Medicines to prevent blockage of vascular access following surgery for formation of arteriovenous fistula or graft

Background

People with advanced kidney disease (called end-stage renal disease) need dialysis to perform kidney functions. In haemodialysis, blood is filtered through a machine. To allow a large enough passage for blood to flow between the person and the machine, an artery and a vein can be surgically joined (to form an arteriovenous fistula) or a prosthetic arteriovenous graft (a substitute for a vein) is used to join the artery to the vein. These access points might last for years but can become blocked or infected. This review investigated if additional medical therapy can keep these dialysis access points patent (i.e. open or unblocked).

Study characteristics and key results

The review authors identified 13 randomised controlled trials (clinical studies where people are randomly put into one of two or more treatment groups; evidence current to August 2020) with 2080 participants. The trials compared antithrombotic medicines (which prevent abnormal clotting in the blood vessels; such as ticlopidine, aspirin, dipyridamole and clopidogrel) and other types of medicine used to prevent blockages in the artery and vein access points for dialysis compared to placebo (dummy treatment). The trials included people with advanced kidney disease receiving dialysis through all types of arteriovenous fistulae or arteriovenous grafts in the arms or legs, or at special sites. We excluded people receiving dialysis via the tummy (called peritoneal dialysis), or studies that compared medical therapy with no treatment. Where possible, we grouped similar studies.

Three trials (339 participants) comparing ticlopidine (an antiplatelet treatment) with placebo showed improved patency in one month. There was insufficient evidence of an effect on blood flow from three trials comparing aspirin with placebo (175 participants) or from two trials using fish oil for 12 months (220 participants). Two trials compared clopidogrel with placebo in 959 participants and found insufficient evidence of an effect between the treatments. Single trials involving 16 to 167 participants found no effect of dipyridamole, dipyridamole plus aspirin, warfarin, sulphinpyrazone (medication that reduces the concentration of uric acid in the blood) or glyceryl trinitrate patch (topical medication that widens blood vessels) compared with placebo. The trial comparing warfarin with placebo was terminated early because of major bleeding in the warfarin group. Two studies reported on related surgical or radiological interventions and found insufficient evidence of an effect on related interventions between placebo and treatment. No studies reported the length of hospital stay. Most studies reported complications ranging from feeling sick to death. However, information was limited and varied between studies. Most were monitored for a short period so that any benefits in the longer term (more than three years) are unclear.

Certainty of the evidence

Overall the certainty of the evidence was low to moderate, meaning that results may change with more research. This is because there were mostly one or two small studies comparing each medication to a placebo. In some studies, using the same medication, they had a different dosage (strength) or were of different study lengths, making them difficult to compare. We also had concerns with the lack of detail reported by studies.

Authors' conclusions: 

The meta-analyses of three studies for ticlopidine (an antiplatelet treatment), which all used the same dose of treatment but with a short follow-up of only one month, suggest ticlopidine may have a beneficial effect as an adjuvant treatment to increase the patency of AVFs and AVGs in the short term. There was insufficient evidence to determine if there was a difference in graft patency between placebo and other treatments such as aspirin, fish oil, clopidogrel, dipyridamole, dipyridamole plus aspirin, warfarin, sulphinpyrazone and GTN patch. The certainty of the evidence was low to moderate due to short follow-up periods, the small number of studies for each comparison, small sample sizes, heterogeneity between trials and risk of bias due to incomplete reporting. Therefore, it appears reasonable to suggest further prospective studies be undertaken to assess the use of these antiplatelet drugs in renal patients with an AVF or AVG.

Read the full abstract...
Background: 

People with end-stage renal disease (ESRD) often require either the formation of an arteriovenous fistula (AVF) or an interposition prosthetic arteriovenous graft (AVG) for haemodialysis. 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). Although some of the complications may be unavoidable, any adjuvant technique or medical treatment aimed at decreasing complications would be welcome. This is the fourth update of the review first published in 2003.

Objectives: 

To assess the effects of adjuvant drug treatment in people with ESRD on haemodialysis via autologous AVFs or prosthetic interposition AVGs.

Search strategy: 

The Cochrane Vascular Information Specialist searched the Cochrane Vascular Specialised Register, CENTRAL, MEDLINE, Embase and CINAHL databases and ClinicalTrials.gov trials register to 6 August 2020.

Selection criteria: 

Randomised controlled trials of active drug versus placebo in people with ESRD undergoing haemodialysis via an AVF or prosthetic interposition AVG.

Data collection and analysis: 

For this update, two review authors (IM, MFAK) independently selected trials for inclusion, extracted data, assessed risk of bias and assessed the certainty of the evidence according to GRADE. We resolved disagreements by discussion or consultation with another review author (ADS). The primary outcome was the long-term fistula or graft patency rate. Secondary outcomes included duration of hospital stay; complications such as infection, aneurysm formation, stenosis and distal limb ischaemia; and number of related surgical or radiological interventions.

Main results: 

For this update, one additional study was suitable for inclusion, making a total of 13 trials with 2080 participants. Overall the certainty of the evidence was low or moderate due to short follow-up periods, heterogeneity between trials, small sample sizes, and risk of bias due to incomplete reporting. Medical adjuvant treatments used in the included trials were aspirin, ticlopidine, dipyridamole, dipyridamole plus aspirin, warfarin, fish oil, clopidogrel, sulphinpyrazone and glyceryl trinitrate (GTN) patch. 

All included studies reported on graft patency by measuring graft thrombosis. There was insufficient evidence to determine if there was a difference in graft patency in studies comparing aspirin versus placebo (odds ratio (OR) 0.40, 95% confidence interval (CI) 0.07 to 2.25; 3 studies, 175 participants; low-certainty evidence). The meta-analysis for graft patency comparing ticlopidine versus placebo favoured ticlopidine (OR 0.45, 95% CI 0.25 to 0.82; 3 studies, 339 participants; moderate-certainty evidence).

There was insufficient evidence to determine if there was a difference in graft patency in studies comparing fish oil versus placebo (OR 0.24, 95% CI 0.03 to 1.95; 2 studies, 220 participants; low-certainty evidence); and studies comparing clopidogrel and placebo (OR 0.40, 95% CI 0.13 to 1.19; 2 studies, 959 participants; moderate-certainty evidence). Similarly, there was insufficient evidence to determine if there was a difference in graft patency comparing the effect of dipyridamole versus placebo (OR 0.46, 95% CI 0.11 to 1.94; 1 study, 42 participants, moderate-certainty evidence) and dipyridamole plus aspirin versus placebo (OR 0.64, CI 0.16 to 2.56; 1 study, 41 participants; moderate-certainty evidence); comparing low-intensity warfarin with placebo (OR 1.76, 95% CI 0.78 to 3.99; 1 study, 107 participants; low-certainty evidence); comparing sulphinpyrazone versus placebo (OR 0.43, 95% CI 0.03 to 5.98; 1 study, 16 participants; low-certainty evidence) and comparing GTN patch and placebo (OR 1.26, 95% CI 0.63 to 2.54; 1 study, 167 participants; moderate-certainty evidence). The single trial evaluating warfarin was terminated early because of major bleeding events in the warfarin group.

Only two studies published data on the secondary outcome of related interventions (surgical or radiological); 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.  Most studies reported complications ranging from mortality to nausea. However, data on complications were limited and reporting varied between studies.

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