Inhibidores de la fosfodiesterasa 5 para la hipertensión pulmonar
Resumen
Antecedentes
La hipertensión pulmonar (HP) comprende un grupo de afecciones complejas y heterogéneas, caracterizadas por aumento de la presión arterial pulmonar, que lleva, sin tratamiento, a insuficiencia cardíaca derecha y muerte. La HP incluye el Grupo 1 de hipertensión arterial pulmonar (HAP) de la Organización Mundial de la Salud (OMS). El grupo 2 consiste en HP debida a cardiopatía izquierda (HP‐CPI); El grupo 3 comprende la HP como resultado de enfermedades pulmonares o hipoxia, o ambas; El grupo 4 incluye la HP debida a oclusión tromboembólica crónica de la vasculatura pulmonar (TECHP) y, el Grupo 5, los casos de HP debido a mecanismos poco claros o multifactoriales, como los trastornos hematológicos, sistémicos o metabólicos. Los inhibidores de la fosfodiesterasa 5 (PDE5) aumentan la vasodilatación e inhiben la proliferación.
Objetivos
Determinar la eficacia de los inhibidores de la PDE5 para la hipertensión pulmonar en adultos y niños.
Métodos de búsqueda
Se hicieron búsquedas en CENTRAL, MEDLINE, Embase, CINAHL y en Web of Science hasta el 26 septiembre 2018. Se hicieron búsquedas manuales de artículos de revisión, registros de ensayos clínicos y listas de referencias de artículos recuperados.
Criterios de selección
Se incluyeron ensayos controlados aleatorios que compararon inhibidores de PDE5 versus placebo u otros tratamientos específicos de la HAP, durante al menos 12 semanas. Se incluyen análisis separados para cada grupo de HP.
Obtención y análisis de los datos
Los estudios identificados mediante la búsqueda se importaron a una base de datos de control de referencias. Se recuperó la versión de texto completo de los estudios relevantes, y dos autores de la revisión extrajeron los datos de forma independiente. Los resultados primarios fueron: cambio en la clase funcional de la OMS, la distancia de caminata de seis minutos (6MWD) y la mortalidad. Los resultados secundarios fueron: los parámetros hemodinámicos, la calidad de vida/nivel de salud, la disnea, el empeoramiento clínico (hospitalización/intervención) y los eventos adversos. Cuando fue apropiado se realizaron metanálisis y análisis de subgrupos por la gravedad de la función pulmonar, el diagnóstico de la enfermedad del tejido conectivo y el patrón radiológico de la fibrosis. Se evaluó la evidencia mediante los criterios GRADE y se diseñaron tablas de “Resumen de resultados”.
Resultados principales
Se incluyeron 36 estudios con 2999 pacientes (que presentaban hipertensión pulmonar de todas las causas) en la revisión final. Los ensayos se realizaron durante un promedio de 14 semanas y algunos duraron hasta 12 meses. Dos ensayos incluyeron específicamente niños.
En 19 ensayos se incorporaron pacientes con HAP del grupo 1. Fue más probable que los pacientes con HAP tratados con inhibidores de la PDE5 mejoraran la clase funcional de la OMS (odds ratio [OR] 8,59; intervalo de confianza [IC] del 95%: 3,95 a 18,72; cuatro ensayos, 282 participantes), caminaran 48 metros más en la 6MWD (IC del 95%: 40 a 56; ocho ensayos, 880 participantes), y fue un 22% menos probable que murieran durante un período de una media de 14 semanas (IC del 95%: 0,07 a 0,68; ocho ensayos, 1119 participantes) en comparación con un placebo (evidencia de certeza alta). El número necesario a tratar para prevenir una muerte adicional fue de 32 participantes. El riesgo de eventos adversos fue mayor con los inhibidores de la PDE5, especialmente la cefalea (OR 1,97; IC del 95%: 1,33 a 2,92; cinco ensayos, 848 participantes), las molestias gastrointestinales (OR 1,63; IC del 95%: 1,07 a 2,48; cinco ensayos, 848 participantes), el rubor (OR 4,12; IC del 95%: 1,83 a 9,26; tres ensayos, 748 participantes), y los dolores musculares y articulares (OR 2,52; IC del 95%: 1,59 a 3,99; cuatro ensayos, 792 participantes).
Los datos que comparan los inhibidores de la PDE5 con un placebo (aunque fueran parte de otros tratamientos específicos de la HAP) se vieron limitados por el reducido número de ensayos incluidos. Los pacientes con HAP que recibieron los inhibidores de la PDE5 más el tratamiento combinado caminaron 19,66 metros adicionales en seis minutos (IC del 95%: 9 a 30; cuatro ensayos, 509 participantes) en comparación con un placebo (evidencia de certeza moderada). Hubo ensayos limitados que comparan los inhibidores de la PDE5 directamente con otro tratamiento específico de la HAP (antagonistas de receptores de endotelina [ARE]). Los pacientes que recibieron los inhibidores de la PDE5 caminaron 49 metros más que los que recibieron los ARE (IC del 95%: 4 a 95; dos ensayos, 36 participantes) (evidencia de certeza baja). No hubo evidencia de una diferencia en la clase funcional de la OMS ni la mortalidad entre los dos tratamientos.
Cinco ensayos compararon los inhibidores de la PDE5 con un placebo en la HP secundaria a cardiopatía izquierda (HP‐CPI). La calidad de los datos fue baja debido a la imprecisión y la incongruencia en los ensayos. En los pacientes con HP‐CPI hubo baja probabilidad de una mejoría en la clase funcional de la OMS con los inhibidores de la PDE5 en comparación con el placebo (OR 0,53; IC del 95%: 0,32 a 0,87; tres ensayos, 285 participantes), y los que recibieron los inhibidores de la PDE5 caminaron 34 metros más en comparación con el placebo (IC del 95%: 23 a 46; tres ensayos, 284 participantes). No hubo evidencia de diferencias en la mortalidad. Cinco ensayos compararon los inhibidores de la PDE5 con el placebo en la HP secundaria a enfermedad/hipoxia pulmonar, principalmente en la EPOC. Los datos fueron de baja calidad debido a la imprecisión del efecto y la incongruencia en los ensayos. Hubo una mejoría pequeña de 27 metros en la 6MWD con los inhibidores de la PDE5 en comparación con el placebo en los pacientes con HP debido a enfermedad pulmonar. No hubo evidencia de empeoramiento de la hipoxia con los inhibidores de la PDE5, aunque los datos fueron limitados. Tres estudios compararon los inhibidores de la PDE5 con un placebo u otro tratamiento específico de la HAP en la enfermedad tromboembólica crónica. No hubo diferencias significativas en ninguno de los resultados. La calidad de los datos fue baja debido a la imprecisión del efecto y la heterogeneidad en los ensayos.
Conclusiones de los autores
Los inhibidores de la PDE5 parecen tener efectos beneficiosos claros para la HAP del grupo 1. Sildenafil, tadalafil y vardenafil son efectivos en este contexto clínico, y los médicos deben considerar el perfil de efectos secundarios para cada paciente cuando eligen el inhibidor de la PDE5 a prescribir.
Aunque parece haber algún beneficio con la administración de inhibidores de la PDE5 en la HP‐cardiopatía izquierda, no puede precisarse qué tipo de cardiopatía izquierda se beneficiaría sobre la base de estudios en su mayoría pequeños y a corto plazo. Estos datos indican el posible efecto perjudicial en la cardiopatía valvular. No hay beneficios claros de los inhibidores de la PDE5 en la hipertensión pulmonar secundaria a las enfermedades pulmonares ni en la enfermedad tromboembólica crónica. Se requiere investigación adicional sobre los mecanismos de la hipertensión pulmonar secundaria a cardiopatía izquierda y para considerar cuidadosamente qué subconjunto de pacientes puede beneficiarse con los inhibidores de la PDE5. Los ensayos futuros sobre HP‐CPI deben tener poder estadístico suficiente, un seguimiento a largo plazo e incluir datos hemodinámicos invasivos, la clase funcional de la OMS, la distancia de caminata de seis minutos y el empeoramiento clínico.
PICO
Resumen en términos sencillos
Inhibidores de la PDE5 para la hipertensión pulmonar
Pregunta de la revisión:
El objetivo era examinar si el grupo de fármacos conocidos como inhibidores de la PDE5 (que dilatan los vasos sanguíneos del pulmón) puede ser útil en pacientes con hipertensión pulmonar (aumento de presión en los vasos sanguíneos pulmonares). Los investigadores Cochrane recopilaron y analizaron todos los estudios pertinentes para responder a esta pregunta y encontraron 36 estudios.
Por qué es importante la revisión:
Cerca de tres individuos de cada 1000 presentan hipertensión pulmonar, debida a diferentes causas. Esta situación puede reducir la capacidad de ejercicio y la calidad de vida y llevar a más hospitalizaciones y muerte prematura. Un grupo de fármacos conocidos como inhibidores de la PDE5 pueden mejorar la circulación sanguínea del lado derecho 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 36 estudios con 2999 pacientes. Los ensayos se realizaron durante un promedio de 14 semanas y algunos duraron hasta 12 meses. La mayoría de los ensayos incluyeron adultos, y dos ensayos incluyeron específicamente niños.
En 19 ensayos, se incorporó a los pacientes con hipertensión arterial pulmonar del grupo 1 (hereditaria, desconocida, debida a enfermedades del tejido conectivo). Los pacientes a los que se les indicó inhibidores de la PDE5 se compararon con los pacientes a los que no se los indicaron. Esta revisión demuestra que los pacientes que recibieron inhibidores de la PDE5 caminaron en promedio 48 metros más en seis minutos (ocho ensayos, 880 pacientes). También mejoraron la clase funcional (con reducción de las limitaciones físicas asociadas a la HP) y fue menos probable que murieran (evidencia de certeza alta). Fue también más probable que presentaran efectos secundarios, como la cefalea, el rubor y los dolores musculares.
Cinco ensayos incorporaron a pacientes con hipertensión pulmonar debida a cardiopatía izquierda. Esta revisión demuestra que los pacientes que recibieron inhibidores de la PDE5 pudieron caminar en promedio 34 metros más en seis minutos (tres ensayos, 284 pacientes; evidencia de baja certeza). Sin embargo, no hubo diferencias en la supervivencia, en comparación con los que no recibieron los inhibidores de la PDE5. Cinco ensayos incorporaron a pacientes con hipertensión pulmonar debida a enfermedades pulmonares (en su mayoría, enfermedad pulmonar obstructiva crónica y algunos, fibrosis pulmonar idiopática). Con los inhibidores de la PDE5, los pacientes pudieron caminar 27 metros adicionales en seis minutos (evidencia de certeza baja), pero sin diferencias en la supervivencia, en comparación con los que no recibieron los inhibidores de la PDE5. Tres ensayos incorporaron a pacientes con hipertensión pulmonar debida a coágulos sanguíneos; no hubo diferencias significativas en los resultados para los que recibieron los inhibidores de la PDE5 en comparación con los que no los recibieron.
Limitaciones:
Hubo evidencia de buena calidad para los pacientes con hipertensión arterial pulmonar, lo que brinda cierta confianza de que los resultados son correctos. La certeza fue más baja para la evidencia de los pacientes con hipertensión pulmonar debida a cardiopatía. Esta calificación se debió a que hubo pocos ensayos, al número reducido de participantes y a que los ensayos fueron muy diferentes entre sí, lo que dificulta establecer conclusiones firmes.
Conclusiones de los autores
Summary of findings
| Group 1 Pulmonary arterial hypertension ‐ PDE5i compared to placebo | ||||||
| Patient or population: people with pulmonary arterial hypertension | ||||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect | № of participants | Certainty of the evidence | Comments | |
| Risk with placebo | Risk with PDE5i | |||||
| Improvement in WHO functional class | 61 per 1000 | 358 per 1000 | OR 8.59 | 282 | ⊕⊕⊕⊕ | ‐ |
| Six‐minute walk distance | Ranges from 170 ‐ 319 ma | MD 48 metres higher | ‐ | 880 | ⊕⊕⊕⊝b | 6MWD in PAH MCID is 41 metres |
| Mortality | 41 per 1000 | 9 per 1000 | OR 0.22 | 1119 | ⊕⊕⊕⊕ | ‐ |
| Quality of life SF‐36: (scores 1 to 100, higher scores indicate better QoL) EQ‐5D questionnaire: (higher scores indicate worse QoL) CHFQ: (lower scores indicate worse QoL) | Galiè 2005a found a statistically significant improvement in all SF‐36 domains for sildenafil‐treated participants, and when compared to placebo in physical functioning (P < 0.001), general health (P < 0.001), and vitality (P < 0.05). There was also a statistically significant improvement in placebo‐treated participants in the physical functioning domain. Galiè 2005a found statistically significant improvements for the EQ‐5D current health status (P < 0.01) and utility index (P < 0.01). | 163 (2 RCTs) | ‐ | Data considered too heterogeneous to meta‐analyse | ||
| PAP | ‐ | MD 6.43 mmHg lower (8.13 lower to 4.74 lower) | ‐ | 453 | ⊕⊕⊕⊝b | The higher the mean PAP, the worse the PH |
| RAP | ‐ | MD 1.35 mmHg lower (2.34 lower to 0.36 lower) | ‐ | 341 | ⊕⊕⊕⊕ | The higher the RAP, the worse the PH |
| Cardiac index | ‐ | MD 0.28L/min/m2 higher (0.16 higher to 0.4 higher) | ‐ | 239 | ⊕⊕⊕⊝b | The lower the cardiac index, the worse the PH |
| PVR | ‐ | MD 4.74 WU lower (6.13 lower to 3.35 lower) | ‐ | 266 | ⊕⊕⊕⊕ | The higher the PVR. the worse the PH |
| *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 | ||||||
| aPost‐treatment values for participants in the placebo group were presented in two studies only; the remaining included studies presented a mean difference only. | ||||||
| Group 1 Pulmonary arterial hypertension ‐ PDE5i compared to placebo, on combination therapy | ||||||
| Patient or population: people with pulmonary arterial hypertension | ||||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect | № of participants | Certainty of the evidence | Comments | |
| Risk with placebo, on combination therapy | Risk with PDE5i | |||||
| Improvement in WHO functional class | 263 per 1000 | 300 per 1000 | OR 1.20 | 227 | ⊕⊕⊕⊝ | ‐ |
| Six‐minute walk distance | Ranges from 341 ‐ 377 mb | MD 20 metres higher | ‐ | 509 | ⊕⊕⊕⊝ | 6MWD in PAH MCID is 41 metres |
| Mortality | 32 per 1000 | 9 per 1000 | OR 0.26 | 492 | ⊕⊕⊕⊝ | ‐ |
| Quality of life physical functioning on SF‐36 (higher scores indicate better quality of life) | 0.3 (4.7 higher to 4.1 higher) | 7.8 (3.6 higher to 12.1 higher) | ‐ | 267 (1 RCT) | ⊕⊕⊕⊝ | ‐ |
| PAP | ‐ | MD 4.58 mmHg lower | ‐ | 387 | ⊕⊕⊕⊕ | The higher the PAP, the worse the pulmonary hypertension |
| Cardiac output | ‐ | MD 0.87 L/min higher | ‐ | 310 | ⊕⊕⊕⊕ | The lower the cardiac output, the worse the pulmonary hypertension |
| PVR | ‐ | SMD 0.48 lower | ‐ | 303 | ⊕⊕⊕⊕ | The higher the PVR, the worse the pulmonary hypertension |
| *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 | ||||||
| aDowngraded due to imprecision owing to small participant numbers and inconsistent direction of effect. | ||||||
| Group 1 Pulmonary Arterial Hypertension ‐ PDE5i compared to ERA | ||||||
| Patient or population: people with pulmonary arterial hypertension | ||||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect | № of participants | Certainty of the evidence | Comments | |
| Risk with ERA | Risk with PDE5i | |||||
| Improvement in WHO functional class | 339 per 1000 | 325 per 1000 | OR 0.94 | 244 | ⊕⊕⊕⊝ | ‐ |
| Six‐minute walk distance | Ranges from 290 ‐ 354 mb | MD 49 higher | ‐ | 36 | ⊕⊕⊝⊝ | 6MWD in PAH MCID is 41 metres |
| Mortality | 14 per 1000 | 45 per 1000 | OR 3.19 | 272 | ⊕⊕⊕⊝ | ‐ |
| Quality of life Kansas City Cardiomyopathy Quality‐of‐Life questionnaire (higher scores indicate better quality of life) | ‐ | MD 22 higher | ‐ | 25 | ⊕⊕⊝⊝ | ‐ |
| PAP | ‐ | MD 7.00 mmHg lower (4.82 lower to 18.82 higher) | ‐ | 11 (1 RCT) | ⊕⊕⊝⊝ | The higher the mean PAP, the worse the PH |
| RAP | ‐ | MD 2 mmHg higher (2.14 lower to 6.14 higher) | ‐ | 11 (1 RCT) | ⊕⊕⊝⊝ | The higher the RAP, the worse the PH |
| Cardiac index | ‐ | MD 0 L/min/m2 higher (0.49 lower to 0.49 higher) | ‐ | 11 (1 RCT) | ⊕⊕⊝⊝ | The lower the cardiac index, the worse the PH |
| PVR | ‐ | MD 0 WU lower (1.93 lower to 1.93 higher) | ‐ | 11 (1 RCT) | ⊕⊕⊝⊝ | The higher the PVR. the worse the PH |
| *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 | ||||||
| aDowngraded once due to imprecision. | ||||||
| Group 2 Pulmonary hypertension due to left‐heart disease ‐ PDE5i compared to placebo | ||||||
| Patient or population: people with pulmonary hypertension due to left‐heart disease | ||||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect | № of participants | Certainty of the evidence | Comments | |
| Risk with placebo | Risk with PDE5i | |||||
| Improvement in WHO functional class | 403 per 1000 | 263 per 1000 | OR 0.53 | 285 | ⊕⊕⊕⊝ | ‐ |
| Six‐minute walk distance | No data reported | MD 34 metres higher | ‐ | 284 | ⊕⊕⊕⊝ | ‐ |
| Mortality | 22 per 1000 | 27 per 1000 (6 to 114) | OR 1.27 (0.28 to 5.80) | 286 | ⊕⊕⊕⊝ | ‐ |
| Quality of life | 19.83 points higher (8.23 higher to 31.44 higher) | 12.05 points higher (1.14 higher to 22.96 higher) | ‐ | 52 (1 RCT) | ⊕⊕⊝⊝ | Kansas City Cardiomyopathy Questionnaire (higher scores reflect better health status) |
| Mean PAP | ‐ | MD 10.17 mmHg lower | ‐ | 130 | ⊕⊕⊕⊝ | The higher the mean PAP, the worse the pulmonary hypertension |
| Cardiac index | ‐ | MD 0.07 L/min/m2 higher | ‐ | 96 | ⊕⊕⊕⊝ | The lower the cardiac index, the worse the pulmonary hypertension |
| *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 | ||||||
| aDowngraded due to high heterogeneity and inconsistent direction of effect. | ||||||
| Group 3 Pulmonary hypertension due to lung disease ‐ PDE5i compared to placebo | ||||||
| Patient or population: people with pulmonary hypertension due to lung disease | ||||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect | № of participants | Certainty of the evidence | Comments | |
| Risk with placebo | Risk with PDE5i | |||||
| Improvement in WHO functional class | 50 per 1000 | 700 per 1000 | OR 44.33 | 40 | ⊕⊕⊝⊝ | ‐ |
| Six‐minute walk distance | Ranges from 237 ‐ 297 metres | MD 27 metres higher | ‐ | 350 | ⊕⊕⊕⊕ | ‐ |
| Mortality | ‐ | ‐ | ‐ | No studies | ‐ | ‐ |
| Quality of life | ‐ | MD 0.19 higher | ‐ | 238 | ⊕⊕⊕⊝ | SF‐36 overall quality of life (higher scores indicate better quality of life) |
| Mean PAP | ‐ | MD 0.14 mmHg lower | ‐ | 61 | ⊕⊕⊕⊝ | The higher the mean PAP, the worse the pulmonary hypertension |
| Cardiac index | ‐ | MD 0.3 L/min/m2 higher | ‐ | 28 | ⊕⊕⊝⊝ | The lower the cardiac index, the worse the pulmonary hypertension |
| PVR | ‐ | MD 1.31 WU lower | ‐ | 28 | ⊕⊕⊝⊝ | The higher the PVR, the worse the pulmonary hypertension |
| RAP | ‐ | MD 0.36 mmHg higher | ‐ | 28 | ⊕⊕⊝⊝ | The higher the RAP, the worse the pulmonary hypertension |
| *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 | ||||||
| aDowngraded twice due to imprecision owing to small participant numbers. | ||||||
| Group 4 Pulmonary hypertension due to CTEPH ‐ PDE5i compared to placebo | ||||||
| Patient or population: people with pulmonary hypertension due to CTEPH | ||||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect | № of participants | Certainty of the evidence | Comments | |
| Risk with comparison (placebo/sildenafil) | Risk with PDE5i | |||||
| Improvement in WHO functional class | 0 per 1000 | 444 per 1000 | OR 17.18 | 19 | ⊕⊕⊝⊝ | ‐ |
| Six‐minute walk distance ‐ sildenafil compared to placebo | Baseline 331 metres | MD 18 metres higher | ‐ | 19 | ⊕⊕⊝⊝ | ‐ |
| Six‐minute walk distance ‐ sildenafil compared to bosentan | Ranges from 422 ‐ 455 metres | MD 20 metres higher | ‐ | 227 | ⊕⊕⊕⊝ | ‐ |
| Mortality ‐ sildenafil versus placebo | No deaths reported | not estimable | 20 | ⊕⊕⊝⊝ | ‐ | |
| Mortality ‐ sildenafil versus bosentan | 40 per 1000 | 54 per 1000 | OR 1.36 (0.22 to 8.48) | 106 | ⊕⊕⊝⊝ | ‐ |
| Quality of life | ‐ | MD 0.26 lower | ‐ | 34 | ⊕⊕⊝⊝ | CamPHOR scale; higher scores indicate worse quality of life |
| Mean PAP ‐ sildenafil versus placebo | ‐ | MD 6.2 mmHg lower | ‐ | 19 | ⊕⊕⊝⊝ | The higher the PAP, the worse the pulmonary hypertension |
| Mean PAP ‐ sildenafil versus bosentan | ‐ | MD 0.76 mmHg higher | ‐ | 227 | ⊕⊕⊕⊝ | The higher the PAP, the worse the pulmonary hypertension |
| Cardiac index ‐ sildenafil versus placebo | ‐ | MD 0 L/min/m2 higher | ‐ | 19 | ⊕⊕⊝⊝ | The lower the cardiac index, the worse the pulmonary hypertension |
| Cardiac index ‐ sildenafil versus bosentan | ‐ | MD 0.04 L/min/m2 higher | ‐ | 227 | ⊕⊕⊕⊝ | The lower the cardiac index, the worse the pulmonary hypertension |
| PVR ‐ sildenafil versus placebo | ‐ | MD 0.89 WU lower | ‐ | 19 | ⊕⊕⊝⊝ | The higher the PVR, the worse the pulmonary hypertension |
| PVR ‐ sildenafil versus bosentan | ‐ | MD 0.01 WU lower | ‐ | 227 | ⊕⊕⊕⊝ | The higher the PVR, the worse the pulmonary hypertension |
| *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 | ||||||
| aDowngraded twice due to imprecision owing to small participant numbers in only one trial. | ||||||
| Mixed pulmonary hypertension group 2 ‐ 4 ‐ PDE5i compared to placebo | ||||||
| Patient or population: people with pulmonary hypertension group 2 ‐ 4 | ||||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect | № of participants | Certainty of the evidence | Comments | |
| Risk with placebo | Risk with PDE5i | |||||
| Improvement in WHO functional class | Study population | OR 11.31 | 146 | ⊕⊕⊕⊝ | ‐ | |
| 137 per 1000 | 642 per 1000 | |||||
| Six‐minute walk distance | No data provided | MD 51 metres higher | ‐ | 106 | ⊕⊕⊕⊝ | ‐ |
| Mortality | ‐ | ‐ | no studies | ‐ | ‐ | ‐ |
| Quality of life | ‐ | ‐ | no studies | ‐ | ‐ | ‐ |
| PASP | ‐ | MD 10 mmHg lower | ‐ | 146 | ⊕⊕⊕⊝ | The higher the PASP, the worse the pulmonary hypertension |
| *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 | ||||||
| aDowngraded due to imprecision owing to small participant numbers. | ||||||
Antecedentes
Descripción de la afección
La hipertensión pulmonar (HP) (definida como una presión media de la arteria pulmonar ≥ 25 mmHg en reposo en el cateterismo de corazón derecho) comprende un grupo complejo de enfermedades (ver Tabla 1), caracterizado por una mayor poscarga ventricular derecha, que lleva en último término a insuficiencia cardíaca derecha (McLaughlin 2009). La mayor poscarga puede deberse a la transmisión pasiva de las presiones del lado izquierdo altas (hipertensión pulmonar poscapilar), obstrucción del lecho arterial pulmonar (hipertensión pulmonar precapilar) o una combinación de ambas. La hipertensión arterial pulmonar (Grupo 1 de HAP‐OMS) es un grupo de enfermedades en que existe hipertensión pulmonar ante una mayor resistencia vascular pulmonar. La disponibilidad más reciente de fármacos y tratamientos orientados al lecho arterial pulmonar ha generado esperanzas de una mejoría en cuadros que anteriormente tenían un pronóstico muy malo. Aunque la HAP es poco frecuente, la HP secundaria a cardiopatía izquierda y enfermedad pulmonar es mucho más común. La disponibilidad de fármacos con eficacia en la HAP ha generado gran interés en el uso de estos fármacos en otras formas de hipertensión pulmonar.
