Tratamiento médico adyuvante para aumentar la permeabilidad de las fístulas e injertos arteriovenosos
Resumen
Antecedentes
Las personas con insuficiencia renal terminal (IRT) suelen necesitar la formación de una fístula arteriovenosa (FAV) o un injerto arteriovenoso (IAV) protésico de interposición para la hemodiálisis. Estos lugares de acceso deberían tener una vida útil prolongada y una baja tasa de complicaciones (p.ej., trombosis, infección, estenosis, aneurisma e isquemia distal de la extremidad). Aunque algunas de las complicaciones pueden ser inevitables, cualquier técnica o tratamiento médico adyuvante destinado a disminuirlas sería bienvenido. Esta es la cuarta actualización de la revisión publicada por primera vez en 2003.
Objetivos
Evaluar los efectos del tratamiento farmacológico adyuvante en personas con IRT en la hemodiálisis mediante FAV autólogas o IAV protésicos de interposición.
Métodos de búsqueda
El documentalista del Grupo Cochrane Vascular (Cochrane Vascular) realizó búsquedas en el registro especializado del grupo, en las bases de datos CENTRAL, MEDLINE, Embase y CINAHL y en el registro de ensayos ClinicalTrials.gov hasta el 6 de agosto de 2020.
Criterios de selección
Ensayos controlados aleatorizados (ECA) de fármaco activo versus placebo en personas con IRT sometidos a hemodiálisis mediante una FAV o un IAV protésico de interposición.
Obtención y análisis de los datos
Para esta actualización, dos autores de la revisión (IM, MFAK) seleccionaron de forma independiente los ensayos para inclusión, extrajeron los datos, evaluaron el riesgo de sesgo y valoraron la certeza de la evidencia según el método GRADE. Los desacuerdos se resolvieron mediante debate o consulta con otro autor de la revisión (ADS). El desenlace principal fue la tasa de permeabilidad de la fístula o del injerto a largo plazo. Los desenlaces secundarios incluyeron la duración de la estancia hospitalaria; complicaciones como la infección, la formación de aneurismas, la estenosis y la isquemia distal de la extremidad; así como el número de intervenciones quirúrgicas o radiológicas relacionadas.
Resultados principales
En esta actualización fue adecuado para inclusión un estudio adicional, lo que hace un total de 13 ensayos con 2080 participantes. En general, la certeza de la evidencia fue baja o moderada debido a los cortos períodos de seguimiento, la heterogeneidad entre los ensayos, los pequeños tamaños muestrales y el riesgo de sesgo debido al informe incompleto. Los tratamientos médicos adyuvantes utilizados en los ensayos fueron la aspirina, la ticlopidina, el dipiridamol, el dipiridamol más aspirina, la warfarina, el aceite de pescado, el clopidogrel, la sulfinpirazona y el parche de trinitrato de glicerilo (TNG).
Todos los estudios incluidos informaron sobre la permeabilidad del injerto midiendo la trombosis del mismo. No hubo evidencia suficiente para determinar si había una diferencia en la permeabilidad del injerto en los estudios que compararon aspirina versus placebo (odds ratio [OR] 0,40; intervalo de confianza [IC] del 95%: 0,07 a 2,25; tres estudios, 175 participantes; evidencia de certeza baja). El metanálisis para la permeabilidad del injerto que comparó ticlopidina versus placebo favoreció a la ticlopidina (OR 0,45; IC del 95%: 0,25 a 0,82; tres estudios, 339 participantes; evidencia de certeza moderada).
No hubo evidencia suficiente para determinar si hubo una diferencia en la permeabilidad del injerto en los estudios que compararon el aceite de pescado con placebo (OR 0,24; IC del 95%: 0,03 a 1,95; dos estudios, 220 participantes; evidencia de certeza baja); ni en los estudios que compararon clopidogrel y placebo (OR 0,40; IC del 95%: 0,13 a 1,19; dos estudios, 959 participantes; evidencia de certeza moderada). Del mismo modo, no hubo evidencia suficiente para determinar si hubo una diferencia en la permeabilidad del injerto al comparar el efecto del dipiridamol versus placebo (OR 0,46; IC del 95%: 0,11 a 1,94; un estudio, 42 participantes; evidencia de certeza moderada) y el dipiridamol más aspirina versus placebo (OR 0,64; IC: 0,16 a 2,56; un estudio, 41 participantes; evidencia de certeza moderada); al comparar la warfarina de baja intensidad con placebo (OR 1,76; IC del 95%: 0,78 a 3,99; un estudio, 107 participantes; evidencia de certeza baja); al comparar la sulfinpirazona versus placebo (OR 0,43; IC del 95%: 0,03 a 5,98; un estudio, 16 participantes; evidencia de certeza baja) ni al comparar el parche de TNG y placebo (OR 1,26; IC del 95%: 0,63 a 2,54; un estudio, 167 participantes; evidencia de moderada certeza). El único ensayo que evaluó la warfarina se terminó antes de tiempo debido a los eventos de hemorragia grave en el grupo de warfarina.
Sólo dos estudios publicaron datos sobre el desenlace secundario de las intervenciones (quirúrgicas o radiológicas) relacionadas; no hubo evidencia suficiente para determinar si había una diferencia en las intervenciones relacionadas entre los grupos de tratamiento y placebo. Ninguno de los estudios incluidos informó sobre la duración de la estancia hospitalaria. La mayoría de los estudios informaron complicaciones que variaron desde la mortalidad hasta las náuseas. Sin embargo, los datos sobre las complicaciones fueron limitados y los informes variaron entre los estudios.
Conclusiones de los autores
Los metanálisis de tres estudios sobre la ticlopidina (un tratamiento antiplaquetario), en los que se utilizó la misma dosis de tratamiento, pero con un breve seguimiento de sólo un mes, indican que la ticlopidina podría tener un efecto beneficioso como tratamiento adyuvante para aumentar la permeabilidad de las FAV y los IAV a corto plazo. No hubo evidencia suficiente para determinar si hubo una diferencia en la permeabilidad del injerto entre el placebo y otros tratamientos como la aspirina, el aceite de pescado, el clopidogrel, el dipiridamol, el dipiridamol más aspirina, la warfarina, la sulfinpirazona y el parche de TNG. La certeza de la evidencia fue baja a moderada debido a los cortos períodos de seguimiento, el escaso número de estudios en cada comparación, los pequeños tamaños muestrales, la heterogeneidad entre los ensayos y el riesgo de sesgo debido al informe incompleto. Por consiguiente, parece razonable indicar que se realicen más estudios prospectivos para evaluar el uso de estos fármacos antiplaquetarios en pacientes con enfermedad renal con una FAV o un IAV.
PICO
Resumen en términos sencillos
Medicamentos para prevenir la obstrucción del acceso vascular después de una cirugía para la formación de una fístula o un injerto arteriovenoso
Antecedentes
Las personas con enfermedad renal avanzada (insuficiencia renal terminal) necesitan diálisis para realizar las funciones renales. En la hemodiálisis, la sangre se filtra a través de una máquina. Para permitir un paso lo suficientemente grande para que la sangre fluya entre la persona y la máquina, se puede unir quirúrgicamente una arteria y una vena (para formar una fístula arteriovenosa) o se utiliza un injerto arteriovenoso protésico (un sustituto de una vena) para unir la arteria con la vena. Estos puntos de acceso pueden durar años, pero pueden bloquearse o infectarse. Esta revisión investigó si el tratamiento médico adicional puede mantener estos puntos de acceso a la diálisis permeables (es decir, abiertos o desbloqueados).
Características de los estudios y resultados clave
Los autores de la revisión identificaron 13 ensayos controlados aleatorizados (estudios clínicos en los que las personas se colocan al azar en uno de dos o más grupos de tratamiento; evidencia actual hasta agosto de 2020) con 2080 participantes. Los ensayos compararon medicamentos antitrombóticos (que previenen la coagulación anormal en los vasos sanguíneos; como la ticlopidina, la aspirina, el dipiridamol y el clopidogrel) y otros tipos de medicamentos utilizados para prevenir las obstrucciones en los puntos de acceso arterial y venoso para la diálisis, en comparación con el placebo (tratamiento simulado). Los ensayos incluyeron a personas con enfermedad renal avanzada que recibían diálisis a través de todo tipo de fístulas o injertos arteriovenosos en los brazos o las piernas, o en lugares especiales. Se excluyeron las personas que recibían diálisis a través de la barriga (llamada diálisis peritoneal), o los estudios que compararon tratamiento médico con ningún tratamiento. Siempre que fue posible se agruparon los estudios similares.
Tres ensayos (339 participantes) que compararon la ticlopidina (un tratamiento antiplaquetario) con placebo mostraron una mejoría de la permeabilidad en un mes. No hubo evidencia suficiente de un efecto sobre el flujo sanguíneo a partir de los datos agrupados de tres ensayos que compararon la aspirina con placebo (175 participantes) o de dos ensayos que utilizaban aceite de pescado durante 12 meses (220 participantes). Dos ensayos compararon el clopidogrel con placebo en 959 participantes y de nuevo mostraron que no había evidencia suficiente de un efecto entre los tratamientos. Ensayos individuales con 16 a 167 participantes no encontraron efectos del dipiridamol, el dipiridamol más la aspirina, la warfarina, la sulfinpirazona (medicamento que reduce la concentración de ácido úrico en la sangre) o el parche de trinitrato de glicerilo (medicamento tópico que ensancha los vasos sanguíneos) en comparación con el placebo. Un ensayo que comparó la warfarina con placebo se terminó antes de tiempo debido a hemorragias graves en el grupo de warfarina. Dos estudios informaron sobre las intervenciones quirúrgicas o radiológicas relacionadas y encontraron que no hubo evidencia suficiente de un efecto sobre las intervenciones relacionadas entre el placebo y el tratamiento. Ningún estudio informó sobre la duración de la estancia hospitalaria. La mayoría de los estudios informaron complicaciones que van desde la sensación de malestar hasta la muerte. Sin embargo, la información era limitada y varió entre los estudios. La mayoría de ellos fueron monitorizados durante un corto período de tiempo, por lo que cualquier efecto beneficioso a largo plazo (más de tres años) no está claro.
Certeza de la evidencia
En general, la certeza de la evidencia fue baja a moderada, lo que significa que los resultados podrían cambiar con más estudios de investigación. Esto se debe a que en su mayoría había uno o dos estudios pequeños que compararon cada medicamento con un placebo. Algunos estudios que utilizaron la misma medicación tenían una dosis (concentración) diferente o tenían una duración de estudio distinta, lo que dificulta su comparación. También es preocupante la falta de detalles proporcionados por los estudios.
