Aspirin (ASA) or aspirin and dipyridamole (ASA/DIP) versus placebo or nothing

In all six trials study medication was started prior to bypass surgery, mostly 48 hours before the operation (Clyne 1987; Donaldson 1985; Goldman 1984; Green 1982; Kohler 1984; McCollum 1991). Doses ranged from 300 mg to 325 mg ASA and 75 mg DIP, given two and three times daily. Participants were randomised before surgery. Duration of treatment was six weeks in the Clyne 1987 trial but at least 12 to 24 months in the other trials. The percentage of participants with critical leg ischaemia (CLI) ranged from 60% to 80%, with the exception of Donaldson 1985 which only included participants with disabling intermittent claudication.

Aspirin (ASA) or aspirin and dipyridamole (ASA/DIP) versus pentoxifylline (PTX)

Two studies were included, comparing 1000 mg or 1500 mg ASA to 1200 mg PTX daily (Lucas 1984; Raithel 1987). Participant characteristics and graft type were similar in both trials. While Raithel 1987's participants all received prosthetic grafts, Lucas 1984 also included participants with venous grafts. More than 90% of Raithel 1987's participants had CLI compared to only 55% in the Lucas 1984 trial.

Aspirin and dipyridamole (ASA/DIP) versus indobufen (IND)

We found only one multicentre double‐blind randomised clinical trial including participants operated on for a prosthetic polytetrafluoroethylene (PTFE) femoropopliteal graft for inclusion (D'Addato 1992).

Aspirin and dipyridamole (ASA/DIP) versus vitamin K antagonists (VKA)

We include two trials in this category (BOA 2000; Schneider 1979), comparing ASA or ASA and DIP with VKA. The Dutch BOA 2000 trial included a much higher number of participants than the Schneider 1979 trial; prosthetic grafts were included in the BOA 2000 trial. It should be noted that participants receiving ASA in the BOA 2000 trial were treated with a dose of only 80 mg, while all other trials included in this review compared doses of 600 mg to 1500 mg daily, sometimes with additional DIP.

Aspirin and dipyridamole (ASA/DIP) versus low molecular weight heparin (LMWH)

We include one open, randomised clinical trial for comparison of LMWH (Fragmin) and ASA and DIP (Edmondson 1994). Participants were assessed for their clinical outcomes on the seventh postoperative day.

Ticlopidine (TIC) versus nothing

Only one double‐blind trial (Becquemin 1997) could be included for analysis, which randomised 243 participants after surgery. All participants received autologous saphenous vein grafts.

Aspirin versus prostaglandin E1 (PGE1)

One open, randomised clinical trial compared ASA to PGE1 on a background of 15,000 IU of heparin for early graft occlusion, within three days postoperatively, in 100 participants who all received autologous saphenous vein grafts (Gruss 1991).

Aspirin versus naftidrofuryl

We could consider only one trial in the analysis that compared ASA to naftidrofuryl (Noppeney 1988). This study, which commenced on postoperative day one, randomised 99 participants who all had prosthetic PTFE grafts.

Clopidogrel and ASA (Clopidogrel/ASA) versus ASA alone

A single trial evaluated the comparison between clopidogrel with ASA versus ASA alone (CASPAR 2010), which was a large trial of 851 randomised, receiving a mixture of venous and prosthetic grafts.

Primary graft patency

The effect of ASA or ASA/DIP on infrainguinal bypass patency was assessed in six trials (Clyne 1987; Donaldson 1985; Goldman 1984; Green 1982; Kohler 1984; McCollum 1991). The OR from the random‐effects model for primary occlusion at 12 months for all grafts was 0.42 (95% confidence interval (CI) 0.22 to 0.83; P = 0.01, I² = 72%, participants = 952), showing a positive effect of ASA on infrainguinal grafts at one year (Analysis 1.1).
Three of these studies had unit of analysis issues, with multiple grafts or re‐randomisation of participants (Clyne 1987; Donaldson 1985; Kohler 1984). The association becomes attenuated when these studies are excluded (OR 0.36, 95% CI 0.13 to 0.99; P = 0.05, participants = 651).