En la HAP, la mayor resistencia vascular pulmonar es resultado del engrosamiento y el remodelamiento vascular de las arteriolas de tamaño pequeño y mediano, la necrosis fibrinoide, la formación de lesiones plexiformes, concéntricas o excéntricas y la pérdida del tono vascular. Este proceso de hiperplasia e hipertrofia celular es mediado por el calcio intracelular y la proteína quinasa C, citoquinas inflamatorias y la alteración del metabolismo energético. La remodelación y la vasoconstricción causan hipoxia, lo que resulta en más vasoconstricción e hipoxia (Guignabert 2013; Sim 2010).
La hipertensión pulmonar se clasifica en cinco grupos de afecciones clínicas múltiples, agrupadas según la semejanza de los cuadros clínicos y las características fisiopatológicas y hemodinámicas, con estrategias diferenciadas de tratamiento para cada grupo. La hipertensión arterial pulmonar (HAP) del grupo 1 incluye la HAP idiopática y hereditaria y la HAP debida a enfermedad de las arteriolas pulmonares pequeñas como resultado de trastornos del tejido conectivo, fármacos o toxinas, hipertensión pulmonar portal y otras causas (ver Tabla 1). La hipertensión arterial pulmonar resulta de una mayor resistencia vascular pulmonar por vasculopatía oclusiva de las arteriolas y arterias pulmonares pequeñas. La hipertensión arterial pulmonar es una enfermedad poco frecuente, con una prevalencia de 10 a 52 casos por millón (Ling 2012; Peacock 2007). Sin embargo, el cribado de la hipertensión pulmonar por todas las causas demuestra una prevalencia de 320 casos por 100 000 (Strange 2012).
El grupo 2 consiste en la hipertensión pulmonar debida a cardiopatía izquierda, causada por un aumento del flujo a través de la vasculatura pulmonar o de las presiones pulmonares (p.ej. enfermedad de la válvula mitral, enfermedad del ventrículo izquierdo y miopatías constrictivas). El grupo 3 comprende la hipertensión pulmonar como resultado de enfermedades pulmonares o hipoxia, o ambas, causado por una disminución en el lecho vascular pulmonar (p.ej. enfermedad pulmonar intersticial) o por enfermedades que provocan vasoconstricción hipóxica. El Grupo 4 se refiere a los casos de hipertensión pulmonar debida a oclusión tromboembólica crónica de la vasculatura pulmonar, y el Grupo 5 comprende los casos de hipertensión pulmonar debida a mecanismos poco claros o multifactoriales o ambos, como los trastornos hematológicos, sistémicos o metabólicos (ver Tabla 1) (McLaughlin 2009). Sigue siendo poco claro el grado en que los grupos 2 a 5 de la OMS presentan cambios del lecho arterial pulmonar análogos al Grupo1 de la OMS (y por lo tanto responden de manera similar a los fármacos). Además, los posibles efectos perjudiciales de la vasodilatación arterial selectiva (edema pulmonar en el grupo 2 de la OMS e hipoxia en el grupo 3) quizás impliquen un perfil de riesgo/beneficio muy diferente de los mismos fármacos utilizados en la HAP.
Los pacientes con HAP a menudo consultan por síntomas de disnea, fatiga, síncope e insuficiencia cardíaca derecha (Galiè 2016b). El cateterismo del corazón derecho sigue siendo el valor de referencia del diagnóstico para confirmar la hipertensión pulmonar y para investigar con mayor profundidad las posibles causas y los objetivos de tratamiento. La hipertensión arterial pulmonar se define como una presión media de la arteria pulmonar igual a o mayor que 25 mmHg; una presión de enclavamiento de la arteria pulmonar, una presión de la aurícula izquierda o una presión diastólica final del ventrículo izquierdo menor que o igual a 15 mmHg; y una resistencia vascular pulmonar mayor que tres unidades de Wood (Galiè 2016b). La elevación de la presión de enclavamiento de la arteria pulmonar indica hipertensión pulmonar secundaria a cardiopatía izquierda. En los pacientes con HAP confirmada se debe realizar la prueba de vasodilatación aguda para evaluar la vasorreactividad pulmonar, ya que una proporción pequeña puede responder muy favorablemente al tratamiento con bloqueantes de los canales de calcio en dosis altas a largo plazo (McLaughlin 2009).
Después del interrogatorio, la exploración física, el electrocardiograma, el ecocardiograma y la radiografía de tórax, otros estudios en pacientes con hipertensión pulmonar deben incluir: pruebas de función pulmonar y tomografía computadorizada de alta resolución del tórax para evaluar la enfermedad pulmonar subyacente; un centellograma de ventilación/perfusión para evaluar para la hipertensión pulmonar tromboembólica crónica; las pruebas de función tiroidea, la serología autoinmunitaria, el cribado para el VIH y la hepatitis para evaluar para las etiologías fundamentales; y una prueba de caminata de seis minutos o ejercicios, biomarcadores para monitorizar la respuesta al tratamiento y para el pronóstico (Galiè 2016b).
La evolución natural y el pronóstico de la hipertensión pulmonar varían entre los grupos de la OMS. Sin embargo la presencia de hipertensión pulmonar de forma independiente del grupo de la OMS representa en general la presencia de una enfermedad progresiva y con frecuencia mortal. Entre las variables predictivas independientes que se sabe son de mal pronóstico se incluye la clase funcional de la OMS avanzada, el bajo rendimiento en la prueba de caminata de seis minutos, la presión auricular derecha alta, la disfunción ventricular derecha significativa, evidencia de insuficiencia ventricular derecha, pro‐péptido natriurético tipo B (PNB) elevado e índice cardíaco bajo (Thenappan 2007).
Descripción de la intervención
En años recientes, se han introducido nuevos tratamientos para la HAP, con una mejoría en la tasa de supervivencia a un año de un 84% en comparación con un 68% en los años ochenta (Archer 2009). Los objetivos del tratamiento son lograr un estado asociado a una buena calidad de vida y tolerancia al ejercicio con bajo riesgo de mortalidad y mantener la función ventricular derecha, con el uso de oxígeno suplementario y el tratamiento de la causa subyacente. La disfunción endotelial subyacente de la arteria pulmonar en el grupo 1 de HAP permite el uso de tratamientos específicos que promueven la vasorrelajación y la supresión de la proliferación celular dentro de la pared de la arteria pulmonar, incluido el óxido nítrico y los inhibidores de la fosfodiesterasa 5 (PDE5i, prostanoides, antagonistas de receptores de endotelina y bloqueantes de los canales de calcio) (McLaughlin 2009).
De qué manera podría funcionar la intervención
El óxido nítrico funciona como un vasodilatador pulmonar mediante la activación de la guanilatociclasa soluble, lo que estimula la producción de monofosfato de guanosina cíclico (GMPc). A su vez, el GMPc activa la fosfatasa de la cadena liviana de miosina, que disminuye la fosforilación de la miosina para reducir el tono vascular pulmonar. El aumento del GMPc intracelular también inhibe la entrada de calcio, y de ese modo se reduce el calcio intracelular, lo que lleva a menos hipertrofia e hiperplasia, así como efectos antiproliferativos y proapoptóticos que pueden revertir la remodelación de las arterias pulmonares. El óxido nítrico también inhibe el reclutamiento, la adherencia y la agregación de plaquetas (Sim 2010).
Sin embargo, no está libre de riesgos la administración de óxido nítrico. Los niveles altos de óxido nítrico inhalado pueden llevar a estrés oxidativo y causar daño tisular, lesión por reperfusión y reacción inflamatoria pulmonar. El óxido nítrico inhalado se absorbe rápidamente en el torrente sanguíneo, donde se convierte a metahemoglobina, y esto deteriora en lugar de mejorar la liberación de oxígeno (Sim 2010).
El tipo de fosfodiesterasa 5 (PDE5) reduce específicamente la actividad de la enzima que degrada el GMPc, y de este modo aumenta la síntesis de este último compuesto. Se piensa que los inhibidores de la fosfodiesterasa 5 no induce el mismo nivel de oxidación que el óxido nítrico inhalado (Ghofrani 2004d). Los inhibidores de la fosfodiesterasa 5 que se han investigado para el uso en el Grupo 1 de HAP son: sildenafil, tadalafil y vardenafil. Se ha demostrado en ensayos clínicos que estos agentes mejoran la distancia de caminata de seis minutos y la hemodinamia (Archer 2009; Galiè 2016b; McLaughlin 2009).
Los datos están menos claros para los pacientes del grupo 2 a 5 de la OMS, en quienes esta clase de fármaco puede ser potencialmente nocivo. Participan diferentes factores biopatológicos y fisiopatológicos en el desarrollo de hipertensión pulmonar en estos pacientes. La naturaleza de la arteriopatía pulmonar puede ser muy diferente (p.ej. vasoconstricción hipóxica y obstrucción del lecho vascular pulmonar en el grupo 3; obstrucción trombótica en el grupo 4). Las consecuencias de la vasodilatación arterial pulmonar "selectiva" también pueden ser perjudiciales (edema pulmonar en el grupo 2 de la OMS e hipoxia en el grupo 3). Por lo tanto, al igual que con otros vasodilatadores pulmonares selectivos, una reducción de la resistencia vascular pulmonar (RVP) y la presión arterial pulmonar (PAP) por los inhibidores de la PDE5 puede no mejorar el bienestar general de los pacientes, especialmente en los grupos no relacionados con la HAP (2 a 5) (Guazzi 2012).
En teoría, los inhibidores de la fosfodiesterasa 5 pueden mejorar la funcionalidad en los pacientes del grupo 2 con cardiopatía izquierda. En estudios anteriores que incorporaron pacientes con insuficiencia cardíaca, se ha demostrado que el óxido nítrico es responsable de la regulación del tono vascular, y la infusión de NG‐monometil‐L‐arginina, un inhibidor de la sintasa del óxido nítrico, causó menos vasoconstricción en los pacientes con insuficiencia cardíaca en comparación con los que presentan una resistencia vascular pulmonar normal (Cooper 1996). Los ensayos que usan sildenafil en pacientes con hipertensión pulmonar del grupo 2 han presentado alguna evidencia sobre la mejoría en la capacidad de ejercicio, la eficiencia de la ventilación y la calidad de vida (Lewis 2007). Sin embargo, otros estudios han demostrado dilatación pulmonar irregular como consecuencia de que el óxido nítrico y los análogos pueden aumentar la precarga debido a un ventrículo izquierdo con compliancia deficiente, con el consiguiente aumento significativo de la presión de enclavamiento de la arteria pulmonar (que puede incluso precipitar un edema agudo de pulmón) (Bocchi 1994).
Además, los ensayos que utilizan otros tratamientos específicos de la HAP, como el epoprostenol y los antagonistas de receptores de endotelina, en pacientes hipertensión pulmonar de grupo 2, demostraron un mayor riesgo de hospitalizaciones, evolución de la enfermedad e hipoxemia. Es posible que los pacientes con disfunción del ventrículo izquierdo no puedan tolerar el aumento del flujo en un lecho vascular pulmonar con dilatación reciente (Guazzi 2012).
Los pacientes del grupo 3 con enfermedad pulmonar crónica pueden presentar un empeoramiento del desajuste entre ventilación y perfusión y mayor hipoxemia. Un estudio en pacientes con hipertensión pulmonar asociada a enfermedad pulmonar obstructiva crónica demostró una mejoría de las presiones de la arteria pulmonar, aunque con empeoramiento de la oxigenación arterial (Blanco 2010).
Por qué es importante realizar esta revisión
Tras los adelantos recientes en la comprensión de los mecanismos fisiopatológicos y los tratamientos para la hipertensión pulmonar, más los aportes significativos sobre el tema en la última década, se programó resumir la evidencia actual en relación con la administración de los inhibidores de la PDE5 en la hipertensión pulmonar.
El objetivo de esta revisión fue cuantificar los beneficios potenciales de los inhibidores de la PDE5 en pacientes con HAP en cuanto a las mediciones hemodinámicas y los resultados centrados en el paciente, y sopesarlos en relación con los posibles efectos perjudiciales, para guiar la preferencia de los pacientes, la elección del tratamiento por parte de los médicos y las guías para los encargados de formular políticas.
Esta revisión también examina la evidencia disponible para determinar si hay efectos beneficiosos o perjudiciales potenciales con el uso de los inhibidores de la PDE5 en pacientes con hipertensión pulmonar del grupo 2 o 5.
Esta revisión se basa en una revisión anterior (Kanthapillai 2004), ya que se han desarrollado conceptos adicionales acerca de la fisiopatología, y se publicaron varios ensayos controlados aleatorios más recientes que utilizaron los inhibidores de la PDE5.
Objetivos
Determinar la eficacia de los inhibidores de la PDE5 para la hipertensión pulmonar en adultos y niños.
Métodos
Criterios de inclusión de estudios para esta revisión
Tipos de estudios
Se incluyen ensayos controlados aleatorios (ECA) simple o doble ciego en que se comparan inhibidores de la PDE5 con un placebo u otro tratamiento. Se denominan "aleatorios" los estudios descritos por el autor como "aleatorios" en cualquier apartado del informe del estudio. Todos los ensayos definidos como tales, publicados o no, en cualquier idioma, cumplían los requisitos para la inclusión.
Tipos de participantes
Se incluyen pacientes con un diagnóstico de hipertensión pulmonar de cualquier causa que requirió tratamiento médico de la afección. La hipertensión pulmonar se define según criterios aceptados (Galiè 2016b; McLaughlin 2009).
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La comparación 1 evalúa específicamente los efectos de los inhibidores de la PDE5 en comparación con el placebo en el grupo 1 de HAP, confirmada con una presión media de la arteria pulmonar ≥ 25 mmHg por cateterismo de corazón derecho.
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La comparación 2 compara los inhibidores de la PDE5 con placebo en los pacientes con HAP que reciben tratamiento combinado.
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La comparación 3 compara los inhibidores de la PDE5 con los pacientes que reciben ARE.
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La comparación 4 incluye los pacientes con hipertensión pulmonar del grupo 2 con un diagnóstico de hipertensión pulmonar y cardiopatía izquierda, según la definición de los autores.