Authors' conclusions
Summary of findings
| Aspirin compared to placebo in increasing patency of arteriovenous fistula or graft | ||||||
| Patient or population: people with ESRD receiving haemodialysis through an arteriovenous fistula or graft | ||||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect | № of participants | Certainty of the evidence | Comments | |
|---|---|---|---|---|---|---|
| Risk with placebo | Risk with aspirin | |||||
| Graft thrombosis (28 days to 18 months) | Study population | OR 0.40 | 175 | ⊕⊕⊝⊝ | — | |
| 385 per 1000 | 200 per 1000 | |||||
| Duration of hospital stay | — | — | — | — | — | No data on duration of hospital stay. |
| Complications (28 days to 18 months) | See comment | 175 (3 RCTs) | ⊕⊕⊝⊝ Lowb | Andrassy 1974 reported a greater risk of gastric pain and epistaxis (11% aspirin vs 4% placebo) but the risk of GI bleeding or wound haematoma was 4% in both groups. Harter 1979 reported no bleeding or other complications. Sreedhara 1994 stated that 34 participants experienced adverse events that resulted in discontinuation of study medication (combination of dipyridamole, aspirin or placebo). However, these participants were considered to have completed the study protocol. The most common adverse events were GI bleeding and nausea across all study groups. There were also 7 mortalities during the study. Information on adverse events was not provided by comparison. | ||
| Number of related surgical or radiological interventions | — | — | — | — | — | No data on number of related surgical or radiological interventions. |
| *The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; ESRD: end‐stage renal disease; GI: gastrointestinal; OR: odds ratio; RCT: randomised controlled trial. | ||||||
| GRADE Working Group grades of evidence | ||||||
| aDowngraded two levels: significant heterogeneity (I2 = 79%) and small pooled sample size, confidence interval included threshold value. | ||||||
| Ticlopidine compared to placebo in increasing patency of arteriovenous fistula or graft | ||||||
| Patient or population: people with ESRD receiving haemodialysis through an arteriovenous fistula or graft | ||||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect | № of participants | Certainty of the evidence | Comments | |
|---|---|---|---|---|---|---|
| Risk with placebo | Risk with ticlopidine | |||||
| Fistulae thromboses (up to 1 month) | Study population | OR 0.45 | 339 | ⊕⊕⊕⊝ | — | |
| 226 per 1000 | 116 per 1000 | |||||
| Duration of hospital stay | — | — | — | — | — | No data on duration of hospital stay. |
| Complications (up to 1 month) | See comment | 339 (3 RCTs) | ⊕⊕⊝⊝ Lowa,b | Grontoft 1985 reported 2 bleeding complications in the ticlopidine group and 2 bleeding complications in placebo group. Grontoft 1998 reported 45 complications, including hepatic, haematological, haemostatic, cutaneous, gastrointestinal, cardiovascular and other miscellaneous complications affecting 30 participants receiving ticlopidine. There were 39 complications in participants receiving placebo. There were 5 deaths in the placebo group and 2 in the ticlopidine group. Fiskerstrand 1985 reported the development of a rash in 1 single participant treated with ticlopidine. There were no data on mortality. | ||
| Number of related surgical or radiological interventions | — | — | — | — | — | No data on number of related surgical or radiological interventions. |
| *The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; ESRD: end‐stage renal disease; OR: odds ratio; RCT: randomised controlled trial. | ||||||
| GRADE Working Group grades of evidence | ||||||
| aDowngraded one level: methods of random sequence generation and allocation concealment were unclear for two studies (Fiskerstrand 1985; Grontoft 1985). | ||||||
| Dipyridamole compared to placebo for increasing patency of arteriovenous graft | ||||||
| Patient or population: people with ESRD receiving haemodialysis through an arteriovenous graft | ||||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect | № of participants | Certainty of the evidence | Comments | |
|---|---|---|---|---|---|---|
| Risk with placebo | Risk with dipyridamole | |||||
| Graft thrombosis (up to 18 months) | Study population | OR 0.46 | 42 | ⊕⊕⊕⊝ | — | |
| 316 per 1000 | 175 per 1000 | |||||
| Duration of hospital stay | — | — | — | — | — | No data on duration of hospital stay. |
| Complications (up to 18 months) | See comments | 42 | ⊕⊕⊝⊝ Lowb | Sreedhara 1994 stated that 34 participants experienced adverse events which resulted in discontinuation of study medication (combination of dipyridamole, aspirin or placebo). However, these participants were considered to have completed the study protocol. The most common adverse events were GI bleeding and nausea across all study groups. There were also 7 mortalities during the study. Information on adverse events was not provided by comparison. | ||
| Number of related surgical or radiological interventions | — | — | — | — | — | The included study in this comparison did not include data on number of related surgical or radiological interventions |
| *The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; ESRD: end‐stage renal disease; GI: gastrointestinal; OR: odds ratio; RCT: randomised controlled trial. | ||||||
| GRADE Working Group grades of evidence | ||||||
| aDowngraded one level: small sample size, large confidence interval which includes threshold value. | ||||||
| Dipyridamole + aspirin compared to placebo for improving patency of arteriovenous graft | ||||||
| Patient or population: people with ESRD receiving haemodialysis through an arteriovenous graft | ||||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect | № of participants | Certainty of the evidence | Comments | |
|---|---|---|---|---|---|---|
| Risk with placebo | Risk with dipyridamole + aspirin | |||||
| Graft thrombosis (up to 18 months) | Study population | OR 0.64 | 41 | ⊕⊕⊕⊝ | — | |
| 316 per 1000 | 228 per 1000 | |||||
| Duration of hospital stay | — | — | — | — | — | No data on duration of hospital stay. |
| Complications (up to 18 months) | See comment | 41 | ⊕⊕⊝⊝ Lowb | Sreedhara 1994 stated that 34 participants experienced adverse events which resulted in discontinuation of study medication (combination of dipyridamole, aspirin or placebo). However, these participants were considered to have completed the study protocol. The most common adverse events were GI bleeding and nausea across all study groups. There were also 7 mortalities during the study. Information on adverse events is not provided by comparison. | ||
| Number of related surgical or radiological interventions | — | — | — | — | — | No data on number of related surgical or radiological interventions. |
| *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). AV: arteriovenous; CI: confidence interval; ESRD: end‐stage renal disease; GI: gastrointestinal; OR: odds ratio; RCT: randomised controlled trial. | ||||||
| GRADE Working Group grades of evidence | ||||||
| aDowngraded one level: small sample size, large confidence interval which includes threshold value. | ||||||
| Warfarin compared to placebo for improving patency of arteriovenous graft | ||||||
| Patient or population: people with ESRD receiving haemodialysis through an arteriovenous graft | ||||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect | № of participants | Certainty of the evidence | Comments | |
|---|---|---|---|---|---|---|
| Risk with placebo | Risk with warfarin | |||||
| Graft thrombosis (up to 37 months) | Study population | OR 1.76 | 107 | ⊕⊕⊝⊝ | — | |
| 608 per 1000 | 732 per 1000 | |||||
| Duration of hospital stay | — | — | — | — | — | No data on duration of hospital stay. |
| Complications (up to 37 months) | See comments | 107 | ⊕⊕⊝⊝ Lowb | Crowther 2002 reported 6 major bleeds in 5 participants: 3 upper GI bleeds, 1 cerebral haematoma after a road traffic accident and 1 femoral artery injury after coronary angiography. All 5 were also receiving antiplatelet therapy at the time of the bleeding event. A further 18 participants (7 allocated to placebo) experienced a minor bleeding event (P = 0.30). There were 5 deaths in the treatment group and 7 in the placebo group. | ||
| Number of related surgical or radiological interventions | — | — | — | — | — | No data on number of related surgical or radiological interventions. |
| *The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; ESRD: end‐stage renal disease; GI: gastrointestinal; OR: odds ratio; RCT: randomised controlled trial. | ||||||
| GRADE Working Group grades of evidence | ||||||
| aDowngraded two levels: serious imprecision – large confidence interval which included the threshold value; protocol for warfarin dosing changed after interim analysis; 40% of participants received antiplatelet therapy (aspirin) during the study period. | ||||||
| Fish oil compared to placebo for improving patency of arteriovenous graft | ||||||
| Patient or population: people with ESRD receiving haemodialysis through an arteriovenous graft | ||||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect | № of participants | Certainty of the evidence | Comments | |
|---|---|---|---|---|---|---|
| Risk with placebo | Risk with fish oil | |||||
| Graft thrombosis (up to 12 months) | Study population | OR 0.24 | 220 | ⊕⊕⊝⊝ | — | |
| 495 per 1000 | 191 per 1000 | |||||
| Duration of hospital stay | — | — | — | — | — | No data on duration of hospital stay. |
| Complications (up to 12 months) | See comment | 196 | ⊕⊕⊕⊝ Moderateb | Lok 2012; 16 participants died (8 in each study arm) | ||
| Radiological or surgical intervention (up to 12 months) | Study population | OR 0.64 | 196 | ⊕⊕⊕⊝ | — | |
| 495 per 1000 | 385 per 1000 | |||||
| *The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). AV: arteriovenous; CI: confidence interval; ESRD: end‐stage renal disease; OR: odds ratio; RCT: randomised controlled trial. | ||||||
| GRADE Working Group grades of evidence | ||||||
| aDowngraded one level: significant heterogeneity (I2 = 76%). | ||||||
| Clopidogrel compared to placebo for increasing patency of arteriovenous fistula | ||||||
| Patient or population: people with ESRD receiving haemodialysis through an arteriovenous fistula | ||||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect | № of participants | Certainty of the evidence | Comments | |
|---|---|---|---|---|---|---|
| Risk with placebo | Risk with clopidogrel | |||||
| Fistula thrombosis (42 days to 6 months) | Study population | OR 0.40 | 959 | ⊕⊕⊕⊝ | — | |
| 197 per 1000 | 89 per 1000 | |||||
| Duration of hospital stay | — | — | — | — | — | No data on duration of hospital stay. |
| Complication: all bleeding (up to 6 months)
| Study population | OR 1.06 (0.55 to 2.03) | 970 | ⊕⊕⊕⊝
| Combining data from Dember 2008 and Ghorbani 2009 found no clear evidence of a difference in bleeding between the clopidogrel and placebo groups. | |
| 39 per 1000 | 41 per 1000 (22 to 78) | |||||
| Complication: mortality (up to 6 months) | Study population | OR 1.00 (0.32 TO 3.14) | 970 (2 RCTs) | ⊕⊕⊕⊝
| Combining data from Dember 2008 and Ghorbani 2009 showed no clear evidence of a difference in mortality between the clopidogrel and placebo groups. | |
| 12 per 1000 | 12 per 1000 (4 to 38) | |||||
| Number of related surgical or radiological interventions (42 days) | Study population | OR 0.69 | 866 | ⊕⊕⊕⊝ | — | |
| 23 per 1000 | 16 per 1000 | |||||
| *The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). AV: arteriovenous; CI: confidence interval; ESRD: end‐stage renal disease; OR: odds ratio; RCT: randomised controlled trial. | ||||||
| GRADE Working Group grades of evidence | ||||||
| aDowngraded one level: imprecision concern as confidence interval included both clinical decision threshold and small event numbers. | ||||||
| Sulphinpyrazone compared to placebo for increasing patency of arteriovenous fistula or graft | ||||||
| Patient or population: people with ESRD receiving haemodialysis through an arteriovenous fistula or arteriovenous graft | ||||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect | № of participants | Certainty of the evidence | Comments | |
|---|---|---|---|---|---|---|
| Risk with placebo | Risk with sulphinpyrazone | |||||
| Graft thrombosis (up to 3 months) | Study population | OR 0.43 (0.03 to 5.98) | 16 | ⊕⊕⊝⊝ | — | |
| 250 per 1000 | 125 per 1000 | |||||
| Duration of hospital stay | — | — | — | — | — | No data on duration of hospital stay. |
| Complications (up to 3 months) | See comments | — | — | ⊕⊕⊝⊝ Lowa | 1 participant in the placebo group in Michie 1977 developed mild GI bleeding and pericarditis, which subsequently progressed to severe hypotension, shock and death. | |
| Number of related surgical or radiological interventions | — | — | — | — | — | No data on number of related surgical or radiological interventions. |
| *The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; ESRD: end‐stage renal disease; GI: gastrointestinal; OR: odds ratio; RCT: randomised controlled trial. | ||||||
| GRADE Working Group grades of evidence | ||||||
| aDowngraded two levels: very serious imprecision as very small sample size and total events. | ||||||
| GTN patch compared to placebo for increasing patency of arteriovenous fistula | ||||||
| Patient or population: people with ESRD receiving haemodialysis through an arteriovenous fistula | ||||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect | № of participants | Certainty of the evidence | Comments | |
|---|---|---|---|---|---|---|
| Risk with placebo | Risk with GTN patch | |||||
| Fistula failure (6 weeks) | Study population | OR 1.26 | 167 | ⊕⊕⊕⊝ | — | |
| 235 per 1000 | 279 per 1000 | |||||
| Duration of hospital stay | — | — | — | — | — | No data on length of hospital stay. |
| Complications (6 weeks) | See comment | 167 | ⊕⊕⊕⊝ | Field 2016 included a list of common systemic and localised adverse effects associated with GTN usage, and reported "no statistically significant differences" between the GTN patch and placebo. | ||
| Number of related surgical or radiological interventions | — | — | — | — | — | No data on number of related surgical or radiological interventions. |
| *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). AV: arteriovenous; CI: confidence interval; ESRD: end‐stage renal disease; GTN: glyceryl trinitrate; OR: odds ratio. | ||||||
| GRADE Working Group grades of evidence | ||||||
| aDowngraded one level: serious imprecision as small sample size and events. | ||||||
Background
Description of the condition
People with end‐stage renal disease (ESRD) continue to die prematurely despite continuing advances in our knowledge on dialysis. People receiving long‐term haemodialysis require an autologous (using the individual's own tissue) arteriovenous fistula (AVF; when an artery is connected to a vein) or an interposition prosthetic arteriovenous graft (AVG; when an artery is connected to a vein through an artificial graft) for access. These access sites should ideally have a long life and a low rate of complications (e.g. thrombosis, infection, stenosis, aneurysm formation and distal limb ischaemia). AVF is the preferred form of vascular access in these patients due to fewer complications (Sidway 2008), but more recent recommendations matching haemodialysis access strategy to the individual Life Plan for End Stage Kidney Disease (ESKD), include consideration of an interposition prosthetic AVG as a suitable alternative in some cases (Lok 2020). Long‐term (up to four or five years) patency rates demonstrate that autologous AVFs have the best outcomes with fewer surgical interventions (Churchill 1992; Metha 1991; Pisoni 2002). Complications from haemodialysis access result in frequent hospitalisation of people with ESRD and often require further intervention.