When we performed the analysis for venous grafts alone, there was no difference in primary graft patency between the treatment groups at one, three and six months (OR 0.76, 95% CI 0.26 to 2.25, P = 0.62; OR 0.85, 95% CI 0.54 to 1.35, P = 0.50; and OR 0.88, 95% CI 0.59 to 1.31; P = 0.53, respectively, participants = 642 for all) (all fixed‐effect analyses) (Analysis 2.1; Analysis 2.2; Analysis 2.3). At 12 months post‐operation there was a possible increase in occlusion in the control group (OR 0.69, 95% CI 0.48 to 0.99; P = 0.05, participants = 642) (fixed‐effect), but this was not seen at 24 months in the random‐effects model analysis, (OR 1.03; 95% CI 0.32 to 3.28; P = 0.96, I² = 79%, participants = 620) (Analysis 2.4; Analysis 2.5).

Analysis for prosthetic grafts, however, showed a much stronger positive effect of ASA on primary patency as calculated from four studies (Clyne 1987; Donaldson 1985; Goldman 1984; Green 1982): ORs of 0.14 (95% CI 0.04 to 0.51; P = 0.003, participants = 157) at one month; 0.31 (95% CI 0.14 to 0.66; P = 0.003, participants = 222) at three months; 0.21 (95% CI 0.11 to 0.41; P < 0.00001, participants = 222) at six months; and 0.19 (95% CI 0.10 to 0.36, participants = 222) at 12 months (Analysis 2.6; Analysis 2.7; Analysis 2.8; Analysis 2.10). Primary patency at nine months was only evaluated in a single study, with an OR of 0.17 (95% CI 0.04 to 0.67, participants = 65) (Analysis 2.9).

Removal of the trials associated with unit of analysis issues meant that we could not conduct data analysis for venous grafts at one, three, six,12, and 24 months as only one study remained. For prosthetic grafts, the OR was 0.25 (95% CI 0.05 to 1.30; P = 0.10, participants = 102) at one month; 0.30 (95% CI 0.09 to 1.01; P = 0.05, participants = 102) at three months; 0.31 (95% CI 0.13 to 0.74; P = 0.008, participants = 102) at six months; and 0.23 (95% CI 0.10 to 0.54; P = 0.0008, participants = 102) at 12 months, all fixed‐effect models. For all comparisons the overall effect was reduced, and for months one and three the association no longer favoured ASA or ASA/DIP.

Secondary graft patency

McCollum 1991 reported on secondary patency of the failed grafts, but the time frame of the reported cases is unclear. The study reported that of the 172 failed grafts (86 in each treatment group), eight in the ASA/DIP group and four in the placebo group were restored by re‐operation but it is unclear if all failed grafts were re‐operated. McCollum 1991 also reported that the cumulative secondary patency rate for the ASA/DIP group was 80% at one year, 73% at two years and 63% at three years, and 74%, 64% and 61% respectively for the placebo group. Because the number of participants that were included to derive these values was unclear, we cannot use them in meta‐analysis.

Side effects of treatment and complications

Side effects were reported in five studies (Clyne 1987; Donaldson 1985; Green 1982; Kohler 1984; McCollum 1991) and the fixed‐effect model found an OR of 1.55 (95% CI 1.00 to 2.41; P = 0.05, participants = 913) for general side effects (Analysis 1.2). However, when Clyne 1987, Donaldson 1985 and Kohler 1984 were removed due to unit of analysis issues the association was attenuated with an OR of 1.34 (95% CI 0.83 to 2.16; P = 0.23, participants = 598). Six studies evaluated side effects specific to the gastrointestinal tract (Clyne 1987; Donaldson 1985; Goldman 1984; Green 1982; Kohler 1984; McCollum 1991), and found no differences between the two treatment groups (OR 1.44, 95% CI 0.92 to 2.24; P = 0.11, participants = 952) in the fixed‐effect model. When Clyne 1987Donaldson 1985 and Kohler 1984 were removed due to unit of analysis issues there was very little change in the outcome (OR 1.38, 95% CI 0.87 to 2.21; P = 0.17, participants = 651).