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La comparación 5 incluye los pacientes con hipertensión pulmonar del grupo 3 con un diagnóstico de hipertensión pulmonar y enfermedad pulmonar, según la definición de los autores.
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La comparación 6 incluye los pacientes con hipertensión pulmonar del grupo 4 con un diagnóstico de hipertensión pulmonar y enfermedad tromboembólica crónica (HPTEC), según la definición de los autores.
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La comparación 7 incluye pacientes con hipertensión pulmonar de los grupos 2 a 5 con diagnóstico de hipertensión pulmonar según la definición de los autores.
Se buscó especificar los subgrupos de pacientes adultos (mayores de 18 años) y una población pediátrica de menos de 18 años.
Tipos de intervenciones
Se incluyen estudios que comparan cualquier tipo de inhibidores de la PDE5 por cualquier vía de administración con placebo u otro tratamiento para la hipertensión pulmonar. Se incluyen estudios con cointervenciones siempre que no sean parte del tratamiento asignado al azar. Se buscó realizar análisis de subgrupos según las cointervenciones usadas. En los casos en que los estudios eran demasiado heterogéneos para los metanálisis, se los describe en forma narrativa.
Tipos de medida de resultado
Resultados primarios
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Cambio en la clase funcional de la OMS
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Distancia de caminata de seis minutos (6MWD)
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Mortalidad
Resultados secundarios
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Parámetros hemodinámicos, incluido el cambio en la presión media de la arteria pulmonar, cambio en el gasto cardíaco y el índice cardíaco
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Capacidad de ejercicio además de la distancia de caminata de seis minutos
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Calidad de vida/nivel de salud, por cualquier escala validada
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Puntuación de disnea, incluida la escala analógica visual o la escala de Borg
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Hospitalización/intervención
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Eventos adversos
El informe en el estudio de uno o más de los resultados enumerados en la presente no fue un criterio de inclusión para la revisión.
Métodos de búsqueda para la identificación de los estudios
Búsquedas electrónicas
We identified trials from searches of the following databases up to 26 September 2018:
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The Cochrane Airways Group Register of Trials;
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Cochrane Central Register of Controlled Trials (CENTRAL) through the Cochrane Register of Studies Online (crso.cochrane.org);
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MEDLINE (Ovid) 1950 to 26 September 2018;
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Embase (Ovid) 1974 to 26 September 2018;
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US National Institutes of Health Ongoing Trials Register ClinicalTrials.gov (www.clinicaltrials.gov);
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World Health Organization International Clinical Trials Registry Platform (apps.who.int/trialsearch/).
We provide the database search strategies in Appendix 1. We searched all databases from their inception to the present, with no restriction on language of publication. We searched for handsearched conference abstracts and grey literature through the CENTRAL database.
Búsqueda de otros recursos
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 translated any relevant article into English for potential inclusion. Where data were missing, we attempted to contact the trial investigators.
Obtención y análisis de los datos
Selección de los estudios
Two review authors (HB and ZB) independently screened all abstracts to determine if they met the inclusion criteria for the review. We sought full‐text publications for those papers that possibly or definitely met the inclusion criteria. Two review authors independently reviewed all full‐text articles to determine eligibility, recording reasons for ineligibility of those that did not. We resolved any disagreements through discussion, or by seeking consensus from a third review author (AB). We included a PRISMA study flow diagram in the full review to document the screening process, and included a Characteristics of included studies table (Moher 2009).
Extracción y manejo de los datos
Two review authors (HB and ZB) independently extracted data from included studies, and where appropriate, pooled data in the Cochrane statistical software Review Manager 5 for further analysis (RevMan 2014). We used a data collection form that we piloted on one study 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.
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Intervention: type of PDE5 inhibitor, 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.
Evaluación del riesgo de sesgo de los estudios incluidos
Two review authors (HB and ZB) independently assessed the included studies for risks of bias using the Cochrane 'Risk of bias' assessment tool (Higgins 2011). We assessed the following domains.
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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 potential sources of bias.
We judged each potential source of bias as low risk, 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 contributed to that outcome.
Assessment of bias in conducting the systematic review
We conducted the review according to the previously published protocol, and justified any deviations from it in the Differences between protocol and review section of the review.
Medidas del efecto del tratamiento
Where possible, we pooled and presented results from dichotomous data as odds ratios (ORs). Where possible, we presented results from continuous variables and calculated the mean difference (MD) or standardised mean difference (SMD) where scales are combined, with the 95% confidence interval (95% CI). Where we combined data from rating scales in a meta‐analysis, we ensured that they were entered with a consistent direction of effect (e.g. lower scores always indicate improvement). If both change from baseline and endpoint scores were available for continuous data, we used change from baseline scores. Where outcomes were reported at multiple time points, we consistently extracted and included the latest reported time point, but also considered outcomes reported at other time points. We only combined data reported at different time points if this was 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 were 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.
Cuestiones relativas a la unidad de análisis
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). Where rate ratios were reported in a study, we analysed them on that basis. We planned to only meta‐analyse data from cluster‐randomised controlled trials if the available data have been adjusted (or could be adjusted) to account for the clustering, however there were no cluster‐randomised controlled trials identified for inclusion.
Manejo de los datos faltantes
We contacted investigators in order to verify key study characteristics including methods of randomisation, and obtained missing numerical outcome data where possible (e.g. when we identified a study as an abstract only). Where this was not possible, and the missing data were thought to introduce serious bias, we took this into consideration in the GRADE rating for affected outcomes. We planned to only meta‐analyse data from cluster‐RCTs if the available data had been adjusted (or could be adjusted), to account for the clustering.
Evaluación de la heterogeneidad
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 to sampling error. We considered significant statistical heterogeneity to be present if the I2 is greater than 50%. Where we identified significant heterogeneity, we attempted to explore possible causes using prespecified subgroup analyses.
Evaluación de los sesgos de notificación
Where sufficient studies were present, we planned to create and examine a funnel plot to explore small‐study and publication biases; however, there are currently insufficient studies.
Síntesis de los datos
We used a fixed‐effects model and performed a sensitivity analysis comparing the fixed‐ and random‐effects model. Where possible we pooled dichotomous outcome variables using a Mantel‐Haenszel OR with 95% CIs. For continuous outcomes, we analysed data as MDs or standardised mean difference (SMD) where scales are combined, with the 95% confidence interval (95% CI). We calculated the number needed to treat for an additional beneficial outcome (NNTB) from the pooled OR and assumed control risk using the formula described in Section 12.5 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011).
'Summary of findings' table
We created seven 'Summary of findings' tables that include WHO functional class status, quality of life, mortality, change in haemodynamics, and six‐minute walk distance. We used the five GRADE considerations (risk of bias, consistency of effect, imprecision, indirectness, and publication bias) to assess the quality of a body of evidence as it relates to the studies that contribute data for the prespecified outcomes. We used the methods and recommendations described in Chapter 11 of the Cochrane Handbook for Systematic Reviews of Interventions (Schüneman 2017), employing GRADEpro software (GRADEpro GDT). 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.
Análisis de subgrupos e investigación de la heterogeneidad
We planned to carry out the following subgroup analyses:
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Paediatric population up to 18 years and an adult population aged 18 years or over.
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Dosage of PDE5 inhibitor.
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Mode of administration.
With the following outcomes in subgroup analyses:
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WHO functional class.
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Mortality.
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Six‐minute walk distance.
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Haemodynamic criteria.
However, there were insufficient studies per comparison to perform meta‐analyses for these subgroups, so we present narrative results (described in‐text where applicable).
Análisis de sensibilidad
We planned to carry out the following sensitivity analyses:
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Exclusion of trials identified as being at high risk of selection bias (described in‐text where applicable).
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Fixed‐effect model compared with random‐effects model (presented in table form).
Results
Description of studies
Results of the search
We identified 4840 citations in the initial search, and after screening abstracts, selected 136 studies for full‐text review. We included 36 trials with 2999 participants in the final review, plus earlier published abstracts, further post hoc analyses and analyses of secondary outcomes (see Figure 1). We also found five ongoing studies (see Characteristics of ongoing studies).
Study flow diagram.
Included studies
Group 1: Pulmonary arterial hypertension
We included all but two of the 36 studies in the final meta‐analysis; Jalalian 2015 included participants with pulmonary hypertension secondary to sickle cell disease, and Machado 2009 included participants with pulmonary hypertension secondary to beta‐thalassemia, and was stopped early due to increased adverse events in the treatment arm. All studies were randomised; 30 were parallel‐controlled and six were cross‐over trials.
Nineteen trials included group 1 PAH participants (Albini 2017; Bharani 2003; Bharani 2007; Boonstra 2005; Galiè 2005a; Galiè 2009; Galiè 2015; Iversen 2009 (specifically Eisenmenger's syndrome); Jing 2011; Mazzanti 2013; Mukhopadhyay 2011; (Barst 2012; Palii 2014 ‐ specifically children with PAH); Sastry 2004; Simonneau 2008; Singh 2006; Vizza 2017a; Wilkins 2005; Zhuang 2014). Most trials recruited participants with WHO functional class II and III (see Characteristics of included studies).
Eleven trials in PAH participants compared a PDE5 inhibitor to placebo: seven trials compared sildenafil to placebo (Barst 2012; Bharani 2003; Boonstra 2005; Galiè 2005a; Palii 2014; Sastry 2004; Singh 2006), three compared tadalafil to placebo (Bharani 2007; Galiè 2009; Mukhopadhyay 2011), and one compared vardenafil to placebo (Jing 2011).
Four studies compared PDE5 inhibitors to placebo, whilst on additional combination therapy (all as add‐on therapy) (Iversen 2009; Simonneau 2008; Vizza 2017a; Zhuang 2014), and four studies (Albini 2017; Galiè 2015; Mazzanti 2013; Wilkins 2005) compared PDE5 inhibitors to endothelin receptor antagonists.
In the PAH trials, sildenafil was prescribed in eight hourly divided doses, with dosages ranging from 20 to 100 mg three times daily. Where multiple doses were compared, we used results from the highest dose where appropriate (e.g. haemodynamics), and aggregated doses where appropriate (e.g. mortality). Tadalafil was dosed 2.5 to 40 mg daily and vardenafil 5 mg twice daily. The duration of trials ranged from two weeks to 12 months, with a mean treatment duration of 14 weeks.
In PAH participants, the primary outcomes of six‐minute walk distance (6MWD) was reported in 15 trials (Albini 2017; Bharani 2003; Bharani 2007; Boonstra 2005; Galiè 2005a; Galiè 2009; Iversen 2009; Jing 2011; Mukhopadhyay 2011; Palii 2014; Sastry 2004; Simonneau 2008; Singh 2006; Vizza 2017a; Zhuang 2014), WHO functional class improvement in seven of 19 trials (Bharani 2007; Galiè 2005a; Galiè 2015; Jing 2011; Mukhopadhyay 2011; Vizza 2017a; Zhuang 2014), and mortality in 13 of 19 trials (Barst 2012; Bharani 2003; Bharani 2007; Galiè 2005a; Galiè 2009; Galiè 2015; Jing 2011; Palii 2014; Sastry 2004; Simonneau 2008; Wilkins 2005; Vizza 2017a; Zhuang 2014). Haemodynamic data were reported in 12 of 19 trials (Albini 2017; Barst 2012; Bharani 2003; Bharani 2007; Galiè 2005a; Iversen 2009; Jing 2011; Mukhopadhyay 2011; Sastry 2004; Simonneau 2008; Singh 2006; Zhuang 2014), For quality of life, two trials used the SF‐36 form (scores 1 to 100, higher scores indicate better quality of life) (Galiè 2005a; Simonneau 2008); minimum clinical improvement difference (MCID) for physical functioning domain for PAH = 13, vitality = 15 (Gilbert 2009). One used a heart failure questionnaire (Sastry 2004), where the higher the score the better the quality of life, and one (Wilkins 2005) used the Kansas City Cardiomyopathy Questionnaire, where higher scores indicated better quality of life. Six trials measured dyspnoea using the Borg dyspnoea scale (MCID for PAH = 1 (Khair 2016)) (Bharani 2003; Bharani 2007; Galiè 2005a; Jing 2011; Sastry 2004; Vizza 2017a). Eleven studies reported adverse events (Albini 2017; Galiè 2005a; Galiè 2009; Galiè 2015; Iversen 2009; Jing 2011; Mukhopadhyay 2011; Sastry 2004; Simonneau 2008; Vizza 2017a; Zhuang 2014).
Group 2: Pulmonary hypertension due to left‐heart disease
Five trials included PH secondary to left‐heart disease (Bermejo 2017 (valvular heart disease); Guazzi 2011a (HFpEF); Hoendermis 2015 (HFpEF); Lewis 2007 (systolic heart failure); Ovchinnov 2015 (diastolic heart failure)). Heart failure was reported as optimally treated according to accepted guidelines at the time of enrolment. All five trials used sildenafil 25 to 75 mg three times daily compared to placebo. Three trials had a 12‐week duration, one trial was for six months (Bermejo 2017), and one trial (Guazzi 2011a) had a 12‐month duration. In terms of primary outcomes, three of the five reported improvement in WHO functional class (Bermejo 2017; Hoendermis 2015; Lewis 2007), three of the five reported 6MWD (Bermejo 2017; Lewis 2007; Ovchinnov 2015), and three of the five reported mortality (Bermejo 2017; Hoendermis 2015; Lewis 2007). Haemodynamic data were assessed using right‐heart catheterisation in three of the five trials (Guazzi 2011a; Hoendermis 2015; Lewis 2007), and pulmonary artery systolic pressure (PASP) using transthoracic ultrasound in one trial (Bermejo 2017). Quality of life was reported in one trial (Hoendermis 2015) using the Kansas City Cardiomyopathy Questionnaire (23 items, a higher score indicating better quality of life), and one trial (Guazzi 2011a) reported dyspnoea. Two trials reported adverse events, including exacerbation of heart failure (Bermejo 2017; Guazzi 2011a).
Group 3: Pulmonary hypertension due to lung disease
Five trials included PH secondary to lung disease, predominantly that of COPD (Blanco 2013; Goudie 2014; Rao 2011; Vitulo 2016), and one with IPF (Han 2013). The duration was 12 to 16 weeks (median 12 weeks). Four compared sildenafil to placebo (Blanco 2013; Han 2013; Rao 2011; Vitulo 2016) and one (Goudie 2014) compared tadalafil to placebo. The primary outcomes of improvement in WHO functional class were reported in only one trial (Rao 2011); 6MWD in all five trials, and no trials reported mortality. Only two trials (Rao 2011; Vitulo 2016) reported haemodynamic data. Blanco 2013 reported quality of life using SFGRQ (although this was reported using median and IQR) and SF‐36. Goudie 2014 reported SF‐36 and Minnesota Questionnaire. Vitulo 2016 reported SF‐36 and BODE index. No trials reported dyspnoea. Three trials reported adverse events, although insufficient data were provided to produce a meta‐analysis.
Group 4: Chronic thromboembolic pulmonary hypertension
Three trials included CTEPH participants (Galiè 2016a; Palazzini 2010; Suntharalingham 2008). All trials used sildenafil, with two (Palazzini 2010; Suntharalingham 2008) comparing to placebo, and Galiè 2016a comparing to bosentan. Trial duration was a mean of 3.5 months. Improvement in functional class was reported in one study, 6MWD in all three studies, mortality in all three studies, and haemodynamic data in all three studies. One study (Suntharalingham 2008) measured quality of life using the CAMPHOR scale (higher scores indicate worse quality of life), and also reported dyspnoea using the Borg scale. Only one study reported adverse events.
Mixed group 2 to 4 pulmonary hypertension
Two trials enrolled participants with PH across WHO Groups 2 and 3 (Dwivedi 2015; Salem 2013), including participants with secondary pulmonary hypertension due to COPD, heart failure, valvular heart disease, and cardiomyopathy. Sildenafil 20 to 50 mg three times daily was compared to placebo. Only improvement in functional class, 6MWD, and PASP were reported.
Group 5: Haematological disorders
Two trials included participants with PH secondary to haematological disorders (Machado 2009 (sickle cell disease); Jalalian 2015 (beta‐thalassemia)). We analysed these trials descriptively and separately.
Excluded studies
We excluded 65 studies for the following reasons: ineligible participant population (6); ineligible intervention (13); ineligible study design (22); extension of a previous study (9); post‐hoc analysis (15) (see Characteristics of excluded studies).
Risk of bias in included studies
We assessed the risks of bias in the included studies using the Cochrane 'Risk of bias' assessment tool (Higgins 2017), and included the domains of allocation, blinding, incomplete outcome data, selective reporting, and other potential sources of bias. Please see Figure 2 for a summary of the 'Risk of bias' findings.
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
Allocation
We assessed random sequence generation as low risk for 23 studies. Albini 2017; Bharani 2003; Bharani 2007; Boonstra 2005; Galiè 2016a; Jalalian 2015; Machado 2009; Mazzanti 2013; Mukhopadhyay 2011; Ovchinnov 2015; Palii 2014; Suntharalingham 2008; Zhuang 2014 were at unclear risk, as they did not report methods of random sequence generation.
We assessed allocation concealment as low risk for 26 studies and unclear risk for Albini 2017; Barst 2012; Bharani 2003; Bharani 2007; Boonstra 2005; Dwivedi 2015; Galiè 2016a; Palazzini 2010, as allocation concealment was not reported. We assessed Mazzanti 2013 and Ovchinnov 2015 as high risk, as each study was reported as an open‐label study.
Blinding
We assessed Bharani 2003; Bharani 2007; Blanco 2013; Boonstra 2005; Galiè 2016a; Palazzini 2010; Palii 2014; Rao 2011; Salem 2013; Suntharalingham 2008; Vitulo 2016 as being at unclear risk, as blinding of participants and personnel was not clearly reported. Ovchinnov 2015 and Mazzanti 2013 were assessed as being at high risk as the trials were reported as open‐label studies, so it was likely that participants knew which intervention they were receiving.
We assessed Albini 2017; Bharani 2003; Bharani 2007; Blanco 2013; Boonstra 2005; Dwivedi 2015; Galiè 2016a; Jalalian 2015; Mukhopadhyay 2011; Ovchinnov 2015; Palazzini 2010; Palii 2014; Rao 2011; Salem 2013; Suntharalingham 2008; Vitulo 2016; Zhuang 2014 as being at unclear risk of detection bias, as methods for blinding of outcomes were not clearly reported. We assessed Mazzanti 2013 as being at high risk, as this trial was reported as open‐label and there were no specified methods to keep outcomes blinded from assessors.
Incomplete outcome data
We assessed attrition bias as unclear risk in 15 studies: Albini 2017; Bharani 2007; Galiè 2005a; Galiè 2009; Galiè 2016a; Goudie 2014; Han 2013; Lewis 2007; Mukhopadhyay 2011; Palii 2014; Salem 2013; Sastry 2004; Simonneau 2008; Singh 2006; Suntharalingham 2008, given that only a proportion of participants who were enrolled completed the study, for reasons which were not given; however, this included both intervention and comparator arms in approximately equal proportions.
For Boonstra 2005 and Dwivedi 2015, about one‐third of enrolled participants did not complete the study, for unknown reasons, so we assigned this a high risk of bias. For Ovchinnov 2015, the number of enrolled participants and the number of completers were not reported, so we rated this at high risk.
Selective reporting
We found reporting bias to be high risk in Boonstra 2005, as only one outcome was reported. Han 2013 was a substudy of the STEP‐IPF trial, and it is not clear if this analysis was planned a priori so we assessed it as high risk. Ovchinnov 2015 only reported quantitative data from the intervention group and not from the comparator group, and no between‐group effect sizes were reported, so we rated it at high risk. Simonneau 2008 reported that they only assessed secondary outcomes if the primary outcomes were significant, although it is unclear if this affected the overall reporting of the trial outcomes, as a number of secondary outcomes were reported; we assessed this as high risk of bias.
Other potential sources of bias
We assessed Albini 2017; Boonstra 2005; Galiè 2016a; Ovchinnov 2015; Palazzini 2010; and Palii 2014 as unclear risk of other bias, as these were abstracts from conference proceedings, and were not recorded in any clinical trials registry, with limited information about methods used and limited data presented to determine if other significant risk was present.