Options for vascular access had remained unchanged for decades, but over the last few years new surgical techniques have emerged including endovascular creation of a fistula (Lok 2017), and external anastomotic support devices – VasQ (Karydis 2020). Additionally, attention has been directed to the role of prosthetic graft lining – allowing early cannulation – and mitigating graft thrombosis, hybrid devices (HeRO), and bioengineered vessels as AVG (Agarwal 2019). Nevertheless no novel systemic administered medical treatments to improve maturation of a fistula, or mitigation of AVF and AVG dysfunction have emerged. Further research into the factors that predict the successful maturation of a newly formed AVF is required (Bashar 2016).
Description of the intervention
Various medical therapies were compared to placebo to measure the effect on the patency of AVFs and AVGs.
How the intervention might work
Successful interventions would aim to increase patency of AVFs and AVGs.
Why it is important to do this review
Although some complications may be unavoidable, any adjuvant technique or medical treatment aimed at decreasing complications would be welcome. It is recognised that up to 85% of cases of vascular access failure may be due to thrombosis caused by myointimal hyperplasia (proliferation of the cells lining the blood vessel), particularly in prosthetic grafts (Kanterman 1995). Current clinical guidelines recommend the use of antiplatelets after the formation of primary AVF for the first two months (Gallieni 2019). There is already some evidence suggesting that the formation of an autologous AVF may be preferable to prosthetic material and that graft surveillance programmes lead to improvements in long‐term graft patency rates (National Kidney Foundation Dialysis Outcome Quality Initiative) (KDOQI Guidelines 2006). However, there is also some accumulating evidence that drug manipulation for people with ESRD and autologous AVF (Dember 2008; Ghorbani 2009), and people with prosthetic interposition AVGs (Lok 2012; Schmitz 2002), may confer additional benefits in terms of long‐term patency and fewer complications.
Objectives
To assess the effects of adjuvant drug treatment in people with ESRD on haemodialysis via autologous AVFs or prosthetic interposition AVGs.
Methods
Criteria for considering studies for this review
Types of studies
All randomised controlled trials (RCTs) of active drug versus placebo in people with ESRD who were undergoing haemodialysis via an AVF or prosthetic interposition AVG. Any method of randomisation was accepted and differences in quality were considered in the analysis. Trials that were not analysed on an intention‐to‐treat basis were included provided that all randomised participants were accounted for.
Types of participants
People with ESRD and receiving haemodialysis through all types of AVFs or AVGs positioned in the upper or lower limb, or at special sites (e.g. axillary artery to axillary vein). We excluded people receiving peritoneal dialysis, although they may have a patent AVF or interposition prosthetic AVG, or awaiting maturation of AF fistula.
Types of interventions
Any drug therapy given to people with ESRD with the aim of improving the patency of AVFs or prosthetic AVGs, compared with placebo. Examples included aspirin in AVFs (Andrassy 1974); and dipyridamole in prosthetic AV grafts (Sreedhara 1994). We excluded studies investigating medical adjuvant therapy versus no treatment or intervention. Local delivery of agents was excluded as adjuvant medical therapy.
Types of outcome measures
Primary outcomes
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Graft patency
It was intended to measure graft patency rates using life tables or Kaplan‐Meier survival curves (Kaplan 1958), but the trials did not provide sufficient data to be pooled. Future updates of this review will incorporate these measures if sufficient data become available. We reported the number of AVF and AVG that occluded during the specified time as reported by the study authors.
Secondary outcomes
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Duration of hospital stay
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Complications such as infection, aneurysm formation, stenosis, distal limb ischaemia
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Number of related surgical or radiological interventions
Search methods for identification of studies
Electronic searches
The Cochrane Vascular Information Specialist conducted systematic searches of the following databases for randomised controlled trials and controlled clinical trials without language, publication year or publication status restrictions:
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the Cochrane Vascular Specialised Register via the Cochrane Register of Studies (CRS‐Web searched from 1 January 2015 to 6 August 2020);
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the Cochrane Central Register of Controlled Trials (CENTRAL) Cochrane Register of Studies Online (CRSO 2020, Issue 7);
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MEDLINE (Ovid MEDLINE Epub Ahead of Print, In‐Process & Other Non‐Indexed Citations, Ovid MEDLINE Daily and Ovid MEDLINE) (searched from 1 January 2015 to 6 August 2020);
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Embase Ovid (searched from 1 January 2015 to 6 August 2020);
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CINAHL Ebsco (searched from 1 January 2015 to 6 August 2020).
The Information Specialist modelled search strategies for other databases on the search strategy designed for CENTRAL. Where appropriate, they were combined with adaptations of the highly sensitive search strategy designed by Cochrane for identifying RCTs and controlled clinical trials (as described in the Cochrane Handbook for Systematic Reviews of Interventions Chapter 6, Lefebvre 2011). Search strategies for major databases are provided in Appendix 1.
The Information Specialist searched the following trials registries on 6 August 2020:
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ClinicalTrials.gov (clinicaltrials.gov);
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the World Health Organization International Clinical Trials Registry Platform (who.int/trialsearch).
Searching other resources
We cross‐checked the reference lists of the included and excluded studies for additional publications that may have been suitable for inclusion.
Data collection and analysis
Selection of studies
For this update, two review authors (IM, MFAK) independently identified possible trials to confirm eligibility for inclusion in the review. We resolved any disagreements by discussion or consultation with the other review author (ADS).
Data extraction and management
Two review authors (IM, MFAK) independently extracted data using proformas designed by Cochrane Vascular. We resolved discrepancies by discussion or consultation with another review author (ADS). We extracted data from the published reference papers directly. We made no attempt to obtain additional unpublished data. All analyses were based on endpoint data from the individual clinical trials. If several trials assessed the effect of the same adjuvant therapy (even if dosage was different) then we amalgamated results.
Assessment of risk of bias in included studies
Two review authors (IM, MFAK) independently assessed the methodological quality of included trials. We resolved disagreements by discussion or consultation with another review author (ADS). We assessed the methodological quality using the risk of bias tool as described in Section 8.5 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). This assesses various domains (random sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessment, incomplete outcome data, selective outcome reporting and other bias) and determines the level of bias for each domain, namely 'low,' 'high' or 'unclear' risk of bias. These assessments are reported for each individual study in the risk of bias tables.
Measures of treatment effect
We performed statistical analysis according to the statistical guidelines for authors in the Cochrane Vascular information (vascular.cochrane.org/preparing-systematic-review). We used odds ratio (OR) with 95% confidence intervals (CI) as the measure of effect for each dichotomous outcome.
Unit of analysis issues
The participant was the unit of analysis.
Three trials had unit of analysis issues that required further evaluation by the review authors (Ghorbani 2009; Grontoft 1985; Grontoft 1998).
The Grontoft 1998 study had a non‐standard design as it allowed people who had an initial failed AVF formation to re‐enter the study after a three‐week 'washout period.' In addition, the published results had to be carefully interpreted as there was confusion between the number of participants within the study compared to the number of operations (i.e. AVF formed), and participants who died were excluded from the published analysis. Overall analysis for this review was undertaken using the number of operations performed on an 'intention‐to‐treat' basis.
We assessed the results of the Ghorbani 2009 study carefully as the original data were not analysed on an 'intention‐to‐treat' basis, but analysed by the number of participants who completed the trial.
Grontoft 1985 also published their analysed results based on the number of participants who completed the trial, not an 'intention‐to‐treat' basis. It was not possible to use the intention‐to‐treat numbers because there were insufficient data regarding the original randomisation groups. Therefore, we used the numbers of participants who completed the trial.
Dealing with missing data
Analysis was on a complete case basis and we made no attempt to contact study authors for further follow‐up data. It was not necessary to contact study authors for additional data.
Assessment of heterogeneity
We used the I2 statistic to assess for heterogeneity between grouped trials. We considered an I2 value greater than 50% as substantial heterogeneity. Some trials contained low participant numbers and therefore the power of this test was likely to be low if a small P value was used (Higgins 2011).
Assessment of reporting biases
There were insufficient studies identified to create funnel plots to assess reporting bias.