Major bleeding was similar between the treatment groups for two trials (Green 1982; McCollum 1991) (OR 1.88, 95% CI 0.85 to 4.16; P = 0.12, participants = 598) in the fixed‐effect model. Minor bleeding was only evaluated in one study (Clyne 1987), with an OR of 0.73 (95% CI 0.31 to 1.70, participants = 148). Wound or graft infection was only evaluated in McCollum 1991, with similar events in both treatment groups (OR 1.07, 95% CI 0.67 to 1.71, participants = 549).

Limb amputation

Clyne 1987 reported amputations with an OR of 0.55 (95% CI 0.21 to 1.44, grafts = 148), but it should be noted this was one of the studies with multiple grafts in some of the participants (148 grafts in 140 participants) (Analysis 1.3).

Cardiovascular events and mortality

Analysis of cardiovascular events was performed in four trials (Clyne 1987; Donaldson 1985; Green 1982; McCollum 1991) and the random‐effects model found an OR of 1.27 (95% CI 0.43 to 3.80; P = 0.66, I² = 52%, participants = 811) (Analysis 1.4). When Clyne 1987 and Donaldson 1985 were removed for unit of analysis issues, the association was statistically significant, in favour of ASA or ASA/DIP (OR 0.58, 95% CI 0.37 to 0.91; P = 0.02, participants = 598), although it should be noted that McCollum 1991 then comprises 96% of the analysis.

The OR for postoperative death for the fixed‐effect model, as evaluated in four studies (Clyne 1987; Goldman 1984; Green 1982; McCollum 1991) was 0.84 (95% CI 0.56 to 1.26; P = 0.41, participants = 799) (Analysis 1.5). When Clyne 1987 was removed for sensitivity analysis due to unit of analysis issues the resulting OR was 0.77 (95% CI 0.49 to 1.21; P = 0.26, participants = 651). Again McCollum 1991 accounted for a large majority of the weight.

Primary graft patency

The effect of PTX on graft patency when compared to ASA or ASA/DIP treatment could only be evaluated in a formal analysis from two RCTs (Lucas 1984; Raithel 1987) at six months post‐operation. The fixed‐effect model had an OR of 1.32 (95% CI 0.56 to 3.11; P = 0.52, participants = 151) showing no difference between the treatment groups (Analysis 3.3). This analysis should be considered with caution as Lucas 1984 involved multiple grafts and there appeared to be substantial heterogeneity among the sample population. At other time points, only Raithel 1987 provided raw data and showed a similar effect of both drugs on graft patency: OR 2.04 (95% CI 0.18 to 23.07, participants = 118) at one month; OR 1.00 (95% CI 0.27 to 3.65, participants = 118) at three months; and OR 0.91 (95% CI 0.38 to 2.15, participants = 118) at 12 months (Analysis 3.1; Analysis 3.2; Analysis 3.4).

Side effects of treatment and complications

Raithel 1987 reported on side effects that included gastric intolerance, gastric haemorrhage and vertigo, with ORs of 18.04 (95% CI 5.07 to 64.17), 3.11 (95% CI 0.31 to 30.77) and 0.48 (95% CI 0.08 to 2.74) respectively, all with 118 participants (Analysis 3.5). It should be noted that side effects were extrapolated from graphs and therefore may not be completely accurate.

Limb amputation

Amputation was also only evaluated in the Raithel 1987 study, with an OR of 0.38 (95% CI 0.07 to 2.04, participants = 118) (Analysis 3.6).

Cardiovascular events and mortality

Reported only in Raithel 1987, there were six deaths in the ASA group and three in the PTX group, with an OR of 2.11 (95% CI 0.50 to 8.88, participants = 118) (Analysis 3.7). The authors reported that eight of the deaths were from myocardial infarction and one from cardiac failure, but they did not detail which treatment groups they came from.