Effects of interventions
See: Summary of findings for the main comparison Group 1 Pulmonary arterial hypertension ‐ PDE5i compared to placebo; Summary of findings 2 Group 1 Pulmonary arterial hypertension ‐ PDE5i compared to placebo, on combination therapy; Summary of findings 3 Group 1 Pulmonary arterial hypertension ‐ PDE5i compared to ERA; Summary of findings 4 Group 2 Pulmonary hypertension due to left‐heart disease ‐ PDE5i compared to placebo; Summary of findings 5 Group 3 Pulmonary hypertension due to lung disease ‐ PDE5i compared to placebo; Summary of findings 6 Group 4 Pulmonary hypertension due to CTEPH ‐ PDE5i compared to placebo; Summary of findings 7 Mixed Pulmonary hypertension group 2 ‐ 4 ‐ PDE5i compared to placebo
Group 1: Pulmonary arterial hypertension
PDE5 inhibitors compared to placebo
Change in WHO functional class
Four studies assessed change in WHO functional class (Comparison 1). There was a significant improvement in WHO functional class favouring PDE5 inhibitors when compared to placebo, (odds ratio (OR) 8.59, 95% CI 3.95 to 18.72; P < 0.001; 4 trials, 282 participants; I2 = 0%; Analysis 1.1; see Figure 3).
Forest plot of comparison: 1 Group 1 Pulmonary Arterial Hypertension ‐ PDE5i versus placebo, outcome: 1.1 Improvement in WHO functional class.
Six‐minute walk distance
Eight studies assessed 6MWD. There was a significant improvement in 6MWD using PDE5 inhibitors compared to placebo (mean difference between PDE5i and placebo (MD) 48 metres, 95% CI 40 to 56; P <0.001; 8 trials, 880 participants; Analysis 1.2). The effect was clinically significant, with a mean difference of 48 metres (MCID in PAH is 41 metres (Gilbert 2009)). The effect on 6MWD was comparable between drugs (sildenafil MD 57 metres, 95% CI 44 to 69; P < 0.001; 4 trials, 339 participants; tadalafil MD 38 metres, 95% CI 28 to 49; P < 0.001; 3 trials, 477 participants; vardenafil MD 69 metres, 95% CI 41 to 97; P < 0.001; 1 trial, 64 participants). There was significant heterogeneity between trials (I2 = 71; P = 0.03), which is not fully explained by the different drugs used in each trial (subgroup difference I2 = 51%; P = 0.03).
Mortality
There was a significant effect on mortality using PDE5 inhibitors compared to placebo (OR 0.22, 95% CI 0.07 to 0.68, P = 0.009; 8 trials, 1119 participants; Analysis 1.3; see Figure 4). In the placebo group four people out of 100 died, compared to one (95% CI 0 to 3) out of 100 for the PDE5 inhibitor group; see Figure 5. The number needed to treat to prevent one additional death was 32 (95% CI 27 to 78).
Forest plot of comparison: 1 Group 1 Pulmonary Arterial Hypertension ‐ PDE5i versus placebo, outcome: 1.3 Mortality.
Cates Plot for mortality with PDE5 inhibitor treatment in Group 1 PAH
Haemodynamics
There was a significant reduction in the mean PAP (MD −6.43 mmHg, 95% CI −8.13 to −4.74; P < 0.001; 6 trials, 453 participants; Analysis 1.4), in the right arterial pressure (RAP) (MD −1.35 mmHg, 95% CI −2.34 to −0.36; P = 0.008; 3 trials, 341 participants; Analysis 1.5), in cardiac index (MD 0.28 L/min/m2, 95% CI 0.16 to 0.40; P < 0.001; 4 trials, 239 participants; Analysis 1.6), in PVR (MD −4.74 WU, 95% CI −6.13 to −3.35; P < 0.0001; 3 trials, 266 participants; Analysis 1.7), and in PASP (MD −11.62 mmHg, 95% CI −25.18 to 1.94; P = 0.09; 2 trials, 48 participants; Analysis 1.8). There was significant heterogeneity between trials for mean PAP (I2 = 76%; P = 0.01). However, the test for subgroup difference was not significant (P = 0.23; I2 = 31%), suggesting that factors other than different drugs across trials may account for this heterogeneity. There was also significant heterogeneity for cardiac index (I2 = 77%; P = 0.005). The test for subgroup difference (P = 0.03; I2 = 82%) indicated that the difference between different drugs used may account for this heterogeneity.
Exercise capacity other than six‐minute walk distance
Two studies assessed exercise capacity. Sastry 2004 examined time on treadmill (using the Naughton protocol) and found a statistically significant difference favouring sildenafil with post‐treatment sildenafil 686.82 metres (SD 224.02) compared to placebo 475.05 metres (SD 168.02; P < 0.001). Singh 2006 assessed Mets achieved using a modified Bruce exercise protocol. There was a statistically significant difference favouring sildenafil post‐treatment 687 seconds (SD 243.9 sec) compared to placebo 452.1 seconds (SD 165.6 sec) (P < 0.001).
Quality of life
Only two studies assessed quality of life, and data were considered too heterogenous to combine in a meta‐analysis. Galiè 2005a assessed quality of life using two measures: the Medical Outcomes Study 36‐item short form (SF‐36), divided into physical functioning, general health, and vitality domains (scores 1 to 100, higher scores indicate better quality of life), and found a statistically significant improvement in all SF‐36 domains for sildenafil‐treated participants, and when compared to placebo in physical functioning (P < 0.001), general health (P < 0.001), and vitality (P < 0.05). There was also a statistically significant improvement in placebo‐treated participants in the physical functioning domain. They also used the EuroQol 5D (EQ‐5D) questionnaires at baseline and after 12 and 24 weeks of treatment (comprise five dimensions: mobility, self‐care, usual activities, pain/discomfort and anxiety/depression; higher scores indicate worse quality of life). Statistically significant improvements were also observed for the EQ‐5D current health status (P < 0.01) and utility index (P < 0.01).
Sastry 2004 assessed quality of life using a chronic heart failure questionnaire, includes the following domains: dyspnoea, fatigue, and emotional function of daily living; lower scores indicate worse quality of life. There was a statistically significant difference in the fatigue domain (sildenafil post‐treatment score 22.33, SD 4.82 compared to placebo post‐treatment score 20.67, SD 5.19; P = 0.04), and a statistically non‐significant difference in the emotional function domain (sildenafil post‐treatment score 37.33, SD 9.3, compared to placebo post‐treatment score 34.71, SD 10.91; P = 0.06), favouring sildenafil compared with placebo.
Dyspnoea
Five trials assessed dyspnoea: four (Bharani 2003; Bharani 2007; Galiè 2005a; Jing 2011) used the Borg scale and one (Sastry 2004) used a chronic heart failure questionnaire. When we combined the studies using Borg scale, there was a statistically significant improvement in dyspnoea (MD −0.72, 95% CI −0.99 to −0.44; P < 0.001; 4 studies, 239 participants; Analysis 1.9), but the effect size did not meet the minimum clinical improvement difference (MCID = 1, Khair 2016). There was significant heterogeneity across trials (I2 = 64%; P = 0.04), but the test for subgroup differences (I2 = 37%; P = 0.20) suggests that factors other than different drugs may account for differences across the trials.
Hospitalisation/intervention
Three trials (746 participants) reported clinical worsening requiring intervention, including hospitalisation and initiation or addition of new therapy. There was no statistically significant difference, although the effect estimate favoured PDE5 inhibitors compared to placebo (OR 0.58, 95% CI 0.27 to 1.23; P = 0.16; Analysis 1.10).
Adverse events
There were more adverse events in the PDE5 inhibitor participants compared to placebo (Analysis 1.11).
There was a statistically significant increase in headache (OR 1.97, 95% CI 1.33 to 2.92; P < 0.001; 5 studies, 848 participants), in gastrointestinal (GI) upset (OR 1.63, 95% CI 1.07 to 2.48; P = 0.02; 5 studies, 848 participants), in flushing (OR 4.12, 95% CI 1.83 to 9.26; P < 0.001; 3 studies, 748 participants), and in muscle aches and joint pains (OR 2.52, 95% CI 1.59 to 3.99; P < 0.001; 4 studies, 792 participants).
There was no statistically significant difference in epistaxis (OR 2.37, 95% CI 0.83 to 6.77; P = 0.11; 2 studies, 682 participants), in respiratory symptoms (OR 1.74, 95% CI 0.89 to 3.40; P = 0.10; 3 studies, 748 participants), or in visual disturbance (OR 2.04, 95% CI 0.58 to 7.14; P = 0.27; 3 studies, 748 participants).
Although different formulation of drugs were not compared head‐to‐head, when comparing the odds of developing an adverse event, tadalafil appeared to cause greater frequency of headaches (OR 2.86, 95% CI 1.51 to 5.42; P = 0.001) compared to sildenafil (OR 1.43, 95% CI 0.83 to 2.44; P = 0.20), greater GI upset (OR 1.93, 95% CI 1.07 to 3.50; P = 0.03) compared to sildenafil (OR 1.50, 95% CI 0.81 to 2.78; P = 0.19), and greater frequency of muscle and joint pains (OR 4.02, 95% CI 2.05 to 7.89; P < 0.001) compared to sildenafil (OR 1.48, 95% CI 0.93 to 2.99; P = 0.27).
Subgroup analyses
There were no individual patient data to compare outcomes for a paediatric population versus an adult population. Palii 2014 recruited only children with PAH due to congenital cardiac shunts and found benefit in improvement in functional class, mortality (5 of 39 died at 6 to 12 months in the placebo group compared to none of 38 in the sildenafil group), improved exercise tolerance, and improved haemodynamics. Barst 2012 recruited only children with pulmonary arterial hypertension, and found no significant difference in terms of exercise duration or cardiopulmonary haemodynamics.
Almost all trials included participants with WHO functional class II/III. Boonstra 2005 compared participants with WHO FC I/II and III/IV and found that the six‐minute walk distance improved in both groups (49 metres improvement in WHO FC I/II (n = 27) and 54 metres improvement in WHO FC III/IV (n = 42)).
PDE5 inhibitors compared to placebo on additional therapy
Four trials compared PDE5 inhibitors to placebo, whilst on other therapy for pulmonary hypertension (Comparison 2). Iversen 2009 and Vizza 2017a compared sildenafil to placebo as add‐on therapy to bosentan. Simonneau 2008 compared sildenafil to placebo as add‐on therapy to intravenous epoprostenol. Zhuang 2014 compared tadalafil to placebo as add‐on therapy to ambrisentan.
Change in WHO functional class
There was no significant difference in WHO functional class (OR 1.20, 95% CI 0.66 to 2.17; P = 0.55; 2 trials, 227 participants; Analysis 2.1).
Six‐minute walk distance
There was a statistically significant difference in 6MWD using PDE5 inhibitors compared to placebo as add‐on therapy (MD 20, 95% CI 9 to 30; P < 0.001; 4 trials, 509 participants; Analysis 2.2), but this did not meet the MCID threshold (41 metres; Gilbert 2009).
Mortality
There was no statistically significant difference in mortality using PDE5 inhibitors compared to placebo as add‐on therapy (OR 0.26, 95% CI 0.07 to 1.06; P = 0.06; 3 trials, 492 participants; Analysis 2.3).
Haemodynamics
There was a statistically significant reduction in mean PAP (MD −4.58 mmHg, 95% CI −6.14 to −3.01; P < 0.001; 2 trials, 387 participants; Analysis 2.4), and in PVR (SMD −0.48, 95% CI −0.72 to −0.25; P > 0.001; 3 trials, 303 participants; Analysis 2.6) and a statistically significant increase in cardiac output (MD 0.87 L/min, 95% CI 0.53 to 1.21; P < 0.001; 3 trials, 310 participants; Analysis 2.5) using sildenafil compared to placebo as add‐on therapy.
Exercise capacity other than six‐minute walk distance
No studies reported additional exercise testing.
Quality of life
One trial (Simonneau 2008) assessed quality of life using SF‐36. There was a significant improvement in the sildenafil group in terms of physical functioning (MD 0.3, 95% CI 4.7 to 4.1 for placebo versus MD 7.8, 95% CI 3.6 to 12.1 for sildenafil; P = 0.003), general health (MD 1.4, 95% CI 4.8 to 2.1 versus MD 6.6, 95% CI 3.3 to 9.9; P = 0.001), vitality (MD 0.8, 95% CI 3.3 to 4.9 versus MD 10.2, 95% CI 6.2 to 14.2; P = 0.001), social functioning (MD 2.5, 95% CI 7.8 to 2.9 versus MD 4.0, 95% CI 1.1 to 9.2; P = 0.05), and mental health (MD 3.7, 95% CI 7.0 to 0.5 versus MD 3.0, 95% CI 0.1 to 6.2; P = 0.001), but not in physical role (MD 3.6, 95% CI 5.4 to 12.7 versus MD 10.7, 95% CI 2.0 to 19.4; P = 0.20), bodily pain (MD 0.6, 95% CI 4.3 to 5.5 versus MD 5.8, 95% CI 1.0 to 10.6; P = 0.09), or emotional role (MD 4.6, 95% CI 4.2 to 13.5 versus MD 1.8, 95% CI 6.8 to 10.3; P = 0.60).
Dyspnoea
No studies assessed the effect on dyspnoea.
Hospitalisation/intervention
Four studies assessed clinical worsening requiring hospitalisation or additional therapy. There was a statistically significant difference favouring PDE5 inhibitors compared to placebo as add‐on therapy (OR 0.38, 95% CI 0.21 to 0.68; P = 0.001; 4 trials, 717 participants; Analysis 2.7).
Adverse events
There was a statistically significant increased risk of headache (OR 2.49, 95% CI 1.74 to 3.56; P < 0.001; 5 studies, 768 participants), GI upset (OR 1.95, 95% CI 1.30 to 2.93; P = 0.001; 4 studies, 726 participants), muscle and joint pain (OR 2.17, 95% CI 1.28 to 3.67; P = 0.004; 3 studies, 494 participants), and visual disturbance (OR 3.95, 95% CI 0.97 to 16.08; P = 0.06; 2 studies, 368 participants). There was no statistically significant difference in flushing (OR 1.11, 95% CI 0.63 to 1.96; P = 0.71; 2 studies, 368 participants) or epistaxis (OR 1.32, 95% CI 0.34 to 5.12; P = 0.69; 2 studies, 358 participants) Analysis 2.8.
PDE5 inhibitors compared to endothelin receptor antagonists (ERA)
Three trials compared PDE5 inhibitors head‐to‐head with an endothelin receptor antagonist (Comparison 3): Albini 2017 compared monotherapy (ambrisentan or tadalafil) with combination therapy; for the purpose of this meta‐analysis ambrisentan was compared to tadalafil. Galiè 2015 compared ambrisentan monotherapy with tadalafil monotherapy with combination therapy; for this meta‐analysis, ambrisentan 10 mg daily monotherapy was compared to tadalafil 40 mg daily monotherapy. Wilkins 2005 compared sildenafil (50 mg twice daily for 4 weeks, then 50 mg three times daily) with bosentan (62.5 mg twice daily for 4 weeks, then 125 mg twice daily).
Change in WHO functional class
There was no significant difference in WHO functional class (OR 0.94, 95% CI 0.55 to 1.60; P = 0.82; 1 trial, 244 participants; Analysis 3.1).
Six‐minute walk distance
There was a statistically and clinically significant difference in 6MWD favouring sildenafil compared to bosentan (MD 49 metres, 95% CI 4 to 95; P = 0.03; 2 trials, 36 participants; Analysis 3.2). As Galiè 2015 reported 6MWD as median and IQR, it was not possible to include it in the meta‐analysis (Higgins 2011). The median change from baseline distance in the tadalafil group was 23 metres (IQR −8 to 66) compared to the ambrisentan group 27 metres (IQR −14 to 63).
Mortality
There was no significant difference in mortality comparing PDE5 inhibitors to ERA (OR 3.19, 95% CI 0.74 to 13.64; P = 0.12; 2 trials, 272 participants; Analysis 3.3).
Haemodynamics
There was no significant difference in haemodynamics in one small study (32 participants), including mean PAP (MD 7.00, 95% CI −4.82 to 18.82; P = 0.25), RAP (MD 2.00, 95% CI −2.14 to 6.14; P = 0.34), cardiac index (MD 0.00, 95% CI −0.49 to 0.49; P = 1.00), and PVR (MD 0.00, 95% CI −1.93 to 1.93; P = 1.00). Wilkins 2005 assessed participants using cardiac magnetic resonance imaging (MRI) and found no significant difference in cardiac index (MD 0 L/min/m2, 95% CI −0.2 to 0.2).
Exercise capacity other than six‐minute walk distance
No studies reported additional exercise testing.
Quality of life
One study (Wilkins 2005) found a significant difference in quality of life favouring sildenafil compared to bosentan using the Kansas City Cardiomyopathy Quality‐of‐Life questionnaire (higher scores indicate better quality of life) (MD 22.00, 95% CI 9.00 to 35.00; P = 0.009).
Dyspnoea
No studies assessed dyspnoea.
Hospitalisation/intervention
There was a statistically significant incidence of clinical worsening in the ERA group compared to the PDE5 inhibitor group (OR 0.52, 95% CI 0.30 to 0.89; P = 0.02; 2 trials, 275 participants; Analysis 3.9).
Adverse events
Only one trial assessed adverse events (Analysis 3.10). There was no significant difference in headache (OR 1.10, 95% CI 0.65 to 1.87; P = 0.72), GI upset (OR 0.79, 95% CI 0.42 to 1.45; P = 0.44), flushing (OR 0.60, 95% CI 0.27 to 1.33; P = 0.21), muscle or joint pain (OR 1.34, 95% CI 0.60 to 3.00; P = 0.47), or respiratory symptoms (OR 0.80, 95% CI 0.47 to 1.35; P = 0.40).
Group 2: Pulmonary hypertension due to left‐heart disease
Five trials assessed participants with pulmonary hypertension secondary to left‐heart disease (Comparison 4). All trials compared sildenafil with placebo.
Change in WHO functional class
Significantly fewer people receiving sildenafil improved in WHO functional class compared to placebo (OR 0.53, 95% CI 0.32 to 0.87; P = 0.01; 3 trials, 285 participants; Analysis 4.1), although there was considerable heterogeneity between trials (I2 = 67%, P = 0.05).
Six‐minute walk distance
Three studies assessed the 6MWD. There was a significant difference favouring sildenafil (MD 34 metres, 95% CI 23 to 46; P < 0.001; 3 studies, 284 participants; Analysis 4.2; see Figure 6).
Forest plot of comparison: 4 Group 2 Pulmonary hypertension due to left heart disease (sildenafil v placebo), outcome: 4.2 Six‐minute walk distance.
Mortality
Three studies assessed mortality. There was no significant difference between sildenafil and placebo (OR 1.27, 95% CI 0.28 to 5.80; P = 0.76; 3 trials, 286 participants; Analysis 4.3).
Haemodynamics
There was a significant reduction in mean PAP (MD −10.17 mmHg, 95% CI −11.99 to −8.35; P < 0.001, although with significant heterogeneity (I2 = 98%, P < 0.001); 3 trials, 130 participants; Analysis 4.4), transpulmonary pressure gradient (TPG) (MD −14.60 mmHg, 95% CI −15.63 to −13.57; P < 0.001; 1 trial, 44 participants; Analysis 4.6), and PASP (MD −27.60 mmHg, 95% CI −30.37 to −24.83; P < 0.001; 1 trial, 44 participants; Analysis 4.8) using sildenafil compared to placebo. There was no significant difference in cardiac index (MD 0.07 L/min/m2, 95% CI −0.17 to 0.30; P = 0.59; 2 trials, 96 participants; Analysis 4.5) or RAP (MD −1.00 mmHg, 95% CI −3.77 to 1.77; P = 0.48; 1 trial, 34 participants; Analysis 4.7). Bermejo 2017 reported results in median and IQR so we could not combine the data in the meta‐analysis, but there was no significant difference in haemodynamic parameters measured by Doppler echocardiography or magnetic resonance.
