
| 10.3 Oral | 3 | 668 | Std. Mean Difference (Fixed, 95% CI) | ‐0.09 [‐0.25, 0.06] |
| 10.4 Inhaled | 2 | 268 | Std. Mean Difference (Fixed, 95% CI) | ‐0.05 [‐0.29, 0.19] |
| 11 Quality of life Show forest plot | 3 | 271 | Std. Mean Difference (Fixed, 95% CI) | 0.28 [0.04, 0.52] |
| 11.1 Intravenous | 1 | 69 | Std. Mean Difference (Fixed, 95% CI) | 0.78 [0.29, 1.28] |
| 11.2 Oral | 1 | 187 | Std. Mean Difference (Fixed, 95% CI) | 0.07 [‐0.22, 0.36] |
| 11.3 Inhaled | 1 | 15 | Std. Mean Difference (Fixed, 95% CI) | 0.88 [‐0.20, 1.95] |
| 12 Clincal worsening Show forest plot | 12 | 2238 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.67 [0.48, 0.92] |
| 12.1 Intravenous | 2 | 125 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.31 [0.10, 1.01] |
| 12.2 Subcutaneous | 1 | 469 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.81 [0.38, 1.73] |
| 12.3 Oral | 5 | 1126 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.81 [0.53, 1.25] |
| 12.4 Inhaled | 4 | 518 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.42 [0.20, 0.89] |
| 13 Adverse events ‐ syncope Show forest plot | 4 | 560 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.77 [0.42, 1.42] |
| 14 Adverse events ‐ dizziness Show forest plot | 10 | 1939 | Odds Ratio (M‐H, Fixed, 95% CI) | 1.09 [0.84, 1.42] |
| 15 Adverse events ‐ vasodilation Show forest plot | 11 | 2277 | Odds Ratio (M‐H, Fixed, 95% CI) | 5.03 [3.84, 6.58] |
| 16 Adverse events ‐ headache Show forest plot | 12 | 2351 | Odds Ratio (M‐H, Fixed, 95% CI) | 3.16 [2.62, 3.80] |
| 17 Adverse events ‐ jaw pain Show forest plot | 10 | 2149 | Odds Ratio (M‐H, Fixed, 95% CI) | 5.25 [3.96, 6.98] |
| 18 Adverse events ‐ diarrhoea Show forest plot | 10 | 2317 | Odds Ratio (M‐H, Fixed, 95% CI) | 2.81 [2.29, 3.46] |
| 19 Adverse events ‐ leg pain Show forest plot | 2 | 246 | Odds Ratio (M‐H, Fixed, 95% CI) | 2.96 [1.02, 8.62] |
| 20 Adverse events ‐ nausea and vomiting Show forest plot | 12 | 2399 | Odds Ratio (M‐H, Fixed, 95% CI) | 2.39 [1.98, 2.88] |
| 21 Adverse events ‐ abdominal pain Show forest plot | 2 | 465 | Odds Ratio (M‐H, Fixed, 95% CI) | 1.35 [0.75, 2.42] |
| 22 Adverse events ‐ pain in extremity Show forest plot | 6 | 1236 | Odds Ratio (M‐H, Fixed, 95% CI) | 3.36 [2.32, 4.85] |
| 23 Adverse events ‐ myalgia Show forest plot | 3 | 1009 | Odds Ratio (M‐H, Fixed, 95% CI) | 2.75 [1.65, 4.58] |
| 24 Adverse events ‐ upper respiratory tract events Show forest plot | 7 | 1038 | Odds Ratio (M‐H, Fixed, 95% CI) | 1.61 [1.22, 2.13] |
| 25 Adverse events ‐ peripheral oedema Show forest plot | 6 | 1228 | Odds Ratio (M‐H, Fixed, 95% CI) | 1.46 [0.98, 2.17] |
| 26 Adverse events ‐ infusion site reaction Show forest plot | 2 | 580 | Odds Ratio (M‐H, Fixed, 95% CI) | 14.41 [9.16, 22.66] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Improvement in WHO FC Show forest plot | 1 | Odds Ratio (M‐H, Fixed, 95% CI) | Totals not selected | |
| 2 Worsening in WHO FC Show forest plot | 2 | 1188 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.79 [0.60, 1.04] |
| 3 6MWD Show forest plot | 2 | 1199 | Mean Difference (Fixed, 95% CI) | 12.62 [1.90, 23.34] |
| 4 Mortality Show forest plot | 2 | 1199 | Risk Difference (M‐H, Fixed, 95% CI) | 0.02 [‐0.00, 0.04] |
| 5 mPAP Show forest plot | 1 | Mean Difference (Fixed, 95% CI) | Totals not selected | |
| 6 PVR Show forest plot | 1 | Mean Difference (Fixed, 95% CI) | Totals not selected | |
| 7 Cardiac index Show forest plot | 1 | Mean Difference (Fixed, 95% CI) | Totals not selected | |
| 8 RAP Show forest plot | 1 | Mean Difference (Fixed, 95% CI) | Totals not selected | |
| 9 Dyspnoea Show forest plot | 1 | 43 | Mean Difference (Fixed, 95% CI) | ‐0.1 [‐1.40, 1.20] |
| 10 Clinical worsening Show forest plot | 2 | 1199 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.47 [0.37, 0.60] |
| 11 Adverse events‐ dizziness Show forest plot | 2 | 1195 | Odds Ratio (M‐H, Fixed, 95% CI) | 1.04 [0.76, 1.44] |
| 12 Adverse events ‐ headache Show forest plot | 2 | 1195 | Odds Ratio (M‐H, Fixed, 95% CI) | 3.91 [3.07, 4.98] |
| 13 Adverse events ‐ vasodilation Show forest plot | 2 | 1195 | Odds Ratio (M‐H, Fixed, 95% CI) | 2.67 [1.72, 4.17] |
| 14 Adverse events ‐ jaw pain Show forest plot | 2 | 1195 | Odds Ratio (M‐H, Fixed, 95% CI) | 5.33 [3.64, 7.81] |
| 15 Adverse events ‐ diarrhoea Show forest plot | 2 | 1195 | Odds Ratio (M‐H, Fixed, 95% CI) | 3.11 [2.39, 4.05] |
| 16 Adverse events ‐ nausea or vomiting Show forest plot | 2 | 1195 | Odds Ratio (M‐H, Fixed, 95% CI) | 2.92 [2.29, 3.73] |
| 17 Adverse events ‐ pain in extremity Show forest plot | 2 | 1195 | Odds Ratio (M‐H, Fixed, 95% CI) | 2.44 [1.69, 3.52] |
| 18 Adverse events ‐ myalgias Show forest plot | 2 | 1195 | Odds Ratio (M‐H, Fixed, 95% CI) | 3.05 [2.02, 4.58] |
| 19 Adverse events ‐ upper respiratory tract infection Show forest plot | 2 | 1195 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.99 [0.78, 1.26] |