Primary graft patency

The one eligible RCT (D'Addato 1992) compared ASA/DIP to IND in receiving infrainguinal prosthetic PTFE grafts. The study had an OR of 1.67 (95% CI 0.51 to 5.44, participants = 113) for primary patency at three months, OR 1.60 (95% CI 0.60 to 4.27, participants = 113) at six months, OR 1.26 (95% CI 0.56 to 2.85, participants = 113) at nine months and OR 1.34 (95% CI 0.61 to 2.93, participants = 113) at 12 months (Analysis 4.1; Analysis 4.2; Analysis 4.3; Analysis 4.4).

Primary graft patency

This was reported in two trials (BOA 2000; Schneider 1979). Primary graft patency for all grafts showed no difference for coumarin versus aspirin, irrespective of time point: OR 0.88 (95% CI 0.68 to 1.14; P = 0.34, I² = 0%) at three months, OR 0.72 (95% CI 0.27 to 1.96; P = 0.52, I² = 61%) at six months, OR 0.68 (95% CI 0.27 to 1.69; P = 0.40, I² = 67%) at 12 months; and OR 0.64 (95% CI 0.25 to 1.63; P = 0.36, I² = 74%) at 24 months, with 2781 participants included in each outcome (Analysis 5.1; Analysis 5.2; Analysis 5.3; Analysis 5.4). We used a fixed‐effect model at three months, and random‐effects models for months six, 12 and 24, due to high heterogeneity.

Side effects of treatment and complications

In the BOA 2000 trial, haemorrhage necessitating hospital admission was reported for 119 (9%) participants in the coumarin group and 59 (4.5%) in the aspirin group. A total of 16 (1.2%) participants died from fatal bleeding in the coumarin group and 12 (0.9%) participants in the aspirin group. In Schneider 1979 the adverse effects reported were: two participants (0.6%) who stopped coumarin treatment because of bleeding complications and 13 participants (21%) who stopped aspirin for differing reasons.

Limb amputation

The two trials (BOA 2000; Schneider 1979), did not report data on limb salvage or survival that was suitable for formal meta‐analysis. However, in BOA 2000 limb amputation had to be performed in a similar number of participants in each treatment group, with an OR of 0.99 (95% CI 0.75 to 1.30, participants = 2690) (Analysis 5.5).

Cardiovascular events and mortality

Only BOA 2000 reported on cardiovascular events and mortality for this treatment comparison. Myocardial infarction and stroke were similar for both treatment groups, with slightly higher occurrences in the ASA/DIP group: OR 1.45 (95% CI 0.90 to 2.34) and OR 1.34 (95% CI 0.86 to 2.09) respectively; participants = 2690 (Analysis 5.6). Death from all causes, after two years, was similar in both treatment groups, with an OR of 1.02 (95% CI 0.83 to 1.26, participants = 2690) (Analysis 5.7).

Primary graft patency

In Edmondson 1994 primary patency was measured at six and 12 months with little difference between the treatment groups: OR 1.69 (95% CI 0.78 to 3.65, participants = 200), and OR 1.19 (95% CI 0.66 to 2.15, participants = 200), respectively (Analysis 6.1; Analysis 6.2).

Side effects of treatment and complications

No major bleedings or adverse events occurred.

Cardiovascular events and mortality

There were more deaths in the LMWH treatment group compared to the ASA/DIP group: OR 0.18 (95% CI 0.04 to 0.86, participants = 200) (Analysis 6.3).

Primary graft patency

Intention‐to‐treat analysis of one trial (Becquemin 1997) involving participants undergoing bypass with venous grafts showed no difference in primary patency at one month between the treatment groups: OR 3.00 (95% CI 0.12 to 74.37, participants = 243), with a wide confidence interval as only one event occurred by this time point (Analysis 7.1). However, primary patency at six, 12 and 24 months showed increased patency in the TIC treatment group: OR 0.26 (95% CI 0.11 to 0.63, participants = 243) at six months; OR 0.38 (95% CI 0.19 to 0.75, participants = 243) at 12 months; and OR 0.37 (95% CI 0.21 to 0.67, participants = 243) at 24 months (Analysis 7.2; Analysis 7.3; Analysis 7.4).

Primary graft patency

One study (Gruss 1991) reported on the drug comparison of aspirin to PGE1 in participants receiving autologous venous grafts. Early occlusion, within the first three postoperative days, had few events, with an OR of 3.91 (95% CI 0.77 to 19.83, participants = 100) (Analysis 8.1). Longer‐term patency was not reported.