Exercise capacity other than six‐minute walk distance
Two studies reported exercise capacity testing. Hoendermis 2015 reported no significant difference in VO2 peak (treatment effect sildenafil MD 0.2 mL/kg/min‐1 (95% CI ‐0.9 to 1.4) compared to placebo MD 0.70 mL/kg/min‐1 (95% CI −0.3 to 1.6); P = 0.51). Lewis 2007 reported a statistically significant difference in VO2 peak favouring sildenafil (post‐treatment sildenafil MD 1.8 ± 0.7 mL/kg/min‐1 compared to placebo MD 0.27 mL/kg/min‐1; P = 0.02).
Quality of life
One study (Hoendermis 2015) assessed quality of life using the Kansas City Cardiomyopathy Questionnaire (KCCQ: higher scores reflect better health status). The mean change in the KCCQ clinical summary score from baseline to 12 weeks was 12.05 points higher (95% CI 1.14 to 22.96) in the sildenafil group and 19.83 points higher (95% CI 8.23 to 31.44) in the placebo group, although the difference was not significant (P = 0.32).
Dyspnoea
One study (Guazzi 2011a) assessed dyspnoea using the 16‐item Chronic Heart Failure Questionnaire (CHQ) (Guyatt 1989). There was a significant improvement in dyspnoea using sildenafil compared to placebo (MD 1.15, 95% CI 0.51 to 1.79; P < 0.001; 1 trial, 44 participants; Analysis 4.9).
Hospitalisation/intervention
There were mixed results in terms of clinical worsening requiring intervention including hospitalisation. Lewis 2007 (PH with systolic dysfunction) reported no significant difference in clinical worsening (OR 0.32, 95% CI 0.05 to 1.95; P = 0.22; 34 participants; Analysis 4.10), but Bermejo 2017 (valvular heart disease) reported an increased risk of hospitalisations, particularly relating to heart failure in those treated with sildenafil compared to placebo (OR 1.43; 95% CI 0.76 to 2.70; P = 0.05; 200 participants).
Adverse events
Three studies reported adverse events. In Lewis 2007 the incidence of headache occurred more commonly in those treated with sildenafil compared to placebo (1 trial; P < 0.05) but there was no significant difference in terms of arrhythmias, hypotension, diarrhoea, flushing, or myalgia, and no incidence of visual disturbance. Hoendermis 2015 reported that adverse events occurred in 22 participants (85%) who received sildenafil and 21 participants (81%) who received placebo (P = 1.00). Prevalence of known adverse effects of sildenafil, such as headache, dyspepsia, (orthostatic) hypotension, increased erection and respiratory tract infection, were reported to be higher in the sildenafil group, but event data were not supplied. Bermejo 2017 reported an increased risk of gastrointestinal events (OR 2.82, 95% CI 0.91 to 10.41; P = 0.06), and infections (OR 0.22, 95% 0.02 to 1.13; P = 0.05).
Group 3: Pulmonary hypertension due to lung disease
Five trials included participants with pulmonary hypertension secondary to lung disease or hypoxaemia; in four trials this was secondary to COPD, and in one trial secondary to IPF (Comparison 5) (Han 2013) . Four trials compared sildenafil to placebo, and one trial (Goudie 2014) compared tadalafil to placebo.
Change in WHO functional class
One trial assessed improvement in WHO functional class, and found a statically significant improvement using sildenafil compared with placebo (OR 44.33, 95% CI 4.78 to 410.93; P < 0.001; 40 participants; Analysis 5.1).
Six‐minute walk distance
There was a significant improvement in the 6MWD with the use of sildenafil compared to placebo (MD 27 metres, 95% CI 2 to 51; P < 0.001; 5 trials, 350 participants; Analysis 5.2; see Figure 7).
Forest plot of comparison: 5 Group 3 Pulmonary Hypertension due to lung disease, outcome: 5.2 Six‐minute walk distance.
Mortality
No studies assessed mortality.
Haemodynamics
There was no significant difference in terms of mean PAP (MD −0.14 mmHg, 95% CI −6.65 to 6.37; P = 0.97; 2 trials, 61 participants; Analysis 5.4), cardiac index (MD 0.30 L/min/m2, 95% CI −0.14 to 0.74; P = 0.18; 1 trial, 28 participants; Analysis 5.5), RAP (MD 0.36 mmHg, 95% CI −2.76 to 3.48; P = 0.82; 1 trial, 28 participants; Analysis 5.7) and PVR (MD −1.31 mmHg, 95% CI −3.67 to 1.05; P = 0.28; 1 trial, 28 participants; Analysis 5.6).
Exercise capacity other than six‐minute walk distance
Blanco 2013 reported exercise capacity after three months pulmonary rehabilitation and treatment with sildenafil or placebo. There was no difference in the placebo‐corrected difference in the cycle endurance time: −7 seconds, 90% CI −540 to 244; P = 0.77, or maximal exercise tolerance 1 watt, 90% CI −2 to 5; P = 0.60.
Quality of life
Three studies assessed quality of life. Goudie 2014 used SF‐36 (lower scores indicate worse quality of life), and Vitulo 2016 assessed the BODE index and the Minnesota Questionnaire. Han 2013 used the St George's Respiratory Questionnaire (SGRQ), the EuroQOL, and the SF‐36. We pooled data for the SF‐36 physical function, and demonstrated no significant difference in overall quality of life (MD 0.19, 95% CI −0.07 to 0.44; P = 0.15; 2 trials, 238 participants; Analysis 5.3). Blanco 2013 reported outcomes using mean and IQR, so results could not be pooled in the meta‐analysis. There was no significant difference in SGRQ score (placebo‐corrected difference median 1.3, IQR −3.5 to 6.9, P = 0.53), or SF‐36 physical score (median −1.7, IQR −7.2 to 2.3, P = 0.38), or SF‐36 mental score (median 1.6, IQR −3.7 to 8.5 P = 0.64).
Dyspnoea
No studies assessed dyspnoea.
Hospitalisation/intervention
No studies assessed clinical worsening.
Adverse events
Three trials reported adverse events, but none reported event data that could be pooled in a meta‐analysis. Blanco 2013 reported that adverse events were similar across groups. Rao 2011 reported that headache was the most common side effect with sildenafil. Other adverse effects noted were epigastric pain or discomfort, headache, paraesthesias, and numbness. Vitulo 2016 reported that adverse events were observed in five participants in the sildenafil arm. The events were mild to moderate and included headache, diarrhoea, flushing, limb pain, dyspnoea, myalgia, and peripheral oedema. None interrupted the study treatment because of adverse events. No significant adverse effects were reported in the placebo arm. Two studies reported oxygenation parameters. Vitulo 2016 reported no difference in SpO2 or PaO2 in the sildenafil group from the start to the end of the study. Blanco 2013 reported no significant differences in arterial oxygen tension or saturation between the sildenafil and placebo groups.
Group 4: Chronic thromboembolic pulmonary hypertension (CTEPH)
Three trials included CTEPH participants (Galiè 2016a; Palazzini 2010; Suntharalingham 2008; Comparison 6). All trials used sildenafil, two (Palazzini 2010; Suntharalingham 2008) compared to placebo, and Galiè 2016a compared to bosentan.
Change in WHO functional class
Only one trial examined improvement in WHO functional class in CTEPH participants, and found no significant difference in the use of PDE5 inhibitors compared to placebo (OR 17.18, 95% CI 0.78 to 380.84; P = 0.07; 1 trial, 19 participants; Analysis 6.1).
Six‐minute walk distance
There was no significant difference in 6MWD using PDE5 inhibitors when compared to placebo (MD 18 metres, 95% CI −24 to 59; P = 0.41; 1 trial, 19 participants; Analysis 6.2; see Figure 8) or when compared to bosentan (MD 20 metres, 95% CI −28 to 69; P = 0.41; 2 trials, 227 participants).
Forest plot of comparison: 6 Group 4 Pulmonary Hypertension due to CTEPH, outcome: 6.2 Six‐minute walk distance.
Mortality
There were no deaths in either arm in one trial comparing sildenafil with placebo (20 participants). There was no significant difference in mortality in one trial comparing PDE5 inhibitors to bosentan (OR 1.36, 95% CI 0.22 to 8.48; P = 0.74; 106 participants; Analysis 6.3).
Haemodynamics
There was no difference in haemodynamic parameters. There was no difference in mean PAP using PDE5 inhibitors when compared to placebo (MD −6.20 mmHg, 95% CI −12.40 to −0.00; P = 0.05; 1 trial, 19 participants; Analysis 6.4) or when compared to bosentan (MD 0.76 mmHg, 95% CI −3.96 to 5.48; P = 0.75; 2 trials, 227 participants). There was no difference in cardiac index using PDE5 inhibitors when compared to placebo (MD 0.00 L/min/m2, 95% CI −0.40 to 0.40; P = 1.0; 1 trial, 19 participants; Analysis 6.5) or when compared to bosentan (MD 0.04 L/min/m2, 95% CI −0.22 to 0.31; P = 0.76; 2 trials, 227 participants). There was no difference in PVR using PDE5 inhibitors when compared to placebo (MD −0.89, 95% CI −1.85 to 0.06; P = 0.07; 1 trial, 19 participants; Analysis 6.6) or when compared to bosentan (MD −0.01, 95% CI −0.27 to 0.25; P = 0.96; 2 trials, 227 participants). There was no difference in RAP using PDE5 inhibitors when compared to placebo (MD −0.90 mmHg, 95% CI −6.10 to 4.30; P = 0.73; 1 trial, 19 participants; Analysis 6.7) or when compared to bosentan (MD −1.00 mmHg, 95% CI −3.77 to 1.77; P = 0.48; 1 trial, 121 participants).
Exercise capacity other than six‐minute walk distance
No studies reported exercise capacity testing.
Quality of life
Only one trial examined quality of life, using the CamHOR scale (higher scores indicate worse quality of life). There was no significant difference (MD −0.26, 95% CI −1.17 to 0.64; P = 0.57; 34 participants; Analysis 6.8).
Dyspnoea
No trials assessed dyspnoea.
Hospitaisation/intervention
No trials examined clinical worsening.
Adverse events
There were no significant differences in terms of headache (OR 2.57, 95% CI 0.19 to 34.47; P = 0.48; 19 participants; Analysis 6.9) or GI upset (OR 4.50, 95% CI 0.37 to 54.16; P = 0.24; 19 participants) between PDE5‐inhibitors and placebo in one trial.
Mixed group 2 to 4 pulmonary hypertension
We combined two studies in this meta‐analysis: Salem 2013, which included participants with secondary pulmonary hypertension due to valvular heart disease, chronic thromboembolic disease, COPD, IPF, and idiopathic dilated cardiomyopathy, and Dwivedi 2015, which included participants with symptomatic secondary PAH including idiopathic dilated cardiomyopathy, heart failure with preserved ejection fraction, COPD, and other lung parenchymal disease, and valvular heart disease (Comparison 7).
Change in WHO functional class
There was a significant improvement in WHO functional class favouring PDE5 inhibitors (OR 11.31, 95% CI 4.90 to 26.14; P < 0.001; 2 trials, 146 participants; Analysis 7.1).
Six‐minute walk distance
There was a significant difference in 6MWD in one trial favouring PDE5 inhibitors (MD 51 metres, 95% CI 7 to 95; P=0.02; 106 participants; Analysis 7.2).
Mortality
No trials assessed mortality.
Haemodynamics
There was a significant improvement in PASP (MD −10.00 mmHg, 95% CI −11.92 to −8.08; P < 0.001; 2 trials, 146 participants; Analysis 7.3). No other haemodynamic parameters were measured.
Exercise capacity other than six‐minute walk distance
No studies reported exercise capacity testing.
Quality of life
No trials assessed quality of life.
Dyspnoea
No trials assessed dyspnoea.
Hospitalisation/intervention
No trials assessed clinical worsening.
Adverse events
No trials reported adverse events.
Sensitivity analyses
We planned to use the fixed‐effect model a priori to assess effect sizes. We present a comparison of fixed‐ versus random‐effects in Table 2. Where effect sizes differed, this was explained by high heterogeneity between trials.
| Meta‐analysis | Number of studies | Effect measure | Fixed‐effect size and CI | Random‐effect size and CI |
| Group 1 Pulmonary arterial hypertension ‐ PDE5i versus placebo | ||||
| Improvement in WHO functional class | 4 | OR | 8.59 (3.95 to 18.72) | 8.53 (3.90 to 18.67) |
| Six‐minute walk distance | 8 | MD | 48.17 (40.30 to 56.04) | 52.98 (40.74 to 65.23)1 |
| Mortality | 7 | OR | 0.22 (0.07 to 0.68) | 0.28 (0.08 to 0.95) |
| PAP | 5 | MD | −6.33 (−8.12 to −4.53) | −8.94 (−13.73 to −4.15) |
| RAP | 2 | MD | −1.52 (−2.79 to −0.24) | −1.52 (−2.79 to −0.24) |
| Cardiac index | 4 | MD | 0.28 (0.16 to 0.40) | 0.35 (0.08 to 0.61)a |
| PVR | 3 | MD | −4.74 (−6.13 to −3.35) | −5.02 (−7.02 to −3.02) |
| PASP | 2 | MD | −11.62 (−25.18 to 1.94) | −11.62 (−25.18 to 1.94) |
| Dypnoea | 4 | MD | −0.72 (−0.99 to −0.44) | −0.61 (−1.19 to −0.02) |
| Clinical worsening requiring intervention | 3 | OR | 0.58 (0.27 to 1.23) | 0.55 (0.25 to 1.23) |
| Group 1 Pulmonary arterial hypertension ‐ PDE5i versus placebo to on combination therapy | ||||
| Improvement in WHO functional Class | 2 | OR | 1.20 (0.66 to 2.17) | 1.09 (0.41 to 2.92) |
| Six‐minute walk distance | 4 | MD | 19.66 (9.22 to 30.10) | 18.94 (0.23 to 37.65) |
| Mortality | 3 | OR | 0.26 (0.07 to 1.06) | 0.38 (0.04 to 3.81) |
| PAP | 2 | MD | −4.58 (−6.14 to −3.01) | −5.12 (−8.21 to −2.03) |
| Cardiac output | 2 | MD | 0.87 (0.53 to 1.21) | 0.87 (0.53 to 1.21) |
| PVR | 3 | SMD | −0.48 (−0.72 to −0.25) | −0.36 (−0.84 to 0.12)a |
| Clinical worsening | 3 | OR | 0.34 (0.18 to 0.63) | 0.34 (0.18 to 0.63) |
| Group 1 Pulmonary arterial hypertension ‐ PDE5i versus ERA | ||||
| Improvement in WHO functional Class | 1 | OR | 0.94 (0.55 to 1.60) | 0.94 (0.55 to 1.60) |
| Six‐minute walk distance | 2 | MD | 49.38 (3.65 to 95.11) | 49.38 (3.65 to 95.11) |
| Mortality | 2 | OR | 3.19 (0.74 to 13.64) | 3.19 (0.74 to 13.64) |
| Quality of life | 1 | MD | 22.00 (9.00 to 35.00) | 22.00 (9.00 to 35.00) |
| PAP | 1 | MD | 7.00 (−4.82 to 18.82) | 7.00 (−4.82 to 18.82) |
| RAP | 1 | MD | 2.00 (−2.14 to 6.14) | 2.00 (−2.14 to 6.14) |
| Cardiac index | 1 | MD | 0.00 (−0.49 to 0.49) | 0.00 (−0.49 to 0.49) |
| PVR | 1 | MD | 0.00 (−1.93 to 1.93) | 0.00 (−1.93 to 1.93) |
| Clinical worsening | 2 | OR | 0.52 (0.30 to 0.89) | 0.52 (0.30 to 0.89) |
| Group 2 Pulmonary hypertension due to left‐heart disease | ||||
| Improvement in WHO functional Class | 3 | OR | 0.53 (0.32 to 0.87) | 0.70 (0.20 to 2.37) |
| Six‐minute walk distance | 3 | MD | 34.31 (22.75 to 45.87) | 28.44 (‐1.82 to 58.69)a |
| Mortality | 3 | OR | 0.01 (−0.03 to 0.04) | 0.01 (−0.03 to 0.04) |
| Mean PAP | 3 | MD | −10.17 (−11.99 to −8.35) | −6.58 (−22.28 to 9.12)a |
| Cardiac index | 2 | MD | 0.07 (−0.17 to 0.30) | 0.06 (−0.22 to 0.34) |
| TPG | 1 | MD | −14.60 (−15.63 to −13.57) | −14.60 (−15.63 to −13.57) |
| RAP | 1 | MD | −1.00 (−3.77 to 1.77) | −1.00 (−3.77 to 1.77) |
| PASP | 1 | MD | −27.60 (−30.37 to −24.83) | −27.60 (−30.37 to −24.83) |
| Dypnoea | 1 | MD | 1.15 (0.51 to 1.79) | 1.15 (0.51 to 1.79) |
| Clinical worsening requiring intervention | 2 | OR | 1.19 (0.66 to 2.14) | 0.87 (0.22 to 3.46) |
| Group 3 Pulmonary hypertension due to lung disease | ||||
| Improvement in WHO functional Class | 1 | OR | 44.33 (4.78 to 410.93) | 44.33 (4.78 to 410.93) |
| Six‐minute walk distance | 5 | MD | 14.04 (7.05 to 21.02) | 26.70 (2.00 to 51.39)1 |
| Mean PAP | 2 | MD | −0.14 (−6.65 to 6.37) | −0.14 (−6.65 to 6.37) |
| Cardiac index | 1 | MD | 0.30 (−0.14 to 0.74) | 0.30 (−0.14 to 0.74) |
| PVR | 1 | MD | −1.31 (−3.67 to 1.05) | −1.31 (−3.67 to 1.05) |
| RAP | 1 | MD | 0.36 (−2.76 to 3.48) | 0.36 (−2.76 to 3.48) |
| Quality of life | 3 | MD | 0.19 (−0.07 to 0.44) | 0.19 (−0.07 to 0.44) |
| Group 4 Pulmonary hypertension due to CTEPH | ||||
| Improvement in WHO functional Class | 1 | OR | 17.18 (0.78 to 380.85) | 17.18 (0.78 to 380.85) |
| Six‐minute walk distance | 3 | MD | 18.73 (−12.72 to 50.19) | 18.73 (−12.72 to 50.19) |
| Mortality | 2 | OR | 0.01 (−0.06 to 0.08) | 0.01 (−0.06 to 0.08) |
| Mean PAP | 2 | MD | −1.79 (−5.55 to 1.96) | −1.67 (−6.48 to 3.15) |
| Cardiac index | 3 | MD | 0.03 (−0.19 to 0.25) | 0.03 (−0.19 to 0.25) |
| PVR | 3 | MD | −0.07 (−0.32 to 0.18) | −0.12 (−0.50 to 0.25) |
| RAP | 2 | MD | −0.98 (−3.42 to 1.47) | −0.98 (−3.42 to 1.47) |
| Quality of life | 1 | MD | −0.26 (−1.17 to 0.64) | −0.26 (−1.17 to 0.64) |
| Mixed pulmonary hypertension group 2 to 4 | ||||
| Improvement in WHO functional Class | 2 | OR | 11.33 (4.91 to 26.15) | 11.33 (4.91 to 26.15) |
| Six‐minute walk distance | 1 | MD | 50.97 (44.88 to 57.06) | 50.97 (44.88 to 57.06) |
| PASP | 2 | MD | −10.00 (−11.92 to −8.08) | −10.00 (−11.92 to −8.08) |
astatistically high heterogeneity
CI ‐ confidence interval; CTEPH ‐ chronic thromboembolic pulmonary hypertension; OR ‐ odds ratio; MD ‐ mean difference; PAP ‐ pulmonary artery pressure; PASP ‐ pulmonary artery systemic pressure; PDE5i ‐ phosphodiesterase‐5 inhibitor; PVR ‐ pulmonary vascular resistance; RAP ‐ right atrial pressure; SMD ‐ standardised mean difference; TPG ‐ transpulmonary gradient; WHO ‐ World Health Organization
Group 5: Haematological disorders
Jalalian 2015 included 44 participants with beta‐thalassaemia intermedia and pulmonary hypertension on transthoracic echocardiogram, and were treated for six weeks with tadalafil (40 mg daily) or placebo. The authors reported a significant improvement in the PASP (post‐treatment tadalafil MD 34.26 mmHg; SE 1.15, compared to post‐treatment placebo MD 44.57 mmHg; SE 0.56; P < 0.001). In the tadalafil group two participants dropped out due to severe headache and one due to severe oedema. Three other participants experienced a mild headache with initiation of tadalafil, which resolved after one week. No deaths occurred after six weeks of this trial.