Data synthesis
Where there were sufficient data from more than one trial, we performed meta‐analysis using a Mantel‐Haenszel fixed‐effect model. Where there was heterogeneity (I2 greater than 50%), we used a random‐effects model. We used Review Manager 5 software for data synthesis (Review Manager 2014).
Subgroup analysis and investigation of heterogeneity
We did not perform subgroup analysis as there were insufficient data on infection, aneurysm formation and distal limb ischaemia.
Sensitivity analysis
We did not perform sensitivity analysis due to insufficient data.
Summary of findings and assessment of the certainty of the evidence
We created summary of findings tables using GRADEpro GDT to present the main findings of the review for the time point with at which there was the most relevant data from the included studies (Atkins 2004; GRADEpro GDT).
The population consisted of people with ESRD and receiving haemodialysis through an AVF or a prosthetic AVG. We created a summary of finding table for each comparison reported in this review using the main outcomes listed under Types of outcome measures that we considered essential for decision‐making. We evaluated the certainty of the evidence using the GRADE approach (Guyatt 2008). We assigned one of four levels of certainty: high, moderate, low or very low based on overall risk of bias, directness of evidence, inconsistency of results, precision of estimates and risk of publication bias (Higgins 2011).
Results
Description of studies
Results of the search
The search identified 1181 records with 881 records after removal of duplicates. We screened the titles and abstracts and excluded 849 reports. We obtained and read the full‐text of 32 reports (see Figure 1).
Study flow diagram.
One new study fulfilled the criteria for consideration in the review (Field 2016). We excluded 12 additional studies (Chang 2016; Kagimoto 2018; Kochanek 2018; Lee 2017; Lin 2016; Liu 2019; NCT02414841; NCT02495662; NCT03524846; Vanholder 2009; Viecelli 2016; Yeh 2017).
We reclassified three studies included in the previous version of the review (Tanner 2015), and excluded them from the current version as the intraoperative application of human type 1 pancreatic elastase onto the venous anastomosis is not considered a medical treatment (Dwivedi 2014; Hye 2014; Peden 2013).
In total, 13 RCTs fulfilled the criteria for consideration in the review (Andrassy 1974; Crowther 2002; Dember 2008; Field 2016; Fiskerstrand 1985; Ghorbani 2009; Grontoft 1985; Grontoft 1998; Harter 1979; Lok 2012; Michie 1977; Schmitz 2002; Sreedhara 1994).
We excluded 43 studies (Albert 1978; Alexopoulos 2011; Bhomi 2008; Bleyer 2019; Chang 2016; Chen 2013; D'Ayala 2008; de Fijter 1995; Dixon 2009; Dulude 2001; Dwivedi 2014; Fuster 2001; Hye 2014; Janicki 2003; Kaegi 1975; Kagimoto 2018; Kaufman 2003; Kochanek 2018; Kooistra 1994; Krasinski 2004; Lee 2009; Lee 2017; Lin 2007; Lin 2013; Lin 2016; Liu 2019; Malovrh 2009; Mileti 1995; NCT02414841; NCT02495662; NCT03524846; Peden 2013; Peden 2017; Radmilovic 1998; Rouzrokh 2010; Taber 1992; Trimarchi 2006; Vanholder 2009; Viecelli 2016; Wang 2010; Wasse 2014; Yeh 2017; Yuto 2012).
We identified two ongoing trials (NCT04164693; TCTR20190328003).
Included studies
For this update, we included one additional study (Field 2016). We excluded three previously included studies from the last update (Dwivedi 2014; Hye 2014; Peden 2013). Therefore, 13 studies met the inclusion criteria (Andrassy 1974; Crowther 2002; Dember 2008; Field 2016; Fiskerstrand 1985; Ghorbani 2009; Grontoft 1985; Grontoft 1998; Harter 1979; Lok 2012; Michie 1977; Schmitz 2002; Sreedhara 1994). See Characteristics of included studies table for further details.
Three trials compared aspirin versus placebo and included 175 participants (Andrassy 1974; Harter 1979; Sreedhara 1994). The follow‐up times and dosages of aspirin were different in each trial. In Sreedhara 1994, 39 participants undergoing insertion of a new arteriovenous (AV) polytetrafluoroethylene (PTFE) graft were followed up for 18 months. Twenty participants received aspirin 325 mg once daily and the remainder received placebo. Andrassy 1974 included 92 participants undergoing Brescia‐Cimino fistula formation. Of these, 45 participants received aspirin 500 mg once daily whereas the other 47 participants received placebo. The total follow‐up period was 28 days. Finally, Harter 1979 included 44 participants undergoing AV shunt formation between the radial artery and the cephalic vein using silastic (silicone rubber) material with a Teflon adapter. Nineteen participants received aspirin 160 mg once daily and 25 participants received placebo. The follow‐up period was approximately five months.
Sreedhara 1994 also examined the effects of dipyridamole versus placebo with 42 participants in a parallel group trial over a six‐year period. Twenty‐three participants received dipyridamole 75 mg three times a day; the other 19 received the equivalent placebo. All participants were followed up for 18 months.
In a separate arm of the trial, Sreedhara 1994 studied the effect a combination of dipyridamole and aspirin. Forty‐one participants were involved (22 receiving dipyridamole 75 mg plus aspirin 325 mg once daily; 19 participants receiving placebo).
The analyses included only type I participants (participants requiring a new AV expanded polytetrafluoroethylene (ePTFE) graft). Additional data on type II participants (participants with an ePTFE graft that had thrombosed requiring thrombectomy or additional PTFE jump graft) were provided but not included for analysis as we decided this cohort was high risk for thrombosis and did not meet our inclusion criteria.
Three trials compared ticlopidine with placebo with 339 participants undergoing AVF formation or AVG interposition (Fiskerstrand 1985; Grontoft 1985; Grontoft 1998). There were no separate data for participants undergoing either fistula formation or graft interposition. Each participant was given either ticlopidine 250 mg twice daily or the equivalent placebo. All participants were followed up for one month.
Two trials examined the effects of fish oil (4 g once daily) versus placebo, and included 220 participants undergoing graft formation with a follow‐up of 12 months (Lok 2012; Schmitz 2002). Schmitz 2002 enrolled 24 participants (12 participants received fish oil and 12 received an equivalent dose of a control oil). The primary outcome was graft thrombosis, but the authors did not state how they assessed patency. Lok 2012 included 196 participants (99 participants received fish oil and 97 received a placebo oil capsule). The primary outcome was loss of native patency, which was defined as the graft having a primary event of thrombosis or requiring radiological or surgical intervention to maintain patency or promote maturation. However, they provided separate data on graft thrombosis, which was included in the meta‐analysis.
Crowther 2002 compared low‐intensity warfarin treatment (variable dose but a target international normalised ratio (INR) for prothrombin time of 1.4 to 1.9) with placebo. A total of 107 participants were randomised (56 to warfarin and 51 to placebo); all had newly placed PTFE grafts. How the authors assessed patency was not clear in that graft thrombosis was described as the "inability to dialyse or the need for immediate intervention to allow dialysis." This study was terminated early due a high rate of serious adverse events (major bleeding events) in the treatment arm.
Two trials compared clopidogrel versus placebo and included 959 participants (Dember 2008; Ghorbani 2009). Dember 2008 assessed 866 participants for patency failure six weeks after native AVF formation. A total of 436 participants received a loading dose of clopidogrel 300 mg on postoperative day one followed by 75 mg daily and 430 received matching placebo daily. Ghorbani 2009 compared 46 participants who received clopidogrel 75 mg daily with 47 who received placebo. Treatment was initiated seven to 10 days prior to formation of a native AVF and continued for six weeks postoperatively. The primary outcome was fistula failure at eight weeks.
Michie 1977 compared sulphinpyrazone 200 mg four times daily with placebo. Sixteen participants were randomised (eight to each group). There was heterogeneity across the treatment groups (six participants had AVFs and two had bovine interposition grafts in both groups). Participants were followed up for approximately three months or until 33 dialysis sessions had been undertaken.
Field 2016 compared the application of glyceryl trinitrate (GTN) patch 5 mm proximal to the anastomosis for 24 hours versus placebo. The study included 200 participants, with 101 randomised to the treatment group and 99 to placebo. The diameter and patency of the fistula were measured using ultrasound at six weeks.
Most studies assessed patency of AV shunts and grafts by detecting the presence of fistula or graft thrombosis. Andrassy 1974, Dember 2008 and Ghorbani 2009 detected fistula clotting by palpation (touch) and auscultation (listening with a stethoscope). In addition to those parameters, Sreedhara 1994 also included the presence of thrombus that was noticed during introduction of the dialysis needle into the graft, whereas Grontoft 1998 and Field 2016 added the use of Doppler technique to confirm the presence or absence of blood flow. Harter 1979 documented thrombosis by physical removal of thrombi from either the venous or arterial limbs of the shunt when dialysis was initiated. Crowther 2002 defined graft thrombosis as an inability to dialyse or a need for immediate intervention to allow dialysis; and Grontoft 1985 documented patency by stating that each fistula was assessed at regular intervals. Lok 2012 monitored participants biweekly and performed an angiogram if decreasing dialysis flow rates indicated stenosis. Michie 1977 used Doppler, ease of cannulation, palpation and auscultation to assess patency. Fiskerstrand 1985 and Schmitz 2002 did not document how they assessed patency.
Details of whether trials looked at AVF or AVG, as well as patency time are included in the Characteristics of included studies tables.
Excluded studies
See Characteristics of excluded studies table.
For this update, we excluded an additional 12 studies (Chang 2016; Kagimoto 2018; Kochanek 2018; Lee 2017; NCT02495662; Lin 2016; Liu 2019; NCT03524846; NCT02414841; Vanholder 2009; Viecelli 2016; Yeh 2017). We reclassified three included studies from the previous version of the review as excluded (Dwivedi 2014; Hye 2014; Peden 2013). In total there were 43 excluded studies (Albert 1978; Alexopoulos 2011; Bhomi 2008; Bleyer 2019; Chang 2016; Chen 2013; D'Ayala 2008; de Fijter 1995; Dixon 2009; Dulude 2001; Dwivedi 2014; Fuster 2001; Hye 2014; Janicki 2003; Kaegi 1975; Kagimoto 2018; Kaufman 2003; Kochanek 2018; Kooistra 1994; Krasinski 2004; Lee 2009; Lee 2017; Lin 2007; Lin 2013; Lin 2016; Liu 2019; Malovrh 2009; Mileti 1995; NCT02414841; NCT02495662; NCT03524846; Peden 2013; Peden 2017; Radmilovic 1998; Rouzrokh 2010; Taber 1992; Trimarchi 2006; Vanholder 2009; Viecelli 2016; Wang 2010; Wasse 2014; Yeh 2017; Yuto 2012).
We assessed 13 published studies as they appeared to meet the review inclusion criteria, but the study designs did not incorporate a placebo‐controlled group (Albert 1978; Bhomi 2008; Chang 2016; Chen 2013; D'Ayala 2008; Dixon 2009; Fuster 2001; Lee 2009; Lin 2007; Lin 2013; Trimarchi 2006; Wang 2010; Yuto 2012); or were not randomised (Janicki 2003). Malovrh 2009, evaluating the effect of blood volume expansion during surgery, did not use a suitable randomisation method or have placebo‐controlled groups, and was deemed not to meet inclusion criteria.