Primary graft patency

One study (Noppeney 1988) reported graft occlusion in seven of the 50 participants administered naftidrofuryl compared to 10 of the 49 given ASA, with an OR of 1.58 (95% CI 0.55 to 4.54, participants = 99) (Analysis 9.1).

Side effects of treatment and complications

More general side effects were experienced by the ASA group compared to naftidrofuryl: OR 13.86 (95% CI 3.80 to 50.60, participants = 99). Gastrointestinal side effects were also more common in the aspirin group: OR 28.45 (95% CI 3.61 to 223.97, participants = 99). Only two participants reported vertigo, both in the naftidrofuryl treatment group: OR 0.20 (95% CI 0.01 to 4.19, participants = 99). Stomach bleeding was reported in five participants, all in the aspirin treatment group: OR 12.48 (95% CI 0.67 to 232.14, participants = 99) (Analysis 9.2).

Cardiovascular events and mortality

Deaths occurred in both treatment groups, with an OR of 2.73 (95% CI 0.50 to 14.78, participants = 99) (Analysis 9.3).

Primary graft patency

Primary graft patency for all participants was similar between both treatment groups, OR 0.95 (95% CI 0.69 to 1.31, participants = 851) Analysis 10.1. There were more cases of occlusion in the clopidogrel/ASA group, compared to ASA alone, when only venous grafts were included: OR 1.47 (95% CI 0.93 to 2.31, participants = 598), but higher occlusion rates in the ASA alone group for prosthetic grafts: OR 0.53 (95% CI 0.32 to 0.88, participants = 253) (Analysis 11.1; Analysis 11.2).

Side effects of treatment and complications

Total cases of bleeding were fewer in the ASA alone group: OR 2.65 (95% CI 1.69 to 4.15, participants = 851), as were mild bleeding: OR 2.34 (95% CI 1.37 to 4.00, participants = 851) and moderate bleeding: OR 4.13 (95% CI 1.37 to 12.45, participants = 851). Cases of severe bleeding and fatal bleeding were few, and similar between the treatment groups: OR 1.82 (95% CI 0.61 to 5.48, participants = 851) and OR 2.01 (95% CI 0.18 to 22.24, participants = 851), respectively (Analysis 10.2).

When we evaluated graft subgroups, there was still less mild bleeding in the ASA alone group for venous grafts: OR 2.46 (95% CI 1.33 to 4.53, participants = 598), but the occurrence of mild bleeding events was more similar between the treatment groups for prosthetic grafts: OR 1.86 (95% CI 0.67 to 5.21, participants = 253). The same trend was seen for moderate bleeding: venous grafts: OR 5.75 (95% CI 1.26 to 26.17, participants = 598) and prosthetic grafts: OR 2.50 (95% CI 0.48 to 13.13, participants = 253). Severe bleeding was similar between treatment groups for both venous and prosthetic grafts: OR 2.75 (95% CI 0.72 to 10.47, participants = 598) and OR 0.48 (95% CI 0.04 to 5.41, participants = 253), respectively (Analysis 11.3).

Limb amputation

For all grafts, amputations were similar between groups, with slightly higher occurrence in the ASA alone group: OR 0.67 (95% CI 0.41 to 1.08, participants = 851) (Analysis 10.3). Amputation occurrence was also similar between treatment groups for venous grafts: OR 0.91 (95% CI 0.48 to 1.73, participants = 598), but more occurred in the ASA alone group for prosthetic grafts: OR 0.44 (95% CI 0.21 to 0.91, participants = 253) (Analysis 11.4).

Cardiovascular events and mortality

For all graft types, death was similar between both treatment groups: OR 1.44 (95% CI 0.76 to 2.72, participants = 851), which was also the case for both venous and prosthetic grafts: OR 1.43 (95% CI 0.69 to 2.97, participants = 598), and OR 1.49 (95% CI 0.41 to 5.40, participants = 253), respectively (Analysis 10.4; Analysis 11.5).