Machado 2009 included those with pulmonary hypertension secondary to sickle cell disease and tested sildenafil versus placebo. The study was prematurely stopped due to a statistically significant increase in serious adverse events requiring hospitalisation in the sildenafil arm.
Discusión
Resumen de los resultados principales
Esta revisión demuestra el beneficio estadístico y clínico claro con la administración de inhibidores de la PDE5 en el grupo 1 de HAP en comparación con un placebo, en cuanto a la mortalidad, la mejoría de la clase funcional de la OMS, el tiempo hasta el empeoramiento clínico, la hemodinamia, la distancia de caminata de seis minutos (6MWD) y la calidad de vida, incluida la disnea. Los médicos y los pacientes deben conocer los efectos secundarios, especialmente la cefalea, el rubor, las molestias gastrointestinales y los dolores musculares y articulares.
Se utilizaron tres formulaciones de inhibidores de la PDE5: sildenafil, tadalafil y vardenafil. Aunque estos fármacos no se compararon entre sí, se observó una dirección beneficiosa del efecto en los tres. Aunque la magnitud del efecto parecía mayor con el sildenafil en comparación con tadalafil o vardenafil, esta diferencia podría ser debida a un número mayor de estudios y de participantes en el grupo de sildenafil. En cuanto a los eventos adversos, aparentemente fueron más probables la cefalea, las molestias gastrointestinales y los dolores musculares en el grupo que recibió tadalafil en comparación con el de sildenafil.
Se demuestra evidencia heterogénea sobre la administración de los inhibidores de la PDE5 para la cardiopatía izquierda. Los ensayos incluidos fueron heterogéneos en la cardiopatía izquierda secundaria a distintos mecanismos. En general, hubo una mejoría estadística y clínicamente significativa en todos los ensayos en cuanto a la clase funcional de la OMS y la 6MWD y una mejoría en la hemodinamia, la calidad de vida y la disnea, aunque este hecho no implicó un beneficio claro para la mortalidad. No puede precisarse si lo anterior se debe a los estudios con poder estadístico insuficiente. Además, hubo cierta evidencia de exacerbación de la insuficiencia cardíaca en un estudio que incluyó a pacientes con cardiopatía valvular, pero a pesar de ser un efecto secundario potencial comprobado de estos fármacos, pocos estudios informaron de eventos adversos.
No hay beneficios claros de la administración de los inhibidores de la PDE5 en la hipertensión pulmonar secundaria a la enfermedad pulmonar, según este metanálisis. Hubo una diferencia significativa desde el punto de vista estadístico pero no clínico en la 6MWD, y ningún beneficio para la mortalidad, la hemodinamia, la calidad de vida y el empeoramiento clínico. La mayoría de los estudios incorporaron a pacientes con EPOC e hipertensión pulmonar; sólo uno incorporó a paciente con FPI. No hay datos sobre los inhibidores de la PDE5 en otros pacientes con enfermedades pulmonares.
No hubo beneficios significativos con la administración de inhibidores de la PDE5 en la HPTEC, en comparación con el placebo o el bosentán, para la mortalidad, el empeoramiento clínico, la 6MWD y la hemodinamia, pero el número de participantes fue reducido.
Puede haber una mejoría en la hemodinamia cardiopulmonar con la administración de los inhibidores de la PDE5 en la hipertensión pulmonar debida a beta talasemia intermedia. Puede haber evidencia de daño con la administración de inhibidores de la PDE5 en pacientes con hipertensión pulmonar secundaria a anemia de células falciformes.
Compleción y aplicabilidad general de las pruebas
Es suficiente el número de ensayos de alta calidad sobre la administración de inhibidores de la PDE5 en comparación con placebo para el grupo 1 de HAP. El riesgo de sesgo en la mayoría de los ensayos fue bajo, y la dirección del efecto se mantuvo entre los estudios. Los inhibidores de la PDE5 son una de cinco clases de fármacos disponibles para el grupo 1 de HAP. Las guías actuales de la European Society of Cardiology (ESC) clasifican a los pacientes según el nivel del riesgo, que se correlaciona con la supervivencia esperada (Boucly 2017; Hoeper 2017; Kylhammar 2018). Las guías indican la administración de la monoterapia con un inhibidor de la PDE5 o un antagonista de receptores de endotelina (ARE) para pacientes en bajo riesgo y el tratamiento combinado o la prostaciclina intravenosa para los pacientes en alto riesgo. Dos estudios compararon la administración de inhibidores de la PDE5 con los ARE y hallaron un posible beneficio de los ARE en cuanto la 6MWD y la calidad de vida y un beneficio no estadísticamente significativo en la mejoría de la clase funcional de la OMS y el empeoramiento clínico, que favorece los ARE.
En varios estudios recientes se ha sugerido el uso de un tratamiento combinado inicial o escalonado en los pacientes en riesgo intermedio, incluido SAREPHIN 2013 (en que se agregó macitentán a un inhibidor de la PDE5 o prostaciclina no parenteral y demostró retraso del empeoramiento clínico), COMPASS‐2 2014 (en que se agregó bosentán a sildenafil y demostró una mejoría pequeña pero estadísticamente significativa en la 6MWD [22 m] y ningún cambio en la morbilidad o la mortalidad), PACES (Simonneau 2008) (en que se agregó sildenafil a epoprostenol y demostró un retraso en el empeoramiento clínico) y GRIPHON 2015 (en que el agregado de selexipag a la monoterapia demostró un retraso en el empeoramiento clínico). El estudio AMBITION 2015 (incluido en esta revisión) examinó el tratamiento combinado inicial y demostró una reducción del fracaso clínico y una mejoría de la 6MWD.
La hipertensión pulmonar secundaria a cardiopatía izquierda (HP‐CPI) es, con gran diferencia, la causa más común de hipertensión pulmonar, y la presencia de HP‐CPI empeora la supervivencia (Strange 2012). Eran heterogéneos los estudios que incluyeron pacientes con HP‐CPI; cuando se agruparon los estudios, hubo un beneficio para los parámetros del ejercicio y la calidad de vida, pero un mayor riesgo de exacerbaciones de la insuficiencia cardíaca. Estudios previos (Jiang 2014; Lindman 2012) se demostró un beneficio hemodinámico agudo en estos pacientes, pero sigue la polémica con respecto al efecto a largo plazo. Bermejo 2017 sugirió un beneficio inicial en la 6MWD a los tres meses (aunque no fue estadísticamente significativo), pero este efecto desapareció a los seis meses, sin diferencia en el efecto entre los dos grupos. En cambio, el otro estudio a largo plazo (Guazzi 2011a [12 meses]) demostró un beneficio continuo y persistente en la hemodinamia con el transcurso del tiempo. Lo anterior indica que puede explicarse la controversia a través de la heterogeneidad en la causa de cardiopatía izquierda que lleva a la hipertensión pulmonar.
La evidencia de hipertensión pulmonar secundaria a enfermedad pulmonar estaba limitada a los pacientes con EPOC. Aunque hubo un estudio pequeño (un subestudio planificado a priori de un ensayo más amplio) en pacientes con FPI, es difícil extrapolar la evidencia presentada en este metanálisis más allá de la población con EPOC. Teóricamente, el empeoramiento del desajuste ventilación‐perfusión inducido por los vasodilatadores pulmonares pueden causar disnea y desmejoramiento clínico (Smith 2013), pero los estudios incluidos no evaluaron la disnea, y se presentaron datos limitados sobre el desmejoramiento clínico. Los ensayos adicionales deben incluir estos resultados.
No todos los estudios incluyeron una evaluación de resultados fidedigna y apropiada. En los ensayos de HP‐CPI, aunque el diagnóstico inicial de la mayoría de los participantes se realizó mediante cateterismo de corazón derecho, la evaluación de resultados se realizó con medidas no invasivas como la presión sistólica de la arteria pulmonar en el ecocardiograma transtorácico. Estudios previos (Farber 2011) han demostrado que estas técnicas no invasivas no siempre se correlacionan con la hemodinamia invasiva, sobre todo en los pacientes con cardiopatía izquierda. Además, se demostró que la presencia de hipertensión pulmonar en la cardiopatía izquierda reduce la tolerancia al ejercicio y aumenta las hospitalizaciones por insuficiencia cardíaca (Vachiéry 2013). Sin embargo, a pesar de estos resultados, sólo tres de cinco estudios informaron de la tolerancia al ejercicio, y sólo dos de cinco informaron de las exacerbaciones de la insuficiencia cardíaca. Los estudios adicionales sobre HP‐CPI deben incluir la 6MWD, los datos hemodinámicos invasivos, el empeoramiento clínico (incluidas las exacerbaciones de la insuficiencia cardíaca) y tener el poder estadístico suficiente para detectar una diferencia en estos resultados.
Calidad de la evidencia
Para los ensayos con pacientes con HAP del grupo 1 que comparan los inhibidores de la PDE5 con un placebo, la certeza de la evidencia fue alta en todos los resultados salvo la distancia de caminata de seis minutos y el índice cardíaco, cuya calificación se disminuyó a moderada por la heterogeneidad alta, aunque el efecto se mantuvo entre los ensayos. La calidad de la evidencia se vio reducida por el número pequeño de participantes en los ensayos de HAP que comparan los inhibidores de la PDE5 con un placebo mientras se administra el tratamiento complementario y los que comparan los inhibidores de la PDE5 con los ARE. El seguimiento fue de hasta 12 meses, pero el seguimiento promedio fue de sólo 14 semanas. Para los efectos a más largo plazo pueden ser útiles los datos de registro del mundo real o de estudios sin ocultación.
Aunque hubo cinco estudios que examinaron la HP‐CPI, los números de cada estudio fueron reducidos, y fue significativa la heterogeneidad de los estudios. Ovchinnov 2015 fue un estudio de calidad deficiente, en que no se informó de la asignación al azar, la ocultación de la asignación, los abandonos ni los cruzamientos, y sólo se presentaron datos cuantitativos del grupo de intervención.
Sesgos potenciales en el proceso de revisión
Esta revisión se realizó en conformidad con las normas Cochrane establecidas. Dos autores de la revisión examinaron de forma independiente los resultados de la búsqueda y las discrepancias se resolvieron mediante discusión y consenso. La búsqueda bibliográfica no se limitó por idioma. Es posible el sesgo de publicación, con lo que podría haber llevado a una sobrestimación del efecto la falta de identificación de ensayos negativos no publicados.
Acuerdos y desacuerdos con otros estudios o revisiones
Los resultados son compatibles con las guías actuales de ESC/ERS (Galiè 2016b), que recomiendan la administración de inhibidores de la PDE5 para la monoterapia como nivel de evidencia IA/B en pacientes de la clase funcional de la OMS I ‐ III, y como nivel de evidencia IIb en pacientes de la clase funcional de la OMS IV (dado que hay evidencia más sólida del efecto del tratamiento combinado y las prostaciclinas intravenosas). De manera similar, las guías actuales de ESC/ERS no recomiendan la administración de inhibidores de la PDE5 para la hipertensión pulmonar relacionada con cardiopatía izquierda o enfermedad pulmonar. Cuando se utilizan los inhibidores de la PDE5 como parte del tratamiento combinado, se debe ser cuidadoso al combinarlos con riociguat, debido a los efectos secundarios potenciales y a la falta de beneficios clínicos adicionales (Galiè 2015b).
Ningún ensayo comparó los inhibidores de la PDE5 entre sí, y es poco probable que se realicen estudios de este tipo dados los beneficios generales de esta clase de fármacos. Los datos indican que puede haber un mejor efecto del tratamiento con sildenafil en comparación con tadalafil, pero este resultado puede estar influido por el mayor número de estudios realizados sobre sildenafil en comparación con tadalafil. Es probable que la elección del agente esté sesgada e influida por el perfil de los pacientes individuales en lo que se refiere a los efectos secundarios. El estudio SITAR (Frantz 2014) hizo rotar a los participantes del sildenafil al tadalafil, y halló un aumento inicial de los efectos secundarios incluida la cefalea y las molestias gastrointestinales, pero mejoraron con el transcurso del tiempo.
Los datos que no demuestran ningún beneficio claro de la administración de inhibidores de la PDE5 en pacientes con hipertensión pulmonar asociada a enfermedad pulmonar son compatibles con las guías de ESC (Galiè 2016b) y con otros datos publicados sobre el tratamiento específico de la HP en pacientes con enfermedad pulmonar intersticial. Han 2013 (hipertensión pulmonar asociada a la enfermedad pulmonar) fue un subestudio predefinido del ensayo STEP‐IPF (Zisman 2010), que incorporó a pacientes con fibrosis pulmonar idiopática (FPI) y no encontró ningún beneficio en cuanto a la 6MWD, las exacerbaciones ni la mortalidad.
De manera interesante, no pareció haber un beneficio significativo con la administración de inhibidores de la PDE5 en pacientes con HPTEC. En las guías de ESC/ERS actuales (Galiè 2016b) se recomienda la endarterectomía pulmonar quirúrgica como tratamiento de primera línea sobre la base de los datos del registro internacional a largo plazo que demuestran un beneficio de mortalidad (Delcroix 2016), y la administración de riociguat en los pacientes que no son candidatos para la cirugía (Ghofrani 2013). Por lo tanto, podrían considerarse estos tratamientos podrían considerarse en lugar de los inhibidores de la PDE5.
Study flow diagram.
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
Forest plot of comparison: 1 Group 1 Pulmonary Arterial Hypertension ‐ PDE5i versus placebo, outcome: 1.1 Improvement in WHO functional class.
Forest plot of comparison: 1 Group 1 Pulmonary Arterial Hypertension ‐ PDE5i versus placebo, outcome: 1.3 Mortality.
Cates Plot for mortality with PDE5 inhibitor treatment in Group 1 PAH
Forest plot of comparison: 4 Group 2 Pulmonary hypertension due to left heart disease (sildenafil v placebo), outcome: 4.2 Six‐minute walk distance.
Forest plot of comparison: 5 Group 3 Pulmonary Hypertension due to lung disease, outcome: 5.2 Six‐minute walk distance.
Forest plot of comparison: 6 Group 4 Pulmonary Hypertension due to CTEPH, outcome: 6.2 Six‐minute walk distance.
Comparison 1 Group 1 Pulmonary Arterial Hypertension ‐ PDE5i versus placebo, Outcome 1 Improvement in WHO functional class.
Comparison 1 Group 1 Pulmonary Arterial Hypertension ‐ PDE5i versus placebo, Outcome 2 Six‐minute walk distance.
Comparison 1 Group 1 Pulmonary Arterial Hypertension ‐ PDE5i versus placebo, Outcome 3 Mortality.
Comparison 1 Group 1 Pulmonary Arterial Hypertension ‐ PDE5i versus placebo, Outcome 4 PAP.
Comparison 1 Group 1 Pulmonary Arterial Hypertension ‐ PDE5i versus placebo, Outcome 5 RAP.
Comparison 1 Group 1 Pulmonary Arterial Hypertension ‐ PDE5i versus placebo, Outcome 6 CI.
Comparison 1 Group 1 Pulmonary Arterial Hypertension ‐ PDE5i versus placebo, Outcome 7 PVR.
Comparison 1 Group 1 Pulmonary Arterial Hypertension ‐ PDE5i versus placebo, Outcome 8 PASP.
Comparison 1 Group 1 Pulmonary Arterial Hypertension ‐ PDE5i versus placebo, Outcome 9 Dyspnoea.
Comparison 1 Group 1 Pulmonary Arterial Hypertension ‐ PDE5i versus placebo, Outcome 10 Clinical worsening requiring intervention.
Comparison 1 Group 1 Pulmonary Arterial Hypertension ‐ PDE5i versus placebo, Outcome 11 Adverse events.
Comparison 2 Group 1 Pulmonary Arterial Hypertension ‐ PDE5i versus placebo, on combination therapy, Outcome 1 Improvement in WHO functional Class.
Comparison 2 Group 1 Pulmonary Arterial Hypertension ‐ PDE5i versus placebo, on combination therapy, Outcome 2 Six‐minute walk distance.
Comparison 2 Group 1 Pulmonary Arterial Hypertension ‐ PDE5i versus placebo, on combination therapy, Outcome 3 Mortality.
Comparison 2 Group 1 Pulmonary Arterial Hypertension ‐ PDE5i versus placebo, on combination therapy, Outcome 4 PAP.
Comparison 2 Group 1 Pulmonary Arterial Hypertension ‐ PDE5i versus placebo, on combination therapy, Outcome 5 Cardiac Output.
Comparison 2 Group 1 Pulmonary Arterial Hypertension ‐ PDE5i versus placebo, on combination therapy, Outcome 6 PVR.
Comparison 2 Group 1 Pulmonary Arterial Hypertension ‐ PDE5i versus placebo, on combination therapy, Outcome 7 Clinical worsening.
Comparison 2 Group 1 Pulmonary Arterial Hypertension ‐ PDE5i versus placebo, on combination therapy, Outcome 8 Adverse events.
Comparison 3 Group 1 Pulmonary Arterial Hypertension ‐ PDE5i versus ERA, Outcome 1 Improvement in WHO functional class.
Comparison 3 Group 1 Pulmonary Arterial Hypertension ‐ PDE5i versus ERA, Outcome 2 Six‐minute walk distance.
Comparison 3 Group 1 Pulmonary Arterial Hypertension ‐ PDE5i versus ERA, Outcome 3 Mortality.
Comparison 3 Group 1 Pulmonary Arterial Hypertension ‐ PDE5i versus ERA, Outcome 4 PAP.
Comparison 3 Group 1 Pulmonary Arterial Hypertension ‐ PDE5i versus ERA, Outcome 5 RAP.
Comparison 3 Group 1 Pulmonary Arterial Hypertension ‐ PDE5i versus ERA, Outcome 6 CI.
Comparison 3 Group 1 Pulmonary Arterial Hypertension ‐ PDE5i versus ERA, Outcome 7 PVR.
Comparison 3 Group 1 Pulmonary Arterial Hypertension ‐ PDE5i versus ERA, Outcome 8 Quality of life.
Comparison 3 Group 1 Pulmonary Arterial Hypertension ‐ PDE5i versus ERA, Outcome 9 Clinical worsening requiring hospitalisation.
Comparison 3 Group 1 Pulmonary Arterial Hypertension ‐ PDE5i versus ERA, Outcome 10 Adverse events.
Comparison 4 Group 2 Pulmonary hypertension due to left heart disease (sildenafil v placebo), Outcome 1 Improvement in WHO functional class.
Comparison 4 Group 2 Pulmonary hypertension due to left heart disease (sildenafil v placebo), Outcome 2 Six‐minute walk distance.
Comparison 4 Group 2 Pulmonary hypertension due to left heart disease (sildenafil v placebo), Outcome 3 Mortality.
Comparison 4 Group 2 Pulmonary hypertension due to left heart disease (sildenafil v placebo), Outcome 4 mean PAP.
Comparison 4 Group 2 Pulmonary hypertension due to left heart disease (sildenafil v placebo), Outcome 5 Cardiac Index.
Comparison 4 Group 2 Pulmonary hypertension due to left heart disease (sildenafil v placebo), Outcome 6 TPG.