We excluded Dwivedi 2014, Hye 2014, and Peden 2013, which were included in the previous review, as the treatment was applied intraoperatively by applying the solution on the anastomosis and is considered not to be a form of medical treatment. Similarly, Lee 2017 based their comparison on the application of intraoperative solution. Peden 2017 was a prospective observational follow‐up of Hye 2014 at three‐year follow‐up using the same application of the treatment. Bleyer 2019 also used the same treatment with the same method of treatment application.
Rouzrokh 2010 presented unclear results, which included an assessment of fistula patency, but the timeframe of treatment or assessment was not documented. Therefore, these data could not be included for analysis. Wasse 2014 provided data on the percentage of participants who were successfully using their AVG or AVG at six months but did not provide data to calculate the number of thromboses and, therefore, patency. There are multiple reasons why a fistula may not be used after creation besides loss of patency, therefore, we excluded this study.
One Dutch randomised placebo‐controlled trial examined the effect of fish oil and placebo (de Fijter 1995). However, the trial outcomes did not include fistula patency and participants included both those receiving haemodialysis and peritoneal dialysis. One study examining the effect of sulphinpyrazone versus placebo included some participants who also received warfarin either at the start or during the trial and, the method for randomisation was not clearly concealed (Kaegi 1975). We excluded Kooistra 1994 because they assessed long‐standing (more than six weeks old) AVFs, and studied the concurrent initiation of recombinant human erythropoietin with antiplatelet agent, which we deemed a confounding factor. Another study analysed the effects of clopidogrel and aspirin versus placebo on rates of thrombosis in PTFE grafts (Kaufman 2003). However, the total number of thrombotic episodes in each group could not be determined from the results. One trial examined the effects of pentoxifylline versus placebo on rates of thrombosis in external AVFs (Radmilovic 1998). As this method of fistula formation is now obsolete, including this study would be inappropriate. One trial sought to assess the effects of CJC‐1004 (a locally acting antithrombotic agent) on graft occlusion (Dulude 2001). However, this was published as an abstract and, despite a literature search, we found no follow‐up paper. Similarly, there were no relevant data in Alexopoulos 2011, Krasinski 2004, and Taber 1992.
Viecelli 2016 included people receiving peritoneal dialysis.
Kochanek 2018 and Yeh 2017 reported the effect of antiplatelet use on maintaining patency of dysfunctional AVF after percutaneous angioplasty rather than primary patency of the graft. Kagimoto 2018 reported the effect of omega‐3 on lowering remnant‐like lipoprotein in people receiving haemodialysis, in an abstract which is not relevant to this review, and we found no full text on further search.
NCT02495662 was terminated early due to slow recruitment. Outcomes from NCT02414841 were reported but not included in this review due to reasons relating to application of treatment on anastomosis intraoperatively. Reported results from NCT03524846 were not relevant to the review. Mileti 1995 published no data or results.
The intervention in Lin 2016 was not considered to be a medical therapy. Liu 2019 did not compare their intervention against a placebo. Vanholder 2009 did not meet inclusion criteria based on study design.
Ongoing studies
We identified two ongoing trials (NCT04164693; TCTR20190328003). See Characteristics of ongoing studies table.
Risk of bias in included studies
See the risk of bias tables in the Characteristics of included studies table and Figure 2; Figure 3.
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
Allocation
Crowther 2002, Dember 2008, Field 2016, Ghorbani 2009, Lok 2012, and Schmitz 2002 utilised a permuted block randomisation schedule performed via an independent operator and were at low risk of allocation bias. The Grontoft 1998 study used an independent statistician and a minimisation scheme based on four weighted stratification variables, implying that allocation concealment was acceptable.
Andrassy 1974 used an independent statistician but the precise method of randomisation was not stated, and Sreedhara 1994 stated a predetermined schedule was used for randomisation but exact details were not provided. These were classed at unclear risk of selection bias.
Fiskerstrand 1985, Grontoft 1985, Harter 1979, and Michie 1977 did not provide sufficient data to allow a judgement of bias.
Blinding
Dember 2008, Field 2016, Ghorbani 2009, Lok 2012, and Sreedhara 1994 had thorough blinding of participants and assessors, providing a low risk of performance and detection bias.
Participants who developed a short‐term indication for warfarin therapy were not excluded from analysis in the Crowther 2002 study and it is, therefore, unclear if there may have been an element of performance bias. However, it is clear that detection bias was low risk as the clinical staff who assessed graft thrombosis were blinded to allocation assignment.
Harter 1979 and Schmitz 2002 clearly stated that participants were blinded to treatment allocation, indicating a low risk of performance bias, but did not provide sufficient data on outcome assessment to allow a judgement of detection bias.
Grontoft 1998 allowed re‐entry of participants into the study after secondary randomisation, and this may have led to unblinding of the participants.
Andrassy 1974, Fiskerstrand 1985, Grontoft 1985, and Michie 1977 did not provide sufficient data to allow a judgement of bias.
Incomplete outcome data
Andrassy 1974, Harter 1979, Lok 2012, and Michie 1977 had no missing data and were at low risk of attrition bias.
In Schmitz 2002, only 1/24 participants were lost to follow‐up; and 12/107 randomised within the Sreedhara 1994 study were lost to follow‐up or did not complete the study. Both were at low risk of attrition bias.
Crowther 2002 followed up all participants and ascertained the outcome for all participants, indicating a low risk of attrition bias. When data were analysed, participants who had a renal transplant developed a clinical indication for the active treatment in this study (i.e. warfarin) or had their AVG removed were censored.
Dember 2008 did not assess patency in 11 participants at six weeks and Ghorbani 2009 required re‐analysis of the published data as the study authors did not perform analysis on an intention‐to‐treat basis but no participants were lost to follow‐up. Eighteen participants did not complete the study protocol. These were at high risk of attrition bias.
Grontoft 1985 performed analysis on the number of participants who completed the trial. As data were not provided within the publication of the initial randomisation groups it was therefore not possible to determine if, and how many, participants did not complete the trial. This was at high risk of attrition bias.
In Field 2016, 13 participants did not receive the allocated treatment after randomisation, and 20 participants had incomplete data. Only participants who received treatment were included in the final analysis (per‐protocol analysis). This was at high risk of attrition bias.
In Grontoft 1998, data were missing for one participant but an additional 17 participants could not have the AVFs or AVGs evaluated. These were included in the data analysis though. This was at unclear risk of attrition bias.
Fiskerstrand 1985 did not provide sufficient data and was at unclear risk of attrition bias.
Selective reporting
There was no prestudy protocol for nine studies and therefore it is not possible to determine if outcome reporting was selective (Andrassy 1974; Crowther 2002; Fiskerstrand 1985; Ghorbani 2009; Grontoft 1998; Harter 1979; Michie 1977; Schmitz 2002; Sreedhara 1994).
Dember 2008, Field 2016, and Lok 2012 did not deviate from prestudy protocol‐determined outcomes and had a low risk of reporting bias.
Grontoft 1985 provided an 'as treated' analysis, and additional data to permit an 'intention‐to‐treat' analysis was not provided. This was at high risk of reporting bias.
Other potential sources of bias
The Crowther 2002 study protocol was changed after an interim analysis with regards to the dosing of warfarin, and 40% of participants also received additional antiplatelet therapy during the study period. This could have potentially influenced the study outcomes, including the high rate of bleeding reported in this study, and so was it judged at high risk of bias.
Other potential bias within studies included the re‐entry of participants into randomisation after a washout period of three weeks if their first operation failed, which was permitted in the Grontoft 1998 study protocol. Harter 1979 did not have a prespecified enrolment value, and the protocol stated that enrolment would continue until 24 thrombi were observed so was judged at unclear risk of bias.
Andrassy 1974, Dember 2008, Field 2016, Fiskerstrand 1985, Ghorbani 2009, Grontoft 1985, Lok 2012, Michie 1977, Schmitz 2002, and Sreedhara 1994 had no obvious other source of bias and so were at low risk of bias.
Effects of interventions
See: Summary of findings 1 Aspirin compared to placebo in increasing patency of arteriovenous fistula or graft; Summary of findings 2 Ticlopidine compared to placebo in increasing patency of arteriovenous fistula or graft; Summary of findings 3 Dipyridamole compared to placebo for increasing patency of arteriovenous graft; Summary of findings 4 Dipyridamole plus aspirin compared to placebo for improving patency of arteriovenous graft; Summary of findings 5 Warfarin compared to placebo for improving patency of arteriovenous graft; Summary of findings 6 Fish oil compared to placebo for improving patency of arteriovenous graft; Summary of findings 7 Clopidogrel compared to placebo for increasing patency of arteriovenous fistula; Summary of findings 8 Sulphinpyrazone compared to placebo for increasing patency of arteriovenous fistula or graft; Summary of findings 9 Glyceryl trinitrate patch compared to placebo for increasing patency of arteriovenous fistula
See summary of findings Table 1; summary of findings Table 2; summary of findings Table 3; summary of findings Table 4; summary of findings Table 5; summary of findings Table 6; summary of findings Table 7; summary of findings Table 8; summary of findings Table 9.
Primary outcomes
Graft patency
For the primary outcome 'graft patency' the numbers recorded for analyses were the number of grafts that occluded during the specified time period as reported by the study authors. This should be kept in mind when interpreting the presented data.
Graft patency rates as outlined by life tables or Kaplan‐Meier survival curves were not carried out as the description of the trials did not provide sufficient data (Kaplan 1958).
Aspirin versus placebo
Andrassy 1974 reported that 2/45 participants in the aspirin group developed a graft thrombosis compared with 11/47 participants who received placebo (OR 0.15, 95% confidence interval (CI) 0.03 to 0.73). In Harter 1979, 6/19 participants in the aspirin group developed a graft thrombosis compared with 18/25 participants in the placebo group (OR 0.18, 95% CI 0.05 to 0.66). In Sreedhara 1994, 10/20 participants who received aspirin developed a graft thrombosis compared with 6/19 participants on placebo (OR 2.17, 95% CI 0.59 to 7.99).
Due to evidence of heterogeneity (I2 = 79%) we used a random‐effects meta‐analysis. The overall results showed no clear differences between aspirin and placebo (OR 0.40, 95% CI 0.07 to 2.25; 3 studies, 175 participants; low‐certainty evidence; Analysis 1.1).
Ticlopidine versus placebo
Three trials compared ticlopidine with placebo (Fiskerstrand 1985; Grontoft 1985; Grontoft 1998). In Fiskerstrand 1985, 2/8 participants in the ticlopidine group compared with 5/10 participants in the placebo group developed fistulae thromboses at one month (OR 0.33, 95% CI 0.04 to 2.52). In Grontoft 1985, only 2/19 participants who received treatment developed fistulae thromboses compared with 8/17 participants who received placebo (OR 0.13, 95% CI 0.02 to 0.76). In Grontoft 1998, 16/144 participants who received ticlopidine developed thromboses in their fistulae compared with 25/141 participants in the placebo group (OR 0.58, 95% CI 0.30 to 1.14).