Comparison 4 Group 2 Pulmonary hypertension due to left heart disease (sildenafil v placebo), Outcome 7 RAP.
Comparison 4 Group 2 Pulmonary hypertension due to left heart disease (sildenafil v placebo), Outcome 8 PASP.
Comparison 4 Group 2 Pulmonary hypertension due to left heart disease (sildenafil v placebo), Outcome 9 Dyspnoea.
Comparison 4 Group 2 Pulmonary hypertension due to left heart disease (sildenafil v placebo), Outcome 10 Clinical worsening.
Comparison 5 Group 3 Pulmonary Hypertension due to lung disease, Outcome 1 Improvement in WHO functional class.
Comparison 5 Group 3 Pulmonary Hypertension due to lung disease, Outcome 2 Six‐minute walk distance.
Comparison 5 Group 3 Pulmonary Hypertension due to lung disease, Outcome 3 QOL.
Comparison 5 Group 3 Pulmonary Hypertension due to lung disease, Outcome 4 mean PAP.
Comparison 5 Group 3 Pulmonary Hypertension due to lung disease, Outcome 5 Cardiac Index.
Comparison 5 Group 3 Pulmonary Hypertension due to lung disease, Outcome 6 PVR.
Comparison 5 Group 3 Pulmonary Hypertension due to lung disease, Outcome 7 RAP.
Comparison 6 Group 4 Pulmonary Hypertension due to CTEPH, Outcome 1 Improvement in WHO functional class.
Comparison 6 Group 4 Pulmonary Hypertension due to CTEPH, Outcome 2 Six‐minute walk distance.
Comparison 6 Group 4 Pulmonary Hypertension due to CTEPH, Outcome 3 Mortality.
Comparison 6 Group 4 Pulmonary Hypertension due to CTEPH, Outcome 4 mean PAP.
Comparison 6 Group 4 Pulmonary Hypertension due to CTEPH, Outcome 5 Cardiac Index.
Comparison 6 Group 4 Pulmonary Hypertension due to CTEPH, Outcome 6 PVR.
Comparison 6 Group 4 Pulmonary Hypertension due to CTEPH, Outcome 7 RAP.
Comparison 6 Group 4 Pulmonary Hypertension due to CTEPH, Outcome 8 QOL.
Comparison 6 Group 4 Pulmonary Hypertension due to CTEPH, Outcome 9 Adverse events.
Comparison 7 Mixed Pulmonary Hypertension group 2‐4, Outcome 1 Improvement in WHO functional class.
Comparison 7 Mixed Pulmonary Hypertension group 2‐4, Outcome 2 6MWD.
Comparison 7 Mixed Pulmonary Hypertension group 2‐4, Outcome 3 PASP.
| Group 1 Pulmonary arterial hypertension ‐ PDE5i compared to placebo | ||||||
| Patient or population: people with pulmonary arterial hypertension | ||||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect | № of participants | Certainty of the evidence | Comments | |
| Risk with placebo | Risk with PDE5i | |||||
| Improvement in WHO functional class | 61 per 1000 | 358 per 1000 | OR 8.59 | 282 | ⊕⊕⊕⊕ | ‐ |
| Six‐minute walk distance | Ranges from 170 ‐ 319 ma | MD 48 metres higher | ‐ | 880 | ⊕⊕⊕⊝b | 6MWD in PAH MCID is 41 metres |
| Mortality | 41 per 1000 | 9 per 1000 | OR 0.22 | 1119 | ⊕⊕⊕⊕ | ‐ |
| Quality of life SF‐36: (scores 1 to 100, higher scores indicate better QoL) EQ‐5D questionnaire: (higher scores indicate worse QoL) CHFQ: (lower scores indicate worse QoL) | Galiè 2005a found a statistically significant improvement in all SF‐36 domains for sildenafil‐treated participants, and when compared to placebo in physical functioning (P < 0.001), general health (P < 0.001), and vitality (P < 0.05). There was also a statistically significant improvement in placebo‐treated participants in the physical functioning domain. Galiè 2005a found statistically significant improvements for the EQ‐5D current health status (P < 0.01) and utility index (P < 0.01). | 163 (2 RCTs) | ‐ | Data considered too heterogeneous to meta‐analyse | ||
| PAP | ‐ | MD 6.43 mmHg lower (8.13 lower to 4.74 lower) | ‐ | 453 | ⊕⊕⊕⊝b | The higher the mean PAP, the worse the PH |
| RAP | ‐ | MD 1.35 mmHg lower (2.34 lower to 0.36 lower) | ‐ | 341 | ⊕⊕⊕⊕ | The higher the RAP, the worse the PH |
| Cardiac index | ‐ | MD 0.28L/min/m2 higher (0.16 higher to 0.4 higher) | ‐ | 239 | ⊕⊕⊕⊝b | The lower the cardiac index, the worse the PH |
| PVR | ‐ | MD 4.74 WU lower (6.13 lower to 3.35 lower) | ‐ | 266 | ⊕⊕⊕⊕ | The higher the PVR. the worse the PH |
| *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 | ||||||
| aPost‐treatment values for participants in the placebo group were presented in two studies only; the remaining included studies presented a mean difference only. | ||||||
| Group 1 Pulmonary arterial hypertension ‐ PDE5i compared to placebo, on combination therapy | ||||||
| Patient or population: people with pulmonary arterial hypertension | ||||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect | № of participants | Certainty of the evidence | Comments | |
| Risk with placebo, on combination therapy | Risk with PDE5i | |||||
| Improvement in WHO functional class | 263 per 1000 | 300 per 1000 | OR 1.20 | 227 | ⊕⊕⊕⊝ | ‐ |
| Six‐minute walk distance | Ranges from 341 ‐ 377 mb | MD 20 metres higher | ‐ | 509 | ⊕⊕⊕⊝ | 6MWD in PAH MCID is 41 metres |
| Mortality | 32 per 1000 | 9 per 1000 | OR 0.26 | 492 | ⊕⊕⊕⊝ | ‐ |
| Quality of life physical functioning on SF‐36 (higher scores indicate better quality of life) | 0.3 (4.7 higher to 4.1 higher) | 7.8 (3.6 higher to 12.1 higher) | ‐ | 267 (1 RCT) | ⊕⊕⊕⊝ | ‐ |
| PAP | ‐ | MD 4.58 mmHg lower | ‐ | 387 | ⊕⊕⊕⊕ | The higher the PAP, the worse the pulmonary hypertension |
| Cardiac output | ‐ | MD 0.87 L/min higher | ‐ | 310 | ⊕⊕⊕⊕ | The lower the cardiac output, the worse the pulmonary hypertension |
| PVR | ‐ | SMD 0.48 lower | ‐ | 303 | ⊕⊕⊕⊕ | The higher the PVR, the worse the pulmonary hypertension |
| *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 | ||||||
| aDowngraded due to imprecision owing to small participant numbers and inconsistent direction of effect. | ||||||
| Group 1 Pulmonary Arterial Hypertension ‐ PDE5i compared to ERA | ||||||
| Patient or population: people with pulmonary arterial hypertension | ||||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect | № of participants | Certainty of the evidence | Comments | |
| Risk with ERA | Risk with PDE5i | |||||
| Improvement in WHO functional class | 339 per 1000 | 325 per 1000 | OR 0.94 | 244 | ⊕⊕⊕⊝ | ‐ |
| Six‐minute walk distance | Ranges from 290 ‐ 354 mb | MD 49 higher | ‐ | 36 | ⊕⊕⊝⊝ | 6MWD in PAH MCID is 41 metres |
| Mortality | 14 per 1000 | 45 per 1000 | OR 3.19 | 272 | ⊕⊕⊕⊝ | ‐ |
| Quality of life Kansas City Cardiomyopathy Quality‐of‐Life questionnaire (higher scores indicate better quality of life) | ‐ | MD 22 higher | ‐ | 25 | ⊕⊕⊝⊝ | ‐ |
| PAP | ‐ | MD 7.00 mmHg lower (4.82 lower to 18.82 higher) | ‐ | 11 (1 RCT) | ⊕⊕⊝⊝ | The higher the mean PAP, the worse the PH |
| RAP | ‐ | MD 2 mmHg higher (2.14 lower to 6.14 higher) | ‐ | 11 (1 RCT) | ⊕⊕⊝⊝ | The higher the RAP, the worse the PH |
| Cardiac index | ‐ | MD 0 L/min/m2 higher (0.49 lower to 0.49 higher) | ‐ | 11 (1 RCT) | ⊕⊕⊝⊝ | The lower the cardiac index, the worse the PH |
| PVR | ‐ | MD 0 WU lower (1.93 lower to 1.93 higher) | ‐ | 11 (1 RCT) | ⊕⊕⊝⊝ | The higher the PVR. the worse the PH |
| *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 | ||||||
| aDowngraded once due to imprecision. | ||||||
| Group 2 Pulmonary hypertension due to left‐heart disease ‐ PDE5i compared to placebo | ||||||
| Patient or population: people with pulmonary hypertension due to left‐heart disease | ||||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect | № of participants | Certainty of the evidence | Comments | |
| Risk with placebo | Risk with PDE5i | |||||
| Improvement in WHO functional class | 403 per 1000 | 263 per 1000 | OR 0.53 | 285 | ⊕⊕⊕⊝ | ‐ |
| Six‐minute walk distance | No data reported | MD 34 metres higher | ‐ | 284 | ⊕⊕⊕⊝ | ‐ |
| Mortality | 22 per 1000 | 27 per 1000 (6 to 114) | OR 1.27 (0.28 to 5.80) | 286 | ⊕⊕⊕⊝ | ‐ |
| Quality of life | 19.83 points higher (8.23 higher to 31.44 higher) | 12.05 points higher (1.14 higher to 22.96 higher) | ‐ | 52 (1 RCT) | ⊕⊕⊝⊝ | Kansas City Cardiomyopathy Questionnaire (higher scores reflect better health status) |
| Mean PAP | ‐ | MD 10.17 mmHg lower | ‐ | 130 | ⊕⊕⊕⊝ | The higher the mean PAP, the worse the pulmonary hypertension |
| Cardiac index | ‐ | MD 0.07 L/min/m2 higher | ‐ | 96 | ⊕⊕⊕⊝ | The lower the cardiac index, the worse the pulmonary hypertension |
| *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 | ||||||
| aDowngraded due to high heterogeneity and inconsistent direction of effect. | ||||||
| Group 3 Pulmonary hypertension due to lung disease ‐ PDE5i compared to placebo | ||||||
| Patient or population: people with pulmonary hypertension due to lung disease | ||||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect | № of participants | Certainty of the evidence | Comments | |
| Risk with placebo | Risk with PDE5i | |||||
| Improvement in WHO functional class | 50 per 1000 | 700 per 1000 | OR 44.33 | 40 | ⊕⊕⊝⊝ | ‐ |
| Six‐minute walk distance | Ranges from 237 ‐ 297 metres | MD 27 metres higher | ‐ | 350 | ⊕⊕⊕⊕ | ‐ |
| Mortality | ‐ | ‐ | ‐ | No studies | ‐ | ‐ |
| Quality of life | ‐ | MD 0.19 higher | ‐ | 238 | ⊕⊕⊕⊝ | SF‐36 overall quality of life (higher scores indicate better quality of life) |
| Mean PAP | ‐ | MD 0.14 mmHg lower | ‐ | 61 | ⊕⊕⊕⊝ | The higher the mean PAP, the worse the pulmonary hypertension |
| Cardiac index | ‐ | MD 0.3 L/min/m2 higher | ‐ | 28 | ⊕⊕⊝⊝ | The lower the cardiac index, the worse the pulmonary hypertension |
| PVR | ‐ | MD 1.31 WU lower | ‐ | 28 | ⊕⊕⊝⊝ | The higher the PVR, the worse the pulmonary hypertension |
| RAP | ‐ | MD 0.36 mmHg higher | ‐ | 28 | ⊕⊕⊝⊝ | The higher the RAP, the worse the pulmonary hypertension |
| *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 | ||||||
| aDowngraded twice due to imprecision owing to small participant numbers. | ||||||
| Group 4 Pulmonary hypertension due to CTEPH ‐ PDE5i compared to placebo | ||||||
| Patient or population: people with pulmonary hypertension due to CTEPH | ||||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect | № of participants | Certainty of the evidence | Comments | |
| Risk with comparison (placebo/sildenafil) | Risk with PDE5i | |||||
| Improvement in WHO functional class | 0 per 1000 | 444 per 1000 | OR 17.18 | 19 | ⊕⊕⊝⊝ | ‐ |
| Six‐minute walk distance ‐ sildenafil compared to placebo | Baseline 331 metres | MD 18 metres higher | ‐ | 19 | ⊕⊕⊝⊝ | ‐ |
| Six‐minute walk distance ‐ sildenafil compared to bosentan | Ranges from 422 ‐ 455 metres | MD 20 metres higher | ‐ | 227 | ⊕⊕⊕⊝ | ‐ |
| Mortality ‐ sildenafil versus placebo | No deaths reported | not estimable | 20 | ⊕⊕⊝⊝ | ‐ | |
| Mortality ‐ sildenafil versus bosentan | 40 per 1000 | 54 per 1000 | OR 1.36 (0.22 to 8.48) | 106 | ⊕⊕⊝⊝ | ‐ |
| Quality of life | ‐ | MD 0.26 lower | ‐ | 34 | ⊕⊕⊝⊝ | CamPHOR scale; higher scores indicate worse quality of life |
| Mean PAP ‐ sildenafil versus placebo | ‐ | MD 6.2 mmHg lower | ‐ | 19 | ⊕⊕⊝⊝ | The higher the PAP, the worse the pulmonary hypertension |
| Mean PAP ‐ sildenafil versus bosentan | ‐ | MD 0.76 mmHg higher | ‐ | 227 | ⊕⊕⊕⊝ | The higher the PAP, the worse the pulmonary hypertension |
| Cardiac index ‐ sildenafil versus placebo | ‐ | MD 0 L/min/m2 higher | ‐ | 19 | ⊕⊕⊝⊝ | The lower the cardiac index, the worse the pulmonary hypertension |
| Cardiac index ‐ sildenafil versus bosentan | ‐ | MD 0.04 L/min/m2 higher | ‐ | 227 | ⊕⊕⊕⊝ | The lower the cardiac index, the worse the pulmonary hypertension |
| PVR ‐ sildenafil versus placebo | ‐ | MD 0.89 WU lower | ‐ | 19 | ⊕⊕⊝⊝ | The higher the PVR, the worse the pulmonary hypertension |
| PVR ‐ sildenafil versus bosentan | ‐ | MD 0.01 WU lower | ‐ | 227 | ⊕⊕⊕⊝ | The higher the PVR, the worse the pulmonary hypertension |
| *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 | ||||||
| aDowngraded twice due to imprecision owing to small participant numbers in only one trial. | ||||||
| Mixed pulmonary hypertension group 2 ‐ 4 ‐ PDE5i compared to placebo | ||||||
| Patient or population: people with pulmonary hypertension group 2 ‐ 4 | ||||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect | № of participants | Certainty of the evidence | Comments | |
| Risk with placebo | Risk with PDE5i | |||||
| Improvement in WHO functional class | Study population | OR 11.31 | 146 | ⊕⊕⊕⊝ | ‐ | |
| 137 per 1000 | 642 per 1000 | |||||
| Six‐minute walk distance | No data provided | MD 51 metres higher | ‐ | 106 | ⊕⊕⊕⊝ | ‐ |
| Mortality | ‐ | ‐ | no studies | ‐ | ‐ | ‐ |
| Quality of life | ‐ | ‐ | no studies | ‐ | ‐ | ‐ |
| PASP | ‐ | MD 10 mmHg lower | ‐ | 146 | ⊕⊕⊕⊝ | The higher the PASP, the worse the pulmonary hypertension |
| *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 | ||||||
| aDowngraded due to imprecision owing to small participant numbers. | ||||||
| WHO group | Classification |
| Group 1 | Pulmonary arterial hypertension
Pulmonary veno‐occlusive disease/pulmonary capillary haemangiomatosis Persistent pulmonary hypertension of the newborn |
| Group 2 | Pumonary hypertension due to left heart disease
Valvular heart disease Congenital post‐capillary obstructive lesions |
| Group 3 | Pulmonary hypertension due to chronic lung disease or chronic hypoxaemia, or both
|
| Group 4 | Pulmonary hypertension due to pulmonary artery obstruction
|
| Group 5 | Pulmonary hypertension with unclear mechanisms
|
| PAH: pulmonary arterial hypertension | |
| Meta‐analysis | Number of studies | Effect measure | Fixed‐effect size and CI | Random‐effect size and CI |
| Group 1 Pulmonary arterial hypertension ‐ PDE5i versus placebo | ||||
| Improvement in WHO functional class | 4 | OR | 8.59 (3.95 to 18.72) | 8.53 (3.90 to 18.67) |
| Six‐minute walk distance | 8 | MD | 48.17 (40.30 to 56.04) | 52.98 (40.74 to 65.23)1 |
| Mortality | 7 | OR | 0.22 (0.07 to 0.68) | 0.28 (0.08 to 0.95) |
| PAP | 5 | MD | −6.33 (−8.12 to −4.53) | −8.94 (−13.73 to −4.15) |
| RAP | 2 | MD | −1.52 (−2.79 to −0.24) | −1.52 (−2.79 to −0.24) |
| Cardiac index | 4 | MD | 0.28 (0.16 to 0.40) | 0.35 (0.08 to 0.61)a |
| PVR | 3 | MD | −4.74 (−6.13 to −3.35) | −5.02 (−7.02 to −3.02) |
| PASP | 2 | MD | −11.62 (−25.18 to 1.94) | −11.62 (−25.18 to 1.94) |
| Dypnoea | 4 | MD | −0.72 (−0.99 to −0.44) | −0.61 (−1.19 to −0.02) |
| Clinical worsening requiring intervention | 3 | OR | 0.58 (0.27 to 1.23) | 0.55 (0.25 to 1.23) |
| Group 1 Pulmonary arterial hypertension ‐ PDE5i versus placebo to on combination therapy | ||||
| Improvement in WHO functional Class | 2 | OR | 1.20 (0.66 to 2.17) | 1.09 (0.41 to 2.92) |
| Six‐minute walk distance | 4 | MD | 19.66 (9.22 to 30.10) | 18.94 (0.23 to 37.65) |
| Mortality | 3 | OR | 0.26 (0.07 to 1.06) | 0.38 (0.04 to 3.81) |
| PAP | 2 | MD | −4.58 (−6.14 to −3.01) | −5.12 (−8.21 to −2.03) |
| Cardiac output | 2 | MD | 0.87 (0.53 to 1.21) | 0.87 (0.53 to 1.21) |
| PVR | 3 | SMD | −0.48 (−0.72 to −0.25) | −0.36 (−0.84 to 0.12)a |
| Clinical worsening | 3 | OR | 0.34 (0.18 to 0.63) | 0.34 (0.18 to 0.63) |
| Group 1 Pulmonary arterial hypertension ‐ PDE5i versus ERA | ||||
| Improvement in WHO functional Class | 1 | OR | 0.94 (0.55 to 1.60) | 0.94 (0.55 to 1.60) |