The overall result of the meta‐analysis favoured ticlopidine (OR 0.45, 95% CI 0.25 to 0.82; 3 studies, 339 participants; moderate‐certainty evidence; Analysis 2.1).
Dipyridamole versus placebo
One trial that examined the effect of dipyridamole versus placebo followed participants for up to 18 months (Sreedhara 1994). Four of 23 participants taking dipyridamole developed thrombosis compared to 6/19 participants taking placebo. The overall result showed no evidence of a difference between dipyridamole and placebo (OR 0.46, 95% CI 0.11 to 1.94; 1 study, 42 participants; moderate‐certainty evidence; Analysis 3.1).
Dipyridamole plus aspirin versus placebo
The Sreedhara 1994 trial used a parallel group design to examine the effect of dipyridamole plus aspirin versus placebo on graft thrombosis. Five of 22 participants who received a combination of dipyridamole and aspirin developed a graft thrombosis compared to 6/19 participants who received placebo (OR 0.64, CI 0.16 to 2.56; 1 study, 41 participants; moderate‐certainty evidence; Analysis 4.1).
Warfarin versus placebo
One trial that examined the effect of low‐intensity warfarin treatment versus placebo followed up participants for 37 months (before the trial was terminated prematurely due to a significant increase in bleeding in the treatment group) (Crowther 2002). The overall result showed no evidence of a difference in graft thrombosis between warfarin and placebo (OR 1.76, CI 0.78 to 3.99; 1 study, 107 participants; low‐certainty evidence; Analysis 5.1).
Fish oil versus placebo
Two studies examined the effects of fish oil versus placebo on graft thrombosis (Lok 2012; Schmitz 2002). In Schmitz 2002, 2/12 participants taking fish oil developed a thrombosis compared with 9/12 participants who received placebo. The overall result favoured fish oil (OR 0.07, 95% CI 0.01 to 0.49). In Lok 2012, 33/99 participants taking fish oil had graft thrombosis at 12 months compared with 45/97 participants who received placebo (OR 0.58, 95% CI 0.32 to 1.03).
Due to evidence of heterogeneity (I2 = 76%), we used a random‐effects meta‐analysis. The overall results showed no evidence of a difference between fish oil and placebo (OR 0.24, 95% CI 0.03 to 1.95; 2 studies, 220 participants; low‐certainty evidence; Analysis 6.1).
Clopidogrel versus placebo
Dember 2008 reported that 53/436 participants in the clopidogrel group and 84/430 participants in the placebo arm developed fistula thrombosis at six weeks (OR 0.57, 95% CI 0.39 to 0.83). In Ghorbani 2009, 2/46 participants in the clopidogrel group compared with 10/47 participants in the placebo group had AVF failure at eight weeks (OR 0.17, 95% CI 0.03 to 0.82).
Due to evidence of heterogeneity (I2 = 54%), we used a random‐effects meta‐analysis. The overall results showed no evidence of a difference in graft thrombosis between clopidogrel and placebo (OR 0.40, 95% CI 0.13 to 1.19; 2 studies, 959 participants; moderate‐certainty evidence; Analysis 7.1).
Sulphinpyrazone versus placebo
Michie 1977 examined the effects of sulphinpyrazone versus placebo on native fistulae or bovine graft thrombosis. One of eight participants taking sulphinpyrazone developed a graft thrombosis compared with 2/8 participants taking placebo (although two participants in the placebo group did not complete the study protocol). The overall results showed no evidence of a difference between sulphinpyrazone and placebo (OR 0.43, 95% CI 0.03 to 5.98; 1 study, 16 participants; low‐certainty evidence; Analysis 8.1).
Glyceryl trinitrate patch versus placebo
Field 2016 examined the effects of a GTN patch on venous diameter of the anastomosis and fistula failure. Twenty‐four of 86 participants in the treatment group (GTN patch) and 19/81 in the placebo arm experienced fistula failure at six weeks (OR 1.26, 95% CI 0.63 to 2.54; 1 study, 167 participants; moderate‐certainty evidence; Analysis 9.1).
Secondary outcomes
Data on the secondary outcome measures outlined in the Criteria for considering studies for this review section were not specific enough to allow pooled analysis.
Duration of hospital stay
No studies reported data on duration of hospital stay.
Complications
Aspirin versus placebo
Andrassy 1974 comparing aspirin and placebo reported a greater risk of gastric pain and epistaxis with aspirin (11% with aspirin versus 4% with placebo) for participants but the risk of gastrointestinal bleeding or wound haematoma was the same in both groups (4% in both arms).
There were no reported gastrointestinal haemorrhages or other complications in Harter 1979.
Sreedhara 1994 stated that 34 participants experienced adverse events that resulted in discontinuation of study medication (combination of dipyridamole, aspirin or placebo). However, these participants were considered to have completed the study protocol. The most common adverse events were gastrointestinal bleeding and nausea across all study groups. There were also seven mortalities during the course of the study. Information on adverse events was not provided by comparison.
Ticlopidine versus placebo
The only adverse event reported by Fiskerstrand 1985 was the development of a rash in a single participant treated with ticlopidine. There were no data on mortality.
Grontoft 1985 reported two episodes of bleeding in each group, consisting of one haemorrhagic diathesis, one gastrointestinal bleeding, one cannulation side bleeding and one haematuria.
Grontoft 1998 reported data on 45 complications, including hepatic, haematological, haemostatic, cutaneous, gastrointestinal, cardiovascular and other miscellaneous complications affecting 30 participants receiving ticlopidine (Grontoft 1998). There were 39 complications recorded in participants receiving placebo. There were four deaths in the placebo group and two in the ticlopidine group.
Dipyridamole versus placebo
See 'Aspirin versus placebo' section above for information on Sreedhara 1994.
Dipyridamole plus aspirin versus placebo
See 'Aspirin versus placebo' section above for information on Sreedhara 1994.
Warfarin versus placebo
Crowther 2002 was terminated early because of major bleeding events in the warfarin group. Six major bleeds occurred in five participants: three upper gastrointestinal bleeds, one cerebral haematoma after a road traffic accident and one femoral artery injury after coronary angiography. All five participants experiencing major bleeding events were also taking antiplatelet therapy at the time of the bleeding event. A further 18 participants (seven allocated to placebo) experienced a minor bleeding event; however, according to the study authors there was no significant difference between the two groups (P = 0.30). There were five deaths in the treatment group and seven in the placebo group.
Fish oil versus placebo
Lok 2012 compared fish oil versus placebo and reported that 16 participants died (8 in each study arm) after starting the study medication but before 12 months of follow‐up were completed.
Schmitz 2002 did not report complications.
Clopidogrel versus placebo
Dember 2008 reported data on bleeding complications and mortality occurring within 30 days of completion of study medications for participants taking clopidogrel and placebo. Overall, bleeding events were similar for both groups (2.9% with clopidogrel versus 2.8% with placebo; P = 0.84), as was all‐cause mortality (0.9% in both groups) as reported by the study authors.
Ghorbani 2009 evaluating the effects of clopidogrel included information on bleeding and mortality. There was gastrointestinaI bleeding in 2.1% of the clopidogrel group and 3.2% of the placebo group (P = 0.31), and non‐gastrointestinal tract bleeding in 5.3% of the clopidogrel group and 4.3% in the placebo group (P = 0.63). There were two mortalities in both study arms. There was no severe bleeding during the active treatment period and no deaths were attributable to bleeding.
Combining bleeding data from Dember 2008 and Ghorbani 2009 showed no clear difference in bleeding between the clopidogrel and placebo groups (OR 1.06, 95% CI 0.55 to 2.03; 2 studies, 970 participants; Analysis 7.2).
Combining mortality data from Dember 2008 and Ghorbani 2009 showed no clear difference in mortality between the clopidogrel and placebo groups (OR 1.00, 95% CI 0.32 to 3.14; 2 studies, 970 participants; Analysis 7.3).
Sulphinpyrazone versus placebo
Michie 1977 study, comparing sulphinpyrazone versus placebo, reported one death in the placebo group; the participant had mild gastrointestinal bleeding and pericarditis, which subsequently progressed to severe hypotensive episode and irreversible shock.
Glyceryl trinitrate patch versus placebo
Field 2016 included a list of common systemic and localised adverse effects associated with GTN usage, and reported "no statistically significant differences" between the GTN patch and placebo.
Overall the certainty of the evidence for complications was low or moderate due to short follow‐up periods, heterogeneity between trials, small sample sizes, and risk of bias due to incomplete reporting.
Number of related surgical or radiological interventions
Two studies reported on this outcome (Dember 2008; Lok 2012).
Lok 2012 compared fish oil and placebo, and found no evidence of differences in radiological or surgical interventions in the intervention group when compared with the placebo group (38/99 with fish oil versus 48/97 with placebo; OR 0.64, 95% CI 0.36 to 1.12; 1 study, 196 participants; moderate‐certainty evidence; Analysis 6.2).
Dember 2008 compared clopidogrel versus placebo, and reported the frequency of additional interventions required to maintain patency in AVFs (7/436 participants with clopidogrel versus 10/430 participants with placebo; OR 0.69, 95% CI 0.26 to 1.82; 1 study, 866 participants; moderate‐certainty evidence; Analysis 7.4).
Subgroup and sensitivity analyses
We were unable to undertake subgroup or sensitivity analyses due to insufficient data.
Discussion
Summary of main results
Ten of the 13 included studies individually revealed a beneficial effect with the active drug compared to placebo (Andrassy 1974; Dember 2008; Fiskerstrand 1985; Ghorbani 2009; Grontoft 1985; Grontoft 1998; Harter 1979; Lok 2012; Michie 1977; Schmitz 2002). However, there may be an element of bias due to clinical heterogeneity with the dose and length of follow‐up in the aspirin trials. In addition, one of the aspirin trials was conducted over 40 years ago with a relatively high dose of aspirin (500 mg once daily) (Andrassy 1974). It should be noted that there was a marked discrepancy between results in the aspirin versus placebo trials, with Sreedhara 1994 favouring placebo and Andrassy 1974 and Harter 1979 favouring aspirin. Sreedhara 1994 postulated several possible biochemical and pharmacological actions of aspirin that may have worsened its results.
The results in the ticlopidine trials clearly favoured antiplatelet treatment, using a dose of 250 mg twice daily, although the follow‐up time was only one month (Fiskerstrand 1985; Grontoft 1985; Grontoft 1998). In modern clinical practice, this drug is rarely used due to newer and safer antiplatelet medications, such as the structurally related clopidogrel, which does not have the same adverse‐effect profile (Tanner 2016).
Crowther 2002, comparing warfarin against placebo, had the longest follow‐up at 37 months. Despite this, there was no beneficial effect on the group of participants treated with warfarin. This study was stopped prematurely due to serious adverse effects. Therefore, the risk–benefit does not favour anticoagulation unless there is another established indication.
Schmitz 2002 and Lok 2012 studied the effect of fish oil on graft patency and both trials favoured treatment. However, there was statistically significant heterogeneity between the trials (despite the same dose and length of follow‐up) and the random‐effects meta‐analysis showed no evidence of a difference between the treatments.
Michie 1977 appeared to show a benefit in terms of reducing graft thrombosis in participants treated with sulphinpyrazone. However, this study was conducted over 30 years ago with relatively small participant numbers and over a short follow‐up period (three months). Again, there is insufficient evidence from a single trial to make judgements on its use.
The clopidogrel versus placebo trials individually showed a potential beneficial effect on graft thrombosis in favour of clopidogrel 75 mg/day but the random‐effects meta‐analysis showed no clear evidence of a difference between the study arms (Dember 2008; Ghorbani 2009). There was statistical heterogeneity and the weighting of the meta‐analysis was biased towards the much larger Dember trial (Dember 2008).
Field 2016 showed no clear evidence of a benefit of using GTN patch 24 hours after fistula formation in helping improve patency of the graft at six weeks.
Only two studies published data on the secondary outcome of related interventions (surgical or radiological) (Dember 2008; Lok 2012); there was insufficient evidence to determine if there was a difference in related interventions between placebo and treatment groups. None of the included studies reported on the duration of hospital stay. Duration of hospital stay is likely to be affected by factors outside the scope of this study and other confounding factors would limit the value of including this outcome in any analyses. Most studies reported complications in both groups of varying severity (mortality, gastrointestinal bleeding, pain, nausea, etc.). However, data on complications were limited and reporting varied between studies.
It appears, therefore, that at least in the short term, antiplatelet drugs such as ticlopidine may have some clinical advantages compared with placebo. No trials with follow‐up longer than 36 months demonstrated a beneficial effect of antithrombotic or antiplatelet treatment to increase patency of AVFs and AVGs, thus their long‐term effect remains unclear.
Overall completeness and applicability of evidence
Many of the comparisons included only one or two studies while data on the secondary outcome measures outlined in the Criteria for considering studies for this review section were either not sufficiently specific to allow pooled analysis or were not reported.
No trials with follow‐up longer than 36 months demonstrated a beneficial effect of antithrombotic or antiplatelet treatment to increase patency of AVFs and AVGs, thus their long‐term effect remains unclear. The current review and included articles did not look specifically at the effect of local medical therapy on the most common sites of stenosis (applied to the graft or anastomosis). This could be an area for future studies to focus on in greater detail.
Quality of the evidence
See summary of findings Table 1; summary of findings Table 2; summary of findings Table 3; summary of findings Table 4; summary of findings Table 5; summary of findings Table 6; summary of findings Table 7; summary of findings Table 8; summary of findings Table 9.
There were limitations in this review. First, some of the trials are not recent (the most recent was from 2016 but four were 35 or more years old). Additionally, most of the trials had a short period of follow‐up and many of the comparisons included only one or two studies and the study sample sizes were small, leading to imprecision. We identified risk of bias due to the variation in detail provided in the study reports. Finally, there was evidence of heterogeneity in the aspirin, fish oil and clopidogrel trials. Therefore, the overall certainty of the evidence within this review varied from low to moderate.
Potential biases in the review process
We performed a thorough search for potential studies.
It is important to be aware that specific methods used in individual studies will have evolved over time.
There were unit of analysis issues for three trials (Ghorbani 2009; Grontoft 1985; Grontoft 1998).
Grontoft 1998 had a non‐standard design as it allowed participants who had an initial failed AVF formation to re‐enter the study after a three week 'washout period.' According to the study authors, 25 participants re‐entered the trial (12 in the placebo group and 13 in the ticlopidine group). In addition, the published results had to be carefully interpreted as there was confusion between the number of participants within the study compared to the number of operations (i.e. AVFs formed), and participants who died were excluded from the published analysis. Overall analysis for this review was undertaken using the number of operations performed on an intention‐to‐treat basis. In total, 258 participants were randomised with 285 operations.
We had to assess the results of Ghorbani 2009 carefully as the original data were not analysed on an intention‐to‐treat basis, but analysed by the number of participants who completed the trial.
Grontoft 1985 also published their analysed results based on the number of participants who completed the trial, not on an intention‐to‐treat basis. As review authors it was not possible to use the intention‐to‐treat numbers because there were insufficient data regarding the original randomisation groups. Therefore, we used the numbers of participants who completed the trial.
For the primary outcome 'graft patency', the numbers recorded for analyses were the number of grafts that occluded during the specified time period as reported by the study authors. This should be remembered when interpreting the presented data. A Keplen Meir patency graph would be a better way to measure this outcome. However, this was not feasible due to the heterogeneity in reporting and the small number of studies.
AVFs generally last longer compared to synthetic grafts. Six studies investigated the outcome of treatment in AVF, six studies in AVG and one study included both AVF and AVG. The effect of treatment was pooled for AVF and AVG as the number of studies for each treatment was limited.
Previous and current reviews have reported fistula/graft patencies as the primary outcome. A separate analysis of functional patency (i.e. successful needling and haemodialysis) would be more representative and applicable in clinical practise and will be considered in review updates.
Agreements and disagreements with other studies or reviews
One meta‐analysis published by Coleman 2010 found a beneficial effect of antiplatelet agents in reducing thrombosis in AVFs but not with AVGs. There is significant cross‐over with our review however, as Coleman 2010 included 10 studies in their meta‐analysis, and eight of these studies are also included within our review. For our review, Dixon 2009 was deemed unsuitable for inclusion as there was cross‐over between participants who were prescribed aspirin prior to the trial and Kooistra 1994 assessed participants who had concurrent administration of recombinant human erythropoietin and aspirin, so this was deemed to be confounding.
Study flow diagram.
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
Comparison 1: Aspirin versus placebo, Outcome 1: Graft thrombosis
Comparison 2: Ticlopidine versus placebo, Outcome 1: Fistulae thromboses at 1 month
Comparison 3: Dipyridamole versus placebo, Outcome 1: Graft thrombosis
Comparison 4: Dipyridamole plus aspirin versus placebo, Outcome 1: Graft thrombosis
Comparison 5: Warfarin versus placebo, Outcome 1: Graft thrombosis
Comparison 6: Fish oil versus placebo, Outcome 1: Graft thrombosis
Comparison 6: Fish oil versus placebo, Outcome 2: Radiological or surgical interventions
Comparison 7: Clopidogrel versus placebo, Outcome 1: Graft thrombosis
Comparison 7: Clopidogrel versus placebo, Outcome 2: Complications: all bleeding
Comparison 7: Clopidogrel versus placebo, Outcome 3: Complications: mortality
Comparison 7: Clopidogrel versus placebo, Outcome 4: Radiological or surgical interventions
Comparison 8: Sulphinpyrazone versus placebo, Outcome 1: Graft thrombosis
Comparison 9: Glyceryl trinitrate (GTN) patch versus placebo, Outcome 1: Graft thrombosis
| Aspirin compared to placebo in increasing patency of arteriovenous fistula or graft | ||||||
| Patient or population: people with ESRD receiving haemodialysis through an arteriovenous fistula or graft | ||||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect | № of participants | Certainty of the evidence | Comments | |
|---|---|---|---|---|---|---|
| Risk with placebo | Risk with aspirin | |||||
| Graft thrombosis (28 days to 18 months) | Study population | OR 0.40 | 175 | ⊕⊕⊝⊝ | — | |
| 385 per 1000 | 200 per 1000 | |||||
| Duration of hospital stay | — | — | — | — | — | No data on duration of hospital stay. |
| Complications (28 days to 18 months) | See comment | 175 (3 RCTs) | ⊕⊕⊝⊝ Lowb | Andrassy 1974 reported a greater risk of gastric pain and epistaxis (11% aspirin vs 4% placebo) but the risk of GI bleeding or wound haematoma was 4% in both groups. Harter 1979 reported no bleeding or other complications. Sreedhara 1994 stated that 34 participants experienced adverse events that resulted in discontinuation of study medication (combination of dipyridamole, aspirin or placebo). However, these participants were considered to have completed the study protocol. The most common adverse events were GI bleeding and nausea across all study groups. There were also 7 mortalities during the study. Information on adverse events was not provided by comparison. | ||
| Number of related surgical or radiological interventions | — | — | — | — | — | No data on number of related surgical or radiological interventions. |
| *The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; ESRD: end‐stage renal disease; GI: gastrointestinal; OR: odds ratio; RCT: randomised controlled trial. | ||||||
| GRADE Working Group grades of evidence | ||||||
| aDowngraded two levels: significant heterogeneity (I2 = 79%) and small pooled sample size, confidence interval included threshold value. | ||||||
| Ticlopidine compared to placebo in increasing patency of arteriovenous fistula or graft | ||||||
| Patient or population: people with ESRD receiving haemodialysis through an arteriovenous fistula or graft | ||||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect | № of participants | Certainty of the evidence | Comments | |
|---|---|---|---|---|---|---|
| Risk with placebo | Risk with ticlopidine | |||||
| Fistulae thromboses (up to 1 month) | Study population | OR 0.45 | 339 | ⊕⊕⊕⊝ | — | |
| 226 per 1000 | 116 per 1000 | |||||
| Duration of hospital stay | — | — | — | — | — | No data on duration of hospital stay. |
| Complications (up to 1 month) | See comment | 339 (3 RCTs) | ⊕⊕⊝⊝ Lowa,b | Grontoft 1985 reported 2 bleeding complications in the ticlopidine group and 2 bleeding complications in placebo group. Grontoft 1998 reported 45 complications, including hepatic, haematological, haemostatic, cutaneous, gastrointestinal, cardiovascular and other miscellaneous complications affecting 30 participants receiving ticlopidine. There were 39 complications in participants receiving placebo. There were 5 deaths in the placebo group and 2 in the ticlopidine group. Fiskerstrand 1985 reported the development of a rash in 1 single participant treated with ticlopidine. There were no data on mortality. | ||
| Number of related surgical or radiological interventions | — | — | — | — | — | No data on number of related surgical or radiological interventions. |
| *The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; ESRD: end‐stage renal disease; OR: odds ratio; RCT: randomised controlled trial. | ||||||
| GRADE Working Group grades of evidence | ||||||
| aDowngraded one level: methods of random sequence generation and allocation concealment were unclear for two studies (Fiskerstrand 1985; Grontoft 1985). | ||||||
| Dipyridamole compared to placebo for increasing patency of arteriovenous graft | ||||||
| Patient or population: people with ESRD receiving haemodialysis through an arteriovenous graft | ||||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect | № of participants | Certainty of the evidence | Comments | |
|---|---|---|---|---|---|---|
| Risk with placebo | Risk with dipyridamole | |||||