| Six‐minute walk distance | 2 | MD | 49.38 (3.65 to 95.11) | 49.38 (3.65 to 95.11) |
| Mortality | 2 | OR | 3.19 (0.74 to 13.64) | 3.19 (0.74 to 13.64) |
| Quality of life | 1 | MD | 22.00 (9.00 to 35.00) | 22.00 (9.00 to 35.00) |
| PAP | 1 | MD | 7.00 (−4.82 to 18.82) | 7.00 (−4.82 to 18.82) |
| RAP | 1 | MD | 2.00 (−2.14 to 6.14) | 2.00 (−2.14 to 6.14) |
| Cardiac index | 1 | MD | 0.00 (−0.49 to 0.49) | 0.00 (−0.49 to 0.49) |
| PVR | 1 | MD | 0.00 (−1.93 to 1.93) | 0.00 (−1.93 to 1.93) |
| Clinical worsening | 2 | OR | 0.52 (0.30 to 0.89) | 0.52 (0.30 to 0.89) |
| Group 2 Pulmonary hypertension due to left‐heart disease | ||||
| Improvement in WHO functional Class | 3 | OR | 0.53 (0.32 to 0.87) | 0.70 (0.20 to 2.37) |
| Six‐minute walk distance | 3 | MD | 34.31 (22.75 to 45.87) | 28.44 (‐1.82 to 58.69)a |
| Mortality | 3 | OR | 0.01 (−0.03 to 0.04) | 0.01 (−0.03 to 0.04) |
| Mean PAP | 3 | MD | −10.17 (−11.99 to −8.35) | −6.58 (−22.28 to 9.12)a |
| Cardiac index | 2 | MD | 0.07 (−0.17 to 0.30) | 0.06 (−0.22 to 0.34) |
| TPG | 1 | MD | −14.60 (−15.63 to −13.57) | −14.60 (−15.63 to −13.57) |
| RAP | 1 | MD | −1.00 (−3.77 to 1.77) | −1.00 (−3.77 to 1.77) |
| PASP | 1 | MD | −27.60 (−30.37 to −24.83) | −27.60 (−30.37 to −24.83) |
| Dypnoea | 1 | MD | 1.15 (0.51 to 1.79) | 1.15 (0.51 to 1.79) |
| Clinical worsening requiring intervention | 2 | OR | 1.19 (0.66 to 2.14) | 0.87 (0.22 to 3.46) |
| Group 3 Pulmonary hypertension due to lung disease | ||||
| Improvement in WHO functional Class | 1 | OR | 44.33 (4.78 to 410.93) | 44.33 (4.78 to 410.93) |
| Six‐minute walk distance | 5 | MD | 14.04 (7.05 to 21.02) | 26.70 (2.00 to 51.39)1 |
| Mean PAP | 2 | MD | −0.14 (−6.65 to 6.37) | −0.14 (−6.65 to 6.37) |
| Cardiac index | 1 | MD | 0.30 (−0.14 to 0.74) | 0.30 (−0.14 to 0.74) |
| PVR | 1 | MD | −1.31 (−3.67 to 1.05) | −1.31 (−3.67 to 1.05) |
| RAP | 1 | MD | 0.36 (−2.76 to 3.48) | 0.36 (−2.76 to 3.48) |
| Quality of life | 3 | MD | 0.19 (−0.07 to 0.44) | 0.19 (−0.07 to 0.44) |
| Group 4 Pulmonary hypertension due to CTEPH | ||||
| Improvement in WHO functional Class | 1 | OR | 17.18 (0.78 to 380.85) | 17.18 (0.78 to 380.85) |
| Six‐minute walk distance | 3 | MD | 18.73 (−12.72 to 50.19) | 18.73 (−12.72 to 50.19) |
| Mortality | 2 | OR | 0.01 (−0.06 to 0.08) | 0.01 (−0.06 to 0.08) |
| Mean PAP | 2 | MD | −1.79 (−5.55 to 1.96) | −1.67 (−6.48 to 3.15) |
| Cardiac index | 3 | MD | 0.03 (−0.19 to 0.25) | 0.03 (−0.19 to 0.25) |
| PVR | 3 | MD | −0.07 (−0.32 to 0.18) | −0.12 (−0.50 to 0.25) |
| RAP | 2 | MD | −0.98 (−3.42 to 1.47) | −0.98 (−3.42 to 1.47) |
| Quality of life | 1 | MD | −0.26 (−1.17 to 0.64) | −0.26 (−1.17 to 0.64) |
| Mixed pulmonary hypertension group 2 to 4 | ||||
| Improvement in WHO functional Class | 2 | OR | 11.33 (4.91 to 26.15) | 11.33 (4.91 to 26.15) |
| Six‐minute walk distance | 1 | MD | 50.97 (44.88 to 57.06) | 50.97 (44.88 to 57.06) |
| PASP | 2 | MD | −10.00 (−11.92 to −8.08) | −10.00 (−11.92 to −8.08) |
| astatistically high heterogeneity CI ‐ confidence interval; CTEPH ‐ chronic thromboembolic pulmonary hypertension; OR ‐ odds ratio; MD ‐ mean difference; PAP ‐ pulmonary artery pressure; PASP ‐ pulmonary artery systemic pressure; PDE5i ‐ phosphodiesterase‐5 inhibitor; PVR ‐ pulmonary vascular resistance; RAP ‐ right atrial pressure; SMD ‐ standardised mean difference; TPG ‐ transpulmonary gradient; WHO ‐ World Health Organization | ||||
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Improvement in WHO functional class Show forest plot | 4 | 282 | Odds Ratio (M‐H, Fixed, 95% CI) | 8.59 [3.95, 18.72] |
| 1.1 Sildenafil | 1 | 146 | Odds Ratio (M‐H, Fixed, 95% CI) | 10.24 [3.69, 28.47] |
| 1.2 Tadalafil | 2 | 72 | Odds Ratio (M‐H, Fixed, 95% CI) | 7.71 [1.88, 31.72] |
| 1.3 Vardenafil | 1 | 64 | Odds Ratio (M‐H, Fixed, 95% CI) | 5.59 [0.66, 47.07] |
| 2 Six‐minute walk distance Show forest plot | 8 | 880 | Mean Difference (Fixed, 95% CI) | 48.17 [40.30, 56.04] |
| 2.1 Sildenafil | 4 | 339 | Mean Difference (Fixed, 95% CI) | 56.91 [44.40, 69.41] |
| 2.2 Tadalafil | 3 | 477 | Mean Difference (Fixed, 95% CI) | 38.46 [27.60, 49.31] |
| 2.3 Vardenafil | 1 | 64 | Mean Difference (Fixed, 95% CI) | 69.0 [41.00, 97.00] |
| 3 Mortality Show forest plot | 8 | 1119 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.22 [0.07, 0.68] |
| 3.1 Sildenafil | 5 | 634 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.23 [0.05, 0.98] |
| 3.2 Tadalafil | 2 | 421 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.50 [0.05, 5.63] |
| 3.3 Vardenafil | 1 | 64 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.08 [0.00, 1.82] |
| 4 PAP Show forest plot | 6 | 453 | Mean Difference (Fixed, 95% CI) | ‐6.43 [‐8.13, ‐4.74] |
| 4.1 Sildenafil | 4 | 333 | Mean Difference (Fixed, 95% CI) | ‐7.34 [‐9.35, ‐5.33] |
| 4.2 Tadalafil | 1 | 56 | Mean Difference (Fixed, 95% CI) | ‐3.67 [‐7.55, 0.21] |
| 4.3 Vardenafil | 1 | 64 | Mean Difference (Fixed, 95% CI) | ‐5.3 [‐10.60, ‐0.00] |
| 5 RAP Show forest plot | 3 | 341 | Mean Difference (Fixed, 95% CI) | ‐1.35 [‐2.34, ‐0.36] |
| 5.1 Sildenafil | 2 | 277 | Mean Difference (Fixed, 95% CI) | ‐1.20 [‐2.30, ‐0.11] |
| 5.2 Vardenafil | 1 | 64 | Mean Difference (Fixed, 95% CI) | ‐2.0 [‐4.30, 0.30] |
| 6 CI Show forest plot | 4 | 239 | Mean Difference (Fixed, 95% CI) | 0.28 [0.16, 0.40] |
| 6.1 Sildenafil | 2 | 152 | Mean Difference (Fixed, 95% CI) | 0.47 [0.28, 0.66] |
| 6.2 Tadalafil | 1 | 28 | Mean Difference (Fixed, 95% CI) | 0.02 [‐0.18, 0.22] |
| 6.3 Vardenafil | 1 | 59 | Mean Difference (Fixed, 95% CI) | 0.4 [0.10, 0.70] |
| 7 PVR Show forest plot | 3 | 266 | Mean Difference (Fixed, 95% CI) | ‐4.74 [‐6.13, ‐3.35] |
| 7.1 Sildenafil | 1 | 146 | Mean Difference (Fixed, 95% CI) | ‐3.87 [‐5.67, ‐2.08] |
| 7.2 Tadalafil | 1 | 56 | Mean Difference (Fixed, 95% CI) | ‐7.32 [‐10.42, ‐4.22] |
| 7.3 Vardenafil | 1 | 64 | Mean Difference (Fixed, 95% CI) | ‐4.7 [‐7.80, ‐1.60] |
| 8 PASP Show forest plot | 2 | 48 | Mean Difference (Fixed, 95% CI) | ‐11.62 [‐25.18, 1.94] |
| 8.1 Sildenafil | 1 | 24 | Mean Difference (Fixed, 95% CI) | ‐7.0 [‐23.64, 9.64] |
| 8.2 Tadalafil | 1 | 24 | Mean Difference (Fixed, 95% CI) | ‐20.75 [‐44.14, 2.64] |
| 9 Dyspnoea Show forest plot | 4 | 239 | Mean Difference (Fixed, 95% CI) | ‐0.72 [‐0.99, ‐0.44] |
| 9.1 Sildenafil | 2 | 155 | Mean Difference (Fixed, 95% CI) | ‐0.57 [‐0.90, ‐0.24] |
| 9.2 Tadalafil | 1 | 20 | Mean Difference (Fixed, 95% CI) | ‐0.64 [‐1.65, 0.37] |
| 9.3 Vardenafil | 1 | 64 | Mean Difference (Fixed, 95% CI) | ‐1.15 [‐1.70, ‐0.60] |
| 10 Clinical worsening requiring intervention Show forest plot | 3 | 746 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.58 [0.27, 1.23] |
| 10.1 Sildenafil | 1 | 277 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.46 [0.17, 1.25] |
| 10.2 Tadalafil | 1 | 405 | Odds Ratio (M‐H, Fixed, 95% CI) | 1.28 [0.27, 5.95] |
| 10.3 Vardenafil | 1 | 64 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.21 [0.02, 2.46] |
| 11 Adverse events Show forest plot | 5 | Odds Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 11.1 Headache | 5 | 848 | Odds Ratio (M‐H, Fixed, 95% CI) | 1.97 [1.33, 2.92] |
| 11.2 GI upset | 5 | 848 | Odds Ratio (M‐H, Fixed, 95% CI) | 1.63 [1.07, 2.48] |
| 11.3 Flushing | 3 | 748 | Odds Ratio (M‐H, Fixed, 95% CI) | 4.12 [1.83, 9.26] |
| 11.4 Muscle and joint pain | 4 | 792 | Odds Ratio (M‐H, Fixed, 95% CI) | 2.52 [1.59, 3.99] |
| 11.5 Epistaxis | 2 | 682 | Odds Ratio (M‐H, Fixed, 95% CI) | 2.37 [0.83, 6.77] |
| 11.6 Respiratory symptoms | 3 | 748 | Odds Ratio (M‐H, Fixed, 95% CI) | 1.74 [0.89, 3.40] |
| 11.7 Visual disturbance | 3 | 748 | Odds Ratio (M‐H, Fixed, 95% CI) | 2.04 [0.58, 7.14] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Improvement in WHO functional Class Show forest plot | 2 | 227 | Odds Ratio (M‐H, Fixed, 95% CI) | 1.20 [0.66, 2.17] |
| 2 Six‐minute walk distance Show forest plot | 4 | 509 | Mean Difference (Fixed, 95% CI) | 19.66 [9.22, 30.10] |
| 3 Mortality Show forest plot | 3 | 492 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.26 [0.07, 1.06] |
| 4 PAP Show forest plot | 2 | 387 | Mean Difference (Fixed, 95% CI) | ‐4.58 [‐6.14, ‐3.01] |
| 5 Cardiac Output Show forest plot | 3 | 310 | Mean Difference (Fixed, 95% CI) | 0.87 [0.53, 1.21] |
| 6 PVR Show forest plot | 3 | 303 | Std. Mean Difference (Fixed, 95% CI) | ‐0.48 [‐0.72, ‐0.25] |
| 7 Clinical worsening Show forest plot | 4 | 717 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.38 [0.21, 0.68] |
| 8 Adverse events Show forest plot | 5 | Odds Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 8.1 Headache | 5 | 768 | Odds Ratio (M‐H, Fixed, 95% CI) | 2.49 [1.74, 3.56] |
| 8.2 GI upset | 4 | 726 | Odds Ratio (M‐H, Fixed, 95% CI) | 1.95 [1.30, 2.93] |
| 8.3 Flushing | 2 | 368 | Odds Ratio (M‐H, Fixed, 95% CI) | 1.11 [0.63, 1.96] |
| 8.4 Muscle and joint pain | 3 | 494 | Odds Ratio (M‐H, Fixed, 95% CI) | 2.17 [1.28, 3.67] |
| 8.5 Epistaxis | 2 | 358 | Odds Ratio (M‐H, Fixed, 95% CI) | 1.32 [0.34, 5.12] |
| 8.6 Visual disturbance | 2 | 368 | Odds Ratio (M‐H, Fixed, 95% CI) | 3.95 [0.97, 16.08] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Improvement in WHO functional class Show forest plot | 1 | Odds Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 2 Six‐minute walk distance Show forest plot | 2 | 36 | Mean Difference (Fixed, 95% CI) | 49.38 [3.65, 95.11] |
| 3 Mortality Show forest plot | 2 | 272 | Odds Ratio (M‐H, Fixed, 95% CI) | 3.19 [0.74, 13.64] |
| 4 PAP Show forest plot | 1 | Mean Difference (Fixed, 95% CI) | 7.00 [‐4.82, 18.82] | |
| 5 RAP Show forest plot | 1 | Mean Difference (Fixed, 95% CI) | 2.0 [‐2.14, 6.14] | |
| 6 CI Show forest plot | 1 | Mean Difference (Fixed, 95% CI) | 0.0 [‐0.49, 0.49] | |
| 7 PVR Show forest plot | 1 | Mean Difference (Fixed, 95% CI) | 0.0 [‐1.93, 1.93] | |
| 8 Quality of life Show forest plot | 1 | Mean Difference (Fixed, 95% CI) | Subtotals only | |
| 9 Clinical worsening requiring hospitalisation Show forest plot | 2 | 275 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.52 [0.30, 0.89] |
| 10 Adverse events Show forest plot | 1 | Odds Ratio (M‐H, Fixed, 95% CI) | Totals not selected | |
| 10.1 Headache | 1 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] | |
| 10.2 GI upset | 1 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] | |
| 10.3 Flushing | 1 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] | |
| 10.4 Muscle or joint pain | 1 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] | |
| 10.5 Respiratory symptoms | 1 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] | |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Improvement in WHO functional class Show forest plot | 3 | 285 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.53 [0.32, 0.87] |
| 2 Six‐minute walk distance Show forest plot | 3 | 284 | Mean Difference (Fixed, 95% CI) | 34.31 [22.75, 45.87] |
| 3 Mortality Show forest plot | 3 | 286 | Odds Ratio (M‐H, Fixed, 95% CI) | 1.27 [0.28, 5.80] |
| 4 mean PAP Show forest plot | 3 | 130 | Mean Difference (Fixed, 95% CI) | ‐10.17 [‐11.99, ‐8.35] |
| 5 Cardiac Index Show forest plot | 2 | 96 | Mean Difference (Fixed, 95% CI) | 0.07 [‐0.17, 0.30] |
| 6 TPG Show forest plot | 1 | Mean Difference (Fixed, 95% CI) | Totals not selected | |
| 7 RAP Show forest plot | 1 | Mean Difference (Fixed, 95% CI) | Totals not selected | |
| 8 PASP Show forest plot | 1 | Mean Difference (Fixed, 95% CI) | Totals not selected | |
| 9 Dyspnoea Show forest plot | 1 | Mean Difference (Fixed, 95% CI) | Totals not selected | |
| 10 Clinical worsening Show forest plot | 2 | 234 | Odds Ratio (M‐H, Random, 95% CI) | 0.87 [0.22, 3.46] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Improvement in WHO functional class Show forest plot | 1 | Odds Ratio (M‐H, Fixed, 95% CI) | Totals not selected | |
| 2 Six‐minute walk distance Show forest plot | 5 | 350 | Mean Difference (Random, 95% CI) | 26.70 [2.00, 51.39] |
| 3 QOL Show forest plot | 2 | 238 | Mean Difference (Random, 95% CI) | 0.19 [‐0.07, 0.44] |
| 4 mean PAP Show forest plot | 2 | 61 | Mean Difference (Fixed, 95% CI) | ‐0.14 [‐6.65, 6.37] |
| 5 Cardiac Index 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 RAP Show forest plot | 1 | Mean Difference (Fixed, 95% CI) | Totals not selected | |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Improvement in WHO functional class Show forest plot | 1 | Odds Ratio (M‐H, Fixed, 95% CI) | Totals not selected | |
| 2 Six‐minute walk distance Show forest plot | 3 | Mean Difference (Fixed, 95% CI) | Subtotals only | |
| 2.1 Sildenafil versus placebo | 1 | 19 | Mean Difference (Fixed, 95% CI) | 17.5 [‐23.90, 58.90] |
| 2.2 Sildenafil versus bosentan | 2 | 227 | Mean Difference (Fixed, 95% CI) | 20.42 [‐27.95, 68.79] |
| 3 Mortality Show forest plot | 2 | Odds Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 3.1 Sildenafil versus placebo | 1 | 20 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] |
| 3.2 Sildenafil versus bosentan | 1 | 106 | Odds Ratio (M‐H, Fixed, 95% CI) | 1.36 [0.22, 8.48] |
| 4 mean PAP Show forest plot | 3 | Mean Difference (Fixed, 95% CI) | Subtotals only | |
| 4.1 Sildenafil versus placebo | 1 | 19 | Mean Difference (Fixed, 95% CI) | ‐6.2 [‐12.40, ‐0.00] |
| 4.2 Sildenafil versus bosentan | 2 | 227 | Mean Difference (Fixed, 95% CI) | 0.76 [‐3.96, 5.48] |
| 5 Cardiac Index Show forest plot | 3 | Mean Difference (Fixed, 95% CI) | Subtotals only | |
| 5.1 Sildenafil versus placebo | 1 | 19 | Mean Difference (Fixed, 95% CI) | 0.0 [‐0.40, 0.40] |
| 5.2 Sildenafil versus bosentan | 2 | 227 | Mean Difference (Fixed, 95% CI) | 0.04 [‐0.22, 0.31] |
| 6 PVR Show forest plot | 3 | Mean Difference (Fixed, 95% CI) | Subtotals only | |
| 6.1 Sildenafil versus placebo | 1 | 19 | Mean Difference (Fixed, 95% CI) | ‐0.89 [‐1.85, 0.06] |
| 6.2 Sildenafil versus bosentan | 2 | 227 | Mean Difference (Fixed, 95% CI) | ‐0.01 [‐0.27, 0.25] |
| 7 RAP Show forest plot | 2 | Mean Difference (Fixed, 95% CI) | Subtotals only | |
| 7.1 Sildenafil versus placebo | 1 | 19 | Mean Difference (Fixed, 95% CI) | ‐0.9 [‐6.10, 4.30] |
| 7.2 Sildenafil versus bosentan | 1 | 121 | Mean Difference (Fixed, 95% CI) | ‐1.0 [‐3.77, 1.77] |
| 8 QOL Show forest plot | 1 | Mean Difference (Fixed, 95% CI) | Totals not selected | |
| 9 Adverse events Show forest plot | 1 | Odds Ratio (M‐H, Fixed, 95% CI) | Totals not selected | |
| 9.1 Headache | 1 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] | |
| 9.2 GI upset | 1 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] | |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Improvement in WHO functional class Show forest plot | 2 | 146 | Odds Ratio (M‐H, Fixed, 95% CI) | 11.31 [4.90, 26.14] |
| 2 6MWD Show forest plot | 1 | Mean Difference (Fixed, 95% CI) | Totals not selected | |
| 3 PASP Show forest plot | 2 | 146 | Mean Difference (Fixed, 95% CI) | ‐10.0 [‐11.92, ‐8.08] |