| Graft thrombosis (up to 18 months) | Study population | OR 0.46 | 42 | ⊕⊕⊕⊝ | — | |
| 316 per 1000 | 175 per 1000 | |||||
| Duration of hospital stay | — | — | — | — | — | No data on duration of hospital stay. |
| Complications (up to 18 months) | See comments | 42 | ⊕⊕⊝⊝ Lowb | Sreedhara 1994 stated that 34 participants experienced adverse events which resulted in discontinuation of study medication (combination of dipyridamole, aspirin or placebo). However, these participants were considered to have completed the study protocol. The most common adverse events were GI bleeding and nausea across all study groups. There were also 7 mortalities during the study. Information on adverse events was not provided by comparison. | ||
| Number of related surgical or radiological interventions | — | — | — | — | — | The included study in this comparison did not include data on number of related surgical or radiological interventions |
| *The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; ESRD: end‐stage renal disease; GI: gastrointestinal; OR: odds ratio; RCT: randomised controlled trial. | ||||||
| GRADE Working Group grades of evidence | ||||||
| aDowngraded one level: small sample size, large confidence interval which includes threshold value. | ||||||
| Dipyridamole + aspirin compared to placebo for improving patency of arteriovenous graft | ||||||
| Patient or population: people with ESRD receiving haemodialysis through an arteriovenous graft | ||||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect | № of participants | Certainty of the evidence | Comments | |
|---|---|---|---|---|---|---|
| Risk with placebo | Risk with dipyridamole + aspirin | |||||
| Graft thrombosis (up to 18 months) | Study population | OR 0.64 | 41 | ⊕⊕⊕⊝ | — | |
| 316 per 1000 | 228 per 1000 | |||||
| Duration of hospital stay | — | — | — | — | — | No data on duration of hospital stay. |
| Complications (up to 18 months) | See comment | 41 | ⊕⊕⊝⊝ Lowb | Sreedhara 1994 stated that 34 participants experienced adverse events which resulted in discontinuation of study medication (combination of dipyridamole, aspirin or placebo). However, these participants were considered to have completed the study protocol. The most common adverse events were GI bleeding and nausea across all study groups. There were also 7 mortalities during the study. Information on adverse events is not provided by comparison. | ||
| Number of related surgical or radiological interventions | — | — | — | — | — | No data on number of related surgical or radiological interventions. |
| *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). AV: arteriovenous; CI: confidence interval; ESRD: end‐stage renal disease; GI: gastrointestinal; OR: odds ratio; RCT: randomised controlled trial. | ||||||
| GRADE Working Group grades of evidence | ||||||
| aDowngraded one level: small sample size, large confidence interval which includes threshold value. | ||||||
| Warfarin compared to placebo for improving patency of arteriovenous graft | ||||||
| Patient or population: people with ESRD receiving haemodialysis through an arteriovenous graft | ||||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect | № of participants | Certainty of the evidence | Comments | |
|---|---|---|---|---|---|---|
| Risk with placebo | Risk with warfarin | |||||
| Graft thrombosis (up to 37 months) | Study population | OR 1.76 | 107 | ⊕⊕⊝⊝ | — | |
| 608 per 1000 | 732 per 1000 | |||||
| Duration of hospital stay | — | — | — | — | — | No data on duration of hospital stay. |
| Complications (up to 37 months) | See comments | 107 | ⊕⊕⊝⊝ Lowb | Crowther 2002 reported 6 major bleeds in 5 participants: 3 upper GI bleeds, 1 cerebral haematoma after a road traffic accident and 1 femoral artery injury after coronary angiography. All 5 were also receiving antiplatelet therapy at the time of the bleeding event. A further 18 participants (7 allocated to placebo) experienced a minor bleeding event (P = 0.30). There were 5 deaths in the treatment group and 7 in the placebo group. | ||
| Number of related surgical or radiological interventions | — | — | — | — | — | No data on number of related surgical or radiological interventions. |
| *The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; ESRD: end‐stage renal disease; GI: gastrointestinal; OR: odds ratio; RCT: randomised controlled trial. | ||||||
| GRADE Working Group grades of evidence | ||||||
| aDowngraded two levels: serious imprecision – large confidence interval which included the threshold value; protocol for warfarin dosing changed after interim analysis; 40% of participants received antiplatelet therapy (aspirin) during the study period. | ||||||
| Fish oil compared to placebo for improving patency of arteriovenous graft | ||||||
| Patient or population: people with ESRD receiving haemodialysis through an arteriovenous graft | ||||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect | № of participants | Certainty of the evidence | Comments | |
|---|---|---|---|---|---|---|
| Risk with placebo | Risk with fish oil | |||||
| Graft thrombosis (up to 12 months) | Study population | OR 0.24 | 220 | ⊕⊕⊝⊝ | — | |
| 495 per 1000 | 191 per 1000 | |||||
| Duration of hospital stay | — | — | — | — | — | No data on duration of hospital stay. |
| Complications (up to 12 months) | See comment | 196 | ⊕⊕⊕⊝ Moderateb | Lok 2012; 16 participants died (8 in each study arm) | ||
| Radiological or surgical intervention (up to 12 months) | Study population | OR 0.64 | 196 | ⊕⊕⊕⊝ | — | |
| 495 per 1000 | 385 per 1000 | |||||
| *The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). AV: arteriovenous; CI: confidence interval; ESRD: end‐stage renal disease; OR: odds ratio; RCT: randomised controlled trial. | ||||||
| GRADE Working Group grades of evidence | ||||||
| aDowngraded one level: significant heterogeneity (I2 = 76%). | ||||||
| Clopidogrel compared to placebo for increasing patency of arteriovenous fistula | ||||||
| Patient or population: people with ESRD receiving haemodialysis through an arteriovenous fistula | ||||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect | № of participants | Certainty of the evidence | Comments | |
|---|---|---|---|---|---|---|
| Risk with placebo | Risk with clopidogrel | |||||
| Fistula thrombosis (42 days to 6 months) | Study population | OR 0.40 | 959 | ⊕⊕⊕⊝ | — | |
| 197 per 1000 | 89 per 1000 | |||||
| Duration of hospital stay | — | — | — | — | — | No data on duration of hospital stay. |
| Complication: all bleeding (up to 6 months)
| Study population | OR 1.06 (0.55 to 2.03) | 970 | ⊕⊕⊕⊝
| Combining data from Dember 2008 and Ghorbani 2009 found no clear evidence of a difference in bleeding between the clopidogrel and placebo groups. | |
| 39 per 1000 | 41 per 1000 (22 to 78) | |||||
| Complication: mortality (up to 6 months) | Study population | OR 1.00 (0.32 TO 3.14) | 970 (2 RCTs) | ⊕⊕⊕⊝
| Combining data from Dember 2008 and Ghorbani 2009 showed no clear evidence of a difference in mortality between the clopidogrel and placebo groups. | |
| 12 per 1000 | 12 per 1000 (4 to 38) | |||||
| Number of related surgical or radiological interventions (42 days) | Study population | OR 0.69 | 866 | ⊕⊕⊕⊝ | — | |
| 23 per 1000 | 16 per 1000 | |||||
| *The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). AV: arteriovenous; CI: confidence interval; ESRD: end‐stage renal disease; OR: odds ratio; RCT: randomised controlled trial. | ||||||
| GRADE Working Group grades of evidence | ||||||
| aDowngraded one level: imprecision concern as confidence interval included both clinical decision threshold and small event numbers. | ||||||
| Sulphinpyrazone compared to placebo for increasing patency of arteriovenous fistula or graft | ||||||
| Patient or population: people with ESRD receiving haemodialysis through an arteriovenous fistula or arteriovenous graft | ||||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect | № of participants | Certainty of the evidence | Comments | |
|---|---|---|---|---|---|---|
| Risk with placebo | Risk with sulphinpyrazone | |||||
| Graft thrombosis (up to 3 months) | Study population | OR 0.43 (0.03 to 5.98) | 16 | ⊕⊕⊝⊝ | — | |
| 250 per 1000 | 125 per 1000 | |||||
| Duration of hospital stay | — | — | — | — | — | No data on duration of hospital stay. |
| Complications (up to 3 months) | See comments | — | — | ⊕⊕⊝⊝ Lowa | 1 participant in the placebo group in Michie 1977 developed mild GI bleeding and pericarditis, which subsequently progressed to severe hypotension, shock and death. | |
| Number of related surgical or radiological interventions | — | — | — | — | — | No data on number of related surgical or radiological interventions. |
| *The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; ESRD: end‐stage renal disease; GI: gastrointestinal; OR: odds ratio; RCT: randomised controlled trial. | ||||||
| GRADE Working Group grades of evidence | ||||||
| aDowngraded two levels: very serious imprecision as very small sample size and total events. | ||||||
| GTN patch compared to placebo for increasing patency of arteriovenous fistula | ||||||
| Patient or population: people with ESRD receiving haemodialysis through an arteriovenous fistula | ||||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect | № of participants | Certainty of the evidence | Comments | |
|---|---|---|---|---|---|---|
| Risk with placebo | Risk with GTN patch | |||||
| Fistula failure (6 weeks) | Study population | OR 1.26 | 167 | ⊕⊕⊕⊝ | — | |
| 235 per 1000 | 279 per 1000 | |||||
| Duration of hospital stay | — | — | — | — | — | No data on length of hospital stay. |
| Complications (6 weeks) | See comment | 167 | ⊕⊕⊕⊝ | Field 2016 included a list of common systemic and localised adverse effects associated with GTN usage, and reported "no statistically significant differences" between the GTN patch and placebo. | ||
| Number of related surgical or radiological interventions | — | — | — | — | — | No data on number of related surgical or radiological interventions. |
| *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). AV: arteriovenous; CI: confidence interval; ESRD: end‐stage renal disease; GTN: glyceryl trinitrate; OR: odds ratio. | ||||||
| GRADE Working Group grades of evidence | ||||||
| aDowngraded one level: serious imprecision as small sample size and events. | ||||||
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1.1 Graft thrombosis Show forest plot | 3 | 175 | Odds Ratio (M‐H, Random, 95% CI) | 0.40 [0.07, 2.25] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 2.1 Fistulae thromboses at 1 month Show forest plot | 3 | 339 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.45 [0.25, 0.82] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 3.1 Graft thrombosis Show forest plot | 1 | Odds Ratio (M‐H, Fixed, 95% CI) | Totals not selected | |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 4.1 Graft thrombosis Show forest plot | 1 | Odds Ratio (M‐H, Fixed, 95% CI) | Totals not selected | |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 5.1 Graft thrombosis Show forest plot | 1 | Odds Ratio (M‐H, Fixed, 95% CI) | Totals not selected | |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 6.1 Graft thrombosis Show forest plot | 2 | 220 | Odds Ratio (M‐H, Random, 95% CI) | 0.24 [0.03, 1.95] |
| 6.2 Radiological or surgical interventions Show forest plot | 1 | Odds Ratio (M‐H, Fixed, 95% CI) | Totals not selected | |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 7.1 Graft thrombosis Show forest plot | 2 | 959 | Odds Ratio (M‐H, Random, 95% CI) | 0.40 [0.13, 1.19] |
| 7.2 Complications: all bleeding Show forest plot | 2 | 970 | Odds Ratio (M‐H, Fixed, 95% CI) | 1.06 [0.55, 2.03] |
| 7.3 Complications: mortality Show forest plot | 2 | 970 | Odds Ratio (M‐H, Fixed, 95% CI) | 1.00 [0.32, 3.14] |
| 7.4 Radiological or surgical interventions Show forest plot | 1 | Odds Ratio (M‐H, Fixed, 95% CI) | Totals not selected | |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 8.1 Graft thrombosis Show forest plot | 1 | Odds Ratio (M‐H, Fixed, 95% CI) | Totals not selected | |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 9.1 Graft thrombosis Show forest plot | 1 | Odds Ratio (M‐H, Fixed, 95% CI) | Totals not selected | |
